Novel 6h-pyrimido[5,4-b][1,4]oxazine-7(8H)-one derivatives having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase and use thereof

Abstract

The present invention relates to pyrimidooxazinone derivatives or pharmaceutically acceptable salt thereof, a composition for preventing or treating cancer comprising the derivative as an active ingredient, and the like, the pyrimidooxazinone derivatives of the present invention being highly effective in inhibiting ENPP1 activity. Therefore, the present invention can be used for the purpose of treating, preventing, and alleviating cancerous diseases caused by abnormal cell growth. In addition, the pyrimidooxazinone derivatives and pharmaceutically acceptable salt thereof of the present invention effectively inhibit ENPP1 to activate the STING pathway, and thus can be effectively used in preventing or treating cancer.

Description

Novel 6H-pyrimido[5,4-B][1,4]oxazin-7(8H)-one derivatives having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase and their uses

[0001] The present invention relates to a novel pyrimidooxazinone derivative having ectonucleotide pyrophosphatase-phosphodiesterase (ENPP) inhibitory activity or a pharmaceutically acceptable salt thereof, and uses thereof.

[0002] Cancer is a group of diseases characterized by uncontrolled cell proliferation, which can invade or spread to other parts of the body, diminishing the quality of life and ultimately leading to death. Although genetic aberrations are the direct cause of uncontrolled cancer cell proliferation, failure of immune surveillance and / or the absence of an appropriate immune response against cancer cells also contribute to cancer cell proliferation, leading to the formation of a tumor microenvironment (TME) where anti-tumor immune responses are suppressed. Therapeutics for treating this devastating disease have been developed into two broad categories: those that directly target cancer cells themselves, and those that target components of the tumor microenvironment (TME) to prevent further cancer cell proliferation or survival.

[0003] Cancer immunotherapy is a therapeutic approach that targets immune factors present in the tumor-like stromal matrix (TME) to induce immune cells to attack tumor cells. In some cases, cancer immunotherapy aims to promote tumor cell recognition by releasing tumor-associated antigens in the TME (e.g., cancer vaccines). In other cases, cancer immunotherapy aims to promote tumor cell attack by modulating the activity of innate and / or adaptive immune cells (e.g., immune checkpoint blockade).

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

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

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

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

[0008] Systemic administration of type I IFN has demonstrated efficacy in cancer settings, with tumor regression and improved survival rates achieved in preclinical mouse models compared to systemic administration of IFN-beta. However, systemic administration of type I IFN has the drawback of requiring high doses to achieve therapeutically effective doses. In this case, tolerability issues have been reported.

[0009] A recent report presented clinical results of an exogenous STING agonist (a modified cyclic dinucleotide) and showed lower than expected disease control rates despite a marked increase in pro-inflammatory cytokine production.

[0010] Therefore, research into new therapeutic approaches that can activate the cGAS-STING pathway is urgently needed. Accordingly, the inventors of the present invention have confirmed that a novel pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof functions as an ENPP1 inhibitor, thereby completing the present invention.

[0011] The technical problem to be achieved by the present invention is to provide a pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof.

[0012] The technical problem to be achieved by the present invention is to provide a method for producing the above pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof.

[0013] In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the above-mentioned pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] Another object of the present invention is to provide a method for preventing or treating cancer, comprising a step of administering to a subject the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof.

[0015] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0016] To solve the above problem, the present invention provides a pyrimidooxazinone derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof:

[0017] [Chemical Formula 1]

[0018]

[0019] In the above chemical formula 1,

[0020] R 1is independently any one selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkylhalogen, C1-C6 alcohol, CF3 and aryl,

[0021] R 2 is any one selected from the group consisting of substituted or unsubstituted aryl, cycloalkyl and amino, each independently,

[0022] Cy is C4-C 10 Aryl, C3-C 10 Cycloalkyl, C3-C 10 Heteroaryl and C3-C 10 Any one selected from the group consisting of heterocycloalkyl,

[0023] a is 0 or 1, b is an integer from 0 to 2, m is an integer from 0 to 2, and n is 0 or 1.

[0024]

[0025] According to one side, in the above [chemical formula 1], Cy can be any one selected from C6-C9 aryl and C4-C8 heterocycloalkyl.

[0026] According to one side, the above Cy , , , , , , , , , , , , , , , and It can be any one selected from the group consisting of .

[0027] According to one side, the above R 1may be any one independently selected from the group consisting of hydrogen, F, methyl, phenyl, -CF3, -CH2OH and -CH2Cl.

[0028] According to one side, the above R 2 are each independently -NH2, , and It can be any one selected from the group consisting of .

[0029] According to one side, the pyrimidooxazinone derivative represented by the above [chemical formula 1] may be any one selected from the group consisting of the following compounds.

[0030] [Chemical Formula 1-1]

[0031]

[0032] [Chemical Formula 1-2]

[0033] ,

[0034] [Chemical Formula 1-3]

[0035] ,

[0036] [Chemical Formula 1-4]

[0037] ,

[0038] [Chemical Formula 1-5]

[0039] ,

[0040] [Chemical Formula 1-6]

[0041] ,

[0042] [Chemical Formula 1-7]

[0043] ,

[0044] [Chemical Formula 1-8]

[0045] ,

[0046] [Chemical Formula 1-9]

[0047] ,

[0048] [Chemical Formula 1-10]

[0049] ,

[0050] [Chemical Formula 1-11]

[0051]

[0052] [Chemical Formula 1-12]

[0053] ,

[0054] [Chemical Formula 1-13]

[0055] ,

[0056] [Chemical Formula 1-14]

[0057] ,

[0058] [Chemical Formula 1-15]

[0059] ,

[0060] [Chemical Formula 1-16]

[0061] ,

[0062] [Chemical Formula 1-17]

[0063] ,

[0064] [Chemical Formula 1-18]

[0065] ,

[0066] [Chemical Formula 1-19]

[0067] ,

[0068] [Chemical Formula 1-20]

[0069] ,

[0070] [Chemical Formula 1-21]

[0071] ,

[0072] [Chemical Formula 1-22]

[0073]

[0074] [Chemical Formula 1-23]

[0075] ,

[0076] [Chemical Formula 1-24]

[0077] ,

[0078] [Chemical Formula 1-25]

[0079] ,

[0080] [Chemical Formula 1-26]

[0081] ,

[0082] [Chemical Formula 1-27]

[0083] ,

[0084] [Chemical Formula 1-28]

[0085] ,

[0086] [Chemical Formula 1-29]

[0087] ,

[0088] [Chemical Formula 1-30]

[0089]

[0090] [Chemical Formula 1-31]

[0091] ,

[0092] [Chemical Formula 1-32]

[0093] ,

[0094] [Chemical Formula 1-33]

[0095] ,

[0096] [Chemical Formula 1-34]

[0097] ,

[0098] [Chemical Formula 1-35]

[0099] ,

[0100] [Chemical Formula 1-36]

[0101] ,

[0102] [Chemical Formula 1-37]

[0103] and

[0104] [Chemical Formula 1-38]

[0105] .

[0106] According to one side, the above pyrimidooxazinone derivative may inhibit ENPP1 (ectonucleotide pyrophosphatase-phosphodiesterase 1).

[0107] According to one aspect, the pharmaceutically acceptable salt of the pyrimidooxazinone derivative may be at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt, and preferably may be hydrochloride.

[0108]

[0109] According to another embodiment of the present invention, a pharmaceutical composition for preventing or treating cancer is provided, which comprises any one of the above pyrimidooxazinone derivatives, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0110] In addition, the present invention provides a composition for preventing or treating cancer, comprising the above-described pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0111] In addition, the present invention provides a method for preventing or treating cancer, comprising a step of administering the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof to a subject.

[0112] In addition, the present invention provides the use of the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of cancer.

[0113] In addition, the present invention provides a method for diagnosing cancer, comprising a step of administering the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof to a subject.

[0114] In addition, the present invention provides the use of the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof for the manufacture of a drug for diagnosing cancer.

[0115] According to one aspect, the pharmaceutical composition may activate the STING pathway.

[0116] According to one side, the cancer may be at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, and bronchial cancer.

[0117] The present invention relates to a pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the derivative as an active ingredient. The pyrimidooxazinone derivative of the present invention has an excellent ability to inhibit the activity of ENPP1. Therefore, it can be used for the purpose of treating, preventing, and alleviating cancer diseases caused by abnormal cell growth. In addition, the pyrimidooxazinone derivative of the present invention and the pharmaceutically acceptable salt thereof effectively inhibit ENPP1 and activate the STING pathway, and thus can be usefully used for the prevention or treatment of cancer.

[0118] The effects of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below.

[0119] The present inventors have studied pyrimidooxazinone derivatives or pharmaceutically acceptable salts thereof, and as a result, have developed compounds for inhibiting ENPP1, compositions for inhibiting ENPP1, and methods for inhibiting ENPP1. In one aspect, the present inventors have developed novel pyrimidooxazinone derivative compounds for inhibiting ENPP1, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof, or methods for preparing the same, and pharmaceutical compositions containing the same as an active ingredient for preventing or treating cancer. In some embodiments, the method comprises treating a sample with a cell-permeable ENPP1 inhibitor to inhibit cGAMP hydrolysis by ENPP1. In some embodiments, the method comprises administering to a patient or subject a therapeutically effective amount of a cell-permeable ENPP1 inhibitor for treating cancer. The compounds according to one aspect of the present invention, compositions containing the same, or the compounds and compositions can be used for various applications or diseases requiring inhibition of ENPP1.

[0120] From the above results, the present invention provides a pyrimidooxazinone derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof:

[0121] [Chemical Formula 1]

[0122]

[0123] In the above chemical formula 1,

[0124] R 1 is independently any one selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkylhalogen, C1-C6 alcohol, CF3 and aryl,

[0125] R 2 is any one selected from the group consisting of substituted or unsubstituted aryl, cycloalkyl and amino, each independently,

[0126] Cy is C4-C 10 Aryl, C3-C 10 Cycloalkyl, C3-C 10 Heteroaryl and C3-C 10 Any one selected from the group consisting of heterocycloalkyl,

[0127] a is 0 or 1, b is an integer from 0 to 2, m is an integer from 0 to 2, and n is 0 or 1.

[0128] In the present invention, the term “substitution” refers to a reaction in which an atom or atomic group included in a molecule of a compound is replaced with another atom or atomic group.

[0129] In the present invention, the term “chain-like” refers to a molecule having a chain-like structure, and the chain-like structure is a chemical structure in which carbon atoms are connected in a chain shape, and there are straight chain-like structures and branched structures.

[0130] In the present invention, the term “cyclo or ring” refers to a structure in which both ends of the skeleton of an organic compound are connected to form a ring.

[0131] In the present invention, the term “chain or cyclic alkyl group” means a monovalent linear or branched or cyclic saturated hydrocarbon residue consisting solely of carbon and hydrogen atoms, having 1 to 20 carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0132] In the present invention, the term "heterocycloalkyl group" typically refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may be optionally unsubstituted, monosubstituted or polysubstituted, and in the structure of which at least one is selected from a heteroatom of N, O or S.

[0133] In the present invention, the term "aryl group" means an unsaturated aromatic ring compound having 3 to 12 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0134] In the present invention, the term “heteroaryl group” refers to a single ring or multiple condensed rings in which at least one of the atoms constituting the ring has a heteroatom of N, O, or S. Examples of such heteroaryl groups include, but are not limited to, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, an oxazolyl group, a furyl group, a thiophenyl group, and the like.

[0135] In the present invention, the “halogen group” may be fluorine (F), chloride (Cl), bromine (Br), or iodine (I).

[0136] In the present invention, “carbonyl group” means a -C(=O)- group, “sulfonyl group” means a -S(=O)2- group, and “sulfonamide group” means a -S(=O)2-NH- group.

[0137] In the present invention, “alcohol group” means -R-OH, preferably a primary alcohol, and more preferably -CH2OH.

[0138] According to one side, in the above [chemical formula 1], Cy can be any one selected from C6-C9 aryl and C4-C8 heterocycloalkyl.

[0139] According to one side, the above Cy , , , , , , , , , , , , , , , and It can be any one selected from the group consisting of .

[0140] According to one side, the above R 1 may be any one independently selected from the group consisting of hydrogen, F, methyl, phenyl, -CF3, -CH2OH and -CH2Cl.

[0141] According to one side, the above R 2 are each independently -NH2, , and It can be any one selected from the group consisting of .

[0142] According to one aspect, the pyrimidooxazinone derivative represented by the above [chemical formula 1] may be any one selected from the group consisting of the following compounds:

[0143] [Chemical Formula 1-1]

[0144]

[0145] [Chemical Formula 1-2]

[0146] ,

[0147] [Chemical Formula 1-3]

[0148] ,

[0149] [Chemical Formula 1-4]

[0150] ,

[0151] [Chemical Formula 1-5]

[0152] ,

[0153] [Chemical Formula 1-6]

[0154] ,

[0155] [Chemical Formula 1-7]

[0156] ,

[0157] [Chemical Formula 1-8]

[0158] ,

[0159] [Chemical Formula 1-9]

[0160] ,

[0161] [Chemical Formula 1-10]

[0162] ,

[0163] [Chemical Formula 1-11]

[0164]

[0165] [Chemical Formula 1-12]

[0166] ,

[0167] [Chemical Formula 1-13]

[0168] ,

[0169] [Chemical Formula 1-14]

[0170] ,

[0171] [Chemical Formula 1-15]

[0172] ,

[0173] [Chemical Formula 1-16]

[0174] ,

[0175] [Chemical Formula 1-17]

[0176] ,

[0177] [Chemical Formula 1-18]

[0178] ,

[0179] [Chemical Formula 1-19]

[0180] ,

[0181] [Chemical Formula 1-20]

[0182] ,

[0183] [Chemical Formula 1-21]

[0184] ,

[0185] [Chemical Formula 1-22]

[0186]

[0187] [Chemical Formula 1-23]

[0188] ,

[0189] [Chemical Formula 1-24]

[0190] ,

[0191] [Chemical Formula 1-25]

[0192] ,

[0193] [Chemical Formula 1-26]

[0194] ,

[0195] [Chemical Formula 1-27]

[0196] ,

[0197] [Chemical Formula 1-28]

[0198] ,

[0199] [Chemical Formula 1-29]

[0200] ,

[0201] [Chemical Formula 1-30]

[0202]

[0203] [Chemical Formula 1-31]

[0204] ,

[0205] [Chemical Formula 1-32]

[0206] ,

[0207] [Chemical Formula 1-33]

[0208] ,

[0209] [Chemical Formula 1-34]

[0210] ,

[0211] [Chemical Formula 1-35]

[0212] ,

[0213] [Chemical Formula 1-36]

[0214] ,

[0215] [Chemical Formula 1-37]

[0216] and

[0217] [Chemical Formula 1-38]

[0218] .

[0219] According to one side, the above pyrimidooxazinone derivative may inhibit ENPP1 (ectonucleotide pyrophosphatase-phosphodiesterase 1).

[0220] According to one aspect, the pharmaceutically acceptable salt of the pyrimidooxazinone derivative may be at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt, and preferably may be hydrochloride.

[0221]

[0222] According to another embodiment of the present invention, a pharmaceutical composition for preventing or treating cancer is provided, comprising any one of the above pyrimidooxazinone derivatives, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0223] In the present invention, the term “pharmaceutically acceptable salt” means a formulation of a compound that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salt can be obtained by reacting the compound of the present invention with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc., an organic carboxylic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc. In addition, the compound of the present invention can be obtained by reacting it with a base to form a salt such as an alkali metal salt such as an ammonium salt, a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt of an amino acid such as arginine or lysine.

[0224] In addition, the above pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof may include not only a pharmaceutically acceptable salt, but also all salts, hydrates, and solvates that can be prepared by a conventional method.

[0225] In addition, the present invention can provide a method for preventing, treating, and / or diagnosing cancer, comprising a step of administering the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof to a subject.

[0226] In the present invention, the term "prevention" means any act of inhibiting or delaying the occurrence, spread or recurrence of cancer by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0227] The term "pharmaceutical composition" in the present invention refers to a composition manufactured for the purpose of preventing or treating a disease, and may be formulated and used in various forms according to conventional methods. For example, it may be formulated in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and may be formulated and used in the form of topical preparations, suppositories, and sterile injectable solutions.

[0228] In the present invention, "including as an active ingredient" means that the ingredient is included in an amount necessary or sufficient to realize a desired biological effect. In actual application, the amount included as an active ingredient can be determined by considering the amount for treating the target disease and not causing other toxicity, and may vary depending on various factors such as the disease or condition being treated, the form of the composition being administered, the size of the subject, or the severity of the disease or condition. A person of ordinary skill in the art to which the present invention pertains can empirically determine the effective amount of an individual composition without undue experimentation.

[0229] In addition, the pharmaceutical composition of the present invention may, depending on each formulation, additionally include one or more pharmaceutically acceptable carriers in addition to the above-described effective ingredients.

[0230] The pharmaceutically acceptable carrier may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components, and may further include other conventional additives such as antioxidants, buffers, and bacteriostatic agents, if necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate the composition into an injectable formulation such as an aqueous solution, suspension, or emulsion, or into a pill, capsule, granule, or tablet. Furthermore, the composition may be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

[0231]

[0232] The composition of the present invention can be administered orally or parenterally in a pharmaceutically effective amount depending on the intended method, and the term “pharmaceutically effective amount” of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined based on factors including the patient’s health condition, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field.

[0233] Accordingly, the pharmaceutical composition of the present invention can be administered to a subject to prevent, treat, and / or diagnose cancer, and the cancer may be skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, or bronchial cancer, and is not limited thereto, but preferably, it may be a cancer having a higher acidity than normal cells and a characteristic in which cytotoxicity is inhibited by a tubulin polymerization inhibitor.

[0234] In the present invention, the term “subject” is not limited to a mammal such as a livestock or a human that requires prevention, treatment, and / or diagnosis of cancer, but may preferably be a human.

[0235] The pharmaceutical composition of the present invention can be formulated in various forms for administration to a subject, and a representative form of a parenteral administration form is an injectable form, preferably an isotonic aqueous solution or suspension. The injectable form can be prepared using a suitable dispersing or wetting agent and a suspending agent according to a technique known in the art. For example, each component can be dissolved in saline or a buffer to be formulated for injection. In addition, oral administration forms include, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers, and these formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and a lubricant (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). The above tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally may further contain a disintegrating agent such as starch, agar, alginic acid or its sodium salt, an absorbent, a coloring agent, a flavoring agent and / or a sweetening agent. The above formulations may be prepared by conventional mixing, granulating or coating methods.

[0236] In addition, the pharmaceutical composition of the present invention may further include auxiliary agents such as preservatives, wetting agents, emulsifying agents, salts for osmotic pressure control or buffers, and other therapeutically useful substances, and may be formulated according to conventional methods.

[0237] The pharmaceutical composition according to the present invention can be administered via various routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular. The dosage of the active ingredient can be appropriately selected based on various factors, such as the route of administration, the patient's age, sex, weight, and severity of the condition. Furthermore, the composition of the present invention can be administered in combination with known compounds capable of enhancing the desired effect.

[0238] The pharmaceutical composition according to the present invention may be administered to humans or animals orally or parenterally, such as intravenously, subcutaneously, intranasally, or intraperitoneally. Oral administration also includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, and intravenous injection, as well as drip methods.

[0239] In the pharmaceutical composition of the present invention, the total effective amount of the pyrimidooxazinone derivative or the pharmaceutically acceptable salt thereof according to the present invention can be administered to a patient as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease, but can typically be administered repeatedly several times a day at an effective dose of 100 ㎍ to 3,000 mg per administration for adults. However, the concentration of the pyrimidooxazinone derivative or the pharmaceutically acceptable salt thereof can be determined by taking into consideration various factors such as the route of administration and the number of treatments as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate.

[0240] In addition, the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route, and administration method as long as it exhibits the effects of the present invention, and the pharmaceutical composition of the present invention may additionally include a known anticancer agent in addition to the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases.

[0241] In addition, the present invention provides a composition for preventing or treating cancer, comprising the above-described pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0242] In addition, the present invention provides a method for preventing or treating cancer, comprising a step of administering the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof to a subject.

[0243] In addition, the present invention provides the use of the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of cancer.

[0244] In addition, the present invention provides a method for diagnosing cancer, comprising a step of administering the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof to a subject.

[0245] In addition, the present invention provides the use of the pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof for the manufacture of a drug for diagnosing cancer.

[0246] According to one aspect, the pharmaceutical composition may activate the STING pathway.

[0247] According to one side, the cancer may be at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, and bronchial cancer.

[0248]

[0249] The meaning of the cGAS-STING pathway in the present invention is as follows. Cytoplasmic double-stranded DNA can enter the cell from outside through vesicular transfer from microbial infection or nearby dead cells. Cytoplasmic DNA can also arise from damaged genomic DNA or mitochondrial DNA inside the cell. Once cytoplasmic DNA appears, it can be detected by various DNA sensors such as RNA polymerase III, DDX41, DAI, IFI6, cGAS, LEEFIP1, DHX9, DHX36, Ku70, and AIM2. cGAS (cyclic-GMP-AMP synthase) is a cytoplasmic protein that exists as a dimer and is composed of two DNA binding domains and a nucleotidyltransferase domain (which converts ATP and GTP into the cyclic dinucleotide 2'3-cGAMP with 2'5' and 3'5' phosphodiester bonds). Furthermore, cGAMP acts as a second messenger and binds to STING with high affinity (Kd ~ 4 nM) to induce type 1 IFN expression. STING (also known as TMEM173, MITA, and MPYS) is an endoplasmic reticulum (ER)-anchored protein containing four transmembrane domains at the N-terminus and a dimerization domain at the C-terminus. Upon cGAMP binding, STING forms a tetramer and translocates from the ER to the ER-Golgi intermediate compartment. In the Golgi apparatus, STING recruits and activates TBK1 (Tank binding kinase 1). Activated TBK1 phosphorylates the C-terminal domain of STING, which then recruits and activates IRF3 (interferon regulatory factor 3). Activated IRF3 then translocates to the nucleus, where it upregulates the expression of immune-stimulated genes (ISGs) and type 1 IFNs. After activation, STING is transported to endolysosomes for degradation, thereby terminating cGAS-STING pathway activation.

[0250] In the present invention, the meaning of ecto-nucleotide pyrophosphatases / phosphodiesterases is as follows. The class of phosphodiesterases includes ecto-nucleotide pyrophosphatases / phosphodiesterases. Ecto-nucleotide pyrophosphatases / phosphodiesterases (ENPP) or nucleotide pyrophosphatases / phosphodiesterases (NPP) are a group of enzymes of ectonucleotidases that hydrolyze pyrophosphate and phosphodiester bonds of their substrates to produce nucleotide 5'-monophosphates (or phospholipids and phosphocholines). In some embodiments, the ENPP enzyme family comprises seven enzyme members (ENPP-1, ENPP-2, ENPP-3, ENPP-4, ENPP-5, ENPP-6, and ENPP-7) that are ecto-nucleotidases with similar protein structures located on the cell surface.

[0251] ENPP enzymes typically have a modular structure containing a catalytic domain of approximately 400 amino acids. This catalytic domain is not related to phospholipases, nudix hydrolases, or ectonucleotide triphosphate dephosphohydrolases, although they exhibit partially overlapping activities. ENPPs 1 and 3 have a transmembrane domain at the N-terminus and a nuclease-like domain at the C-terminus, and are predicted to be type 2 single-spanning transmembrane proteins with their catalytic domains facing the extracellular space. ENPP 2, which lacks a transmembrane domain at the N-terminus or C-terminus, has a signal peptide at the N-terminus and is predicted to be secreted extracellularly. ENPPs 4, 5, 6, and 7, which contain a putative N-terminal signal peptide and a C-terminal transmembrane domain, are predicted to be type 1 single-spanning transmembrane proteins with their catalytic domains also facing the extracellular space.

[0252] ENPP1, 2, and 3 are known to use nucleotides and their derivatives as substrates to produce nucleoside monophosphates (ENPP1, 2, 3) or nucleoside diphosphates (ENPP1, 2). Only ENPP2 is known to utilize lysophospholipids. ENPP6 and 7 are known to use choline phosphate esters as substrates and produce choline phosphate. ENPP4 and 5 have no known substrates.

[0253] ENPP1, also known as NPP1 or PC-1, is a type II transmembrane glycoprotein expressed in many tissues (pancreas, kidney, bladder, and liver). ENPP1 is crucial for purinergic signaling, which plays a crucial role in the regulation of cardiovascular, neuronal, immune, and hematological functions in mammals. ENPP1 catalyzes the hydrolysis of ATP or GTP to AMP or GMP to generate inorganic pyrophosphate (PPi). Because inorganic pyrophosphate normally regulates mineralization in bone and cartilage, the production of PPi by ENPP1 makes ENPP1 a central regulator of bone and cartilage development. In contrast to the inhibitory effect of excess PPi produced by ENPP1 in joint tissues, calcium phosphate formation from PPi produced by ENPP1 is essential for mineralization of bone tissue. ENPP1 has broad specificity and hydrolyzes a variety of substrates, including phosphodiester linkages in nucleotides and nucleotide sugars and pyrophosphate linkages in nucleotides and nucleotide sugars.

[0254] Recently, ENPP1 has been shown to play a crucial role in the immunological response to various external signals that activate the cGAS-STING pathway. Exploratory studies on the enzymatic activity of cGAMP molecules have revealed that ENPP1 functions as a major cGAMP hydrolase. Consistent with these findings, ENPP1 knockout mice demonstrated a significantly longer cGAMP half-life, indicating that cGAMP half-life is highly dependent on ENPP1.

[0255] Bisphosphothionate analogs of cGAMP that are resistant to ENPP1 hydrolysis have been shown to activate STING more than 10-fold compared to cGAMP alone, suggesting that delaying or reducing cGAMP hydrolysis by ENPP1 inhibition would significantly enhance STING activation. Inhibition of ENPP1 has been reported to attenuate Pseudo-Raevis virus infection and reduce Mycobacterium tuberculosis infection by inducing the presence of persistent cGAMP, thereby activating the STING pathway.

[0256] Accordingly, one aspect of the present invention provides an inhibitor of ENPP1, a cGAMP-degrading polypeptide. As mentioned above, the present invention includes the following: 1) an ENPP1 inhibitor; 2) a method for inhibiting the ENPP1 enzyme with the ENPP1 inhibitor; 3) a method for inhibiting the hydrolase activity of ENPP1 toward cGAMP; 4) a method for enhancing the signal output of STING pathway activation; 5) a method for inhibiting tumor growth in a suitable mouse tumor model in a monotherapy or combination therapy setting.

[0257] In some embodiments, inhibition of ENPP1 means that the activity of ENPP1 is reduced by at least 10%, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, compared to a control that is not treated with the compound. In some embodiments, inhibition of ENPP1 means that the activity of ENPP1 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 that is not treated with the compound.

[0258] In some embodiments, the cell-permeable ENPP1 inhibitor is an inhibitor as described herein. In some embodiments, the cell-permeable ENPP1 inhibitor is an inhibitor according to any one of the compounds selected from the group consisting of a pyrimidooxazinone derivative compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0259]

[0260] The terms used in the examples are for illustrative purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as "comprise" or "have" are intended to specify the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, but should be understood to not preclude the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0261] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the embodiments pertain. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0262] The present invention is susceptible to various modifications and embodiments. Specific embodiments are illustrated in the drawings and described in detail in the following detailed description. However, this is not intended to limit the present invention to specific embodiments, but rather to encompass all modifications, equivalents, and alternatives falling within the spirit and technical scope of the present invention. In describing the present invention, detailed descriptions of related known technologies will be omitted if they are deemed to obscure the gist of the present invention.

[0263] <Manufacturing Example 1>

[0264] Core synthesis

[0265]

[0266]

[0267]

[0268] Step 1: Dissolve 6-chloro-5-methoxypyrimidin-4-amine 1 (1.0 eq) in dichloromethane (0.40 M) in a round-bottomed flask. Slowly add boron tribromide (5.0 eq) at 25 °C and stir at 40 °C for 3 hours. Slowly add methanol at -10 °C to stop the reaction. Then, stir at 25 °C for 12 hours. Concentrate the mixture under reduced pressure, dissolve in ethyl acetate, and pour in water. Add saturated aqueous sodium carbonate solution to adjust the hydrogen ion concentration to 9-10, and discard the organic layer. Adjust the hydrogen ion concentration of the aqueous layer to 5-6 with 5.0 M aqueous hydrogen chloride solution, and extract with ethyl acetate and dichloromethane. Afterwards, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 4-amino-6-chloropyrimidin-5-ol 2 (13% yield).

[0269]

[0270] Step 2: Dissolve 4-amino-6-chloropyrimidin-5-ol 2 (1.0 equiv) in dimethylformamide (1.0 M) in a round-bottomed flask, add potassium carbonate (2.0 equiv) and ethyl 2-bromo-2-methylpropionate 3 (1.0 equiv). Stir at 60 °C for 16 h. Cool the mixture to 25 °C, filter the yellow precipitate, and purify with distilled water (dichloromethane:methanol = 15:1) to obtain 4-chloro-6,6-dimethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one 4 (53% yield).

[0271] <snar>

[0272]

[0273]

[0274] Step 1: Dissolve 4 (1.0 equiv.), 5 (1.1 equiv.) and diisopropylethylamine (3.0 equiv.) in n-butanol (0.20 M) in a round-bottomed flask and stir at 100 °C for 12 h. After the reaction is complete, pour in distilled water and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography (dichloromethane and 6 (43-86% yield) was obtained through a methanol mixture.

[0275]

[0276] Step 2: Place 6 (1.0 eq) in a round-bottomed flask and dissolve in dichloromethane (0.10 M). Then, add a hydrochloride solution (4.0 M in 1,4-dioxane, 20 eq) and stir at 25 °C for 4 hours. After the reaction was complete, the resulting solid was concentrated under reduced pressure, washed with diethyl ether, filtered, and dried to obtain 7 (64–99% yield).

[0277]

[0278] Step 3: Add 7 (1.0 equivalent), 9 (1.1 equivalent) and triethylamine (3.0 equivalent) to a round bottom flask and dissolve in dichloromethane (0.087 M). Stir at 25 °C for 18 hours. After the reaction is complete, pour distilled water into the mixture and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography (dichloromethane and 10 (33-49% yield) was obtained through a methanol mixture.

[0279]

[0280] Step 4: Place 10 (1.0 eq) in a round-bottomed flask and dissolve in dichloromethane (0.10 M). Then, add a hydrochloride solution (4.0 M in 1,4-dioxane, 20 eq) and stir at 25 °C for 4 hours. After the reaction was complete, the resulting solid was concentrated under reduced pressure, washed with diethyl ether, filtered, and dried to obtain 11 (82–99% yield).

[0281]

[0282] [Example 1] 4-(6,6-dimethyl-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-1,4-diazepain-1-sulfamide hydrochloride

[0283]

[0284]

[0285] LCMS (ESI) m / z([M+H] + ) calcd for C 13 H 21 N6O4S: 357.14, found: 357.20.

[0286]

[0287] [Example 2] N-(1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)akepan-4-yl)sulfamide hydrochloride

[0288]

[0289]

[0290] LCMS (ESI) m / z([M+H] + ) calcd for C 14 H 23 N6O4S: 371.15, found: 371.21.

[0291]

[0292] [Example 3] N-((1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)azepan-4-yl)methyl)sulfamide hydrochloride

[0293]

[0294]

[0295] LCMS (ESI) m / z([M+H] + ) calcd for C 15 H 25 N6O4S: 385.17, found: 385.21.

[0296]

[0297] [Example 4] N-((1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-4-phenylpiperidin-4-yl)methyl)sulfamide hydrochloride

[0298]

[0299]

[0300] 1 H NMR (400 MHz, MeOD-d4) δ 7.99 (s, 1H), 7.49 - 7.40 (m, 4H), 7.28 (t,J= 6.9 Hz, 1H), 4.28 (d,J= 13.2 Hz, 2H), 3.42 (t,J= 11.2 Hz, 2H), 3.18 (brs, 2H), 2.28 (d,J= 12.5 Hz, 2H), 2.03 (t,J= 10.3 Hz, 2H), 1.54 (s, 6H).

[0301]

[0302] [Example 5] N-((1-(6,6-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-4-(trifluoromethyl)piperidin-4-yl)methyl)sulfamide hydrochloride

[0303]

[0304]

[0305] LCMS (ESI) m / z([M+H] + ) calcd for C 15 H 22 F3N6O3S: 365.16, found: 365.19.

[0306]

[0307] [Example 6] 4-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)piperazine-1-sulfamide hydrochloride

[0308]

[0309]

[0310] 1 H NMR (400 MHz, MeOD-d4) δ 8.17 (s, 1H), 4.12 - 3.95 (m, 4H), 3.26 - 3.19 (m, 4H), 1.57 (s, 6H).

[0311]

[0312] [Example 7] N-(1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)piperidin-4-yl)sulfamide hydrochloride

[0313]

[0314]

[0315] 1 H NMR (400 MHz, MeOD-d4) δ 8.15 (s, 1H), 4.59 - 4.51 (m, 2H), 3.62 - 3.51 (m, 1H), 3.39 (t,J= 12.1 Hz, 2H), 2.19 - 2.10 (m, 2H), 1.71 - 1.58 (m, 2H), 1.57 (s, 6H).

[0316]

[0317] [Example 8] N-((1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)piperidin-4-yl)methyl)sulfamide hydrochloride

[0318]

[0319]

[0320] 1 H NMR (400 MHz, MeOD-d4) δ 7.97 (s, 1H), 4.76 - 4.67 (m, 2H), 3.01 - 2.91 (m, 4H), 1.89 - 1.81 (m, 3H), 1.51 (s, 6H), 1.29 - 1.21 (m, 2H).

[0321]

[0322] [Example 9] N-(2-(1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)piperidin-4-yl)ethyl)sulfamide hydrochloride

[0323]

[0324]

[0325] 1 H NMR (400 MHz, MeOD-d4) δ 8.12 (s, 1H), 4.72 - 4.65 (m, 2H), 3.18 - 3.07 (m, 4H), 1.94 - 1.76 (m, 3H), 1.59 - 1.49 (m, 8H), 1.38 - 1.25 (m, 2H).

[0326]

[0327] [Example 10] N-((1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-3-methylpiperidin-3-yl)methyl)sulfamide hydrochloride

[0328]

[0329]

[0330] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 6.52 (brs, 3H), 3.88 (d,J= 12.1 Hz, 1H), 3.76 (d,J= 13.4 Hz, 1H), 3.30 (d,J= 13.7 Hz, 1H), 2.83 (d,J= 11.0 Hz, 1H), 2.69 (d,J= 14.1 Hz, 1H), 1.60 - 1.54 (m, 3H), 1.44 (s, 6H), 1.31 - 1.28 (m, 1H), 0.86 (s, 3H).

[0331]

[0332] [Example 11] N-((1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-4-(hydroxymethyl)piperidin-4-yl)methyl)sulfamide hydrochloride

[0333]

[0334]

[0335] 1 H NMR (400 MHz, MeOD-d4) δ 8.19 (s, 1H), 4.09 - 4.05 (m, 2H), 3.91 - 3.86 (m, 2H), 3.51 (s, 2H), 3.37 (brs, 1H), 3.14 (s, 2H), 1.75 - 1.67 (m, 4H), 1.60 (s, 6H).

[0336]

[0337] [Example 12] N-(1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-4-methylpiperidin-4-yl)sulfamide hydrochloride

[0338]

[0339]

[0340] 1 H NMR (400 MHz, MeOD-d4) δ 8.17 (s, 1H), 4.36 - 4.28 (m, 2H), 3.76 (t,J= 12.2 Hz, 2H), 2.23 - 2.14 (m, 2H), 1.66 (t,J= 12.5 Hz, 2H), 1.58 (s, 6H), 1.48 (s, 3H).

[0341]

[0342] [Example 13] N-((1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-4-methylpiperidin-4-yl)methyl)sulfamide hydrochloride

[0343]

[0344]

[0345] 1 H NMR (400 MHz, MeOD-d4) δ 8.09 (s, 1H), 4.15 - 4.05 (m, 2H), 3.79 - 3.69 (m, 2H), 2.94 (s, 2H), 1.74 - 1.65 (m, 2H), 1.55 (s, 6H), 1.51 - 1.43 (m, 2H), 1.06 (s, 3H).

[0346]

[0347] [Example 14] N-(2-(1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-4-methylpiperidin-4-yl)ethyl)sulfamide hydrochloride

[0348]

[0349]

[0350] 1 H NMR (400 MHz, MeOD-d4) δ 8.10 (s, 1H), 4.12 - 4.03 (m, 2H), 3.80 - 3.69 (m, 2H), 3.12 - 3.07 (m, 2H), 1.68 - 1.60 (m, 4H), 1.58 - 1.50 (m, 8H), 1.10 (s, 3H).

[0351]

[0352] [Example 15] N-(1-(1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)piperidin-4-yl)ethyl)sulfamide hydrochloride

[0353]

[0354] 1 H NMR (400 MHz, MeOD-d4) δ 8.17 (d,J= 1.5 Hz, 1H), 4.79 - 4.70 (m, 2H), 3.30 - 3.20 (m, 1H), 3.21 - 3.11 (m, 2H), 2.07 - 1.97 (m, 1H), 1.91 - 1.81 (m, 1H), 1.79 - 1.69 (m, 1H), 1.58 (s, 6H), 1.56 - 1.36 (m, 2H), 1.25 (d,J= 6.7 Hz, 3H).

[0355]

[0356] [Example 16] N-((1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)piperidin-3-yl)methyl)sulfamide hydrochloride

[0357]

[0358]

[0359] 1 H NMR (400 MHz, MeOD-d4) δ 8.01 (s, 1H), 4.77 - 4.69 (m, 1H), 4.52 - 4.44 (m, 1H), 3.15 - 3.06 (m, 1H), 3.00 (dd,J= 13.1, 5.5 Hz, 1H), 2.94 - 2.85 (m, 2H), 1.95 - 1.75 (m, 3H), 1.67 - 1.51 (m, 7H), 1.42 - 1.28 (m, 1H).

[0360]

[0361] [Example 17] 9-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-3,9-diazaspiro[5.5]undecane-3-sulfamide hydrochloride

[0362]

[0363]

[0364] 1 H NMR (400 MHz, MeOD-d4) δ 8.07 (s, 1H), 3.91 - 3.86 (m, 4H), 3.16 - 3.12 (m, 4H), 1.71 - 1.67 (m, 4H), 1.65 - 1.61 (m, 4H), 1.54 (s, 6H).

[0365]

[0366] [Example 18] 9-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2,9-diazaspiro[5.5]undecane-2-sulfamide hydrochloride

[0367]

[0368]

[0369] 1 H NMR (400 MHz, MeOD-d4) δ 7.99 (s, 1H), 4.07 - 3.98 (m, 2H), 3.68 - 3.59 (m, 2H), 3.13 - 3.06 (m, 2H), 3.01 (s, 2H), 1.77 - 1.64 (m, 4H), 1.59 - 1.54 (m, 2H), 1.51 (s, 6H), 1.50 - 1.45 (m, 2H).

[0370]

[0371] [Example 19] 8-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2,8-diazaspiro[4.5]decane-2-sulfamide hydrochloride

[0372]

[0373]

[0374] LCMS (ESI) m / z([M+H] + ) calcd for C 16 H 25 N6O4S: 397.17, found: 397.23.

[0375]

[0376] [Example 20] N-(7-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-7-azaspiro[3.5]nonan-2-yl)sulfamide hydrochloride

[0377]

[0378]

[0379] 1 H NMR (400 MHz, MeOD-d4) δ 8.14 (s, 1H), 3.95 - 3.86 (m, 3H), 3.84 - 3.78 (m, 2H), 2.42 - 2.35 (m, 2H), 1.90 - 1.82 (m, 2H), 1.81 - 1.74 (m, 2H), 1.74 - 1.67 (m, 2H), 1.56 (s, 6H).

[0380]

[0381] [Example 21] 7-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2,7-diazaspiro[3.5]nonane-2-sulfamide hydrochloride

[0382]

[0383]

[0384] 1 H NMR (400 MHz, MeOD-d4) δ 8.18 (s, 1H), 3.93 - 3.89 (m, 4H), 3.65 (s, 4H), 1.96 - 1.92 (m, 4H), 1.58 (s, 6H).

[0385]

[0386] [Example 22] N-(6-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-6-azaspiro[2,5]octan-1-yl)sulfamide hydrochloride

[0387]

[0388]

[0389] LCMS (ESI) m / z([M+H] + ) calcd for C 15 H 23 N6O4S: 383.15, found: 383.21.

[0390]

[0391] [Example 23] 7-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2,7-diazaspiro[4.4]nonane-2-sulfamide hydrochloride

[0392]

[0393]

[0394] LCMS (ESI) m / z([M+H] + ) calcd for C 15 H 23 N6O4S: 383.15, found: 383.24.

[0395]

[0396] [Example 24] N-((1R,5S,6S)-3-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)sulfamide hydrochloride

[0397]

[0398]

[0399] LCMS (ESI) m / z([M+H] + ) calcd for C 13 H 19 N6O4S: 355.12, found: 355.14.

[0400]

[0401] [Example 25] N-(4-(chloromethyl)-1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidin-3-yl)sulfamide

[0402]

[0403]

[0404] 1 H NMR (400 MHz, MeOD-d4) δ 8.14 (s, 1H), 4.26 - 4.20 (m, 1H), 4.20 - 4.04 (m, 3H), 3.89 (dd,J= 11.2, 5.7 Hz, 1H), 3.81 - 3.72 (m, 1H), 3.71 - 3.65 (m, 1H), 2.95 - 2.82 (m, 1H), 1.57 (d,J= 2.6 Hz, 6H).

[0405]

[0406] [Example 26] N-((3-(chloromethyl)-1-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)pyrrolidin-3-yl)methyl)sulfamide

[0407]

[0408]

[0409] LCMS (ESI) m / z([M+H] + ) calcd for C 14 H 22 ClN6O4S: 405.11, found: 405.19

[0410]

[0411] [Example 27] 2-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2,7-diazaspiro[3.5]nonane-7-sulfamide hydrochloride

[0412]

[0413]

[0414] 1 H NMR (400 MHz, MeOD-d4) δ 8.14 (s, 1H), 4.23 (s, 4H), 3.17 - 3.12 (m, 4H), 2.01 (t,J= 5.2 Hz, 4H), 1.58 (s, 6H).

[0415]

[0416] [Example 28] 2-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2,6-diazaspiro[3.5]nonane-6-sulfamide hydrochloride

[0417]

[0418]

[0419] 1 H NMR (400 MHz, MeOD-d4) δ 8.04 (s, 1H), 4.20 - 4.02 (m, 4H), 3.25 (s, 2H), 3.11 - 3.04 (m, 2H), 1.86 - 1.78 (m, 2H), 1.74 - 1.66 (m, 2H), 1.54 (s, 6H).

[0420]

[0421] [Example 29] 2-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2,6-diazaspiro[3.4]octane-6-sulfamide hydrochloride

[0422]

[0423]

[0424] LCMS (ESI) m / z([M+H] + ) calcd for C 14 H 21 N6O4S: 369.13, found: 369.19.

[0425] <Manufacturing Example 2>

[0426]

[0427] Step 1: Dissolve 4 (1.0 equiv.), 5 (1.1 equiv.) and diisopropylethylamine (3.0 equiv.) in n-butanol (0.20 M) in a round-bottomed flask and stir at 100 °C for 12 h. After the reaction is complete, pour in water and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography (dichloromethane and 6 (43-86% yield) was obtained through a methanol mixture.

[0428]

[0429] Step 2: Place 6 (1.0 eq) in a round-bottomed flask and dissolve in dichloromethane (0.10 M). Then, add a hydrochloride solution (4.0 M in 1,4-dioxane, 20 eq) and stir at 25 °C for 4 hours. After the reaction was complete, the resulting solid was concentrated under reduced pressure, washed with diethyl ether, filtered, and dried to obtain 7 (64–99% yield).

[0430]

[0431] Step 3: Dissolve chlorosulfonyl isocyanate (1.0 equiv) in anhydrous dichloromethane (1.0 M) in a vial. Add t-butanol (1.0 equiv) dropwise to the reaction mixture at 0 °C. Stir for 30 minutes to synthesize 9. Dissolve 4 (1.0 equiv) and 5 (1.0 equiv) in dichloromethane (0.087 M) in a bottom flask, and add the synthesized 9 solution (1.1 equiv) and triethylamine (3.0 equiv). Stir the mixture at 40 °C for 14 hours. After the reaction is complete, pour distilled water into the mixture and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography (dichloromethane and 10 (31% yield) was obtained through a methanol mixture.

[0432]

[0433] Step 4: Place 10 (1.0 eq) in a round-bottomed flask and dissolve in dichloromethane (0.10 M). Then, add a hydrochloride solution (4.0 M in 1,4-dioxane, 20 eq) and stir at 25 °C for 4 hours. After the reaction was complete, the resulting solid was concentrated under reduced pressure, washed with diethyl ether, filtered, and dried to obtain 11 (82–99% yield).

[0434]

[0435]

[0436] [Example 30] N-(4-(((6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)methyl)phenyl)sulfamide hydrochloride

[0437]

[0438]

[0439] LCMS (ESI) m / z([M+H] + ) calcd for C 15 H 19 N6O3S: 379.12, found: 379.21.

[0440]

[0441]

[0442] Step 1: In a round-bottomed flask, add 6,6-dimethyl-4-(2,6-diazaspiro[3.5]nonan-2-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one hydrochloride 1 (1.0 equiv.) and alkyl(yl)sulfonyl chloride (1.1 equiv.) and dissolve in dichloromethane (0.087 M). Stir at 25 °C for 18 h. After the reaction is complete, pour water into the mixture and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate and concentrate under reduced pressure. Column chromatography (dichloromethane and 2 (67-75% yield) was obtained through a methanol mixture.

[0443]

[0444] [Example 31] 4-(6-(cyclopropylsulfonyl))-2,6-diazaspiro[3.5]nonan-2-yl)-6,6-dimethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

[0445]

[0446]

[0447] 1 H NMR (400 MHz, MeOD-d4) δ 7.92 (s, 1H), 4.02 (d,J= 9.2 Hz, 2H), 3.95 (d,J= 8.7 Hz, 2H), 3.41 (s, 2H), 3.29 - 3.22 (m, 2H), 2.55 - 2.44 (m, 1H), 1.87 - 1.80 (m, 2H), 1.73 - 1.65 (m, 2H), 1.50 (s, 6H), 1.10 - 0.98 (m, 4H).

[0448]

[0449] [Example 32] 6,6-Dimethyl-4-(6-(thiophene-2-ylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

[0450]

[0451]

[0452] 1 H NMR (400 MHz, MeOD-d4) δ 7.93 (s, 1H), 7.86 (d,J= 4.7 Hz, 1H), 7.63 (d,J= 3.5 Hz, 1H), 7.24 (t,J= 4.5 Hz, 1H), 4.02 (d,J= 8.7 Hz, 2H), 3.94 (d,J= 9.2 Hz, 2H), 3.17 (s, 2H), 3.05 - 2.98 (m, 2H), 1.75 - 1.70 (m, 4H), 1.51 (s, 6H).

[0453]

[0454] [Example 33] 6,6-Dimethyl-4-(6-tosyl-2,6-diazaspiro[3.5]nonan-2-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

[0455]

[0456] 1 H NMR (400 MHz, MeOD-d4) δ 7.92 (s, 1H), 7.68 (d,J= 7.9 Hz, 2H), 7.43 (d,J= 8.1 Hz, 2H), 4.01 (d,J= 9.1 Hz, 2H), 3.92 (d,J= 8.8 Hz, 2H), 3.16 - 3.09 (m, 2H), 2.95 (s, 2H), 2.44 (s, 3H), 1.72 - 1.65 (m, 4H), 1.51 (s, 6H).

[0457]

[0458] <Manufacturing Example 3>

[0459] <Suzuki coupling>

[0460]

[0461]

[0462] Step 1:

[0463] Reaction method 1: In a round-bottom flask, dissolve 4 (1.0 equivalent), 5 (1.1 equivalent), and potassium carbonate (3.0 equivalent) in 1,4-dioxane (0.10 M) and water (0.010 M) under nitrogen. Then, add tetrakis(triphenylphosphine)palladium(0) (0.10 equivalent), inject nitrogen into the solution for 5 minutes, and stir at 110 °C for 16 hours. After the reaction is complete, filter through a Celite filter, pour water into the mixture, and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography (ethyl acetate and 6 (41-68% yield) was obtained through a hexane mixture.

[0464] Reaction method 2: In a round-bottom flask, dissolve 4 (1.0 equivalent), 5 (1.1 equivalent), and cesium carbonate (3.0 equivalent) in 1,4-dioxane (0.10 M) and water (0.050 M) under nitrogen. Then, add tetrakis(triphenylphosphine)palladium(0) (0.1 equivalent), inject nitrogen into the solution for 5 minutes, and stir for 4 hours at 120 °C in a microwave oven. After the reaction is complete, filter through a Celite filter, pour water into the mixture, and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography (ethyl acetate and 6 (37-71% yield) was obtained through a hexane mixture.

[0465]

[0466] Step 2: Place 6 (1.0 eq) in a round-bottomed flask and dissolve in dichloromethane (0.10 M). Then, add a hydrochloride solution (4.0 M in 1,4-dioxane, 20 eq) and stir at 25 °C for 4 hours. After the reaction was complete, the resulting solid was concentrated under reduced pressure, washed with diethyl ether, filtered, and dried to obtain 7 (89–100% yield).

[0467]

[0468] Step 3: Add 7 (1.0 equivalent), 9 (1.1 equivalent) and triethylamine (3.0 equivalent) to a round bottom flask and dissolve in dichloromethane (0.087 M). Stir at 25 °C for 18 hours. After the reaction is complete, pour water into the mixture and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography (dichloromethane and 10 (29-55% yield) was obtained through a methanol mixture.

[0469]

[0470] Step 4: Place 10 (1.0 eq) in a round-bottomed flask and dissolve in dichloromethane (0.10 M). Then, add a hydrochloride solution (4.0 M in 1,4-dioxane, 20 eq) and stir at 25 °C for 4 hours. After the reaction was complete, the resulting solid was concentrated under reduced pressure, washed with diethyl ether, filtered, and dried to obtain 11 (94–100% yield).

[0471]

[0472] [Example 34] N-(4-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)benzyl)sulfamide hydrochloride

[0473]

[0474]

[0475] 1 H NMR (400 MHz, MeOD-d4) δ 8.53 (s, 1H), 8.07 (d,J= 8.3 Hz, 2H), 7.55 (d,J= 8.4 Hz, 2H), 4.29 (s, 2H), 1.59 (s, 6H).

[0476]

[0477] [Example 35] N-(3-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)benzyl)sulfamide hydrochloride

[0478]

[0479] 1 H NMR (400 MHz, MeOD-d4) δ 8.56 (s, 1H), 8.16 (s, 1H), 7.96 (d,J= 7.6 Hz, 1H), 7.54 - 7.45 (m, 2H), 4.30 (s, 2H), 1.61 (s, 6H).

[0480]

[0481] [Example 36] N-(4-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-2-fluorobenzyl)sulfamide hydrochloride

[0482]

[0483]

[0484] 1 H NMR (400 MHz, MeOD-d4) δ 8.53 (s, 1H), 8.00 (dd,J= 8.1, 1.6 Hz, 1H), 7.88 (dd,J= 11.7, 1.6 Hz, 1H), 7.68 - 7.63 (m, 1H), 4.34 (s, 2H), 1.60 (s, 6H).

[0485] 19 F NMR (377 MHz, MeOD-d4) δ -120.53.

[0486]

[0487] [Example 37](R)-N-(1-(4-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)phenyl)ethyl)sulfamide hydrochloride

[0488]

[0489]

[0490] 1 H NMR (400 MHz, MeOD-d4) δ 8.56 (s, 1H), 8.05 (d,J= 8.3 Hz, 2H), 7.56 (d,J= 8.3 Hz, 2H), 4.63 (q,J= 7.9, 7.1 Hz, 1H), 1.59 (s, 6H), 1.54 (d,J= 6.9 Hz, 3H).

[0491]

[0492] [Example 38] 6-(6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfamide hydrochloride

[0493]

[0494]

[0495] 1 H NMR (400 MHz, MeOD -d4) δ 8.51 (s, 1H), 7.96 - 7.89 (m, 2H), 7.27 (d,J= 7.4 Hz, 1H), 4.38 (s, 2H), 3.45 (t,J= 5.8 Hz, 2H), 3.06 (t,J= 6.0 Hz, 2H), 1.58 (s, 6H).

[0496]

[0497] Experimental Example 1. ENPP1 Enzyme Assay

[0498] The compounds of Examples 1 to 38 manufactured as described above were tested as follows.

[0499] ENPP1 hydrolyzes nucleotides or nucleotide derivatives, producing nucleoside-5'-monophosphate and pyrophosphate. ENPP1 also hydrolyzes 2'3'-cGAMP to produce 5'-adenosine monophosphate (AMP) and 5'-guanosine monophosphate (GMP). The AMP produced from this reaction is measured using the AMP-Glo® kit (Promega). The AMP-Glo® kit consists of two reagents. The first reagent terminates the AMP-producing enzymatic reaction, removes ATP, and converts the produced AMP to ADP. The second reagent converts ADP to ATP, which is used to generate luminescence in the luciferase reaction. The amount of luminescence measured above is proportional to the amount of AMP produced by ENPP1.

[0500] The final reaction mixture for the evaluation system contains 50 mM Tris (pH 8.5) buffer, 250 mM NaCl, 0.5 mM CaCl2, 1 μM ZnCl2, 5% glycerol, and 1% DMSO. Serially diluted ENPP1 inhibitors (typically ranging from 10 μM to 0.5 nM) are pre-incubated with human recombinant ENPP1 enzyme (R&D systems) at 3 ng / reaction for 5–10 min at room temperature (RT). The reaction is initiated by the addition of cGAMP (at a final concentration of 5 μM) and incubated at 37°C for 90 min. At the end of the reaction, the reaction is stopped by the addition of 10 μL of AMP-Glo ​​first reagent and incubated at RT for 1 h. After the above storage, 20 μl of AMP detection solution (1:100 ratio of AMP-Glo ​​II reagent and Kinase-Glo) was added and stored at room temperature for 1 hour. The luminescence signal was measured using a Victor® plate reader (Perkin Elmer). The maximum activity control (containing enzyme and substrate in the presence of 1% DMSO; MAX) and the minimum activity control (containing substrate and 1% DMSO; MIN) were evaluated simultaneously. In each experiment, serially diluted standard ENPP1 inhibitors were tested together. IC for % residual activity versus compound concentration 50 The values ​​were determined by fitting inhibition curves using the three-parameter method in GraphPad Prism® software. Serially diluted samples of a compound were tested in duplicate or more, and the average IC for each compound was calculated. 50 The value was calculated.

[0501] The experimental results are shown in Table 2 below based on Table 1 below.

[0502] As shown, it was confirmed that the exemplary compounds of the present invention have excellent ENPP1 inhibitory activity.

[0503] Enzyme activity ABCIC 50 (uM)acitivity < 5 uM5 uM < activity < 10 uMactivity > 10 uM

[0504]

[0505] Example number Enzyme activity 1C2C3A4A5A6C7C8C9C10C11A12C13C14C15B16C17C18A19A20C21A22A23A24A25C26C27C28A29A30C31C32C33C34C35C36C37C38C

[0506]

[0507] Although the embodiments described above have been described with limited drawings, those skilled in the art will appreciate that various technical modifications and variations can be applied based on the above. For example, appropriate results can still be achieved even if the described techniques are performed in a different order than described, and / or components of the described systems, structures, devices, circuits, etc. are combined or combined in a different manner than described, or are replaced or substituted with other components or equivalents.

[0508] Therefore, other implementations, other manufacturing examples and equivalents to the patent claims also fall within the scope of the claims described below.

[0509] This invention was completed with the support of the Ministry of Health and Welfare-Healthcare Research and Development Project => Discovery of Innovative Nucleic Acid Detection Pathway Regulator for TNBC Treatment (2ME1650:20230101~20231231) and the Future Original Medical Engineering Technology Development Project => Development of Theragnosis Technology for Controlling Intractable Diseases (2E32330:20230101~20231231:).< / snar>

Claims

1. A pyrimidooxazinone derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 is independently any one selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkylhalogen, C1-C6 alcohol, CF3 and aryl, R 2 is any one selected from the group consisting of substituted or unsubstituted aryl, cycloalkyl and amino, each independently, Cy is C4-C 10 Aryl, C3-C 10 Cycloalkyl, C3-C 10 Heteroaryl and C3-C 10 Any one selected from the group consisting of heterocycloalkyl, a is 0 or 1, b is an integer from 0 to 2, m is an integer from 0 to 2, and n is 0 or 1.

2. In paragraph 1, In the above [chemical formula 1], Cy is one selected from C6-C9 aryl, C4-C8 heterocycloalkyl, A pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof.

3. In paragraph 2, The above Cy is , , , , , , , , , , , , , , , and A pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof, wherein the derivative is selected from the group consisting of:

4. In paragraph 1, The above R 1 A pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof, wherein each independently is one selected from the group consisting of hydrogen, F, methyl, phenyl, -CF3, -CH2OH and -CH2Cl.

5. In paragraph 1, The above R 2 are each independently -NH2, , and A pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof, wherein the derivative is selected from the group consisting of:

6. In paragraph 1, A pyrimidooxazinone derivative represented by the above [chemical formula 1] is characterized in that it is one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] [Chemical Formula 1-2] , [Chemical Formula 1-3] , [Chemical Formula 1-4] , [Chemical Formula 1-5] , [Chemical Formula 1-6] , [Chemical Formula 1-7] , [Chemical Formula 1-8] , [Chemical Formula 1-9] , [Chemical Formula 1-10] , [Chemical Formula 1-11] [Chemical Formula 1-12] , [Chemical Formula 1-13] , [Chemical Formula 1-14] , [Chemical Formula 1-15] , [Chemical Formula 1-16] , [Chemical Formula 1-17] , [Chemical Formula 1-18] , [Chemical Formula 1-19] , [Chemical Formula 1-20] , [Chemical Formula 1-21] , [Chemical Formula 1-22] [Chemical Formula 1-23] , [Chemical Formula 1-24] , [Chemical Formula 1-25] , [Chemical Formula 1-26] , [Chemical Formula 1-27] , [Chemical Formula 1-28] , [Chemical Formula 1-29] , [Chemical Formula 1-30] [Chemical Formula 1-31] , [Chemical Formula 1-32] , [Chemical Formula 1-33] , [Chemical Formula 1-34] , [Chemical Formula 1-35] , [Chemical Formula 1-36] , [Chemical Formula 1-37] and [Chemical Formula 1-38] .

7. In paragraph 1, The above pyrimidooxazinone derivative is a pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof, characterized in that it inhibits ENPP1 (ectonucleotide pyrophosphatase-phosphodiesterase 1).

8. In paragraph 1, A pharmaceutically acceptable salt of the pyrimidooxazinone derivative, characterized in that the pharmaceutically acceptable salt is at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

9. In paragraph 8, A pharmaceutically acceptable salt of the above pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt of the above pyrimidooxazinone derivative is a hydrochloride.

10. A pharmaceutical composition for preventing or treating cancer, comprising a pyrimidooxazinone derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as an active ingredient.

11. In paragraph 10, A pharmaceutical composition for preventing or treating cancer, characterized in that the pharmaceutical composition activates the STING pathway.

12. In paragraph 10, A pharmaceutical composition for preventing or treating cancer, characterized in that the cancer is at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, and bronchial cancer.

13. A method for preventing or treating cancer, comprising administering to a subject a pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

14. Use of a pyrimidooxazinone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for the manufacture of a drug for the prevention or treatment of cancer.

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