RU2847296C1 - Novel naphthyridinone derivative having ectonucleotide pyrophosphatase-phosphodiesterase inhibitory activity, and use thereof - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to a compound selected from a naphthyridinone derivative represented by formula 1, a pharmaceutically acceptable salt thereof or its stereoisomer, which have the ability to inhibit ectonucleotide pyrophosphatase-phosphodiesterase (ENPP1) and activate the STING pathway. In formula 1, R₁ is hydrogen or C₁-C₁₃ alkyl group; R₂ is -ZR₃-(R₄)_m; Z is present or absent, wherein when Z is present, Z is -NH- or -NMe; R₃ is C₃-C₁₀ heterocyclic group or C₆-C₁₀ aryl group, where C₃-C₁₀ heterocyclic group includes at least one heteroatom selected from N; when Z is absent, R₄ is C₁-C₁₃ alkyl group, t-butoxycarbonyl group (Boc), -(C_mH_2m)NR₅R₆, sulphonamide group (-NHS(O)₂R₆), sulfamoyl group (-NHS(O)₂NHR₆), a sulphonamide group, a sulfamoylalkyl group (-(C_mH_2m)NHS(O)₂NHR₆), a sulfamoylalkyl group (-(C_mH_2m)NR₅S(O)₂NHR₆) or a phosphoryl group (-P(O)R₅R₆), or is bonded to the same carbon as the carbon bonded to R₃, to form 5–7 membered saturated heterocycle containing at least one heteroatom from N, or is bonded to the carbon adjacent to the carbon bonded to R₃ to form 5–7 membered saturated heterocycle containing at least one heteroatom from N; when Z is present, R₄ is -(C₂H₄)NCH₃S(O)₂NH₂ or is bonded to the carbon adjacent to the carbon bonded to R₃ to form 5–7 membered saturated heterocycle containing at least one heteroatom from N; R₃ can be further substituted with one or two fluorine atoms or one chlorine atom in addition to R₄; m is integer from 1 to 4. C₁-C₁₃ alkyl group includes at least one substitute selected from the group consisting of an amino group (-NR₅R₆), sulphonamide group (-NHS(O)₂-), sulphonyl group (-S(O)₂-) and a phosphoryl group (-P(O)R₅R₆); 5–7 membered saturated heterocycle formed by bonding with same carbon or carbon adjacent to carbon bonded with R₃ is substituted -S(O)₂NH₂; each of R₅ and R₆ is independently hydrogen, C₁-C₆ alkyl group, C₆-C₁₀ aryl group, C₃-C₁₀ heteroaryl group and is substituted with at least one of hydrogen and C₁-C₁₃ alkyl group, where C₃-C₁₀ heteroaryl group includes at least one heteroatom selected from S. Invention also relates to specific compounds, an ENPP1 inhibitor, an activator of the STING signalling pathway and a pharmaceutical composition containing said compounds.

EFFECT: novel naphthyridinone derivative having ectonucleotide pyrophosphatase-phosphodiesterase inhibitory activity, and use thereof are disclosed.

12 cl, 4 tbl, 148 ex

Description

Field of technology

[1] The present invention relates to a compound selected from a novel naphthyridinone derivative compound having an inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase (ENPP), a pharmaceutically acceptable salt thereof, a hydrate thereof and a stereoisomer thereof, a method for producing the compound and a pharmaceutical composition for preventing, alleviating or treating cancer containing the compound.

State of the art

Disclosure

[2] Cancer is a disease associated with the uncontrolled proliferation of cells that invade or proliferate to other organs, thereby reducing the quality of life and ultimately leading to death. Although genetic aberrations are the direct cause of the uncontrolled proliferation of cancer cells, insufficient immune surveillance and/or the lack of adequate immune response of the immune system to cancer cells is another cause of cancer cell proliferation. In addition, this leads to the formation of primary tumors that have a tumor microenvironment (TME) with suppressed anti-cancer immunity. Cancer cells then progress through the locally advanced stage and eventually develop into metastatic cancer, which invades other organs, causing a decrease in the cure rate and survival of cancer patients. Therapeutic agents for the treatment of such lethal diseases can be broadly divided into two categories. The first category directly targets cancer cells, and the second category targets components of the tumor microenvironment (TME) to prevent further proliferation or survival of cancer cells.

[3] Cancer immunotherapy is a therapeutic approach that targets immune factors present in the TME to induce an attack by immune cells on tumor cells. In some cases, cancer immunotherapy aims to stimulate tumor cell recognition by releasing tumor-associated antigens into the TME (e.g., cancer vaccines). In other cases, cancer immunotherapy aims to stimulate an attack on tumor cells by regulating the activity of innate and/or adaptive immune cells (e.g., immune checkpoint blockade). In still other cases, cancer immunotherapy aims to stimulate tumor death by manipulating patient-derived lymphocytes ex vivo to express chimeric antigen receptors, recognize tumor-surface antigens, and enhance lymphocyte activity (e.g., chimeric antigen receptor T-cell therapy (CAR-T-cell therapy)).

[4] Microbial infections 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 cases, therapeutic agents are substances that enhance or stimulate the host's immune function against pathogenic microorganisms.

[5] The tumor microenvironment (TM) contains malignant tumor cells as well as various types of immune cells (e.g., macrophages, lymphocytes, NK cells, and dendritic cells) and non-immune cells (e.g., tumor-associated fibroblasts, pericytes, endothelial cells, and adipocytes). Meanwhile, the presence of tumor-infiltrating lymphocytes has been reported to result in positive clinical outcomes in response to a variety of immunotherapies in various cancers. Preclinical studies have shown that modulation or upregulation of other types of immune cells other than lymphocytes, particularly innate immune cells, modulates the response of anticancer therapy to tumors. The innate immune system is one of the two major components of the host immune defense system in vertebrates. The primary functions of innate immunity include 1) identifying and removing foreign substances (e.g., bacteria, viruses) from body tissues, 2) attracting immune cells to specific sites by producing cytokines and stimulating adaptive immune responses, and 3) activating the complement cascade. This innate immunity can be activated by recognizing molecular patterns derived from microbial pathogens (pathogen-associated molecular patterns, PAMPs) or debris from damaged cells (damage-associated molecular patterns, DAMPs).

[6] 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 the innate immune response. The cGAS-STING (cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes), a type of cytoplasmic DNA sensor, signaling pathway is involved in 1) the recognition of cytoplasmic DNA resulting from microbial infection or damage to self-DNA, and 2) type 1 interferons (IFNs) by producing chemical factors, mainly activating the transcription factor IRE3.

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

[8] Systemic administration of type 1 IFN has shown proven efficacy in cancer environments, based on tumor regression and improved survival with systemic administration of IFN-beta in a preclinical mouse model. However, systemic administration of type 1 IFN has the problem that a high dose is required to achieve a therapeutically effective amount and obtain therapeutic efficacy. In this case, tolerability issues have been reported.

[9] Recently published clinical results with exogenous STING (modified cyclic dinucleotide) agonists have shown lower disease control rates than expected, despite an apparent increase in proinflammatory cytokine production.

[10] Thus, there is a need to explore new therapeutic modalities that can activate the cGAS-STING signaling pathway.

[11] [Documents of the prior art]

[12] [Patent documents]

[13] China Patent Publication CN 110575458 A

[14] International publication WO 2019/233300 A1

[15] International publication WO 2018/119325 A1

[16] International publication WO 2018/119328 A1

[17] International publication WO 2019/046778 A1

[18] International publication WO 2019/177 971 A1

[19] Japanese Patent Publication JP 2020-15670

[20] International publication WO 2019/051269 A1

[21] US Patent Publication US 2020/0039979 A1

[22] International publication WO 2019/023635 A1

[23] International publication WO 2019/051269 A1

Disclosure

Technical problem

[24] To solve the above problems, the present invention provides a method for enhancing the activity of the cGAS-STING signaling pathway.

[25] One of the objects of the present invention is to provide a novel naphthyridinone derivative compound having inhibitory activity against ENPP1. Another aspect of the present invention is to provide a novel naphthyridinone derivative compound for improving and/or modulating the production of type 1 interferons (IFN) in vivo.

[26] Another object of the present invention is to provide a pharmaceutical composition suitable for the treatment, prevention and alleviation of cancer, containing as an active ingredient a novel naphthyridinone derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or a stereoisomer thereof.

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

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

[29] Another object of the present invention is to provide a method for preventing, alleviating or treating periodontitis, comprising administering the novel naphthyridinone derivative or a pharmaceutical composition containing it to a patient or subject in need thereof.

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

[31] Another object of the present invention is to implement the following mechanism with the active ingredient of the new derivative compound of naphthyridinone, its

a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, or a stereoisomer thereof. In one aspect, the method comprises priming a cancer tumor with an agent for inducing immunogenic cell death (ICD) prior to stimulating the cGAS-STING signaling pathway. In another aspect, the method comprises blocking the degradation of an endogenous STING ligand prior to priming a cancer tumor with an agent for inducing ICD. In another aspect, the method comprises using an inhibitor of 2',3'-cGAMP-degrading polypeptide in combination with an agent for inducing ICD for the treatment of cancer. In one aspect, the present invention provides a method for developing an inhibitor of 2',3'-cGAMP-degrading polypeptide and a detailed assay method for assessing the enzymatic activity of the cGAMP-degrading polypeptide.

Technical solution

[32] In order to solve the above-described technical problems, in one aspect, 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, a solvate thereof, and a stereoisomer thereof:

[33] [Formula 1]

[34]

[35] where

[36] R ₁ represents hydrogen, a C ₁ -C ₁₃ alkyl group or a C ₃ -C ₁₀ cyclic group;

[37] R ₂ is -ZR ₃ -(R ₄ ) _m ;

[38] Z is present or absent, wherein 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 -;

[39] n is an integer between 0 and 8;

[40] R ₃ is a C ₃ -C ₁₀ cyclic group, a C ₃ -C ₁₀ heterocyclic group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group;

[41] R ₄ represents 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 cyclic group, C ₃ -C ₁₀ heteroaryl group, C ₃ -C ₁₀ heterocyclic group, -C(O)-(C ₁ -C ₁₃ alkyl), tert-butoxycarbonyl 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 ), carboxyl group (-C(O)OH), a nitrile group (-CN), a sulfonamide group (-NHS(O) ₂ R ₆ ), a urea group, a sulfamoyl group (-NHS(O) ₂ NHR ₆ ), a sulfonamide group, a sulfamoylalkyl group (-(C _{m H m+2} ) NHS(O) ₂ NHR ₆ ), a sulfamoylalkyl group (-(C _m H _m+2 ) NR ₅ S(O) ₂ NHR ₆ ), a sulfide group (-SR ₆ ), a sulfone group (-S(O) ₂ R ₆ ), or a phosphoryl group (-P(O)R ₅ R ₆ ), or is bonded to the same carbon as the carbon bonded to R ₃ to form a 3- to 7-membered saturated ring, is bonded to the same carbon as the carbon bonded to R ₃ to form a 3- to 7-membered a saturated heterocycle containing at least one heteroatom from N, O and S, is bonded to a carbon adjacent to the carbon bonded to R ₃ to form a 3-7-membered saturated ring, or is bonded to a carbon adjacent to the carbon bonded to R ₃ to form a 3-7-membered saturated heterocycle containing at least one heteroatom from N, O and S;

[42] m is an integer between 1 and 4;

[43] wherein the C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclic group comprises at least one substituent selected from the group consisting of 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 ), carboxyl group (-C(O)OH), nitrile group (-CN), urea group (-NR ₅ (C=O) NR ₆ -), sulfonamide group (-NHS(O) ₂ -), sulfide group (-S-), sulfonyl group (-S(O) ₂ -), phosphoryl group (-P(O)R ₅ R ₆ ), C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclic group, and

[44] The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group or C ₃ -C ₁₀ heterocyclic group comprises at least one substituent selected from the group consisting of hydrogen, hydroxyl group, halogen group, carbonyl group (-(C=O)R ₅ R ₆ ), C ₁ -C ₃ alkyl group substituted or unsubstituted by halogen or C ₃ -C ₁₀ heterocyclic group, C ₁ -C ₃ alkoxy group substituted or unsubstituted by halogen or C ₃ -C ₁₀ heterocyclic 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 ), carboxyl group (-C(O)OH), nitrile group (-CN), urea group (-NR ₅ (C=O)NR ₆ -), sulfonamide group (-NHS(O) ₂ -), sulfide group (-S-), sulfonyl group (-S(O)2-), phosphoryl group (-P(O)R ₅ R ₆ ), C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclic group; and

[45] each of R ₅ and R ₆ independently represents hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkenyl group, a C ₁ -C ₆ alkynyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ heteroaryl group, a C ₃ -C ₁₀ heterocyclic group, or R ₅ , together with the nitrogen or carbon atom bonded to R ₆ , forms a 3- to 7-membered saturated ring comprising at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ , and is substituted by at least one of hydrogen, a C ₁ -C ₁₃ alkyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group or cyano group,

[46] where the _C3 - _C10 heteroaryl group and the _C3 - _C10 heterocyclic group comprise at least one heteroatom selected from the group consisting of N, O, and S.

Beneficial effects

[47] The compound according to the present invention is capable of effectively inhibiting the activity of ENPP1.

Accordingly, the compound can be used to treat, prevent and alleviate cancers caused by abnormal cell growth.

[48] The compound of the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutical composition for the prevention or treatment of cancer containing it as an active ingredient effectively inhibit ENPP1 to activate the STING signaling pathway and thus are useful for the prevention or treatment of cancer and the prevention of cancer metastasis.

[49] Cancer diseases that can be treated, prevented, and ameliorated by administering the compound of the present invention include stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, scleroderma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma, and myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, fibroadenoma, and the like.

[50] In particular, the compound of the present invention is effective for preventing, alleviating or treating diseases associated with ENPP 1.

The best option for implementation

[51] Definitions

[52] Unless the context clearly dictates otherwise, all numbers, numerical values, and/or expressions that represent ingredients, reaction conditions, polymer compositions, and blend amounts used in the description are approximations that reflect, among other things, various measurement errors that inevitably occur in the process of obtaining these numerical values. For this reason, it should be understood that in all cases the term "about" should be considered as a modification of all numbers, numerical values, and/or expressions. Furthermore, when numerical ranges are disclosed in the description, these ranges are continuous and include all numbers from the minimum to the maximum, including the maximum in each range, unless otherwise specified. Furthermore, when a range refers to an integer, it includes all integers from the minimum to the maximum, including the maximum, within the range, unless otherwise specified.

[53] It should be understood that in the description, when a range is mentioned in relation to a parameter, the parameter encompasses all digital values, including endpoints, disclosed within the range. For example, the range "5-10" includes the digital values 5, 6, 7, 8, 9, and 10, as well as arbitrary subranges such as the ranges 6-10, 7-10, 6-9, and 7-9, and any digital values such as 5.5, 6.5, 7.5, 5.5-8.5, and 6.5-9, between the corresponding integers that fall within the range. Additionally, for example, a range of "10% to 30%" encompasses all whole numbers, including numbers such as 10%, 11%, 12%, and 13%, as well as 30%, and any sub-ranges such as the ranges of 10% to 15%, 12% to 18%, or 20% to 30%, and any numbers such as 10.5%, 15.5%, and 25.5%, between the respective whole numbers that fall within the range.

[54] As used herein, the terms "individual"(s), "subject"(s), and "patient"(s) mean any mammal(s). In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. None of the terms require or are limited to a situation characterized by the observation (e.g., continuous or intermittent) of healthcare professionals (e.g., physicians, staff nurses, nursing assistants, physician assistants, laborers, or hospice workers).

[55] The term "treatment" means an attempt to prevent the development or reversal of disease-related damage. Accordingly, the term "treatment" refers to both therapeutic and prophylactic actions. Those in need of treatment include the state in which the disease is developing and the state in which the disease is to be prevented. In the treatment of tumors, a therapeutic agent may act to directly reduce the pathology of tumor cells or to make tumor cells more susceptible to treatment with other therapeutic agents, such as radiation, chemotherapy, and/or immunotherapy. As used herein, the term "alleviated" or "treated" means a feature that approaches a normalized value as measured by conventional statistical tests. A feature approaching the normalized value is, for example, a value obtained from a healthy patient or individual that differs from the normalized value by less than 50%, preferably less than 25%, and more preferably less than 10%, and even more preferably has a small difference from the normalized value.

[56] The term "treatment of cancer" means any one or more of the following: 1) inhibition of tumor growth, including i) slowing or ii) stopping growth; 2) decreasing the number of tumor cells; 3) maintaining tumor size; 4) reducing tumor size; 5) inhibition of tumor cell infiltration into peripheral organs, including i) reducing or ii) slowing, or iii) completely preventing; 6) inhibition of metastasis, including i) reducing or ii) slowing, or iii) completely preventing; and 7) enhancing the anti-tumor immune response, which can cause i) maintaining tumor size, ii) reducing tumor size, iii) slowing tumor growth, or iv) reducing, slowing, or preventing invasion.

[57] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound disclosed herein that somewhat alleviates the symptoms of the disease or condition being treated (such as cancer or inflammatory disease, periodontal disease, or soft tissue mineralization). In some embodiments, the result is 1) a reduction and/or alleviation of the signs, symptoms, or causes of the disease, or 2) any other desired change in a biological system in a clinical setting. In some embodiments, a suitable "effective" amount for any individual case is determined using techniques such as a dose escalation study.

[58] In some embodiments, the term "effective amount" refers to an effective amount for inhibiting ENPP1 by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), at least about 60% (60% inhibition), at least about 70% (70% inhibition), at least about 80% (80% inhibition), or at least about 90% (90% inhibition), when an amount of a compound disclosed herein is administered, i.e., one or more doses, as part of monotherapy or combination therapy, when compared to the activity of ENPP1 in a subject not receiving the compound, or when comparing the activity of ENPP1 before or after treatment with the compound.

[59] In some embodiments, the term "therapeutically effective amount" refers to an amount effective to reduce the tumor burden of a subject by about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, when administered an amount of a compound disclosed herein, i.e., one or more doses, as part of a monotherapy or combination therapy, when compared to the tumor burden in a subject not receiving the compound, or when comparing the tumor burden before or after treatment with the compound. As used herein, the term "tumor burden" means the total tumor tissue mass of a subject having cancer.

[60] In some embodiments, the term "therapeutically effective amount" refers to the dose used for radiotherapy required to observe a tumor reduction in a subject of about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, when an amount of a compound disclosed herein is administered, i.e., one or more doses, as part of a monotherapy or combination therapy, compared to the dose of radiotherapy required to observe a tumor reduction in a subject not receiving the compound.

[61]

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

[63] As a result of continuous studies aimed at solving 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 present inventors have developed a novel naphthyridinone derivative compound for inhibiting ENPP1, a pharmaceutically acceptable salt, hydrate, and stereoisomer thereof, a method for producing them, and a pharmaceutical composition for the prevention or treatment of cancer containing them as an active ingredient. In one embodiment, the method comprises treating a sample with a cell-permeable ENPP1 inhibitor to inhibit the hydrolysis of cGAMP associated with ENPP1. In one embodiment, the method comprises administering to a patient or subject a therapeutically effective amount of a cell-permeable ENPP1 inhibitor for the treatment of cancer. A compound according to one aspect of the present invention, a composition containing the same, or a compound and composition can be used for various applications or diseases requiring the inhibition of ENPP1.

[64] cGAS-STING signaling pathway, immunogenic apoptosis and type 1 IFN production

[65] Cytoplasmic double-stranded DNA can be introduced outside cells as a result of microbial infection or vesicular transfer from adjacent dead cells. Cytoplasmic DNA can also be derived from damaged genomic DNA or mitochondrial DNA inside cells. If 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.

[66] Cyclic GMP-AMP synthase (cGAS) is a cytoplasmic protein present as a dimer and consisting of two DNA-binding domains and a nucleotidyl transferase domain (which converts ATP and GTP into the cyclic dinucleotide 2',3-cGAMP, which has 2',5( and 3',5( phosphodiester linkages). In addition, cGAMP acts as a second messenger and binds to STING with high affinity (K _d ~ 4 nM), inducing the expression of type 1 IFN.

[67] STING (also known as TMEM173, MITA, or MPYS) is an endoplasmic reticulum (ER) anchor protein containing four transmembrane domains at the N-terminus and a dimerization domain at the C-terminus. After binding to cGAMP, STING forms a tetramer and translocates from the ER to the ER-Golgi intermediate compartment. In the Golgi apparatus, STING attracts and activates tank-binding kinase 1 (TBK1), activated TBK1 phosphorylates the C-terminal domain of STING, and STING recruits and activates interferon regulatory factor 3 (IRF3). Activated IRF3 then migrates to the nucleus and promotes the expression of immune-stimulated genes (ISGs) and type 1 IFN. After activation, STING is translocated to endolysosomes and subsequently degraded. At this point, activation of the cGAS-STING signaling pathway ceases.

[68] Immunogenic cell death (ICD)

[69] Immunogenic cell death (ICD), which is a type of cell death, refers to a cellular phenomenon that induces the activation of a controlled immune response. Cell death is characterized by apoptotic morphology and maintains the integrity of the biological membrane. ICD is also characterized by the secretion of DAMPs (e.g., calreticulin, high-mobility group protein 1 (HMGB1), ATP, and Hsp70/90 proteins) and the exposure of polypeptides formed by native or mutated proteins to cells. The exposed polypeptides (acting as antigens) are recognized by dendritic cells (DCs) and subsequently by primary effector T cell lymphocytes to activate the adaptive immune response.

[70] ICD can also be further classified based on the different types of ICD inducers, such as 1) radiation (e.g., UV radiation or gamma radiation), 2) small molecule chemotherapy (e.g., doxorubicin or paclitaxel), and 3) biological agents (e.g., polypeptides, oligosaccharides, lipids, or nucleic acids).

[71] Radiation therapy

[72] Radiation therapy is well known and used to treat patients with a variety of diseases. Radiation therapy is typically used to suppress the death or growth of unwanted tissue (e.g., cancerous tissue). A specific amount of high-energy electromagnetic radiation and/or high-energy particles is directed to minimize unintended damage to desired or healthy tissue while directly damaging unwanted tissue or lesions in the radiation path.

[73] The results of studies conducted so far have shown that since the effect on normal tissue is more dependent on the fraction size than on the dose, a dose fraction of 1.8-2.0 Gy is considered the standard for conventional radiotherapy, and accordingly, the treatment time is increased. In fact, a small dose per fraction induces a tumor effect through mitotic death of cancer cells and repairs sublethal damage to normal tissues after administration. Stereotactic body radiation therapy (SBRT) is an advanced radiation therapy that uses sophisticated image guidance to precisely define the three-dimensional localization of tumors, allowing radiation to be delivered more precisely to cancer cells. In addition to direct cytotoxicity, SBRT has a significant effect on high-dose tumor cell death accompanied by microvascular injury, thereby adding a new mechanism of radiation-induced injury. However, a recent report showed that high-dose radiation induces the expression of nuclease enzymes with attenuated effects of radiation on STING-mediated activation of innate immunity.

[74] Pathogen

[75] As described above, intracellular invasion of pathogen-derived nucleic acids activates the cGAS-STING signaling pathway, thereby enhancing the immune response to the pathogens. In some cases, the pathogen is a virus, such as a DNA virus or an RNA virus. In some cases, the pathogen is a retrovirus. Examples of viruses that activate the cGAS-STING signaling pathway include, but are not limited to, herpes simplex virus 1 (HSV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), influenza A virus (IAV), human immunodeficiency virus (HIV), or human cytomegalovirus (HCMV). In other embodiments, the pathogen is a bacterium. Examples of bacteria include, but are not limited to, Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, and Neisseria gonorrhoeae.

[76] Phosphodiesterases

[77] Phosphodiesterases (PDEs) include cyclic

Nucleotide phosphodiesterases, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterases, DNases, RNases, restriction endonucleases, and a number of lesser-known small-molecular-weight phosphodiesterases. A group of typical PDE enzymes is important for the hydrolysis of the cyclic nucleotides adenosine-3',5'-cyclic monophosphate (cAMP) and guanosine-3',5'-cyclic monophosphate (cGMP) into their inactive 5'-monophosphate.

[78] Cyclic nucleotide phosphodiesterases comprise a group of enzymes that cleave complex phosphodiester bonds of cyclic nucleotide second messenger molecules, namely cAMP and cGMP. They regulate the localization, persistence, and amplification of cyclic nucleotide signals in subcellular domains.

[79] Ectonucleotide pyrophosphatases/phosphodiesterases

[80] The class of phosphodiesterases also includes ectonucleotide pyrophosphatases/phosphodiesterases. Ectonucleotide pyrophosphatases/phosphodiesterases (ENPP) or nucleotide pyrophosphatase/phosphodiesterase (NPP) are a group of ectonucleotidase enzymes that hydrolyze the pyrophosphate and phosphodiester bonds of their substrates to form nucleotide 5'-monophosphates (or phospholipids and phosphocholines). In some embodiments, the ENPP enzyme group includes seven ectonucleotidase enzymes (ENPP-1, ENPP-2, ENPP-3, ENPP-4, ENPP-5, ENPP-6, and ENPP-7) that have a similar protein structure on the cell surface.

[81] ENPP enzymes typically have a modular structure comprising a 400-amino acid catalytic domain. This catalytic domain is not associated with phospholipase, Nudix hydrolase, or ectonucleoside triphosphate diphosphohydrolase, although it exhibits partially overlapping activities. ENPP 1 and ENPP 3 are predicted to have a transmembrane domain at their N-terminus and a nuclease-like domain at their C-terminus and are type 2 single-spanning transmembrane proteins with their catalytic domains directed toward the extracellular domain. ENPP 2, which lacks a transmembrane domain at either the N- or C-terminus, is expected to have a signal peptide at the N-terminus and to be secreted extracellularly. ENPP 4, ENPP 5, ENPP 6, and ENPP 7, which contain putative N-terminal signal peptides and C-terminal transmembrane domains, are also predicted to be single-spanning type 1 transmembrane proteins with their catalytic domains directed toward the extracellular domain.

[82] ENPP 1, ENPP 2, and ENPP 3 are known to form nucleoside monophosphates (ENPP 1, ENPP 2, and ENPP 3) or nucleoside diphosphates (ENPP 1 and ENPP 2) using nucleotides and their derivatives as substrates. Only ENPP2 is known to use lysophospholipids. ENPP 6 and ENPP 7 are known to produce choline phosphates using choline phosphate esters as substrates. There is no known substrate for ENPP 4 and ENPP 5.

[83] ENPP1, also known as NPP1 or PC-1, is a type 2 transmembrane glycoprotein expressed in a number of tissues (pancreas, kidney, bladder, and liver). ENPP1 is essential 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, producing inorganic pyrophosphate (PPi). Overall, since inorganic pyrophosphate regulates bone and cartilage mineralization, PPi production 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 necessary for bone mineralization. ENPP1 has broad specificity and hydrolyzes a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars.

[84] ENPP1 has recently been found to play an important role in the immunological response to various environmental signals that activate the cGAS-STING signaling pathway. A preliminary study of the enzymatic activity that degrades cGAMP molecules revealed that ENPP1 functions as the major cGAMP hydrolase. In line with these results, it was reported that the half-life of cGAMP was significantly dependent on ENPP1, based on the verification of a much longer half-life of cGAMP in ENPP1 knockout mice.

[85] A bisphosphonate analog of cGAMP, which is resistant to ENPP1 hydrolysis, has been shown to activate STING tenfold more efficiently than cGAMP, suggesting that delaying or reducing cGAMP hydrolysis by inhibiting ENPP1 can significantly increase STING activation. ENPP1 inhibition has been reported to induce the presence of persistent cGAMP to activate the STING pathway, thereby attenuating pseudorabies virus infection and reducing Mycobacterium tuberculosis infection.

[87] Accordingly, in one aspect, the present invention provides an ENPP1 inhibitor, which is a cGAMP-degrading polypeptide.

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

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

[90] In one aspect, the ENPP1 inhibitor is an allosteric inhibitor.

[91] In one aspect, the ENPP1 inhibitor is an irreversible inhibitor.

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

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

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

[95] Method of inhibiting ENPP1

[96] As stated above, the present invention includes the following configurations: 1) an ENPP1 inhibitor; 2) a method of inhibiting ENPP1 enzyme using the ENPP1 inhibitor; 3) a method of inhibiting the cGAMP hydrolase activity of ENPP1; 4) a method of improving the output signal of STING pathway activation; and 5) a method of inhibiting tumor growth in a corresponding mouse tumor model under monotherapy or combination therapy.

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

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

[99]

[100]

[101] In some embodiments, the cell-permeable ENPP1 inhibitor is any of the following compounds:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[122] Compound 21: 5-(2-fluoro-4-((isopropylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

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

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

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

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

[127] Compound 26: 5-(isoindolin-5-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[175] Compound 74: ethylhydro(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

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

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

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

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

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

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

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

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

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

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

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

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

[188] Compound 87: 5-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amine)-1,8-naphthyridin-2(1H)-one dihydrochloride;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[204] Compound 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;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[244] Compound 143: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindolin-2-sulfamide hydrochloride;

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

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

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

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

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

[250]

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

[252] In some embodiments, the compounds of the present invention inhibit ENPP 1, which can be determined using an assay for determining enzyme activity in cell-free or cellular systems after treatment with the compounds of the present invention, compared to a control group by an inhibition assay, such as by measuring the IC ₅₀ or EC ₅₀ . In some embodiments, the compounds of the present invention have an IC ₅₀ (or EC ₅₀ ) of 10 μM or less, such as 3 μM or less, 1 μM or less, 500 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 30 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even a lower value.

[253] An assay method that can be used to determine ENPP1 activity may include, but is not limited to, the following assay methods, including cell-free assay systems such as avidity assays, assays using purified enzymes, cell-based assays to determine cell phenotypes such as gene expression assays, and in vivo assays using specific animals.

[254] In some embodiments, the method of the present invention is a method of suppressing the proliferation of cancer cells, wherein the method comprises treating the cells with an effective amount of a compound of the present invention to suppress the proliferation of the cancer cells. In some embodiments, the method may be performed in combination with chemotherapy. Any cancer cells may be used if they are available.

[255] Method of treatment

[256] As mentioned above, the present invention includes methods of inhibiting ENPP1 activity on cGAMP to induce increased cGAMP levels and/or modulation of downstream factors of the STING pathway. A recent report has shown that inhibition of ENPP1 can modulate STING activity in vivo and thus can be used to treat various diseases, such as in cancer immunotherapy or the treatment of infectious diseases. As described above, the method of the present invention is a method of enhancing a STING-mediated response and regulating an immune response in a subject.

[257] In some embodiments, the STING-mediated response comprises an increase in interferon production (e.g., type 1 interferon, type 3 interferon) in the subject. Interferons (IFNs) are a group of signaling proteins produced and released by host cells in response to the presence of one or more pathogens to enhance the defense of surrounding cells against the pathogens. IFNs also perform a variety of other functions: 1) activate immune cells such as NK cells and macrophages, and 2) stimulate host defense by upregulating antigen presentation through increased expression of major histocompatibility complex (MHC) antigens. IFNs are generally divided into three classes: type 1 IFNs, type 2 IFNs, and type 3 IFNs. Mammalian type I IFNs include IFN-α, IFN-β, IFN-δ, IFN-ε, IFN-ε, IFN-ε, IFN-ε, IFN-ε, IFN-ε, IFN-ε, and IFN-ε. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α/ε receptor (IFNAR), which consists of the IFNAR1 and IFNAR2 chains.

[258] Interferons have been studied as anticancer agents due to their antitumor activity, which is characterized by two distinct effects, namely, an intrinsic antitumor and/or immunomodulatory effect. IFNs regulate the expression of a number of genes that directly influence tumor cell growth, proliferation, differentiation, survival, migration, and other specific functions. In some cases, in vitro treatment with type 1 IFNs exerts a direct antiproliferative effect by prolonging all phases of the cell cycle with IFNs. In some cases, CRKL, which is a type of CRK protein activated by type 1 IFNs, interacts with the tumor suppressor small G protein RAP1A to inhibit the RAS family GTPases, resulting in cancer cell growth arrest. IFNs are known to regulate two major apoptotic responses. The two apoptotic responses are the extrinsic (apoptotic receptor-mediated pathway) and intrinsic (mitochondrial) pathways. In response to type 1 IFN, sensor protein activation (e.g., the DR receptor) is upregulated, inducing tumor cell apoptosis.

[259] 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 important roles in anti-cancer immune activity. For example, type 1 IFNs enhance the activity of α/β T cells, γ/β T cells, NK cells, and dendritic cells, and inhibit the activity of immunosuppressive cells, such as the conversion of regulatory T cells, bone marrow-derived suppressor cells, and tumor-associated macrophages. Type 1 IFNs also act directly on tumor cells by enhancing antigen expression and upregulating numerous immune-interacting molecules (e.g., major histocompatibility complex class 1 (MHCI)-recognized stress ligands) and germline immunoreceptors.

[260] In one aspect, the method comprises administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a cancer to treat the cancer in the subject. 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 selected from adrenal cancer, liver cancer, kidney cancer, bladder cancer, breast cancer, colon cancer, gastric cancer, ovarian cancer, cervical cancer, uterine cancer, esophageal cancer, colorectal cancer, prostate cancer, pancreatic cancer, lung cancer (small cell and non-small cell), thyroid cancer, carcinoma, sarcoma, glioblastoma, melanoma, and head and neck cancer. In one embodiment, the cancer is lymphoma.

[261] In one embodiment, the effective amount of the compound ranges from about 10 ng to about 100 mg, such as from about 10 ng to about 50 ng, from about 50 ng to about 150 ng, from about 150 ng to about 250 ng, from about 250 ng to about 500 ng, from about 500 ng to about 750 ng, from about 750 ng to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 50 μg, from about 50 μg to about 150 μg, from about 150 μg to about 250 μg, from about 250 μg to about 500 μg, from about 500 μg to about 750 μg, from about 750 mcg to about 1 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, or about 50 mg to about 100 mg. The amount may be a single dose or a total daily 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.

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

[263] Combination therapy

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

[265] The term "co-administration" or "in combination with" includes the administration of two or more therapeutic agents simultaneously, in parallel, or sequentially, without any particular time limitation. In some embodiments, the agonists or agents are simultaneously present in cells or subjects or simultaneously exert a biological or therapeutic effect. In some embodiments, the therapeutic agents are presented as an identical composition or unit dosage form. In some embodiments, the therapeutic agents are separate compositions or unit dosage forms. In some embodiments, the first therapeutic agent is administered before the administration of the second therapeutic agent (e.g., 5 minutes before, 15 minutes before, 30 minutes before, 45 minutes before, 1 hour before, 2 hours before, 4 hours before, 6 hours before, 12 hours before, 24 hours before, 48 hours before, 72 hours before, 96 hours before, 1 week before, 2 weeks before, 3 weeks before, 4 weeks before, 5 weeks before, 6 weeks before, 8 weeks before, 12 weeks before), when administered concomitantly with the administration of the second therapeutic agent, or after the administration of the second therapeutic agent (e.g., 5 minutes after, 15 minutes after, 30 minutes after, 45 minutes after, 1 hour after, 2 hours after, 4 hours after, 6 hours after, 12 hours after, 24 hours after, 48 hours after, 72 hours after, 96 hours after, 1 week after, 2 weeks after, 3 weeks after, 4 weeks after, 5 weeks after, 6 weeks after, 8 weeks after, or 12 weeks after).

[266] "Concomitant administration" of an additional therapy based on a known therapeutic agent or a composition comprising a disclosed compound of the present invention means a combination of the compound and a second agent or an additional therapy such that both the known agent and the composition comprising the disclosed compound have therapeutic effects. Concomitant administration may include the simultaneous or prior administration of drugs in combination with the administration of a compound of the present invention. The routes of administration of the two agents may vary, and typical routes of administration are described in detail below. Those skilled in the art will readily determine the appropriate timing, sequence, and dosage for the drug or therapy and the compound described herein.

[267] "Concomitant administration" of an additional therapy based on a known therapeutic agent or a composition comprising a disclosed compound of the present invention means a combination of the compound and a second agent or an additional therapy such that both the known agent and the composition comprising the disclosed compound have therapeutic effects. Concomitant administration may include the simultaneous or prior administration of drugs in combination with the administration of a compound of the present invention. The routes of administration of the two agents may vary, and typical routes of administration are described in detail below. Those skilled in the art will readily determine the appropriate timing, sequence, and dosage for the drug or therapy and the compound described herein.

[268] For the treatment of cancer, ENPP1 inhibitor compounds can be administered in combination with a chemotherapeutic agent selected from the group consisting of alkylating agents, antimetabolites, antitumor antibiotics, plant alkaloids, taxanes, nucleoside analogs, anthracyclines, thymidylate-targeting agents, apoptosis modulators, cell cycle control inhibitors, colony-stimulating factor 1 receptor inhibitors, CD47 inhibitors, and others.

[269] Combination with immunotherapeutic agents

[270] For the treatment of cancer, ENPP1 inhibitor compounds can be administered in combination with an immunotherapeutic agent. The immunotherapeutic agent is an agonist suitable for treating cancer by inducing, enhancing, or inhibiting an immune response. In some embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. Any immunosuppressant can be used. For example, the immune checkpoint inhibitor can be, but is not limited to, a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a programmed death protein 1 (PD-1) inhibitor, or a programmed death ligand 1 (PD-L1) inhibitor. Examples of an immune checkpoint inhibitor include, but are not limited to, ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, and the like. In some embodiments, the immunotherapeutic agent is an immunocellular therapy. Any suitable cellular therapy can be used, and examples include, but are not limited to, chimeric antigen receptor T-cell therapy, chimeric antigen receptor NK cell therapy, and other cellular therapies.

[271] For the treatment of cancer, an ENPP1 inhibitor compound may be administered in combination with a suitable cancer vaccination regimen, such as a dendritic cell-based vaccine that promotes Th1/ _Th17 immunity. In some cases, an ENPP1 inhibitor compound is suitable for use as an adjuvant therapy in combination with Th17-inducing vaccination.

[272] Combination with radiation therapy

[273] For the treatment of cancer, an ENPP1 inhibitor compound may be administered in combination with radiation therapy. In some embodiments, an ENPP1 inhibitor compound may be administered before or after radiation therapy. The combination of radiation therapy and administration of a compound of the present invention may provide a synergistic therapeutic effect. When a subject is subjected to radiation therapy (RT) at an appropriate dose and/or frequency during radiation therapy (RT), the subject may produce cGAMP. An ENPP1 inhibitor compound may enhance the therapeutic efficacy for the subject by preventing the destruction of the cGAMP produced, compared to the level of cGAMP obtained, for example, with RT alone. Accordingly, details of the methods of the present invention include administering a reduced dose and/or frequency and/or regimen of radiation therapy compared to the dose and/or frequency and/or reduction in the therapeutic effect of radiation therapy alone. In some embodiments, radiation therapy is administered in combination with a compound of the present invention at a dosage and/or frequency effective to reduce the risk of radiation injury, such as the risk of radiation injury to the subject expected at a therapeutically effective amount.

[274] In one embodiment, the method comprises administering to a subject an ENPP1 inhibitor prior to radiation therapy. In one embodiment, the method comprises administering to a subject an ENPP1 inhibitor after subjecting 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.

[275] Combination with an anti-cancer vaccine

[276] For the treatment of cancer, an ENPP1 inhibitor compound may be administered in combination with a cancer vaccine. In some embodiments, the ENPP1 inhibitor compound may be administered before or after administration of the cancer vaccine.

[277] Combination with CAR-T

[278] For the treatment of cancer, an ENPP1 inhibitor compound may be administered in combination with CAR-T cells. In some embodiments, the ENPP1 inhibitor compound may be administered before or after the administration of CAR-T cells.

[279] Monotherapy

[280] Therapy promoting myocardial regeneration

[281] In one aspect, a therapy for myocardial regeneration may comprise administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a pathological change due to a myocardial infarction to treat the subject.

[282] Treatment regimen for hypophosphatemia

[283] In one aspect, methods for treating hypophosphatemia may comprise administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a pathological change caused by hereditary hypophosphatemia to treat the subject.

[284] Pharmaceutical composition

[285] Pharmaceutically acceptable excipients such as fillers, adjuvants, carriers, or diluents are readily available to those skilled in the art. Pharmaceutically acceptable auxiliary substances such as pH modifiers, buffers, isotonicity modifiers, stabilizers, wetting agents, and the like are readily available to those skilled in the art.

[286] In some embodiments, a compound of the present invention is prepared in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers at various concentrations ranging 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, and sucrose, and the like. In some embodiments, the aqueous buffer further includes a nonionic surfactant such as polysorbate 20 or 80. Optionally, the composition may further include a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In another embodiment, the composition is stored at a temperature of about 4°C. The composition can also be lyophilized and typically contains a cryoprotectant such as sucrose, trehalose, lactose, maltose, or mannitol. Lyophilized preparations can be stored even at room temperature for an extended period of time.

[287] Here, the pharmaceutical composition may comprise or consist essentially of a compound described herein, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a tautomer thereof, and further comprises or consists essentially of one or more activators of interest. Any advantageous activator may be used in the present method in combination with a compound of the present invention. In one embodiment, a compound of the present invention and an immune checkpoint inhibitor, as well as an 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, a chemotherapeutic agent (in particular, a chemotherapeutic agent capable of inducing cGAMP production in vivo), and an additional therapeutic agent described herein for combination therapy may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. The compound of the present invention and the second activator (if present) can be administered by the same or different routes. The therapeutic agent can be administered by any suitable route, including, but not limited to, oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, and intratumoral injection into the affected organ.

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

[289] 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 vehicles such as esters, emulsions, syrups or elixirs, suspensions and solutions and/or suspensions reconstituted from non-foaming granules. Such liquid carriers may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, excipients and softening agents.

[290]

[291] Various aspects of the present invention will be described below.

[292] In one aspect, 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, a solvate thereof, and a stereoisomer thereof:

[293] [Formula 1]

[294]

[295] where R ₁ represents hydrogen, a C ₁ -C ₁₃ alkyl group or a C ₃ -C ₁₀ cyclic group;

[296] R ₂ is -ZR ₃ -(R ₄ ) _m ;

[297] Z is present or absent, wherein 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 -;

[298] n is an integer between 0 and 8;

[299] R ₃ is a C ₃ -C ₁₀ cyclic group, a C ₃ -C ₁₀ heterocyclic group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group;

[300] R ₄ represents hydrogen, a hydroxyl group, a halogen group, a C ₁ -C ₁₃ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkenyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ cyclic group, a C ₃ -C ₁₀ heteroaryl group, a C ₃ -C ₁₀ heterocyclic group, -C(O)-(C ₁ -C ₁₃ alkyl), a tert-butoxycarbonyl group (Boc), an amino group (-NR ₅ R ₆ ), (C _m H _m+2 ) NR ₅ R ₆ , a nitro group (-N(O) ₂ ), an amide group (- (C=O) NR ₅ R ₆ ), an ester group (-C(O)OR ₆ ), a carboxyl group (-C(O)OH), a nitrile group (-CN), a sulfonamide group (-NHS(O) ₂ R ₆ ), a urea group, a sulfamoyl group (-NHS(O) ₂ NHR ₆ ), a sulfonamide group, a sulfamoylalkyl group (-(C _m H _m+2 ) NHS(O) ₂ NHR ₆ ), a sulfamoylalkyl group (-(C _m H _m+2 ) NR ₅ S(O) ₂ NHR ₆ ), a sulfide group (-SR ₆ ), a sulfone group (-S(O) ₂ R ₆ ), or a phosphoryl group (-P(O)R ₅ R ₆ ), or is bonded to the same carbon as the carbon bonded to R ₃ to form a 3- to 7-membered saturated ring, bonded to the same carbon as the carbon bonded to R ₃ , with forming a 3- to 7-membered saturated heterocycle containing at least one heteroatom from N, O, and S, is bonded to a carbon adjacent to the carbon bonded to _R3 to form a 3- to 7-membered saturated ring, or is bonded to a carbon adjacent to the carbon bonded to _R3 to form a 3- to 7-membered saturated heterocycle containing at least one heteroatom from N, O, and S; and

[301] m is an integer between 1 and 4;

[302] wherein the C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclic group comprises at least one substituent selected from the group consisting of hydrogen, a hydroxyl group, a halogen group, a C ₁ -C ₁₃ alkyl group, a C ₁ -C ₆ alkoxy group, an amino group (-NR ₅ R ₆ ), a nitro group (-N(O) ₂ ), an amide group (- (C=O) NR ₅ R ₆ ), a carboxyl group (-C(O)OH), a nitrile group (-CN), a urea group (-NR ₅ (C=O) NR ₆ -), a sulfonamide group (-NHS(O) ₂ -), a sulfide group (-S-), a sulfonyl group (-S(O)2-), a phosphoryl group (-P(O)R ₅ R ₆ ), C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclic group, and

[303] The C ₆ -C ₁₀ aryl group, the C ₃ -C ₁₀ heteroaryl group or the C ₃ -C ₁₀ heterocyclic group comprises at least one substituent selected from the group consisting of hydrogen, a hydroxyl group, a halogen group, a carbonyl group (-(C=O)R ₅ R ₆ ), a C ₁ -C ₃ alkyl group substituted or unsubstituted by halogen or a C ₃ -C ₁₀ heterocyclic group, a C ₁ -C ₃ alkoxy group substituted or unsubstituted by halogen or a C ₃ -C ₁₀ heterocyclic group, C ₆ -C ₁₀ phenoxy, an amino group (-NR ₅ R ₆ ), a nitro group (-N(O) ₂ ), an amide group (-(C=O)NR ₅ R ₆ ), a carboxyl group (-C(O)OH), nitrile group (-CN), urea group (-NR ₅ (C=O)NR ₆ -), sulfonamide group (-NHS(O) ₂ -), sulfide group (-S-), sulfonyl group (-S(O) ₂ -), phosphoryl group (-P(O)R ₅ R ₆ ), C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclic group; and

[304] each of R ₅ and R ₆ independently represents hydrogen, a C ₁ -C 6 alkyl group, a C ₁ -C ₆ alkenyl group, a C ₁ -C ₆ alkynyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ heteroaryl group, a C 3 -C ₁₀ heterocyclic group, or R ₅ , together with the nitrogen or carbon atom bonded to R ₆ , forms a 3- to 7-membered saturated ring comprising at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ , and is substituted by at least one of hydrogen, a C ₁ -C ₁₃ alkyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group or cyano group,

[305] wherein the _C3 - _C10 heteroaryl group and the _C3 - _C10 heterocyclic group comprise at least one heteroatom selected from the group consisting of N, O, and S.

[306]

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

[308] The term "aryl" means an aromatic monocarbocyclic C6 group which may be further fused, alone or in combination with another radical, with a 5- or 6-membered carbocyclic group which may be aromatic and may be saturated or unsaturated. Examples of aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and the like. Aryl may be bonded to other groups at appropriate positions on the aromatic ring.

[309] The term "alkoxy" denotes an alkyl group bonded to another group through an oxygen atom (i.e., -O-alkyl). The alkoxy group may be unsubstituted or substituted by one or more suitable substituents. Examples of the alkoxy group include, but are not limited to, 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-dimethylbutyl, -O-2-ethyl-1-butyl, -O-butyl, -O-isobutyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

[310] The term "phenoxy" means a phenyl group bonded to another group through an oxygen atom (i.e., -O-aryl). Phenoxy is unsubstituted or substituted by, but is not limited to, at least one of halogen, alkyl, aryl, or heteroaryl groups.

[311] The term "amino group" means an alkyl group bonded to another group through a nitrogen atom (i.e., -NH- or -N-alkyl). The amino group may be unsubstituted or substituted by one or more suitable substituents. Examples of amino groups include, but are not limited to, (C ₁ -C ₆ )amino, 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-dimethylbutyl, -NH-2-ethyl-1-butyl, -NH-butyl, -NH-isobutyl, -NH-tert-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N,N-dimethyl, -N-methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl-N-butyl, -N-methyl-N-isobutyl, -N-methyl-N-pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N-propyl, -N-ethyl-N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N-hexyl, -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N-propyl-N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl and -N,N-digexyl.

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

[313] The term "heterocyclic group" means a heteroaromatic compound containing at least one heteroatom selected from the group consisting of N, O, and S, unless otherwise specified. Preferably, the heterocyclic group may include, but is not limited to, pyrrolidine, furan, morpholine, piperazine, and piperidine groups, more preferably pyrrolidine, piperidine, piperazine, and morpholine groups.

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

[315]

[316] In one aspect, the present invention provides a compound selected from a naphthyridinone derivative compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, wherein Rx 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.

[317] In one aspect, the present invention provides a compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, wherein 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 phenanthrene, substituted or unsubstituted pyridazine, substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazine, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted quinoline, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrrole, substituted or unsubstituted indole, substituted or unsubstituted purine, substituted or unsubstituted cyclopropane, or substituted or unsubstituted cyclobutene.

[318] In one aspect, the present invention provides a compound selected from a naphthyridinone derivative compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, wherein 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.

[319] In one aspect, the present invention provides a compound selected from a naphthyridinone derivative compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, wherein R ₂ is

[320] In one aspect, the present invention provides a compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, wherein R4 is halogen, a methyl group, an ethyl group, -NH ₂ , -CH ₂ NH ₂ , -CHCH ₃ NH ₂ , -CH(CH ₃ ) ₂ NH ₂ , -CHCH ₃ NHCH ₃ , -CH ₂ NHCH ₂ CH ₃ , -tert-butoxycarbonyl group (Boc),

[321] In one aspect, the present invention provides a compound selected from a naphthyridinone derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, wherein the compound is selected from the group consisting of the following Compound Nos. 1-148:

[322] Selected connections:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[343] Compound 21: 5-(2-fluoro-4-((isopropylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride;

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

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

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

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

[348] Compound 26: 5-(isoindolin-5-yl)-1,8-naphthyridin-2(1H)-one hydrochloride;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[396] Compound 74: ethylhydro(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate;

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

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

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

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

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

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

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

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

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

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

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

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

[409] Compound 87: 5-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amine)-1,8-naphthyridin-2(1H)-one dihydrochloride;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[425] Compound 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;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[465] Compound 143: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindolin-2-sulfamide hydrochloride;

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

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

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

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

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

[471]

[472] The compound of formula 1 according to the present invention can be used in the form of a pharmaceutically acceptable salt prepared from an inorganic or organic acid, and the pharmaceutically acceptable salt preferably includes at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

[473] The compound of formula 1 of the present invention or a pharmaceutically acceptable salt thereof may include a hydrate and a solvate. The hydrate can be formed by binding the compound of formula 1 to a water molecule.

[474] In another aspect, the present invention provides a pharmaceutical composition for the prevention, amelioration or treatment of cancer, comprising a compound according to one aspect of the present invention as an active ingredient.

[475] In another aspect, the present invention provides an ENPP 1 inhibitor comprising a compound according to one aspect of the present invention as an active ingredient.

[476] In another aspect, the present invention provides a STING signaling pathway activator comprising a compound according to one aspect of the present invention as an active ingredient.

[477] In another aspect, the present invention provides a pharmaceutical composition for the prevention, amelioration or treatment of cancer, wherein the cancer is associated with inhibition of ENPP 1.

[478]

[479] In another aspect, the present invention provides a pharmaceutical composition for the prevention, amelioration or treatment of cancer, comprising a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof as an active ingredient.

[480] The pharmaceutical composition of the present invention has an excellent ability to inhibit the activity of ENPP 1.

[481] Accordingly, the pharmaceutical composition of the present invention can be used for the treatment, prevention and amelioration of cancer diseases caused by abnormal cell growth. Cancer diseases that can be prevented, treated or ameliorated by administering the pharmaceutical composition of the present invention include stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, fibrous induration, 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 and fibroadenoma.

[482] In another aspect, the present invention provides an ENPP 1 inhibitor comprising any of the above-described compounds as an active ingredient.

[483] In another aspect, the present invention provides a STING signaling pathway activator comprising any of the above-described compounds as an active ingredient.

[484] The pharmaceutical composition can be applied to experimental animals such as mice, rabbits, rats, guinea pigs or hamsters, preferably to primates, including humans, more preferably to humans, without limitation thereto.

[485] As used herein, the term "treatment" includes alleviation or amelioration of symptoms, reduction in the extent of the disease, delay or amelioration of the progression of the disease, reduction, alleviation, or stabilization of the disease state, partial or complete recovery, prolongation of survival, and other beneficial treatment outcomes.

[486] In addition, in this description, cancer treatment means treatment of all cancer cells, and cancer includes endothelial cell angiogenesis and mitosis (solid tumors, tumor metastases, and benign tumors). For example, cancer includes, but is not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoacanthomas, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, carcinogenic cancer, follicular carcinoma, undifferentiated cancer, papillary cancer, normal hematoma, melanoma, sarcoma, bladder cancer, liver cancer, bile duct cancer, kidney cancer, myeloid diseases, lymphoid diseases, Hodgkin's disease, hair cell cancer, oral cancer, pharyngeal (oral) cancer, lip cancer, tongue cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma and purulent sarcoma.

[487] The content of the active ingredient, namely, the compound represented by formula 1, its pharmaceutically acceptable salt, its hydrate or its solvate is appropriately adjusted by selection by persons skilled in the art depending on the application mode and the method of use of the pharmaceutical composition of the present invention.

[488] For example, the pharmaceutical composition contains a compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof in an amount of 0.1-10% by weight, more preferably 0.5-5% by weight, based on the total weight of the pharmaceutical composition.

[489] The compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be present alone or in combination with a pharmacologically acceptable carrier, excipient, diluent, or additional ingredient in a pharmaceutical composition.

[490] For example, the pharmaceutically acceptable carrier, excipient, and diluent include, but are not limited to, one or more selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, and saline, and a conventional carrier, excipient, or diluent may be used. In addition, the pharmaceutical composition may also include a conventional filler, a dry diluent, a binder, a disintegrating agent, an anticoagulant, a lubricant, a wetting agent, an acidity regulator, a nutrient, a vitamin, an electrolyte, alginic acid or its salt, pectic acid or its salt, a protective colloid, glycerin, a flavoring agent, an emulsifier, a preservative, or the like.

[491] When administered in combination with another antitumor drug for the treatment of cancer or tumors, the compound represented by formula 1 or a pharmaceutically acceptable salt thereof can exhibit a synergistic therapeutic effect with the antitumor drug.

[492] In particular, the pharmaceutical composition may further comprise at least one other anticancer agent or therapeutic agent known to be effective for the treatment or prevention of cancer, in addition to the active ingredient, and accordingly, may be used as a combination therapy administered simultaneously or separately. Other anticancer agents or therapeutic agents that may be used for combination therapy may include, for example, at least one compound selected from the group consisting of Gleevec® (imatinib), Sutent® (sunitinib), Herceptin® (trastuzumab), Velcade® (bortezomib), dexamethasone, Nexavar® (sorafenib), aromatase inhibitors, and kinase inhibitors, but not limited to those listed.

[493] The pharmaceutical composition may be administered orally or parenterally, and may, for example, be administered by various routes including oral, transdermal, subcutaneous, intravenous, or intramuscular. Furthermore, the dosage form of the composition may vary depending on the route of administration and may be prepared using methods well known in the art to provide rapid, prolonged, or delayed release of the active ingredient after administration to mammals. Typically, solid preparations for oral use include tablets, dragees, soft or hard capsules, pills, powders, granules, and the like. These preparations can be prepared, for example, by mixing starch, calcium carbonate, sucrose, lactose, gelatin, or the like. Furthermore, lubricating agents such as magnesium stearate and talc may also be used in addition to simple excipients. Liquid preparations for oral administration include suspensions, liquids and solutions, emulsions, syrups, and the like. In addition to water and liquid paraffin, which are common simple diluents, various excipients, such as wetting agents, sweeteners, flavorings, and preservatives, may be included.

Parenteral dosage forms include creams, lotions, ointments, plasters, liquids and solutions, aerosols, liquid extracts, elixirs, infusions, sachets, patches, injection solutions, and the like. Injectable dosage forms are preferably isotonic aqueous solutions or suspensions.

[494] The pharmaceutical composition may further comprise an adjuvant such as a sterilizer, preservative, stabilizer, wetting agent or emulsification accelerator, salt and/or buffer for regulating osmotic pressure and other therapeutically useful substances. Alternatively, the pharmaceutical composition may be prepared according to a conventional mixing, granulation or coating method, or using a suitable method known in the art.

[495] Furthermore, the dosage of the pharmaceutical composition can be determined taking into account the route of administration, age, sex, severity of the disease and condition of the patient, the rate of absorption of the active ingredient in the body and the rate of inactivation of the active ingredient and drugs used in combination with it, and the pharmaceutical composition can be administered once or in multiple portions. The active ingredient of the pharmaceutical composition is preferably administered orally or parenterally to a mammal including a human in an amount of 0.001-100 mg/kg body weight, preferably 0.01-35 mg/kg body weight, daily, and can be administered once or divided into several doses throughout the day.

[496] In another aspect, the present invention provides a method of treating cancer, comprising administering a therapeutically effective amount of a compound represented by formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[497] Preferably, the method of treatment may further include identifying a patient in need of cancer prevention or treatment prior to administration of the drug.

[498] The term "therapeutically effective amount" as used herein means an amount of an active ingredient that is effective for preventing or treating cancer in a mammal, and the therapeutically effective amount can be controlled by various factors such as the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of dosage form, the age, weight, general health, sex and diet of the patient, the time of administration, the route of administration, the rate of elimination of the composition from the blood, the duration of treatment and drugs used simultaneously. Preferably, as described above, the compound can be administered in an amount of 0.001-100 mg/kg body weight, preferably 0.01-35 mg/kg body weight, daily, once or several times a day in portions, orally or parenterally.

[499] In another aspect, the present invention provides a method for producing a compound selected from a naphthyridinone derivative compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[500]

[501] Meanwhile, the present invention provides a method for producing a naphthyridinone derivative compound represented by formula 1. The production method of the present invention will be described in detail below.

[502] In one embodiment, the compound represented by Formula 1 of the present invention can be obtained by at least one of the following production methods 1 to 4.

[503]

[504] Method of obtaining 1

[505] The naphthyridinone derivative compound of formula 1 according to one aspect of the present invention can be produced according to a production method based on the following reaction scheme 1.

[506] [Reaction Scheme 1]

[507]

[508] Method of obtaining 2

[509] The naphthyridinone derivative compound of formula 1 according to one aspect of the present invention can be produced according to a production method based on the following reaction scheme 2.

[510] [Reaction scheme 2]

[511]

[512] Method of obtaining 3

[513] The naphthyridinone derivative compound of formula 1 according to one aspect of the present invention can be produced according to a production method based on the following reaction scheme 3.

[514] [Reaction scheme 3]

[515]

[516]

[517] Method of obtaining 4

[518] The naphthyridinone derivative compound of formula 1 according to one aspect of the present invention can be produced according to a production method based on the following reaction scheme 4.

[519] [Reaction scheme 4]

[520]

[521] Embodiment of the invention

[522] The present invention will now be described in more detail with reference to Synthesis Examples, Production Examples, Examples, Experimental Examples, and Composition Examples. However, the following Synthesis Examples, Production Examples, Examples, Experimental Examples, and Composition Examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention.

[523]

[524] [Example of receipt 1]

[525] Example of obtaining 1 includes a process for obtaining product 3, product 4, product 7 or product 8.

[526] Example of obtaining 1:

[527] [Reaction Scheme 1]

[528]

[529] Step 1: I (1.0 equiv), palladium(II) acetate (0.050 equiv), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv), Z (1.3 equiv), and potassium carbonate (3.0 equiv) were dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) in a round-bottomed flask and refluxed under nitrogen for 16 h. After completion of the reaction, 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 resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to give 3 (yield 40-60%).

[530]

[531] The following are examples of the present invention obtained in accordance with Step 1 as described above.

[532]

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

[534]

[535] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[536]

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

[538]

[539] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[540]

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

[542]

[543] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[544]

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

[546]

[547] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[548]

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

[550]

[551] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[552]

[553] Step 2: 3 (1.0 equiv) was dissolved in dichloromethane (0.040 M) in a round-bottomed flask. A solution of the hydrochloride (4.0 M in 1,4-dioxane, 0.2 M) was then added, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was washed with diethyl ether, filtered, and dried to give 4 (yield 60-80%).

[554]

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

[556]

[557] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[558]

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

[560]

[561] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[562]

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

[564]

[565] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[566]

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

[568]

[569] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[570]

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

[572]

[573] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[574]

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

[576]

[577] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[578]

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

[580]

[581] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[582]

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

[584]

[585] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[586]

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

[588]

[589] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[590]

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

[592]

[593] LCMS (ESI) calculated for C ₁₆ H ₁₅ N ₃ O [M+H] ⁺ 265.12, found m/z 266.17

[594]

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

[596]

[597] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[598]

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

[600]

[601] LCMS (ESI) calculated for C ₁₇ H ₁₇ N ₃ O [M+H] ⁺ 279.14, found m/z 280.19

[602]

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

[604]

[605] LCMS (ESI) calculated for C ₁₇ H ₁₇ N ₃ O [M+H]+279.14, found m/z 280.29

[606]

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

[608]

[609] LCMS (ESI) calculated for C ₁₉ H ₁₉ N ₃ O [M+H]+305.15, found m/z 306.25

[610]

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

[612]

[613] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[614]

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

[616]

[617] LCMS (ESI) calculated for C ₁₇ H ₁₈ FN ₃ O [M+H] ⁺ 311.14, found m/z 312.03

[618]

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

[620]

[621] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[622]

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

[624]

[625] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[626]

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

[628]

[629] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[630]

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

[632]

[633] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (sq, J=6.7 Hz, 2N).

[634]

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

[636]

[637] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[638]

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

[640]

[641] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (br s, 2H), 3.41 (br s, 2H), 3.11 (t, J=6.1 Hz, 2H)

[642]

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

[644]

[645] LCMS (ESI) calculated for C ₁₇ H ₁₄ FN ₃ O [M+H] ⁺ 295.11, found m/z 296.11

[646]

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

[648]

[649] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[650]

[651] [Preparation of sulfonamide 6]: A solution of tert-butanol (1.0 equiv.) in anhydrous dichloromethane (1.4 M) was added to a round-bottomed flask, and 5 (1.0 equiv.) was slowly added dropwise thereto. Then N,N-dimethylpyridin-4-amine (2.0 equiv.) was added thereto. The solution was stirred at room temperature for 1 h. After completion of the reaction, the reaction product was washed several times with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting colorless powder 6 (yield 80%) was used as a reagent without further purification.

[652]

[653] Step 3: A solution of triethylamine (2.5 eq.) in dichloromethane (0.1 M) was added to a round-bottomed flask. Then 4 (1.0 eq.) and 6 (1.1 eq.) were added thereto, followed by stirring at room temperature for 24 h. After completion of the reaction, the reaction product was concentrated under reduced pressure and dried, and the resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to give 7 (yield 30-60%).

[654]

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

[656]

[657] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[658]

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

[660]

[661] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[662]

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

[664]

[665] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[666]

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

[668]

[669] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[670]

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

[672]

[673] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[674]

[675] Step 4: 7 (1.0 equiv) was dissolved in dichloromethane (0.04 M) in a round-bottomed flask. A solution of the hydrochloride salt (4.0 M in 1,4-dioxane, 0.2 M) was then added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, filtered, and dried to give 8 (yield 40-80%).

[676]

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

[678]

[679] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[680]

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

[682]

[683] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[684]

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

[686]

[687] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[688]

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

[690]

[691] 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).

[692]

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

[694]

[695] ¹ H NMR (400 MHz, Acetone-dg) 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).

[696]

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

[698]

[699] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[700]

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

[702]

[703] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[704]

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

[706]

[707] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[708]

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

[710]

[711] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (f, 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).

[712]

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

[714]

[715] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[716]

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

[718]

[719] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.30 (s, 3H), 8.57 (t, J=5.4 Hz, 11H), 7.71 (dd, J=9.0, 3.2 Hz, JH), 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).

[720]

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

[722]

[723] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (br s, 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).

[724]

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

[726]

[727] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (br 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), 7.21 (d, J=5.0 Hz, 1H), 6.56 (d, J=9.8 Hz, 1H), 6.06 (br s, 4H), 4.53 (q, J=6.8 Hz, 1H), 1.46 (d, J=6.9 Hz, 3H).

[728]

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

[730]

[731] LCMS (ESI) calculated for C ₁₆ H ₁₅ FN ₄ O ₃ S [M+H]+362.08, found m/z 363.53 [732]

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

[734]

[735] LCMS (ESI) calculated for C ₁₆ H ₁₅ FN ₄ O ₃ S [M+H]+362.08, found m/z 363.53 [736]

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

[738]

[739] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[740]

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

[742]

[743] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[744]

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

[746]

[747] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[748]

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

[750]

[751] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[752]

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

[754]

[755] LCMS (ESI) calculated for C ₁₈ H ₁₇ FN ₄ O ₃ S [M+H] ⁺ 389.26, found m/z 389.3

[756]

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

[758]

[759] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[760]

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

[762]

[763] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[764]

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

[766]

[767] LCMS (ESI) calculated for C ₁₈ H ₁₉ FN ₄ O ₃ S [M+H] ⁺ 391.25, found m/z 391.2

[768]

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

[770]

[771] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[772]

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

[774]

[775] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[776]

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

[778]

[779] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[780]

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

[782]

[783] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[784]

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

[786]

[787] LCMS (ESI) calculated for C ₁₇ H ₁₇ FN ₄ O ₃ S [M+H] ⁺ 376.10, found m/z 377.25

[788]

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

[790]

[791] LCMS (ESI) calculated for C ₁₇ H ₁₇ FN ₄ O ₃ S [M+H] ⁺ 376.10, found m/z 377.28

[792]

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

[794]

[795] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[796]

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

[798]

[799] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[800]

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

[802]

[803] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (br s, 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 (br s, 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).

[804]

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

[806]

[807] 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).

[808]

[809] [Reaction Scheme 1-1]

[810]

[811] Step 4: 4 (1.0 equiv) and RSO ₂ Cl (1.1 equiv) were dissolved in dichloromethane (0.08 M) in a round-bottomed flask. Triethylamine (4.5 equiv) was then added thereto, followed by stirring at room temperature for 16 h. After completion of the reaction, water was poured into the mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to afford 9 (yield 30-50%).

[812]

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

[814]

[815] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[816]

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

[818]

[819] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[820]

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

[822]

[823] ¹ H NMR (400 MHz, DMSO-ds) 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).

[824]

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

[826]

[827] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[828]

[829] [Reaction scheme 1-2]

[830]

[831] 4 (1.0 equiv) was dissolved in acetonitrile (0.08 M) in a round-bottomed flask, and then bromotrimethylsilane (5.0 equiv) was added thereto at 0°C, followed by stirring at room temperature for 2 h. The reaction was quenched with methanol, the reaction product was filtered under reduced pressure, and the resulting residue was purified by preparative HPLC to give 10 (yield 14-20%).

[832]

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

[834]

[835] 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).

[836]

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

[838]

[839] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[840]

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

[842]

[843] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[844]

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

[846]

[847] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[848]

[849] [Example of receipt 2]

[850] Example of obtaining 2 includes a process for obtaining product 3, product 4, product 7 or product 8.

[851] Example of obtaining 2:

[852] [Reaction scheme 2]

[853]

[854] Step 1: I (1.0 equiv), palladium(II) acetate (0.050 equiv), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv), Z (1.3 equiv), and potassium carbonate (3.0 equiv) were dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) in a round-bottomed flask and refluxed under nitrogen atmosphere for 16 h. After completion of the reaction, the reaction product was filtered through celite, and the mixture was poured into water, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to give 3 (yield 40-60%).

[855] Step 2: 3 (1.0 equiv) was dissolved in dichloromethane (0.040 M) in a round-bottomed flask. A solution of the hydrochloride (4.0 M in 1,4-dioxane, 0.2 M) was then added, followed by stirring at room temperature for 4 h. After completion of the reaction, the reaction product was concentrated under reduced pressure and the residue was washed with diethyl ether, filtered and dried to give 4 (yield 60-80%).

[856] The following are examples of the present invention obtained according to step 2 as described above.

[857]

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

[859]

[860] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[861]

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

[863]

[864] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[865]

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

[867]

[868] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[869]

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

[871

[872] LCMS (ESI) calculated for C ₁₆ H ₁₅ FN ₄ O [M+H] ⁺ 298.12, found m/z 299.24

[873]

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

[875]

[876] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[877]

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

[879]

[880] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)

[881]

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

[883]

[884] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[885]

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

[887]

[888] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[889]

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

[891]

[892] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[893]

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

[895]

[896] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[897]

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

[899]

[900] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[901]

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

[903]

[904] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[905]

[906] Step 3: A solution of triethylamine (2.5 eq.) in dichloromethane (0.1 M) was added to a round-bottomed flask. Then 4 (1.0 eq.) and 6 (1.1 eq.) were added thereto, followed by stirring at room temperature for 24 h. After completion of the reaction, the reaction product was concentrated under reduced pressure and dried, and the resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to give 7 (yield 30-60%).

[907] Step 4: 7 (1.0 equiv) was dissolved in dichloromethane (0.04 M) in a large-bottomed flask. A solution of the hydrochloride salt (4.0 M in 1,4-dioxane, 0.2 M) was then added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, filtered, and dried to give 8 (yield 40-80%).

[908] The following are examples of the present invention obtained according to step 4 as described above.

[909]

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

[911]

[912] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[913]

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

[915]

[916] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[917]

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

[919]

[920] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[921]

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

[923]

[924] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[925]

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

[927]

[928] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[929]

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

[931]

[932] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[933]

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

[935]

[936] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[937]

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

[939]

[940] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[941]

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

[943]

[944] LCMS (ESI) calculated for C ₁₇ H ₁₈ FN ₅ O ₃ S [M+H] ⁺ 399.11, found m/z 392.35

[945]

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

[947]

[948] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[949]

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

[951]

[952] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[953]

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

[955]

[956] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[957]

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

[959]

[960] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[961]

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

[963]

[964] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[965]

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

[967]

[968] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[969]

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

[971]

[972] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[973]

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

[975]

[976] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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- (f, 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).

[977]

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

[979]

[980] LCMS (ESI) calculated for C ₁₇ H ₁₆ FN ₅ O ₃ S [M+H] ⁺ 389.10, found m/z 390.23 [981]

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

[983]

[984] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[985]

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

[987]

[988] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[989]

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

[991]

[992] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J=5.9 Hz, 1H), 7.37 (d, J=9.8 Hz, H Y), 7.18 (d, J=8.3 Hz, 1H), 7.09 (s, H Y), 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).

[993] [Example of receipt 3]

[994] Example of obtaining 3 includes a process of obtaining product 3, product 4, product 7 or product 8.

[995] Example of obtaining 3:

[996] [Reaction scheme 3]

[997]

[998]

[999] Step 1: 1 (1.0 equiv), 2 (1.3 equiv), and N,N-diisopropylethylamine (3.0 equiv) were dissolved in n-butanol (0.1 M) in a round-bottomed flask and heated under reflux for 16 h. After completion of the reaction, the reaction product was cooled to room temperature, followed by filtration of the precipitated solid to give 3, or water was poured into the mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (1:10 MeOH:CH ₂ Cl ₂ ) to give 3 (yield 40-60%).

[1000]

[1001] [Example 109]: tert-butyl (1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)carbamate

[1002]

[1003] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1004]

[1005] [Example 110]: tert-butyl ((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate

[1006]

[1007] ¹ H NMR (400 MHz, MeOD-d ₆ ) 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).

[1008]

[1009] [Example 111]: tert-butyl (2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)carbamate

[1010]

[1011] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1012]

[1013] [Example 112]: tert-butyl ((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate

[1014]

[1015] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1016]

[1017] Step 2: 3 (1.0 equiv) was dissolved in dichloromethane (0.040 M) in a round-bottomed flask. A solution of the hydrochloride salt (4.0 M in 1,4-dioxane, 0.2 M) was then added, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, washed with diethyl ether, filtered, and dried to give 4 (yield 60-80%).

[1018]

[1019] [Example 113]: 5-(4-aminopiperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[1020]

[1021] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1022]

[1023] [Example 114]: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride [1024]

[1025] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1026]

[1027] [Example 115]: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[1028]

[1029] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1030]

[1031] [Example 116]: 5-(1,4-diazepan-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[1032]

[1033] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1034]

[1035] [Example 117]: 5-(2,8-diazaspiro[4,5]decan-8-yl)-1,8-naphthyridin-2(1H)-one hydrochloride

[1036]

[1037] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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 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).

[1038]

[1039] [Example 118]: 5-(4-(aminomethyl)piperidin-1-yl)-(methyl-1,8-naphthyridin-2(1H)-one hydrochloride

[1040]

[1041] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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 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 Hz, 2H), 1.67-1.51 (m, 2H).

[1042]

[1043] [Preparation of sulfonamide 6]: A solution of tert-butanol (1 eq.) in anhydrous dichloromethane (1.4 M) was added to a round-bottomed flask and 5 (1.0 eq.) was slowly added dropwise. Then N,N-dimethylpyridin-4-amine (2.0 eq.) was added. The solution was stirred at room temperature for 1 h. After completion of the reaction, the reaction product was washed several times with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting colorless powder (yield 80%) was used as a reagent without further purification.

[1044]

[1045] Step 3: A solution of 4 (1.0 equiv) and triethylamine (2.5 equiv) in dichloromethane (0.1 M) was added to a round-bottomed flask. Then 6 (1.1 equiv) was added thereto, followed by stirring at room temperature for 24 h. After completion of the reaction, the reaction product was concentrated under reduced pressure and dried, and the resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to give 7 (yield 30-60%).

[1046]

[1047] [Example 119]: tert-butyl (N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamoyl)carbamate

[1048]

[1049] ¹ H NMR (400 MHz, MeOD-d ₆ ) 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).

[1050]

[1051] [Example 120]: tert-butyl (N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate

[1052]

[1053] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1054]

[1055] [Example 121]: tert-butyl (N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate

[1056]

[1057] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1058]

[1059] [Example 122]: tert-butyl (N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate

[1060]

[1061] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1062]

[1063] Step 4: 7 (1.0 equiv) was dissolved in dichloromethane (0.04 M) in a round-bottomed flask. A solution of the hydrochloride salt (4.0 M in 1,4-dioxane, 0.2 M) was then added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, filtered, and dried to give 8 (yield 40-80%).

[1064]

[1065] [Example 123]: N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamide

[1066]

[1067] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1068]

[1069] [Example 124]: N-((1-(7-oxo-7,8-dihydro-1,8-naphPhiridin-4-yl)piperidin-4-yl)methyl)sulfamide

[1070]

[1071] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1072]

[1073] [Example 125]: N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamide

[1074]

[1075] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1076]

[1077] [Example 126]: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide

[1078]

[1079] ¹ H NMR (400 MHz, Methanol-d ₄ ) 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).

[1080]

[1081] [Example 127]: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide

[1082]

[1083] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1084]

[1085] [Example 128]: N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide

[1086]

[1087] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1088]

[1089] [Example of receipt 4]

[1090] Example of obtaining 4 includes a process for obtaining product 3, product 4, product 7, or product 8.

[1091] Example of obtaining 4:

[1092] [Reaction Scheme 4]

[1093]

[1094]

[1095] Step 1: I (1.0 equiv), palladium(II) acetate (0.050 equiv), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 equiv), Z (1.3 equiv), and potassium carbonate (3.0 equiv) were dissolved in 1,4-dioxane (0.090 M) and water (0.90 M) in a round-bottomed flask and refluxed under nitrogen for 16 h. After completion of the reaction, 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 resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to give 3 (yield 40-60%).

[1096]

[1097] [Example 129]: tert-butyl (3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[1098]

[1099] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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 (f, J=7.6 Hz, 2H), 1.45 (s, 9H).

[1100]

[1101] Step 2: 3 (1.0 equiv) was dissolved in dichloromethane (0.040 M) in a round-bottomed flask. Then a solution of the hydrochloride (4.0 M in 1,4-dioxane, 0.2 M) was added thereto, and then stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and then the resulting residue was washed with diethyl ether, filtered and dried to give 4 (yield 60-80%).

[1102]

[1103] [Example 130]: tert-butyl (4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate

[1104]

[1105] 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).

[1106]

[1107] [Example 131]: 5-(3-(aminophenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[1108]

[1109] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1110]

[1111] [Example 132]: 5-(3-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[1112]

[1113] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1114]

[1115] [Example 133]: 5-(4-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[1116]

[1117] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1118]

[1119] [Example 134]: 5-(4-(2-aminopropan-2-yl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[1120]

[1121] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1122]

[1123] [Example 135]: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride

[1124]

[1125] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1126] [Preparation of sulfonamide 6]: A solution of tert-butanol (1.0 equiv.) in anhydrous dichloromethane (1.4 M) was added to a round-bottomed flask, and 5 (1.0 equiv.) was slowly added dropwise thereto. Then, N,N-dimethylpyridin-4-amine (2.0 equiv.) was added thereto. The solution was stirred at room temperature for 1 h. After completion of the reaction, the reaction product was washed several times with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting colorless powder 6 (yield 80%) was used as a reagent without further purification.

[1127]

[1128] Step 3: A solution of triethylamine (2.5 eq.) in dichloromethane (0.1 M) was added to a round-bottomed flask. Then 4 (1.0 eq.) and 6 (1.1 eq.) were added thereto, followed by stirring at room temperature for 24 h. After completion of the reaction, the reaction product was concentrated under reduced pressure and dried, and the resulting residue was extracted with dichloromethane and water. The resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to give 7 (yield 30-60%).

[1129]

[1130] [Example 136]: tert-butyl (N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[1131]

[1132] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1133]

[1134] [Example 137]: tert-butyl (N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate

[1135]

[1136] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1137]

[1138] [Example 138]: tert-butyl ((7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-diisoquinolin-2(1H)-yl)sulfonyl)carbamate

[1139]

[1140] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1141]

[1142] Step 4: 7 (1.0 equiv) was dissolved in dichloromethane (0.04 M) in a round-bottomed flask. A solution of the hydrochloride salt (4.0 M in 1,4-dioxane, 0.2 M) was then added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, filtered, and dried to give 8 (yield 40-80%).

[1143]

[1144] [Example 139]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)phenyl)sulfamide

[1145]

[1146] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1147]

[1148] [Example 140]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[1149]

[1150] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1151]

[1152] [Example 141]: N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[1153]

[1154] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1155]

[1156] [Example 142]: N-(2-fluoro-4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide

[1157]

[1158] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1159]

[1160] [Example 143]: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindoline-2-sulfamide hydrochloride;

[1161]

[1162] LCMS (ESI) calculated for C ₁₆ H ₁₆ N ₄ O ₃ S [M+H] ⁺ 344.09, found m/z 345.35

[1163]

[1164] [Example 144]: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride

[1165]

[1166] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (br s, 4H), 2.67 (t, J=7.4 Hz, 2H).

[1167]

[1168] [Example 145]: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide hydrochloride

[1169]

[1170] ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[1171]

[1172] [Reaction Scheme 4-1]

[1173]

[1174] 4 (1.0 equiv.) and RSO ₂ Cl (1.1 equiv.) were dissolved in dichloromethane (0.08 M) in a round-bottomed flask, and then triethylamine (4.5 equiv.) was added thereto, followed by stirring at room temperature for 16 h. After completion of the reaction, water was poured into the mixture, followed by extraction with dichloromethane.

The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to afford 9 (yield 30-50%).

[1175]

[1176] [Example 146]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide

[1177]

[1178] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1179]

[1180] [Example 147]: 4-methyl-N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide

[1181]

[1182] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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).

[1183]

[1184] [Example 148]: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide

[1185]

[1186] ¹ H NMR (400 MHz, MeOD-d ₄ ) 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, 3=1.6 Hz, 2N).

[1187]

[1188] [Experimental example]

[1189] The following experiments were performed on Examples 1-148, prepared as described above.

[1190] Experimental Example 1: Assay of ENPP1 Enzyme with cGAMP Substrate

[1191] ENPP1 hydrolyzes nucleotides or nucleotide derivatives to form nucleoside 5'-monophosphate and pyrophosphate. ENPP1 also hydrolyzes 2',3'-cGAMP to form 5'-adenosine monophosphate (AMP) and 5'-guanosine monophosphate (GMP). The AMP produced in the reaction was measured using the AMP-Glo® kit (Promega). The AMP-Glo® kit contains two reagents. The first reagent terminates the enzymatic reaction to produce AMP, removes ATP, and converts the resulting AMP to ADP. The second reagent converts ADP to ATP, which is used to generate luminescence in the luciferase reaction. The measured luminescence is proportional to the amount of AMP produced by ENPP1.

[1192] The final reaction mixture contained 50 mM Tris buffer (pH 8.5), 250 mM NaCl, _0.5 mM CaCl2, ₁ μM ZnCl2, 5% glycerol, and 1% DMSO. Serially diluted ENPP1 inhibitors (typically in the range of 10 μM to 0.5 nM) were pre-stored with recombinant human ENPP1 enzymes (R&D Systems) at 3 ng/reaction and room temperature (RT) for 5–10 min. The reaction was initiated by the addition of cGAMP (at a final concentration of 5 μM) and carried out at 37°C for 90 min. At the end of the reaction, 10 μl of AMP-Glo reagent II were added to stop the reaction, and the product was stored at room temperature for 1 h. After storage, 20 μl of AMP detection solution (a 1:100 mixture of AMP-Glo reagent II and Kinase-Glo) were added and stored at room temperature for 1 h. Luminescence signals were measured using a Victor® plate reader (Perkin Elmer). The maximum activity control (containing enzymes and substrates in the presence of 1% DMSO; MAX) and the minimum activity control (containing substrates and 1% DMSO; MIN) were assessed simultaneously. Serially diluted ENPP1 reference inhibitors were also tested in each experiment. _IC50 , indicating the % residual activity as a function of compound concentration, was determined by fitting the inhibition curves using 3-parameter analysis based on GraphPad Prism® software. Serially diluted samples of one compound were tested two or more times and the mean _IC50 value for each compound was calculated.

[1193] The experimental results are shown in Tables 1 and 2 below.

[1196] [Experimental Example 2]

[1197] The following experiments were performed on the samples obtained as described above.

[1198] Experimental Example 2: Luciferase Assay of HCT116-Dual Cells

[1199] HCT116-Dual™ cells express genes encoding luciferase secreted under the control of the interferon-stimulated gene 54 (ISG54) promoter, along with five interferon-stimulated response elements. The HCT116-Dual™ cell line was used to measure and monitor the activity of interferon regulatory factor 3 (IRF3), which induces type I interferon production and is associated with downstream signaling, and Lucia secreted in the culture medium was used to generate luminescence in the luciferase reaction.

[1200] HCT11 6-Dual™ cells were cultured at 2× ¹⁰⁴ cells/well (93.4 µL) in a 96-well plate for one day in DMEM containing 10% FBS and 25 mM HEPES (pH 7.2-7.5). Cells were treated with 3.3 µL of ENPP1 inhibitor (typically 10 µM) and then 3.3 µL of cGAMP (10 µM) to bring the final volume to 100 µL (the final DMSO concentration was 0.1%). Cells treated with the ENPP1 inhibitor and cGAMP were cultured at 37°C for 4-8 hours, and 50 μl of Quanti-Luc reaction solution were added to 20 μl of cell culture medium to measure luciferase activity. The compound-induced increase in interferon regulatory factor 3 (IRF3) relative to cGAMP was determined as a fold increase.

[1201] The experimental results are shown in Tables 3 and 4 below.

[1204] [Example of composition] At the same time, the new connection,

The compound represented by formula 1 according to the present invention can be prepared in various forms according to the intended purpose. The following are examples of some methods for preparing compositions for incorporating the compound represented by formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

[1205]

[1206] Composition Example 1: Tablet (Direct Compression)

[1207] 5.0 mg of the active ingredient was sieved, mixed with 14.1 mg lactose, 0.8 mg crospovidone USNF and 0.1 mg magnesium stearate, and the mixture was compressed into tablets.

[1208]

[1209] Formulation Example 2: Tablet (Wet Granulation)

[1210] 5.0 mg of the active ingredient was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water and the appropriate amount of the resulting solution was added to the resulting mixture, followed by granulation. The granules were dried, sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

[1211]

[1212] Formulation Example 3: Powders and Capsules

[1213] 5.0 mg of the active ingredient was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. Hard gelatin capsules No. 5 were filled with the resulting mixture using a suitable machine.

[1214]

[1215] Composition Example 4: Injectable Solution

[1216] Injection solutions were prepared by adding 100 mg of the active ingredient, as well as 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ ⋅12H ₂ O and 2.974 mg of distilled water

[1217]

[1218] Although embodiments of the present invention have been described above, it will be obvious to those skilled in the art that the present invention can be implemented in other specific embodiments without changing the technical concepts or essential features of the present invention. Therefore, it should be understood that the above embodiments are illustrative but not limiting in all respects.

Claims (176)

1. A compound selected from a naphthyridinone derivative represented by the following formula 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: , Where R ₁ represents hydrogen or a C ₁ -C ₁₃ alkyl group; R ₂ is -ZR ₃ -(R ₄ ) _m ; Z is present or absent, where when Z is present, Z is -NH- or -NMe; R ₃ is a C ₃ -C ₁₀ heterocyclic group or a C ₆ -C ₁₀ aryl group, wherein the C ₃ -C ₁₀ heterocyclic group comprises at least one heteroatom selected from N; when Z is absent, R ₄ is a C ₁ -C ₁₃ alkyl group, a tert-butoxycarbonyl group (Boc), -(C _m H _2m )NR ₅ R ₆ , a sulfonamide group (-NHS(O) ₂ R ₆ ), a sulfamoyl group (-NHS(O) ₂ NHR ₆ ), a sulfonamide group, a sulfamoylalkyl group (-(C _m H _2m )NHS(O) ₂ NHR ₆ ), a sulfamoylalkyl group (-(C _m H _2m )NR ₅ S(O) ₂ NHR ₆ ) or a phosphoryl group (-P(O)R ₅ R ₆ ), or is bonded to the same carbon as the carbon bonded to R ₃ to form a 5- to 7-membered saturated heterocycle containing at least one heteroatom from N, or is bonded to carbon adjacent to the carbon bonded to R ₃ to form a 5-7 membered saturated heterocycle containing at least one heteroatom from N; when Z is present, R ₄ is -(C ₂ H ₄ )NCH ₃ S(O) ₂ NH ₂ or is bonded to a carbon adjacent to the carbon bonded to R ₃ to form a 5- to 7-membered saturated heterocycle containing at least one heteroatom from N; R ₃ may be further substituted by one or two fluorine atoms or one chlorine atom in addition to R ₄ ; m is an integer from 1 to 4; wherein the C ₁ -C ₁₃ alkyl group comprises at least one substituent selected from the group consisting of an amino group (-NR ₅ R ₆ ), a sulfonamide group (-NHS(O) ₂ -), a sulfonyl group (-S(O) ₂ -) and a phosphoryl group (-P(O)R ₅ R ₆ ), wherein the 5-7-membered saturated heterocycle formed by bonding to the same carbon or to a carbon adjacent to the carbon bonded to R ₃ is substituted with -S(O) ₂ NH ₂ ; and each of R ₅ and R ₆ independently represents hydrogen, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ heteroaryl group, and is substituted by at least one of hydrogen and a C ₁ -C ₁₃ alkyl group, where the _C3 - _C10 heteroaryl group comprises at least one heteroatom selected from S. 2. The compound according to claim 1, wherein R ₁ is hydrogen or a C ₁ -C ₅ alkyl group and R ₃ is a C ₅ -C ₇ heterocyclyl group or a C ₆ -C ₈ aryl group. 3. A compound according to claim 1, wherein R ₁ is hydrogen or a C ₁ -C ₃ alkyl group and R ₃ is substituted or unsubstituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted piperidine or substituted or unsubstituted pyrrolidine. 4. The compound according to claim 1, wherein 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. 5. The compound according to claim 1, wherein R ₂ is or . 6. The compound according to claim 5, wherein R ₄ is a methyl group, an ethyl group, -CH ₂ NH ₂ , -CHCH ₃ NH ₂ , -C(CH ₃ ) ₂ NH ₂ , -CHCH ₃ NHCH ₃ , -CH ₂ NHCH ₂ CH ₃ , -tert-butoxycarbonyl group (Boc), or . 7. A compound selected from the group consisting of the following compounds Nos. 1-148, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: Compound 1: tert-butyl (3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)carbamate; Compound 2: tert-butyl (3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound 3: tert-butyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound 4: tert-butyl (2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound 5: tert-butyl (4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound 7: 5-(3-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 8: 5-(5-amino-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 9: 5-(3-(aminomethyl)-4-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 10: 5-(4-(aminomethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 11: 5-(4-(aminomethyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 12: 5-(4-(aminomethyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 13: 5-(4-(aminomethyl)-2,3-difluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 14: 5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 15: (R)-5-(4-(1-aminoethyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 16: 5-(4-(2-aminopropan-2-yl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 17: (R)-5-(4-(1-(methylaminoethyl)phenyl))-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 18: (S)-5-(4-(1-(methylaminoethyl)phenyl))-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 19: (R)-5-(4-(1-(cyclopropylaminoethyl)phenyl))-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 20: 5-(4-((ethylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 21: 5-(2-fluoro-4-((isopropylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 22: 5-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 23: 5-(3-fluoro-4-((methylamino)methyl)phenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 24: 5-(4-((ethylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 25: 5-(4-((cyclopropylamino)methyl)-3-fluorophenyl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 26: 5-(isoindolin-5-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 27: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 28: 5-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 29: 5-(4-(aminomethyl)phenyl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 30: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamoyl)carbamate; Compound 31: tert-butyl (N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound 32: tert-butyl (N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound 33: tert-butyl (N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound 34: tert-butyl (N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound 35: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide; Compound 36: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide hydrochloride; Compound 37: N-(3-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound 38: N-(2-fluoro-5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 39: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)sulfamide; Compound 40: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound 41: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound 42: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 43: N-(2,3-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 44: N-(3,5-difluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 45: N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 46: (R)-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 47: (S)-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 48: (R)-N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 49: (R)-N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 50: N-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 51: N-ethyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 52: N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride; Compound 53: N-ethyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 54: N-cyclopropyl-N-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 55: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-methylsulfamide hydrochloride; Compound 56: N-ethyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 57: N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)-N-isopropyl)sulfamide hydrochloride; Compound 58: N-cyclopropyl-N-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide hydrochloride; Compound 59: (R)-N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 60: (R)-N-cyclopropyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 61: (S)-N-methyl-N-(1-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 62: (R)-N-(1-(2-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 63: (R)-N-(1-(3-fluoro-4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)phenyl)ethyl)sulfamide hydrochloride; Compound 64: (5-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)isoindolin-2-yl)sulfamide hydrochloride; Compound 65: 7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)dihydroisoquinoline-2(1H)-sulfamide hydrochloride; Compound 66: 6-fluoro-7-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride; Compound 67: N-(4-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound 68: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide; Compound 69: 4-methyl-N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide; Compound 70: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide; Compound 71: N-(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)cyclopropanesulfonamide; Compound 72: diethyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate; Compound 73: diethyl (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphoamidate; Compound 74: ethylhydro(4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonate; Compound 75: (4-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)benzyl)phosphonic acid; Compound 76: 5-((3-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 77: 5-((3-aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 78: 5-((3-aminomethyl-4-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 79: 5-((5-(2-aminoethyl)-2-fluorophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 80: 5-((3-(2-methylphenylethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 81: 5-((4-aminophenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 82: 5-((4-(aminomethyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 83: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 84: 5-((4-((cyclopropylamino)methyl)phenyl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 85: 5-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 86: 5-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 87: 5-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)amine)-1,8-naphthyridin-2(1H)-one dihydrochloride; Compound 88: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride; Compound 89: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound 90: N-(2-fluoro-5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound 91: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound 92: N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound 93: N-methyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound 94: N-ethyl-N-(3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound 95: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)sulfamide dihydrochloride; Compound 96: N-(4-fluoro-3-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenethyl)-N-methylsulfamide dihydrochloride; Compound 97: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)sulfamide dihydrochloride; Compound 98: N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound 99: N-cyclopropyl-N-(4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound 100: N-(3-chloro-4-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)benzyl)sulfamide dihydrochloride; Compound 101: 5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)isoindolin-2-yl)sulfamide dihydrochloride; Compound 102: 7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound 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 104: (6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound 105: (6-fluoro-7-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound 106: (7-fluoro-6-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound 107: N-(5-((7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-2,3-dihydro-1H-inden-2-yl)sulfamide dihydrochloride; Compound 108: (7-(methyl(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide dihydrochloride; Compound 109: tert-butyl (1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)carbamate; Compound 110: tert-butyl ((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate; Compound 111: tert-butyl(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)carbamate; Compound 112: tert-butyl ((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)carbamate; Compound 113: 5-(4-aminopiperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 114: 5-(4-(aminomethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 115: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 116: 5-(1,4-diazepan-1-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 117: 5-(2,8-diazaspiro[4,5]decan-8-yl)-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 118: 5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 119: tert-butyl (N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamoyl)carbamate; Compound 120: tert-butyl (N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate; Compound 121: tert-butyl (N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate; Compound 122: tert-butyl (N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate; Compound 123: N-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)sulfamide; Compound 124: N-((1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide; Compound 125: N-(2-(1-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)ethyl)sulfamide; Compound 126: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide; Compound 127: 8-(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-2,8-diazaspiro[4,5]decane-2-sulfamide; Compound 128: N-((1-(8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)piperidin-4-yl)methyl)sulfamide; Compound 129: tert-butyl (3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound 130: tert-butyl (4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)carbamate; Compound 132: 5-(3-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 133: 5-(4-(aminomethyl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 134: 5-(4-(2-aminopropan-2-yl)phenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 135: 5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one hydrochloride; Compound 136: tert-butyl (N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound 137: tert-butyl (N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamoyl)carbamate; Compound 138: tert-butyl ((7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-diisoquinolin-2(1H)-yl)sulfonyl)carbamate; Compound 139: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)phenyl)sulfamide; Compound 140: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound 141: N-(4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound 142: N-(2-fluoro-4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)sulfamide; Compound 143: 5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)isoindolin-2-sulfamide hydrochloride; Compound 144: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride; Compound 145: (7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamide hydrochloride; Compound 146: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)methanesulfonamide; Compound 147: 4-methyl-N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)benzenesulfonamide and Compound 148: N-(3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)benzyl)thiophene-2-sulfonamide. 8. The compound of claim 1, wherein the pharmaceutically acceptable salt is a salt of an inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. 9. A pharmaceutical composition having the ability to inhibit ectonucleotide pyrophosphatase-phosphodiesterase (ENPP1) and activate the STING pathway, containing a therapeutically effective amount of a compound according to any one of claims 1-8 as an active ingredient and a pharmaceutically acceptable excipient. 10. An ENPP1 inhibitor comprising a compound according to any one of claims 1 to 8 as an active ingredient. 11. A STING signaling pathway activator comprising a compound according to any one of claims 1 to 8 as an active ingredient. 12. The pharmaceutical composition of claim 9, wherein the composition is intended for the prevention, alleviation or treatment of cancer associated with the inhibition of ENPP1.