KR20230090463A - Novel pyridopyrimidine derivatives as a Ectonucleotide pyrophosphatase-phosphodiesterase inhibitors and use thereof - Google Patents

Abstract

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

Description

Novel pyridopyrimidine derivatives as a ectonucleotide pyrophosphatase-phosphodiesterase inhibitors and their use

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

Cancer is a group of diseases associated with uncontrolled cell proliferation that can invade or spread to other parts of the body, reducing quality of life and eventually leading to death. Although genetic aberrations are a direct cause of the uncontrolled proliferation of cancer cells, failure of immune surveillance and/or the absence of an adequate immune counterattack of the immune system against cancer cells is also a cause of cancer cell proliferation, and may also contribute to anticancer immunity. The response leads to the formation of an inhibited tumor microenvironment (TME). Therapeutic agents for treating such fatal diseases have been largely developed into two categories. The first is to directly target cancer cells themselves, and the second is to target components of the tumor microenvironment (TME) to prevent further proliferation or survival of cancer cells.

Cancer immunotherapy is one of the therapeutic approaches that target immune factors present in the TME to induce immune cells to attack tumor cells. In some instances, cancer immunotherapy is aimed at promoting recognition of tumor cells through the release of tumor-associated antigens in the TME (eg, Cancer vaccines). In other cases, cancer immunotherapy aims to promote attack on tumor cells by modulating the activity of innate and/or adaptive immune cells (eg, immune checkpoint blockade).

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

The tumor microenvironment (TME) contains malignant tumor cells as well as various types of immune cells (e.g. macrophages, lymphocytes, NK cells, dendritic cells) and non-immune cells (e.g. cancer-associated fibroblasts (cancer-cells)). associated fibroblast, pericyte, endothelial cells, and adipocytes). On the other hand, it has been reported that the presence of tumor-infiltrating lymphocytes can lead to positive clinical outcomes in response to multiple pipelines of immunotherapy in different types of cancer. In preclinical studies, it has been reported that the regulation or elevation of other types of immune cells other than lymphocytes, especially innate immune cells, regulates the responsiveness of anticancer therapies against tumors. The innate immune system is one of the two major components of the host immune defense system in vertebrates. The main functions of innate immunity are 1) identifying and removing foreign substances (e.g. bacteria, viruses) from body tissues, 2) recruiting immune cells to specific sites by producing cytokines and promoting the adaptive immune response, and 3 ) to activate the complement cascade. Such innate immunity recognizes molecular patterns derived from microbial pathogens (pathogen-associated molecular patterns, PAMPs) or remnants of destroyed cells (damage-associated molecular patterns, DAMPs). Activated.

Pattern recognition receptors (PRRs) are several different types of receptors expressed primarily by innate immune cells and, depending on their ligand specificity, can recognize a particular PAMP or DAMP. Cytoplasmic DNA is a type of molecular pattern recognized by cytoplasmic DNA sensors (a type of PRR) and triggers an innate immune response. The cGAS-STING pathway (cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes), a type of cytoplasmic DNA sensor, recognizes 1) cytoplasmic DNA caused by microbial infection or damage to its own DNA, and 2) produces chemical factors. , mainly involved in all type 1 interferons (IFNs) by activation of the IRE3 transcription factor.

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

Systemic administration of type 1 IFN showed proven efficacy in the cancer setting, with tumor regression and improved survival following systemic injection of IFN-beta in a preclinical mouse model. However, systemic administration of type 1 IFN has a problem in that a high dose is required to reach a therapeutically effective dose for exhibiting therapeutic efficacy. In this case, tolerability problems were reported.

In a recently published report, clinical results of exogenous STING agonists (modified cyclic dinucleotides) were published, resulting in lower-than-expected disease control rates despite apparent increases in pro-inflammatory cytokine production.

Therefore, there is a need for research on new treatment methods capable of activating the cGAS-STING pathway.

Chinese Patent Publication CN 110575458 A International Publication WO 2019/233300 A1 International Publication WO 2018/119325 A1 International Publication WO 2018/119328 A1 International Publication WO 2019/046778 A1 International Publication WO 2019/177971 A1

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

Therefore, one aspect of the present invention is to provide a novel pyridopyrimidine derivative compound having an inhibitory activity on ENPP1. In addition, one aspect of the present invention is to provide a novel pyridopyrimidine derivative compound that enhances and/or regulates the production of type 1 interferon (IFNs) in vivo.

In addition, another object of the present invention is to treat, prevent and alleviate cancer diseases containing a novel pyridopyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or a stereoisomer thereof as an active ingredient Its object is to provide a useful pharmaceutical composition.

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

In addition, another object of the present invention is to provide a method for preventing, reducing or treating infectious diseases comprising administering a novel pyridopyrimidine derivative compound or a pharmaceutical composition containing the compound to a patient or subject in need thereof want to provide

In addition, another object of the present invention is a method for preventing, reducing or treating periodontal disease comprising the step of administering a novel pyridopyrimidine derivative compound or a pharmaceutical composition containing the compound to a patient or subject in need thereof want to provide

In addition, another object of the present invention is a novel pyridopyrimidine derivative compound or a method for preventing, reducing or treating viral diseases comprising administering a pharmaceutical composition containing the compound to a patient or subject in need thereof want to provide

In addition, another object of the present invention is pathological mineralization of soft tissue comprising the step of administering a novel pyridopyrimidine derivative compound or a pharmaceutical composition containing the compound to a patient or subject in need thereof It is intended to provide methods for preventing, reducing, or treating pathological mineralization.

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

In order to solve the above problems, the present invention provides a compound selected from a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:

[Formula 1]

In Formula 1,

X is N or CR ^a ;

R ^a is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ₁ and R ₂ are hydrogen; hydroxy group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; or -C(O)-(C ₁ -C ₁₃ alkyl); is

R ₄ and R ₅ are each independently hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); ester group (-C(O)OR ₆ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); a sulfonamide group (-NHS(O) ₂ R ₆ ); sulfide group (-SR ₆ ); A sulfone group (-S(O) ₂ R ₆ ); or a phosphoryl group (-P(O)R ₆ R ₇ );

R ₃ is -ZAY;

Z is present or absent, and when Z is present, Z is -O-, -CO-, -COO-, -C _n H _n+2 -, -O(C _n H _n+2 )-, -(OC ₂ H ₄ ) _n -, -(C ₂ H ₄ O) _n -, -(C _n H _n+2 )O-, -(C _n H _n+2 )CO-, -(C _n H _n+2 )O (C _m H _m+2 )-, -NR ₆ (C _n H _n+2 )-, -(NR ₆ C ₂ H ₄ ) _n -, -(C ₂ H ₄ NR ₆ ) _n -, -(C _n H _n+2 )NR ₆ -, -C ₃ -C ₁₀ Cyclyl group-; or -C ₃ -C ₁₀ heterocyclyl group-; is

n is an integer from 0 to 8;

A is a C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; or a C ₃ -C ₁₀ heterocyclyl group;

wherein Y is hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); tert-butyloxycarbonyl group (Boc); amino group (-NR ₆ R ₇ ); -(C _m H _m+2 )NR ₆ R ₇ ; nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); ester group (-C(O)OR ₆ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); a sulfonamide group (-NHS(O) ₂ R ₆ ); sulfamoyl group (-NHS(O) ₂ NHR ₆ ); a sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₆ ); a sulfamoylalkyl group (-(C _m H _m+2 )NR ₆ S(O) ₂ NHR ₇ ); sulfide group (-SR ₆ ); A sulfone group (-S(O) ₂ R ₆ ); or a phosphoryl group (-P(O)R ₆ R ₇ );

m is an integer from 0 to 8;

The C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group may be hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₆ (C=O)NR ₇ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₆ R ₇ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group;

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may be hydrogen; hydroxy group; halogen group; a carbonyl group (-(C=O)R ₆ R ₇ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; A C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₆ (C=O)NR ₇ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₆ R ₇ ); C ₆ -C ₁₀ aryl group; It contains one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group;

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

The C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.

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

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

Cancer diseases that can be treated, prevented and alleviated by treatment with the compound according to the present invention include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, scleroderma, uterine cancer, and cervical cancer. , head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, hematological cancer (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, or fibroadenomas, and the like.

The compound according to the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a composition containing the same as an active ingredient can be used as an antiviral therapeutic agent.

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

Justice

Unless otherwise specified, all numbers, values and/or expressions expressing components, reaction conditions, or amounts of components used herein are intended to indicate that such numbers, among other things, are inherently different from the measurement taken to obtain such values. Since these are approximations that reflect uncertainty, they should be understood as being qualified by the term "about" in all cases. Also, when numerical ranges are disclosed herein, such ranges are contiguous and include all values from the minimum value of such range to the maximum value inclusive, unless otherwise indicated. Furthermore, where such ranges refer to integers, all integers from the minimum value to the maximum value inclusive are included unless otherwise indicated.

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

As used herein, the terms "subject(s)", "subject(s)" and "patient(s)" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. Neither term requires, or is limited to, a situation characterized by the supervision (eg, constant or intermittent) of a health care worker (eg, physician, registered nurse, nurse apprentice, physician's assistant, janitor, or hospice worker) It doesn't work.

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

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

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

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

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

In some embodiments, a “therapeutically effective amount” refers to the amount of a compound disclosed in monotherapy or combination therapy, ie, the dose of radiation therapy required to observe tumor shrinkage in subjects not treated with the compound when administered in one or more doses. , about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more or more, an effective amount to reduce about 90% or more.

Hereinafter, the present invention will be described in detail.

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

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

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

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

STING (also known as TMEM173, MITA, MPYS) is an endoplasmic reticulum (ER) anchored protein that contains four transmembrane domains at the N-terminus and a dimerization domain at the C-terminus. Upon cGAMP binding, STING translocates from the ER to the ER-Golgi intermediate compartment by forming tetramers. In the Golgi apparatus, STING recruits and activates TBK1 (Tank binding kinase1). Activated TBK1 phosphorylates the C-terminal domain of STING, and STING recruits and activates IRF3 (interferon regulator factor 3). Then, the activated IRF3 moves to the nucleus and increases the expression of ISG (immune-stimulated genes) and type 1 IFN. After activation, STING is transported to endolysosomes where it is degraded, thereby terminating cGAS-STING pathway activation.

Immunogenic Cell Death (ICD)

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

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

radiation therapy

Radiation therapy is well known and is used for the treatment of patients suffering from various diseases. Radiation therapy is typically used to inhibit the death or growth of undesirable tissue (eg cancerous tissue). The determined amount of high energy electromagnetic radiation and/or high energy particles is aimed at minimizing unintended damage to desirable or healthy tissue while directly damaging undesirable tissue or lesions in the path of the radiation.

According to the research results so far, the effect on normal tissue is more affected by the fraction size than the dose, so the 1.8-2.0-Gy split dose is considered the standard of conventional radiation treatment, and the treatment time is longer. . Indeed, small doses per fraction can induce oncogenic effects by mitotic death of cancer cells while at the same time restoring sub-lethal damage to normal tissues after administration. Stereotactic body radiation therapy (SBRT) is an advanced radiation therapy that uses sophisticated image guidance to accurately locate the tumor in three dimensions so that radiation can be more accurately delivered to cancer cells. In addition to direct cytotoxicity, SBRT has substantial effects on tumor cell death at high doses accompanied by microvascular damage, adding a new mechanism of radiation-induced damage. However, a recent report reports that high-dose radiation can attenuate the effect of radiation on STING-mediated innate immune activation by inducing the expression of nuclease enzymes.

pathogen

As described above, intracellular invasion of nucleic acids derived from pathogens activates the cGAS-STING pathway to increase the immune response to 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. Exemplary viruses that activate the cGAS-STING pathway include, but are not limited to, herpes simplex virus 1 (HSV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papilloma virus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), influenza A virus (IAV), human immunodeficiency virus (HIV), or human Includes cytomegalovirus (HCMV). In other instances, the pathogen is a bacterium. Exemplary bacteria include, but are not limited to, Listeria monocytogenes, Mycobacterium tuberculosis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Ney Seria gonorhoeae.

Phosphodiesterases

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

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

Ecto-nucleotide pyrophosphatases/phosphodiesterases

The class of phosphodiesterases also includes ecto-nucleotide lophosphatases/phosphodiesterases. Ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) or nucleotide pyrophosphatase/phosphodiesterase (NPP) hydrolyzes the pyrophosphate and phosphodiester bonds of their substrates to form nucleotide 5'-mono A family of enzymes of ectonucleotidases that produce phosphate (or phospholipids and phosphocholines). In some embodiments, the ENPP family of enzymes includes seven enzyme members (ENPP-1, ENPP-2, ENPP-3, ENPP-4, ENPP- 5, ENPP-6 and ENPP-7).

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

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

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

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

Bisphosphothionate analogues of cGAMP, which are resistant to ENPP1 hydrolysis, have been shown to activate STING more than 10-fold compared to cGAMP, indicating that delay or reduction of cGAMP hydrolysis by inhibition of ENPP1 significantly inhibits STING activation. imply that it will increase Inhibition of ENPP1 is reported to attenuate Pseudorabis virus infection and reduce Mycobacterium tuberculosis infection by inducing the presence of persistent cGAMP and activating the STING pathway.

Accordingly, one aspect of the present invention provides an inhibitor of ENPP1, which is a cGAMP degradation polypeptide.

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

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

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

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

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

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

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

How to inhibit ENPP1

As mentioned above, the present invention includes the following. 1) ENPP1 inhibitor; 2) a method of inhibiting the ENPP1 enzyme with the ENPP1 inhibitor; 3) a method of inhibiting the hydrolase activity of ENPP1 against cGAMP; 4) how to enhance the signaling output of STING pathway activation; 5) a method of inhibiting tumor growth in an appropriate mouse tumor model in the setting of monotherapy or combination therapy.

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

In some embodiments, the cell permeable ENPP1 inhibitor is an inhibitor referred to herein. In some embodiments, the cell permeable ENPP1 inhibitor is any one of compounds selected from pyridopyrimidine derivative compounds represented by Formula 1, tautomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof. is an inhibitor

[Formula 1]

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

Compound No. 1: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl)carbamate

Compound No. 2: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 3: tert -butyl (4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 4: tert -butyl methyl (4- (3-methyl-2-oxo-1,2,3,4-tetrahydro [2,3- d ] pyrimidin-5-yl) benzyl) carbamate

Compound No. 5: tert -butyl (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)phenyl)propan- 2-day) carbamate

Compound No. 6: tert -butyl (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl) carbamate

Compound No. 7: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl)carbamate

Compound No. 8: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 9: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 10: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) (methyl ) carbamate

Compound No. 11: tert -butyl (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 12: tert -butyl (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)carbamate

Compound No. 13: tert -butyl (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl ) carbamate

Compound No. 14: tert -butyl (3-(3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)carbamate

Compound No. 15: N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide

Compound No. 16: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide

Compound No. 17: tert -butyl (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 18: tert -butyl (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carba mate

Compound No. 19: tert -butyl (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) carbamate

Compound No. 20: tert -butyl (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) carbamate

Compound No. 21: tert -butyl (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carbamate

Compound No. 22: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carbamate

Compound No. 23: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)carbamate

Compound No. 24: tert -butyl (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) benzyl) carbamate

Compound No. 25: 5-(3-aminophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 26: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 27: 5-(4-((aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H -one hydrochloride

Compound No. 28: 3-methyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 29: 5-(4-((aminopropan-2-yl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 30: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

Compound No. 31: 5-(3-aminophenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 32: 5-(3-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 33: 5-(4-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 34: 3-cyclopropyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride

Compound No. 35: 5-(4-(aminomethyl)phenyl)-3-benzyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 36: 5-(3-(aminomethyl)phenyl)-3-(2-hydroxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride

Compound No. 37: 5-(4-(aminomethyl)phenyl)-3-(2-methoxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride

Compound No. 38: 5-(4-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 39: 5-(4-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride

Compound No. 40: 5-(3-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 41: 5-(3-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride

Compound No. 42: 5-(4-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 43: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 44: 5-(3-(aminophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 45: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2(1 H )-one hydrochloride

Compound No. 46: 5-(3-(aminomethyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one trifluoroacetic acid

Compound No. 47: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl) sulfamoyl) carbamate

Compound No. 48: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamoyl) carbamate

Compound No. 49: tert -butyl ( N- (4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 50: tert -butyl ( N -methyl- N -(4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate

Compound No. 51: tert -butyl ( N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )phenyl)propan-2-yl)sulfamoyl)carbamate

Compound No. 52: tert -butyl ( N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate

Compound No. 53: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl ) sulfamoyl) carbamate

Compound No. 54: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 55: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 56: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) -N -methylsulfamoyl)carbamate

Compound No. 57: tert -butyl ( N- (4-(3-benzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 58: tert -butyl ( N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate

Compound No. 59: tert -butyl ( N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate

Compound No. 60: tert -butyl ( N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamoyl)carba mate

Compound No. 61: tert -butyl ( N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

Compound No. 62: tert -butyl ( N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) benzyl) sulfamoyl) carbamate

Compound No. 63: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

Compound No. 64: tert -butyl ( N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) benzyl) sulfamoyl) carbamate

Compound No. 65: tert -butyl ( N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) sulfamoyl) carbamate

Compound No. 66: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) sulfamoyl) carbamate

Compound No. 67: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl) sulfamoyl) carbamate

Compound No. 68: tert -butyl ( N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl) benzyl) sulfamoyl) carbamate

Compound No. 69: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide hydrochloride

Compound No. 70: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

Compound No. 71: N- (4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

Compound No. 72: N -methyl- N -(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride

Compound No. 73: N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)propane -2-day) sulfamide hydrochloride

Compound No. 74: N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl )sulfamide hydrochloride

Compound No. 75: N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide hydro chloride

Compound No. 76: N-(3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)sulfamide hydro chloride

Compound No. 77: N-(4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)sulfamide hydro chloride

Compound No. 78: N-(4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)-N- Methylsulfamide Hydrochloride

Compound No. 79: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methylsulfamide hydro chloride

Compound No. 80: N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)sulfamide hydrochloride

Compound No. 81: N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)methylsulfamide hydrochloride

Compound No. 82: N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

Compound No. 83: N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfa amide hydrochloride

Compound No. 84: N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride

Compound No. 85: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl) sulfamide hydrochloride

Compound No. 86: N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride

Compound No. 87: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride

Compound No. 88: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride

Compound No. 89: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)sulfamide hydrochloride

Compound No. 90: N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl )sulfamide hydrochloride

Compound No. 91: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methanesulfonamide

Compound No. 92: 4-methyl- N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) Benzenesulfonamide

Compound No. 93: 4-methyl- N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) Benzenesulfonamide

Compound No. 94: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesulfonamide

Compound No. 95: 4-methyl- N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) Benzenesulfonamide

Compound No. 96: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesulfonamide

Compound No. 97: tert -butyl (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4 -day) carbamate

Compound No. 98: tert -butyl ((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin- 4-yl)methyl)carbamate

Compound No. 99: tert -butyl (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl)ethyl)carbamate

Compound No. 100: tert -butyl (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)carbamate

Compound No. 101: tert -butyl (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)carbamate;

Compound No. 102: tert -butyl ((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) piperidin-4-yl)methyl)carbamate;

Compound No. 103: tert -butyl (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl)piperidin-4-yl)ethyl)carbamate;

Compound No. 104: tert -butyl 8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2,8-dia jaspiro[4.5]decane-2-carboxylate;

Compound No. 105: 5-(4-aminopiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride ;

Compound No. 106: 5-(4-(aminomethyl)piperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H )- on hydrochloride;

Compound No. 107: 5- (4- (2-aminoethyl) piperidin-1-yl) -3-methyl-3,4-dihydropyrimido [4,5- d ] pyrimidine-2 (1 H )-one hydrochloride;

Compound No. 108: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,3-dimethyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2 (1 H )-one hydrochloride;

Compound No. 109: 5-(4-amino-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H ) -on hydrochloride;

Compound No. 110: 5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1 H )-one hydrochloride;

Compound No. 111: 5-(4-(2-aminoethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine- 2(1 H )-one hydrochloride;

Compound No. 112: 3-methyl-5- (2,8-diazaspiro [4.5] decane-8-yl) -3,4-dihydropyrimido [4,5- d ] pyrimidine-2 ( 1 H )-one hydrochloride;

Compound No. 113: tert -butyl ( N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl) sulfamoyl) carbamate;

Compound No. 114: tert -butyl ( N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)methyl)sulfamoyl)carbamate;

Compound No. 115: tert -butyl ( N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)sulfamoyl)carbamate;

Compound No. 116: tert -butyl ( N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine- 4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate;

Compound No. 117: tert -butyl ( N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl) piperidin-4-yl) sulfamoyl) carbamate;

Compound No. 118: tert -butyl ( N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl)piperidin-4-yl)methyl)sulfamoyl)carbamate;

Compound No. 119: tert -butyl ( N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine -4-yl) piperidin-4-yl) ethyl) sulfamoyl) carbamate;

Compound No. 120: tert -butyl ((8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-2-yl)sulfonyl)carbamate;

Compound No. 121: N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4- 1) sulfamide hydrochloride;

Compound No. 122: N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4 -yl)methyl)sulfamide hydrochloride;

Compound No. 123: N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidine -4-yl)ethyl)sulfamide hydrochloride;

Compound No. 124: N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) piperidin-4-yl)ethyl)sulfamide hydrochloride;

Compound No. 125: N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl)sulfamide hydrochloride;

Compound No. 126: N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)methyl)sulfamide hydrochloride;

Compound No. 127: N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)sulfamide hydrochloride;

Compound No. 128: 3-methyl-5-(2-(sulfamile)-2,8-diazaspiro[4.5]decane-8-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2(1 H )-one hydrochloride;

Compound No. 129: tert -butyl (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino)methyl )phenyl)carbamate;

Compound No. 130: 5-((4-aminobenzyl)amino)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride;

Compound No. 131: tert -butyl ( N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) amino)methyl)phenyl)sulfamoyl)carbamate;

Compound No. 132: tert -butyl N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino )methyl)phenyl)sulfamide hydrochloride; and

Compound No. 133: tert -butyl N- (4-((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino) phenyl) sulfamide.

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

In some embodiments, the compounds of the present invention are used in inhibition assays, eg, to determine the activity of an enzyme in a cell-free or cell system after treatment with a compound of the present invention compared to a control by measuring the IC50 or EC50, respectively. Inhibits ENPP 1 as determined by the assay. In some embodiments, a compound of the present invention is 10 uM or less, for example 3 uM or less, 1 uM or less, 500 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 30 nM or less, have an IC50 value (or EC50 value) of 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even lower.

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

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

treatment method

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

In some embodiments, the STING-mediated response comprises increasing production of interferon (eg, type 1 interferon, type 3 interferon) in the subject. Interferons (IFNs) are a group of signaling proteins produced and released by host cells in response to the presence of one or more pathogens to enhance the defenses of surrounding cells against one or more pathogens. IFNs also have various other functions. 1) activate immune cells such as NK cells and macrophages; 2) Increases host defense by upregulating antigen presentation through increased expression of major histocompatibility complex (MHC) antigens. IFNs are generally classified into three classes: type 1 IFNs, type 2 IFNs, and type 3 IFNs. Mammalian type 1 INFs are IFN-α (alpha), IFN-β (beta), IFN-δ (delta), IFN-ε (epsilon), IFN-κ (kappa), IFN-τ (tau), IFN- ω (omega), and IFN-ζ (zeta). All type 1 IFNs bind to a unique cell surface receptor complex known as the IFN-α/β receptor (IFNAR), which consists of IFNAR1 and IFNAR2 chains.

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

IFNs have extrinsic effects on tumors through the regulation of processes such as angiogenesis, osteoclastogenesis and immunity. Both endogenous and exogenous type 1 IFNs play a major role in the activation of anticancer immunity. For example, enhancing the activity of α / β T cells, γ / δ T cells, NK cells and dendritic cells, as well as inhibiting the activity of immune-suppressive cells, such as regulatory T cells, bone marrow-derived Inhibits the conversion of suppressor cells and tumor-associated macrophages. Type 1 IFNs also act directly on tumor cells to improve antigen expression and are recognized by numerous immune-interacting molecules (e.g. major histocompatibility complex class 1 (MHC I) and germline-encoded immunoreceptors as stress ligands). ) is upregulated.

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

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

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

combination therapy

An ENPP1 inhibitor compound of the present invention may be administered to a subject alone or in combination with an additional active agent or an additional therapy, such as radiation therapy. The terms “agent,” “compound,” and “drug” are used interchangeably herein. In one embodiment, the methods of the present invention administer additional agents, e.g., small molecules, chemotherapeutic agents, antibodies, antibody-drug conjugates, aptamers, proteins, immune checkpoint inhibitors, or radiotherapy, in parallel or sequentially to the subject. or further comprising the step of administering.

“Co-administration” or “in combination with” includes the administration of two or more therapeutic agents simultaneously, concurrently, or sequentially without specific time limits. In some embodiments, agents or agents are simultaneously present in a cell or body of a subject or simultaneously exert a biological or therapeutic effect. In some embodiments, the therapeutic agents are in the same composition or unit dosage form. In some embodiments, the therapeutic agents are in separate compositions or unit dosage form. In some embodiments, the first agent precedes (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks ago), incidentally together, or next time (e.g. 5 minutes, 15 minutes) minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks).

“Concomitant administration” of a known therapeutic agent or additional therapy with a composition comprising a disclosed compound of the present invention is the administration of a compound and a second agent or additional therapy such that both the known agent and the disclosed compound composition have a therapeutic effect. means dosing. Such concomitant administration may include simultaneous or prior administration of drugs in conjunction with administration of a compound of the present invention. The route of administration of the two agents can vary, and representative routes of administration are detailed below. One skilled in the art will have no difficulty determining the appropriate timing, sequence and dosage of drugs or regimens and compounds disclosed herein.

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

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

For the treatment of cancer, the ENPP1 inhibitor compound can be administered in combination with a suitable cancer vaccine regimen, eg, a dendritic cell vaccine that promotes Th1/Th17 immunity. In some cases, ENPP1 inhibitor compounds are suitable for use as adjuvant therapy in combination with Th-17-induced vaccination.

Combination with radiation therapy

For cancer treatment methods, ENPP1 inhibitor compounds can be administered in combination with radiation therapy. In some embodiments, the ENPP1 inhibitor compound can be administered before or after administration of radiation therapy. The combination of radiation therapy and administration of a compound of the present invention may provide a synergistic therapeutic effect. During radiation therapy (RT), production of cGAMP in a subject can be induced when the subject is treated (RT) with a dose and/or frequency of radiation suitable for the subject. The induced cGAMP level can be enhanced by the ENPP1 inhibitor compound preventing degradation of cGAMP, eg, enhancing the level compared to the level achieved with RT alone, thereby enhancing therapeutic efficacy in a subject. As such, the specifics of the methods of the present invention include the administration of a reduced dose and/or frequency/regimen of radiation treatment compared to the dose and/or frequency/reduction of the therapeutic effect of radiation treatment 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 damage to the subject, e.g., that expected to occur under therapeutically effective dosages. It is effective in reducing the risk of radiation damage.

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

pharmaceutical composition

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

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

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

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

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

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

One aspect of the present invention provides a compound selected from a pyridopyrimidine derivative compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:

[Formula 1]

In Formula 1,

X is N or CR ^a ;

R ^a is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ₁ and R ₂ are hydrogen; hydroxy group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; or -C(O)-(C ₁ -C ₁₃ alkyl); is

R ₄ and R ₅ are each independently hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); ester group (-C(O)OR ₆ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); a sulfonamide group (-NHS(O) ₂ R ₆ ); sulfide group (-SR ₆ ); A sulfone group (-S(O) ₂ R ₆ ); or a phosphoryl group (-P(O)R ₆ R ₇ );

R ₃ is -ZAY;

Z is present or absent, and when Z is present, Z is -O-, -CO-, -COO-, -C _n H _n+2 -, -O(C _n H _n+2 )-, -(OC ₂ H ₄ ) _n -, -(C ₂ H ₄ O) _n -, -(C _n H _n+2 )O-, -(C _n H _n+2 )CO-, -(C _n H _n+2 )O (C _m H _m+2 )-, -NR ₆ (C _n H _n+2 )-, -(NR ₆ C ₂ H ₄ ) _n -, -(C ₂ H ₄ NR ₆ ) _n -, -(C _n H _n+2 )NR ₆ -, -C ₃ -C ₁₀ Cyclyl group-; or -C ₃ -C ₁₀ heterocyclyl group-; is

n is an integer from 0 to 8;

A is a C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; or a C ₃ -C ₁₀ heterocyclyl group;

wherein Y is hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); tert-butyloxycarbonyl group (Boc); amino group (-NR ₆ R ₇ ); -(C _m H _m+2 )NR ₆ R ₇ ; nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); ester group (-C(O)OR ₆ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); a sulfonamide group (-NHS(O) ₂ R ₆ ); sulfamoyl group (-NHS(O) ₂ NHR ₆ ); a sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₆ ); a sulfamoylalkyl group (-(C _m H _m+2 )NR ₆ S(O) ₂ NHR ₇ ); sulfide group (-SR ₆ ); A sulfone group (-S(O) ₂ R ₆ ); or a phosphoryl group (-P(O)R ₆ R ₇ );

m is an integer from 0 to 8;

The C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group may be hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₆ (C=O)NR ₇ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₆ R ₇ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group;

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may be hydrogen; hydroxy group; halogen group; a carbonyl group (-(C=O)R ₆ R ₇ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; A C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₆ (C=O)NR ₇ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₆ R ₇ ); C ₆ -C ₁₀ aryl group; It contains one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group;

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

The C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.

In the definition of substituents in the present invention, the term 'alkyl' means an aliphatic hydrocarbon radical. An alkyl can be a "saturated alkyl" that contains no alkenyl or alkynyl moieties, or an "unsaturated alkyl" that contains at least one alkenyl or alkynyl moiety. “Alkenyl” refers to a group containing at least one carbon-carbon double bond, and “alkynyl” refers to a group containing at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, may be cyclic, branched or straight-chain, respectively.

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

The term 'alkoxy' refers to an alkyl group linked to another group through an oxygen atom (ie -O-alkyl). An alkoxy group may be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C1-C6) alkoxy groups such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O-2 -Methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1 -Propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O-3 -Methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl-1 -butyl, -O-butyl, -O-isobutyl, -O-t-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

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

The term 'amino group' refers to an alkyl group linked to another group through a nitrogen atom (ie -NH- or -N-alkyl). The amino group may be unsubstituted or substituted with one or more suitable substituents. Examples of amino groups include (C1-C6) amino groups such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl -2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl , -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2-methyl-2-pentyl, -NH-3-methyl -2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2-ethyl-1-butyl , -NH-butyl, -NH-isobutyl, -NH-t-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N,N-dimethyl, -N -Methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl-N-butyl, -N-methyl-N-isobutyl, -N-methyl-N- Pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N-propyl, -N-ethyl -N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N -Hexyl, , -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N-propyl-N-isobutyl , -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N- Butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N- dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, -N,N-dihexyl.

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

The term 'heterocycle 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 heterocyclyl group may include a pyrrolidine group, a furan group, a morpholine group, a piperazine group, and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, and a mole group. It may include a poring group, but is not limited thereto.

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 is a pyridine group, a pyrazine group, a pyrimidine group, a pyridazine group, a pyrazole group, an imidazole group, a triazole group, an indole group, an oxadiazole group, a thiadiazole group, a quinoline, an isoquinoline group, It may include an isoxazole group, an oxazole group, a thiazole group, and a pyrrole group, but is not limited thereto.

In one aspect of the present invention, R ₄ and R ₅ are each independently hydrogen; or a C ₁ -C ₁₃ alkyl group; wherein X is CH or N, a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a compound selected from stereoisomers thereof provides

In one embodiment, R ₁ is hydrogen; C ₁ -C ₆ alkyl group; C ₃ -C ₁₀ cyclyl group; benzyl group; methoxybenzyl group; hydroxyethyl group; or a methoxyethyl group; and, R ₂ is hydrogen; C ₁ -C ₆ alkyl group; or a benzyl group;

In one embodiment, the A is substituted or unsubstituted benzene; substituted or unsubstituted furan; A substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; A substituted or unsubstituted benzofuran; Substituted or unsubstituted naphthalene; A substituted or unsubstituted anthracene; or substituted or unsubstituted phenathrene; A substituted or unsubstituted pyridazine; A substituted or unsubstituted pyrazine; substituted or unsubstituted imidazole; substituted or unsubstituted pyrazole; Substituted or unsubstituted quinoline; A substituted or unsubstituted pyrimidine; A substituted or unsubstituted pyrrole; A substituted or unsubstituted indole; Or a substituted or unsubstituted purine; substituted or unsubstituted piperidine; substituted or unsubstituted morpholine; A substituted or unsubstituted pyrrolidine; A substituted or unsubstituted cyclopropane; Or it may be substituted or unsubstituted cyclobutane.

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,

, 또는

인, 화학식 1로 표시되는 화합물, 이의 토오토머, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one embodiment, Y is hydrogen, halogen, methyl group, ethyl group, -NH ₂ , tert-butyloxycarbonyl group (Boc),

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

A compound selected from phosphorus, a compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof is provided.

In one aspect of the present invention, the compound is characterized in that any one selected from the group consisting of Compound Nos. 1 to 133, a pyridopyrimidine derivative compound represented by Formula 1, a tautomer thereof, and a pharmaceutical thereof It provides a compound selected from generally acceptable salts, hydrates thereof and stereoisomers thereof:

Compound No. 1: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl)carbamate

Compound No. 2: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 3: tert -butyl (4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 4: tert -butyl methyl (4- (3-methyl-2-oxo-1,2,3,4-tetrahydro [2,3- d ] pyrimidin-5-yl) benzyl) carbamate

Compound No. 5: tert -butyl (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)phenyl)propan- 2-day) carbamate

Compound No. 6: tert -butyl (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl) carbamate

Compound No. 7: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl)carbamate

Compound No. 8: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 9: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 10: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) (methyl ) carbamate

Compound No. 11: tert -butyl (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 12: tert -butyl (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)carbamate

Compound No. 13: tert -butyl (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl ) carbamate

Compound No. 14: tert -butyl (3-(3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)carbamate

Compound No. 15: N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide

Compound No. 16: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide

Compound No. 17: tert -butyl (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

Compound No. 18: tert -butyl (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carba mate

Compound No. 19: tert -butyl (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) carbamate

Compound No. 20: tert -butyl (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) carbamate

Compound No. 21: tert -butyl (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carbamate

Compound No. 22: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carbamate

Compound No. 23: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)carbamate

Compound No. 24: tert -butyl (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) benzyl) carbamate

Compound No. 25: 5-(3-aminophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 26: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 27: 5-(4-((aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H -one hydrochloride

Compound No. 28: 3-methyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 29: 5-(4-((aminopropan-2-yl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 30: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

Compound No. 31: 5-(3-aminophenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 32: 5-(3-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 33: 5-(4-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 34: 3-cyclopropyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride

Compound No. 35: 5-(4-(aminomethyl)phenyl)-3-benzyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 36: 5-(3-(aminomethyl)phenyl)-3-(2-hydroxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride

Compound No. 37: 5-(4-(aminomethyl)phenyl)-3-(2-methoxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride

Compound No. 38: 5-(4-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 39: 5-(4-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride

Compound No. 40: 5-(3-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 41: 5-(3-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride

Compound No. 42: 5-(4-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 43: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 44: 5-(3-(aminophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

Compound No. 45: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2(1 H )-one hydrochloride

Compound No. 46: 5-(3-(aminomethyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one trifluoroacetic acid

Compound No. 47: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl) sulfamoyl) carbamate

Compound No. 48: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamoyl) carbamate

Compound No. 49: tert -butyl ( N- (4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 50: tert -butyl ( N -methyl- N -(4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate

Compound No. 51: tert -butyl ( N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )phenyl)propan-2-yl)sulfamoyl)carbamate

Compound No. 52: tert -butyl ( N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate

Compound No. 53: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl ) sulfamoyl) carbamate

Compound No. 54: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 55: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 56: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) -N -methylsulfamoyl)carbamate

Compound No. 57: tert -butyl ( N- (4-(3-benzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate

Compound No. 58: tert -butyl ( N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate

Compound No. 59: tert -butyl ( N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate

Compound No. 60: tert -butyl ( N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamoyl)carba mate

Compound No. 61: tert -butyl ( N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

Compound No. 62: tert -butyl ( N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) benzyl) sulfamoyl) carbamate

Compound No. 63: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

Compound No. 64: tert -butyl ( N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) benzyl) sulfamoyl) carbamate

Compound No. 65: tert -butyl ( N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) sulfamoyl) carbamate

Compound No. 66: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) sulfamoyl) carbamate

Compound No. 67: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl) sulfamoyl) carbamate

Compound No. 68: tert -butyl ( N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl) benzyl) sulfamoyl) carbamate

Compound No. 69: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide hydrochloride

Compound No. 70: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

Compound No. 71: N- (4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

Compound No. 72: N -methyl- N -(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride

Compound No. 73: N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)propane -2-day) sulfamide hydrochloride

Compound No. 74: N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl )sulfamide hydrochloride

Compound No. 75: N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide hydro chloride

Compound No. 76: N-(3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)sulfamide hydro chloride

Compound No. 77: N-(4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)sulfamide hydro chloride

Compound No. 78: N-(4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)-N- Methylsulfamide Hydrochloride

Compound No. 79: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methylsulfamide hydro chloride

Compound No. 80: N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)sulfamide hydrochloride

Compound No. 81: N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)methylsulfamide hydrochloride

Compound No. 82: N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

Compound No. 83: N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfa amide hydrochloride

Compound No. 84: N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride

Compound No. 85: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl) sulfamide hydrochloride

Compound No. 86: N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride

Compound No. 87: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride

Compound No. 88: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride

Compound No. 89: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)sulfamide hydrochloride

Compound No. 90: N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl )sulfamide hydrochloride

Compound No. 91: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methanesulfonamide

Compound No. 92: 4-methyl- N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) Benzenesulfonamide

Compound No. 93: 4-methyl- N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) Benzenesulfonamide

Compound No. 94: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesulfonamide

Compound No. 95: 4-methyl- N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) Benzenesulfonamide

Compound No. 96: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesulfonamide

Compound No. 97: tert -butyl (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4 -day) carbamate

Compound No. 98: tert -butyl ((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin- 4-yl)methyl)carbamate

Compound No. 99: tert -butyl (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl)ethyl)carbamate

Compound No. 100: tert -butyl (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)carbamate

Compound No. 101: tert -butyl (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)carbamate;

Compound No. 102: tert -butyl ((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) piperidin-4-yl)methyl)carbamate;

Compound No. 103: tert -butyl (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl)piperidin-4-yl)ethyl)carbamate;

Compound No. 104: tert -butyl 8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2,8-dia jaspiro[4.5]decane-2-carboxylate;

Compound No. 105: 5-(4-aminopiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride ;

Compound No. 106: 5-(4-(aminomethyl)piperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H )- on hydrochloride;

Compound No. 107: 5- (4- (2-aminoethyl) piperidin-1-yl) -3-methyl-3,4-dihydropyrimido [4,5- d ] pyrimidine-2 (1 H )-one hydrochloride;

Compound No. 108: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,3-dimethyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2 (1 H )-one hydrochloride;

Compound No. 109: 5-(4-amino-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H ) -on hydrochloride;

Compound No. 110: 5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1 H )-one hydrochloride;

Compound No. 111: 5-(4-(2-aminoethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine- 2(1 H )-one hydrochloride;

Compound No. 112: 3-methyl-5- (2,8-diazaspiro [4.5] decane-8-yl) -3,4-dihydropyrimido [4,5- d ] pyrimidine-2 ( 1 H )-one hydrochloride;

Compound No. 113: tert -butyl ( N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl) sulfamoyl) carbamate;

Compound No. 114: tert -butyl ( N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)methyl)sulfamoyl)carbamate;

Compound No. 115: tert -butyl ( N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)sulfamoyl)carbamate;

Compound No. 116: tert -butyl ( N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine- 4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate;

Compound No. 117: tert -butyl ( N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl) piperidin-4-yl) sulfamoyl) carbamate;

Compound No. 118: tert -butyl ( N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl)piperidin-4-yl)methyl)sulfamoyl)carbamate;

Compound No. 119: tert -butyl ( N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine -4-yl) piperidin-4-yl) ethyl) sulfamoyl) carbamate;

Compound No. 120: tert -butyl ((8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-2-yl)sulfonyl)carbamate;

Compound No. 121: N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4- 1) sulfamide hydrochloride;

Compound No. 122: N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4 -yl)methyl)sulfamide hydrochloride;

Compound No. 123: N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidine -4-yl)ethyl)sulfamide hydrochloride;

Compound No. 124: N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) piperidin-4-yl)ethyl)sulfamide hydrochloride;

Compound No. 125: N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl)sulfamide hydrochloride;

Compound No. 126: N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)methyl)sulfamide hydrochloride;

Compound No. 127: N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)sulfamide hydrochloride;

Compound No. 128: 3-methyl-5-(2-(sulfamile)-2,8-diazaspiro[4.5]decane-8-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2(1 H )-one hydrochloride;

Compound No. 129: tert -butyl (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino)methyl )phenyl)carbamate;

Compound No. 130: 5-((4-aminobenzyl)amino)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride;

Compound No. 131: tert -butyl ( N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) amino)methyl)phenyl)sulfamoyl)carbamate;

Compound No. 132: tert -butyl N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino )methyl)phenyl)sulfamide hydrochloride; and

Compound No. 133: tert -butyl N- (4-((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino) phenyl) sulfamide.

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

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

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

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

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

In another aspect of the present invention, the pharmaceutical composition for preventing, reducing or treating cancer, wherein the cancer is a cancer associated with inhibition of ENPP-1, is provided.

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

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

Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth. Cancer diseases that can be prevented, treated or alleviated by the treatment of the pharmaceutical composition of the present invention include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, scleroderma, uterine cancer, and cervical cancer. , head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, hematological cancer (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, or fibroadenomas, and the like.

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

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

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

As used herein, 'treatment' means alleviation or improvement of symptoms, reduction of extent of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of disease state, partial or complete recovery, prolongation of survival, other beneficial treatment results, etc. It can be used in the meaning of including all.

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

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

For example, the pharmaceutical composition contains the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof in an amount of 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, based on the total weight of the total composition. can be included as

The compound represented by Formula 1 may be included alone in the pharmaceutical composition, or may be included together with other pharmacologically acceptable carriers, excipients, diluents, or auxiliary ingredients.

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

The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of an anticancer agent by being administered in combination with another anticancer agent for treating cancer or tumor.

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

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

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

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

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

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

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

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

Hereinafter, the present invention will be described in detail by production examples, examples, experimental examples, and formulation examples. However, the following preparation examples, examples, experimental examples, and formulation examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following embodiments.

<Production Example>

<Core Synthesis>

Step 1 : Dissolve 4-chloropyridin-2-amine 1 (1.0 equiv.) in tetrahydrofuran (0.35 M) in a round bottom flask, and di- tert -butyl dicarbonate with 4-dimethylaminopyridine (0.05 equiv.) at room temperature. (1.0 equivalent) was added and stirred for 16 hours. After the reaction was completed, water was poured into the mixture and extracted with ethyl acetate. Thereafter, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc:hexanes = 1:8) to obtain tert -butyl(4-chloropyridin-2-yl)carbamate 2 (90% yield).

Step 2 : In a round bottom flask, tert -butyl(4-chloropyridin-2-yl)carbamate 2 (1.0 equiv.) was dissolved in tetrahydrofuran (0.2 M) and n-butyllithium (2.3 equiv.) at -78 °C. ) was added and stirred for 1 hour. Then, anhydrous dimethylformamide (5.0 equivalent) was added to the reaction solution at -78 °C and stirred for an additional 2 hours. After the reaction was completed, water was poured into the mixture and extracted with ethyl acetate. Thereafter, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc:hexanes = 1:8) to obtain tert -butyl(4-chloro-3-formylpyridin-2-yl)carbamate 3 (70% yield).

Step 3-1 : Dissolve tert -butyl(4-chloro-3-formylpyridin-2-yl)carbamate 3 (1.0 equivalent) in toluene (0.8 M) in a round bottom flask and add methylamine 4 (1.5 equivalent) at room temperature. equivalent) was added and stirred for 16 hours. After concentrating the solvent under reduced pressure, tetrahydrofuran (0.3 M) was added at room temperature, sodium borohydride (3.0 equivalent) was added to the reaction solution, and the mixture was further stirred for 24 hours. After the reaction was completed, the solid was washed with water and acetonitrile solvent using a solid filter to obtain 5-chloro-3-methyl-3,4-dihydropyrido [2,3- d ] pyrimidine-2 (1 H )-On 5 (61% yield) was obtained.

^1H NMR (400 MHz, MeOD) δ 8.04 (d, J = 5.5 Hz, 1H), 7.04 (d, J = 5.5 Hz, 1H), 4.59 (d, J = 0.9 Hz, 2H), 3.04 (s, 3H).

Step 3-2 : In a round bottom flask, tert -butyl(4-chloro-3-formylpyridin-2-yl)carbamate 3 (1.0 equivalent) was dissolved in toluene (0.8 M) and cyclopropanamine 6 ( 1.5 eq) was added and stirred for 16 hours. After concentrating the solvent under reduced pressure, tetrahydrofuran (0.3 M) was added at room temperature, sodium borohydride (3.0 equivalent) was added to the reaction solution, and the mixture was further stirred for 24 hours. After the reaction was completed, the solid was washed with water and acetonitrile solvent using a solid filter to obtain 5-chloro-3-cyclopropyl-3,4-dihydropyrido [2,3- d ] pyrimidine-2 (1 H )-one 7 (35% yield) was obtained.

^1H NMR (400 MHz, MeOD) δ 8.01 (d, J = 5.6 Hz, 1H), 7.01 (d, J = 5.6 Hz, 1H), 4.54 (s, 2H), 2.76 - 2.56 (m, 1H), 0.91 - 0.83 (m, 2H), 0.75 - 0.69 (m, 2H).

Step 3-3 : In a round bottom flask, tert -butyl(4-chloro-3-formylpyridin-2-yl)carbamate 3 (1.0 equiv.) was dissolved in toluene (0.8 M) and benzylamine 8 (1.5 equivalent) was added and stirred for 16 hours. After concentrating the solvent under reduced pressure, tetrahydrofuran (0.3 M) was added at room temperature, sodium borohydride (3.0 equivalent) was added to the reaction solution, and the mixture was further stirred for 24 hours. After the reaction was completed, the solid was washed with water and acetonitrile solvent using a solid filter to obtain 3-benzyl-5-chloro-3,4-dihydropyrido [2,3- d ] pyrimidine-2 (1 H )-On 9 (53% yield) was obtained.

^1H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 8.04 (d, J = 5.5 Hz, 1H), 7.40 - 7.27 (m, 5H), 7.03 (d, J = 5.5 Hz, 1H), 4.59 (s, 2H), 4.37 (s, 2H).

Step 3-4 : In a round bottom flask, tert -butyl(4-chloro-3-formylpyridin-2-yl)carbamate 3 (1.0 equivalent) was dissolved in toluene (0.8 M) and ethanolamine 10 (1.5 equivalent) was dissolved at room temperature. equivalent) was added and stirred for 16 hours. After concentrating the solvent under reduced pressure, tetrahydrofuran (0.3 M) was added at room temperature, sodium borohydride (3.0 equivalent) was added to the reaction solution, and the mixture was further stirred for 24 hours. After the reaction was completed, the solid was washed with water and acetonitrile solvent using a solid filter to obtain 5-chloro-3-(2-hydroxyethyl)-3,4-dihydropyrido[2,3- d ]pyridoxine. Midin-2(1 H )-one 11 (77 % yield) was obtained.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.5 Hz, 1H), 4.65 (d, J = 0.8 Hz, 2H), 3.95 - 3.86 (m, 2H), 3.69 - 3.59 (m, 2H).

Step 1 : In a round bottom flask, tert -butyl(4-chloro-3-formylpyridin-2-yl)carbamate 3 (1.0 equivalent) was dissolved in toluene (0.8 M) and 2-methoxyethylamine 12 (1.5 eq) was added and stirred for 16 hours. After concentrating the solvent under reduced pressure, tetrahydrofuran (0.3 M) was added at room temperature, sodium borohydride (3.0 equivalent) was added to the reaction solution, and the mixture was further stirred for 24 hours. After the reaction was completed, the solid was washed with water and acetonitrile solvent using a solid filter to obtain 5-chloro-3-(2-methoxyethyl)-3,4-dihydropyrido[2,3- d ]pyridoxine. Midin-2(1 H )-one 13 (13 % yield) was obtained.

^1H NMR (600 MHz, MeOD) δ 8.00 (d, J = 5.5 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 4.67 (s, 2H), 3.62 (q, J = 3.4 Hz, 4H), 3.36 (s, 3H).

Step 1 : Dissolve tert -butyl(4-chloro-3-formylpyridin-2-yl)carbamate 3 (1.0 equivalent) in toluene (0.8 M) in a round bottom flask and add 4-methoxybenzylamine 14 at room temperature. (1.5 eq) was added and stirred for 16 hours. After concentrating the solvent under reduced pressure, tetrahydrofuran (0.3 M) was added at room temperature, sodium borohydride (3.0 equivalent) was added to the reaction solution, and the mixture was further stirred for 24 hours. After the reaction is completed, the solid is washed with water and acetonitrile solvent using a solid filter to obtain 5-chloro-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3- d ]pyridoxyl. Midin-2(1 H )-one 15 (65 % yield) was obtained.

^1H NMR (400 MHz, MeOD) δ 8.04 (d, J = 5.3 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 5.6 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 4.62 (s, 2H), 4.43 (s, 2H), 3.82 (s, 3H).

Step 1 : In a round bottom flask, pyridomyridine 5 (1.0 equiv) was dissolved in dimethylformamide (0.1 M) and sodium hydride (1.3 equiv) was added at 0 °C. After stirring for 20 minutes, iodomethane (1.30 eq) is added and stirred for 3 hours at room temperature. After the reaction was completed, water was poured into the mixture and extracted with ethyl acetate. Thereafter, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc:hexanes = 1:3) to obtain pyridopyridine 16 (80% yield).

^1H NMR (400 MHz, MeOD) δ 8.13 (dt, J = 5.5, 0.9 Hz, 1H), 7.04 (d, J = 5.5 Hz, 1H), 4.53 (d, J = 0.9 Hz, 2H), 3.36 ( s, 3H), 3.04 (s, 3H).

Step 1 : In a round bottom flask, pyridomyridine 5 (1.0 equiv) was dissolved in dimethylformamide (0.1 M) and sodium hydride (1.3 equiv) was added at 0 °C. After stirring for 20 minutes, benzyl bromide (1.30 equivalent) is added and stirred for 3 hours at room temperature. After the reaction was completed, water was poured into the mixture and extracted with ethyl acetate. Thereafter, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (EtOAc:hexanes = 1:3) to obtain pyridopyridine 17 (80% yield).

^1H NMR (600 MHz, MeOD) δ 8.08 (d, J = 5.4 Hz, 1H), 7.29 (d, J = 7.7 Hz, 2H), 7.24 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 5.4 Hz, 1H), 5.28 (s, 2H), 4.59 (s, 2H), 3.06 (s, 3H).

Step 1 : In a round bottom flask, pyridopyrimidine 18 (1.0 equiv.) was dissolved in dimethylformamide (0.1 M) and sodium hydride (1.3 equiv.) was added at 0 °C. After stirring for 20 minutes, methyl iodide (1.30 eq) is added and stirred for 2 hours at room temperature. After the reaction was completed, water was poured into the mixture and extracted with ethyl acetate. Thereafter, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc:hexanes = 1:3) to obtain pyridopyrimidine 19 (70% yield).

¹ H NMR (400 MHz, MeOD) δ 8.52 (s, 1H), 4.52 (s, 2H), 3.37 (s, 3H), 3.05 (s, 3H).

<Suzuki coupling reaction>

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

[Example 1]: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl)carba mate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.41 - 7.36 (m, 1H), 7.00 (dt, J = 7.7, 1.3 Hz , 1H), 6.93 (d, J = 5.2 Hz, 1H), 4.44 (s, 2H), 2.92 (s, 3H), 1.53 (s, 9H).

[Example 2]: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carba mate

^1H NMR (400 MHz, MeOD) δ 8.16 (d, J = 5.3 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 5.2 Hz, 1H), 4.45 (s, 2H), 4.32 (s, 2H), 2.94 (s, 3H), 1.48 (s, 9H).

[Example 3]: tert -butyl (4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 5.2 Hz, 1H), 4.43 (s, 2H), 4.30 (s, 2H), 2.90 (s, 3H), 1.47 (s, 9H).

[Example 4]: tert -butyl methyl(4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.3 Hz, 1H), 7.61 - 7.51 (m, 2H), 7.32 (d, J = 8.7 Hz, 1H), 6.98 (dd, J = 7.5 , 5.1 Hz, 1H), 6.95 (d, J = 5.3 Hz, 1H), 4.53 (t, J = 1.0 Hz, 3H), 4.49 (s, 2H), 3.02 (s, 4H), 2.95 (s, 3H) ), 1.56 (d, J = 2.6 Hz, 9H).

[Example 5]: tert -butyl (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)phenyl) Propane-2-yl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.07 (d, J = 5.1 Hz, 1H), 7.53 (s, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.96 (dd, J = 7.5, 5.1 Hz, 1H), 4.50 (s, 2H), 2.99 (s, 3H), 1.62 (s, 15H).

[Example 6]: tert -butyl (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl) benzyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.10 (d, J = 5.2 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.13 (t, J = 9.2 Hz, 2H), 6.88 (d, J = 5.3 Hz, 1H), 4.40 (s, 2H), 4.31 (s, 2H), 2.87 (s, 3H), 1.43 (s, 6H).

[Example 7]: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 5.2 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.46 (ddd, J = 8.2, 2.2, 1.2 Hz, 1H), 7.40 (t , J = 7.8 Hz, 1H), 7.00 - 6.97 (m, 1H), 6.93 (d, J = 5.2 Hz, 1H), 4.44 (s, 2H), 2.55 (tt, J = 7.1, 3.9 Hz, 1H) , 1.53 (s, 10H), 0.79 - 0.73 (m, 2H), 0.60 - 0.54 (m, 2H).

[Example 8]: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.30 - 7.23 ( m, 2H), 6.92 (d, J = 5.3 Hz, 1H), 4.41 (s, 2H), 3.35 (s, 2H), 2.53 (tt, J = 7.0, 3.8 Hz, 1H), 1.45 (s, 9H) ), 0.79 - 0.72 (m, 2H), 0.52 (d, J = 3.8 Hz, 2H).

[Example 9]: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 5.3 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 5.1 Hz, 1H), 4.42 (s, 2H), 4.31 (s, 2H), 2.54 (tt, J = 7.1, 3.8 Hz, 1H), 1.47 (s, 9H), 0.75 (q, J = 6.7 Hz, 2H), 0.52 (p, J = 4.7 Hz, 2H).

[Example 10]: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) (methyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.03 (d, J = 5.3 Hz, 1H), 7.33 - 7.25 (m, 4H), 6.83 (dd, J = 5.2, 1.5 Hz, 1H), 4.42 (s, 2H) ), 4.33 (s, 2H), 2.81 (s, 3H), 2.44 (tt, J = 7.1, 3.8 Hz, 1H), 1.37 (s, 9H), 0.68-0.63 (m, 2H), 0.45-0.39 ( m, 2H).

[Example 11]: tert -butyl (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate

^1H NMR (600 MHz, MeOD) δ 8.12 (d, J = 5.2 Hz, 1H), 7.59 - 7.54 (m, 5H), 7.32 - 7.30 (m, 4H), 6.88 (d, J = 5.2 Hz, 1H) ), 4.56 (s, 2H), 4.30 (s, 2H), 4.23 (s, 4H), 1.47 (s, 9H).

[Example 12]: tert -butyl (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl)benzyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 9.3 Hz, 2H), 6.92 (d, J = 5.2 Hz, 1H), 4.57 (s, 2H), 4.29 (s, 2H), 3.68 (t, J = 5.5 Hz, 2H), 3.45 (t, J = 5.5 Hz, 2H), 1.45 (s, 9H).

[Example 13]: tert -butyl (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl )benzyl)carbamate

^1H NMR (600 MHz, MeOD) δ 8.11 (d, J = 5.2 Hz, 1H), 7.41 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 5.2 Hz, 1H), 4.53 (s, 2H), 4.29 (s, 2H), 3.50 (h, J = 4.7 Hz, 4H), 3.26 (s, 3H), 1.46 (s, 9H).

[Example 14]: tert -butyl (3-(3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl)benzyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 9.3 Hz, 2H), 6.92 (d, J = 5.2 Hz, 1H), 4.57 (s, 2H), 4.29 (s, 2H), 3.68 (t, J = 5.5 Hz, 2H), 3.45 (t, J = 5.5 Hz, 2H), 1.45 (s, 9H).

[Example 15]: N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfa Maid

^1H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 8.51 (d, J = 5.3 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 5.2 Hz, 1H) , 7.25 (d, J = 8.6 Hz, 2H), 4.89 (s, 2H), 2.96 (dt, J = 6.9, 3.3 Hz, 1H), 1.18 - 1.08 (m, 2H), 1.01 - 0.88 (m, 2H) ).

[Example 16]: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide

^1H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 5.2 Hz, 3H), 6.93 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 5.1 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 5.39 (s, 2H), 4.51 (s, 2H), 4.31 (s, 1H).

[Example 17]: tert -butyl (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.27 (d, J = 5.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 5.2 Hz, 1H), 4.39 (s, 2H), 4.33 (s, 2H), 3.44 (s, 3H), 2.94 (s, 3H), 1.50 (s, 9H).

[Example 18]: tert -butyl (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl ) carbamate

^1H NMR (600 MHz, MeOD) δ 8.19 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.36 - 7.29 (m, 4H), 7.25 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.92 ( d , J = 5.1 Hz, 1H), 5.35 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 2.93 (s, 3H), 1.47 (s, 9H).

[Example 19]: tert -butyl (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) benzyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.25 (d, J = 5.2 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 5.2 Hz, 1H), 4.35 (s, 2H), 4.29 (s, 2H), 3.42 (s, 3H), 2.92 (s, 3H), 1.45 ( s, 9H).

[Example 20]: tert -butyl (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)carbamate

^1H NMR (600 MHz, MeOD) δ 8.19 (d, J = 5.1 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.5 Hz, 2H), 7.27 - 7.23 (m, 3H), 7.17 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H), 5.35 (s, 2H), 4.40 ( s, 2H), 4.28 (s, 2H), 2.93 (s, 3H), 1.44 (s, 10H).

[Example 21]: tert -butyl (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carba mate

^1H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 4.55 (s, 2H), 4.31 ( s, 2H), 2.94 (s, 3H), 1.47 (s, 9H).

[Example 22]: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carba mate

^1H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.52 - 7.43 (m, 4H), 4.54 (s, 2H), 4.31 (s, 2H), 2.94 (s, 3H), 1.45 (s , 9H).

[Example 23]: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)carba mate

^1H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 7.65 (s, 1H), 7.56 - 7.52 (m, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 4.55 (s, 2H), 2.95 (d, J = 1.1 Hz, 3H), 1.53 (d, J = 1.1 Hz, 9H).

[Example 24]: tert -butyl (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- 1) benzyl) carbamate

^1H NMR (600 MHz, MeOD) δ 8.64 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.39 - 7.32 (m, 2H), 4.55 (s, 2H), 4.35 (s, 2H) ), 2.94 (s, 3H), 1.45 (s, 9H).

Step 2 : Put 3 (1.0 equivalent) in a round bottom flask and dissolve by adding dichloromethane (0.040 M). Thereafter, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) was added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 4 (60-90% yield).

[Example 25]: 5-(3-aminophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.22 (d, J = 5.7 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.46 (t, J = 1.9 Hz, 1H), 7.11 (d, J = 5.7 Hz, 1H), 4.50 (s, 2H), 2.93 (s, 3H).

[Example 26]: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.23 (d, J = 5.8 Hz, 1H), 7.67 (d, J = 7.7 Hz, 2H), 7.55 (d, J = 11.1 Hz, 2H), 7.15 (d, J = 5.7 Hz, 1H), 4.53 (s, 2H), 4.26 (s, 2H), 2.96 (s, 3H).

[Example 27]: 5-(4-((aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H -one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.21 (d, J = 6.0 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 6.1 Hz, 1H), 4.52 (s, 2H), 4.24 (s, 2H), 2.93 (s, 3H).

[Example 28]: 3-methyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.08 - 8.02 (m, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 6.0 Hz, 1H), 6.90 - 6.78 (m, 1H), 4.61 (d, J = 0.9 Hz, 2H), 4.07 (s, 1H), 3.03 (s, 3H) ), 2.67 (s, 2H).

[Example 29]: 5-(4-((aminopropan-2-yl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidine-2(1 H ) -on hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.22 (d, J = 6.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.21 (s, 1H), 4.54 (s, 2H), 2.94 (s, 3H), 1.80 (s, 6H).

[Example 30]: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidine-2(1 H ) -on hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.23 (dt, J = 6.0, 0.8 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.20 (d, J = 6.0 Hz, 1H), 4.53 (d, J = 0.9 Hz, 2H), 4.30 (s, 2H), 2.94 (s, 3H).

[Example 31]: 5-(3-aminophenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.26 (d, J = 6.2 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.57 (s, 1H), 7.30 (d, J = 5.8 Hz, 1H), 4.55 (s, 2H), 2.61 (tt, J = 7.0, 3.7 Hz, 1H), 0.79 (dd, J = 7.0, 1.9 Hz, 2H), 0.63 - 0.58 (m, 2H).

[Example 32]: 5-(3-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.24 (dd, J = 6.1, 2.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.61 (s, 1H), 7.56 (s, 1H), 7.24 (t , J = 5.8 Hz, 1H), 4.55 (d, J = 3.2 Hz, 2H), 4.28 (s, 2H), 2.66 - 2.56 (m, 1H), 0.81 - 0.76 (m, 2H), 0.62 - 0.57 ( m, 2H).

[Example 33]: 5-(4-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.24 (dd, J = 6.1, 2.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.61 (s, 1H), 7.56 (s, 1H), 7.24 (t , J = 5.8 Hz, 1H), 4.55 (d, J = 3.2 Hz, 2H), 4.28 (s, 2H), 2.66 - 2.56 (m, 1H), 0.81 - 0.76 (m, 2H), 0.62 - 0.57 ( m, 2H).

[Example 34]: 3-cyclopropyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.24 (dd, J = 6.1, 2.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.61 (s, 1H), 7.56 (s, 1H), 7.24 (t , J = 5.8 Hz, 1H), 4.55 (d, J = 3.2 Hz, 2H), 4.28 (s, 2H), 2.66 - 2.56 (m, 1H), 0.81 - 0.76 (m, 2H), 0.62 - 0.57 ( m, 2H).

[Example 35]: 5-(4-(aminomethyl)phenyl)-3-benzyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.04 (d, J = 5.7 Hz, 1H), 7.40 - 7.35 (m, 5H), 7.34 - 7.29 (m, 3H), 7.29 - 7.25 (m, 1H), 7.09 (d, J = 5.6 Hz, 1H), 4.68 (s, 2H), 4.56 (s, 2H), 4.46 (s, 2H).

[Example 36]: 5-(3-(aminomethyl)phenyl)-3-(2-hydroxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2(1 H ) -one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.21 (d, J = 5.8 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.53 (s, 2H), 7.14 (d, J = 5.8 Hz, 1H), 4.66 (s, 2H), 4.23 (s, 2H), 3.71 (t, J = 5.3 Hz, 2H), 3.47 (t, J = 5.3 Hz, 2H).

[Example 37]: 5-(4-(aminomethyl)phenyl)-3-(2-methoxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2(1 H ) -one hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.23 (d, J = 6.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 6.3 Hz, 1H), 4.66 (s, 2H), 4.25 (s, 2H), 3.54 (d, J = 2.5 Hz, 4H), 3.28 (s, 3H).

[Example 38]: 5-(4-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 5.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 5.6 Hz, 1H), 4.42 (s, 2H), 4.24 (s, 2H), 3.47 (s, 3H), 2.95 (s, 3H).

[Example 39]: 5-(4-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.22 (d, J = 5.1 Hz, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.7 Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 5.1 Hz, 1H), 5.36 (s, 2H) , 4.41 (s, 2H), 4.21 (s, 2H), 2.93 (s, 3H).

[Example 40]: 5-(3-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 5.7 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.54 - 7.47 (m, 2H), 7.14 (d, J = 5.7 Hz, 1H) ), 4.44 (s, 2H), 4.24 (s, 2H), 3.46 (s, 3H), 2.95 (s, 3H).

[Example 41]: 5-(3-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.23 (d, J = 5.2 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.51 - 7.46 (m, 2H), 7.32 (d, J = 7.8 Hz, 2H) ), 7.27 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.0 Hz, 1H), 7.00 (d, J = 5.3 Hz, 1H), 5.36 (s, 2H), 4.45 (s, 2H) ), 4.22 (s, 2H), 2.95 (d, J = 1.6 Hz, 3H).

[Example 42]: 5-(4-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

¹ H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 7.78 - 7.66 (m, 4H), 4.57 (s, 2H), 4.27 (s, 2H), 2.95 (s, 3H).

[Example 43]: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.91 (s, 1H), 7.79 - 7.73 (m, 3H), 7.71 - 7.68 (m, 1H), 4.61 (s, 2H), 4.28 (s, 2H), 2.97 (s, 3H).

[Example 44]: 5-(3-(aminophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.61 - 7.56 (m, 2H), 4.59 (s, 2H), 2.97 (d, J = 1.2 Hz, 3H).

[Example 45]: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2(1 H ) -on hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.86 (s, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.60 - 7.53 (m, 2H), 4.58 (s, 2H), 4.32 (s, 2H) ), 2.96 (s, 3H).

Step 2-2 (reaction method 2) : Put 7 (1.0 equivalent) in a round bottom flask, add trifluoroacetic acid (85 equivalent) and stir at 80 °C for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 13 (40% yield).

[Example 46]: 5-(3-(aminomethyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one trifluoroacetic acid

^1H NMR (400 MHz, MeOD) δ 8.04 (d, J = 5.5 Hz, 1H), 7.75 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.26 (dt, J = 7.7, 1.4 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.55 (d, J = 0.9 Hz, 2H), 4.44 (d, J = 0.7 Hz, 2H).

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

Step 3 : Add a solution of triethylamine (2.5 equivalents) in dichloromethane (0.1 M) to a round bottom flask. Then, 4 (1.0 equivalent) and 6 (1.1 equivalent) were added and stirred at room temperature for one day. After the reaction was completed, the mixture was concentrated under reduced pressure and dried, and the resulting residue was extracted with dichloromethane and water. The resulting residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 7 (30-70% yield).

[Example 47]: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) phenyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.14 (d, J = 5.1 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.24 (t, J = 2.0 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H), 4.43 (s, 2H), 2.92 (s, 3H), 1.38 (s, 9H).

[Example 48]: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) benzyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.3 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.41 (d, J = 11.7 Hz, 1H), 7.29 (q, J = 3.4 , 2.8 Hz, 1H), 6.94 (d, J = 5.2 Hz, 1H), 4.44 (s, 2H), 4.29 (s, 2H), 2.91 (d, J = 4.5 Hz, 3H), 1.29 (s, 9H) ).

[Example 49]: tert -butyl ( N- (4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.35 (dd, J = 8.2, 3.5 Hz, 2H), 6.92 ( d, J = 5.1 Hz, 1H), 4.43 (d, J = 2.0 Hz, 2H), 4.23 (s, 2H), 2.90 (d, J = 1.9 Hz, 3H), 1.46 (s, 9H).

[Example 50]: tert -butyl ( N -methyl- N- (4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine -5-yl) benzyl) sulfamoyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.54 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 5.3 Hz, 1H), 8.04 (d, J = 5.5 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.59 (s, 2H), 4.48 (s, 23H), 3.04 (s, 3H), 2.94 (s, 3H), 1.54 (s, 9H).

[Example 51]: tert -butyl ( N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl)phenyl)propan-2-yl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 5.3 Hz, 1H), 4.46 (s, 2H), 2.92 (s, 3H), 1.73 (s, 6H), 1.49 (s, 9H).

[Example 52]: tert -butyl ( N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine -5-yl) benzyl) sulfamoyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.14 (d, J = 5.3 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.17 (t, J = 9.2 Hz, 2H), 6.91 (d, J = 5.3 Hz, 1H), 4.43 (s, 2H), 4.33 (s, 2H), 2.92 (s, 3H), 1.46 (s, 9H).

[Example 53]: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )phenyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.15 (d, J = 5.2 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 1.8 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 4.45 (s, 2H), 2.61 - 2.53 (m, 1H), 1.40 ( s, 9H), 0.83 - 0.75 (m, 2H), 0.58 (d, J = 8.0 Hz, 2H).

[Example 54]: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

^1H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.35 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H), 5.75 (s, 1H), 4.32 (s, 2H), 2.33 (s, 1H), 1.91 (s, 1H), 1.33 (s , 9H), 0.65 (d, J = 6.6 Hz, 1H), 0.43 (s, 2H).

[Example 55]: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 5.2 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 5.3 Hz, 1H), 4.43 (s, 2H), 4.28 (s, 2H), 2.56 - 2.52 (m, 1H), 1.47 (s, 9H), 0.75 (q, J = 6.9 Hz, 2H), 0.52 (s, 2H).

[Example 56]: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl) -N -methylsulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.3 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 5.3 Hz, 1H), 4.52 (s, 2H), 4.44 (s, 2H), 2.85 (s, 3H), 2.54 (tt, J = 7.0, 3.8 Hz, 1H), 1.52 (s, 9H), 0.75 (dd, J = 7.3, 5.4 Hz, 2H), 0.56 - 0.50 (m, 2H).

[Example 57]: tert -butyl ( N- (4-(3-benzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate

^1H NMR (600 MHz, MeOD) δ 8.10 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.28 (dd, J = 8.0, 6.5 Hz, 2H), 7.25 - 7.22 (m, 1H), 7.22 - 7.19 (m, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.83 (d, J = 5.2 Hz, 1H), 4.52 (s, 2H), 4.27 (s , 2H), 4.20 (s, 2H), 1.40 (s, 9H).

[Example 58]: tert -butyl ( N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyridonium midin-5-yl)benzyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.03 (d, J = 5.2 Hz, 1H), 7.37 (dd, J = 4.7, 2.1 Hz, 2H), 7.29 (s, 1H), 7.20 (dt, J = 6.1 , 2.3 Hz, 1H), 6.85 (d, J = 5.3 Hz, 1H), 4.50 (s, 2H), 4.19 (s, 2H), 3.60 (t, J = 5.5 Hz, 2H), 3.37 (t, J = 5.5 Hz, 2H), 1.32 (s, 9H).

[Example 59]: tert -butyl ( N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrido midin-5-yl)benzyl)sulfamoyl)carbamate

^1H NMR (600 MHz, MeOD) δ 8.12 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 5.2 Hz, 1H), 4.53 (s, 2H), 4.27 (s, 2H), 3.51 (dd, J = 8.6, 4.0 Hz, 4H), 3.27 (s, 3H), 1.46 (s, 9H).

[Example 60]: tert -butyl ( N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamoyl ) carbamate

^1H NMR (400 MHz, MeOD) δ 8.02 (d, J = 5.2 Hz, 1H), 7.17 (s, 1H), 7.11 - 7.08 (m, 2H), 7.02 (d, J = 7.2 Hz, 1H), 6.81 (d, J = 5.2 Hz, 1H), 4.39 (s, 2H), 4.20 (s, 2H), 1.31 (s, 9H).

[Example 61]: tert -butyl ( N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.27 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 5.2 Hz, 1H), 4.39 (s, 2H), 4.29 (s, 2H), 3.44 (s, 3H), 2.95 (s, 3H), 1.49 (s, 9H).

[Example 62]: tert -butyl ( N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate

^1H NMR (600 MHz, MeOD) δ 8.20 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 7.7 Hz, 2H), 7.25 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 5.35 (s, 2H) , 4.42 (s, 2H), 4.27 (s, 2H), 2.94 (s, 3H), 1.46 (s, 9H).

[Example 63]: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 5.2 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.42 (s, 1H), 7.34 - 7.29 (m, 1H), 7.01 (d , J = 5.2 Hz, 1H), 4.41 (s, 2H), 4.30 (s, 2H), 3.44 (s, 3H), 2.96 (s, 3H), 1.44 (s, 9H).

[Example 64]: tert -butyl ( N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate

^1H NMR (600 MHz, MeOD) δ 8.20 (d, J = 5.1 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.39 (s, 1H), 7.34 - 7.29 (m, 3H), 7.26 (t , J = 7.6 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.95 (d, J = 5.1 Hz, 1H), 5.36 (s, 2H), 4.44 (s, 2H), 4.28 (s , 2H), 2.95 (s, 3H), 1.39 (s, 9H).

[Example 65]: tert -butyl ( N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) benzyl)sulfamoyl)carbamate

¹ H NMR (600 MHz, MeOD) δ 8.65 (s, 1H), 7.55 (s, 4H), 4.55 (s, 2H), 4.30 (s, 2H), 2.94 (s, 3H), 1.47 (s, 9H) ).

[Example 66]: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) benzyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 7.57 (s, 1H), 7.52 (t, J = 6.0 Hz, 3H), 4.57 (s, 2H), 4.31 (s, 2H), 2.96 (s, 3H), 1.43 (s, 9H).

[Example 67]: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) phenyl)sulfamoyl)carbamate

¹ H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.51 - 7.44 (m, 2H), 7.35 - 7.30 (m, 2H), 4.56 (s, 2H), 2.96 (s, 3H), 1.37 (s, 9H).

[Example 68]: tert -butyl ( N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine -4-yl)benzyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.43 - 7.30 (m, 2H), 4.57 (s, 2H), 4.35 (s, 2H) ), 2.95 (s, 3H), 1.46 (s, 9H).

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

[Example 69]: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 5.2 Hz, 1H), 4.45 (s, 2H), 2.92 (s, 3H).

[Example 70]: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.43 (s, 1H), 7.30 - 7.25 (m, 1H), 6.94 (d , J = 5.2 Hz, 1H), 4.44 (s, 2H), 4.28 (s, 2H), 2.91 (s, 3H).

[Example 71]: N- (4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.18 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 6.1 Hz, 1H), 4.56 (s, 2H), 4.30 (s, 2H), 2.94 (s, 3H).

[Example 72]: N -Methyl- N- (4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)sulfamide hydrochloride

^1H NMR (800 MHz, MeOD) δ 8.21 (d, J = 6.3 Hz, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 6.3 Hz, 1H), 4.61 (d, J = 2.5 Hz, 2H), 4.30 (s, 2H), 3.03 (s, 3H), 2.96 (s, 3H).

[Example 73]: N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl )propan-2-yl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 5.3 Hz, 1H), 4.46 (s, 2H), 2.92 (s, 3H), 1.56 (s, 6H).

[Example 74]: N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.20 (d, J = 5.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 6.0 Hz, 1H), 4.55 (s, 2H), 4.35 (s, 2H), 2.95 (s, 3H).

[Example 75]: N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfa amide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.18 (d, J = 6.1 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.24 (d, J = 6.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 4.56 (s, 2H), 2.60 (td, J = 7.0, 3.6 Hz, 1H), 0.83 - 0.76 (m, 2H), 0.61 (q, J = 7.6, 6.1 Hz, 2H).

[Example 76]: N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfa amide hydrochloride

^1H NMR (800 MHz, MeOD) δ 8.20 (d, J = 6.2 Hz, 1H), 7.57 - 7.49 (m, 3H), 7.38 (dt, J = 6.8, 1.6 Hz, 1H), 7.29 - 7.26 (m , 1H), 4.72 (s, 2H), 4.31 (s, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.49 (t, J = 5.3 Hz, 2H).

[Example 77]: N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfa amide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.3 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 5.3 Hz, 1H), 4.44 (s, 2H), 4.30 (s, 2H), 2.54 (tt, J = 7.1, 3.7 Hz, 1H), 0.78 - 0.72 (m, 2H), 0.56 - 0.49 (m , 2H).

[Example 78]: N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)- N -methylsulfamide hydrochloride

^1H NMR (800 MHz, MeOD) δ 8.22 (d, J = 6.2 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 6.2 Hz, 1H), 4.60 (s, 2H), 4.33 (s, 2H), 2.74 (s, 3H), 2.63 (tt, J = 7.1, 3.8 Hz, 1H), 0.84 - 0.80 (m, 2H), 0.64 - 0.60 (m, 2H).

[Example 79]: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methylsulfa amide hydrochloride

^1H NMR (800 MHz, MeOD) δ 8.18 (dd, J = 6.1, 2.0 Hz, 1H), 7.52 (dd, J = 8.2, 2.0 Hz, 2H), 7.33 (dd, J = 7.9, 2.0 Hz, 2H) ), 7.31 - 7.29 (m, 1H), 7.28 - 7.27 (m, 4H), 7.20 (dd, J = 6.0, 1.7 Hz, 1H), 4.59 (s, 2H), 4.44 (s, 2H), 4.26 ( s, 2H).

[Example 80]: N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) Benzyl) sulfamide hydrochloride

^1H NMR (800 MHz, MeOD) δ 8.20 (d, J = 6.2 Hz, 1H), 7.57 - 7.49 (m, 3H), 7.38 (dt, J = 6.8, 1.6 Hz, 1H), 7.29 - 7.26 (m , 1H), 4.72 (s, 2H), 4.31 (s, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.49 (t, J = 5.3 Hz, 2H).

[Example 81]: N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) Benzyl) methylsulfamide hydrochloride

^1H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 8.21 (d, J = 5.6 Hz, 1H), 7.53 - 7.49 (m, 3H), 7.43 - 7.34 (m, 2H), 7.01 (d , J = 5.5 Hz, 1H), 4.50 (s, 2H), 4.16 (d, J = 3.1 Hz, 2H), 3.42 (s, 4H), 3.18 (s, 3H).

[Example 82]: N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.14 (d, J = 5.4 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.41 (s, 1H), 7.30 - 7.22 (m, 1H), 6.98 (d , J = 5.4 Hz, 1H), 4.41 (s, 2H), 4.28 (s, 2H).

[Example 83]: N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl )sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.24 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 6.0 Hz, 1H), 4.50 (s, 2H), 4.30 (s, 2H), 3.48 (s, 3H), 2.96 (s, 3H).

[Example 84]: N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)sulfamide hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.19 (d, J = 5.1 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 5.35 (s, 2H) , 4.42 (s, 2H), 4.28 (s, 2H), 2.93 (s, 3H).

[Example 85]: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.25 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 4.5 Hz, 2H), 7.42 (s, 1H), 7.31 - 7.25 (m, 1H), 6.97 (d, J = 5.2 Hz, 1H), 4.37 (s, 2H), 4.28 (s, 2H), 3.42 (s, 3H), 2.92 (s, 3H).

[Example 86]: N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)sulfamide hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.20 (d, J = 5.1 Hz, 1H), 7.48 (d, J = 4.7 Hz, 2H), 7.42 (s, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.29 - 7.24 (m, 3H), 7.18 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 5.1 Hz, 1H), 5.35 (s, 2H), 4.43 (s, 2H), 4.28 (s, 2H), 2.94 (s, 3H).

[Example 87]: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.89 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 4.60 (s, 2H), 4.33 ( s, 2H), 2.96 (s, 3H).

[Example 88]: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.95 (s, 1H), 7.70 (s, 2H), 7.65 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 4.62 ( s, 2H), 4.35 (s, 2H), 3.66 (s, 2H), 2.97 (s, 3H).

[Example 89]: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.50 (t, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.0, 1.3 Hz, 1H), 7.28 (dq, J = 8.0, 1.3 Hz, 1H), 4.61 (s, 2H), 2.97 (s, 3H).

[Example 90]: N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )benzyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.93 (s, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.49 - 7.37 (m, 2H), 4.60 (s, 2H), 4.38 (s, 2H) ), 2.97 (d, J = 1.0 Hz, 3H).

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

[Example 91]: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methanesulfone amide

^1H NMR (400 MHz, MeOD) δ 8.14 (d, J = 5.3 Hz, 1H), 7.50 (d, J = 7.3 Hz, 2H), 7.41 (s, 1H), 7.33 - 7.28 (m, 1H), 6.93 (d, J = 5.2 Hz, 1H), 4.44 (s, 2H), 4.33 (s, 2H), 2.92 (d, J = 1.4 Hz, 3H), 2.91 (d, J = 1.4 Hz, 3H).

[Example 92]: 4-methyl- N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) benzyl) benzenesulfonamide

^1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 3H), 7.24 (d, J = 7.5 Hz, 1H), 7.16 (s, 1H), 6.83 (d, J = 5.2 Hz, 1H), 4.37 (s, 2H), 4.15 (s, 2H), 2.91 (s, 3H), 2.39 (s, 3H).

[Example 93]: 4-methyl- N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) benzyl) benzenesulfonamide

^1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.39 (dd, J = 8.1, 2.0 Hz, 4H), 4.49 (s, 2H), 4.03 (s, 2H), 2.84 (s, 3H), 2.38 (s, 3H).

[Example 94]: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesul phoneamide

¹ H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.57 (s, 4H), 4.55 (s, 2H), 4.35 (s, 2H), 2.94 (s, 3H), 2.92 (s, 3H) ).

[Example 95]: 4-methyl- N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) benzyl) benzenesulfonamide

^1H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.47 - 7.44 (m, 2H), 7.42 - 7.39 (m, 2H), 7.35 (d , J = 8.1 Hz, 2H), 4.51 (s, 2H), 4.15 (s, 2H), 2.95 (s, 3H), 2.40 (s, 3H).

[Example 96]: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesul phoneamide

¹ H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 7.60 (s, 1H), 7.56 - 7.50 (m, 3H), 4.56 (s, 2H), 4.35 (s, 2H), 2.94 (s , 3H), 2.93 (s, 3H).

<S _N Ar reaction I>

Step 1 : In a round bottom flask, add 1 (1.0 equiv.) and 2 (1.3 equivalents), and N,N -diisopropylethylamine (3.0 equivalents) were dissolved in n -butanol (0.1 M) and refluxed for 16 hours. After the reaction was completed, after cooling to room temperature, the settled solid was filtered to obtain 3 , or water was poured into the mixture and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 3 (70-90% yield).

[Example 97]: tert -butyl (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidine -4-day) carbamate

¹ H NMR (400 MHz, MeOD) δ 8.21 (s, 1H), 4.37 (s, 2H), 3.78 (d, J = 13.5 Hz, 2H), 3.64 - 3.52 (m, 1H), 3.07 - 3.01 (m , 2H), 3.00 (s, 3H), 1.94 (d, J = 12.6 Hz, 2H), 1.59 - 1.48 (m, 2H), 1.45 (s, 9H).

[Example 98]: tert -butyl ((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl)methyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 4.36 (s, 2H), 3.81 (d, J = 12.9 Hz, 2H), 3.00 (s, 3H), 2.98 (d, J = 6.6 Hz, 2H), 2.96 - 2.86 (m, 2H), 1.78 (d, J = 13.7 Hz, 2H), 1.76 - 1.65 (m, 1H), 1.44 (d, J = 2.7 Hz, 9H), 1.34 - 1.25 (m, 2H).

[Example 99]: tert -butyl (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) Piperidin-4-yl)ethyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 4.36 (s, 2H), 3.80 (d, J = 12.9 Hz, 2H), 3.11 (t, J = 7.1 Hz, 2H), 3.00 ( s, 3H), 2.92 (t, J = 12.6 Hz, 2H), 1.81 (d, J = 13.1 Hz, 2H), 1.68 - 1.56 (m, 1H), 1.45 (s, 11H), 1.38 - 1.26 (m , 2H).

[Example 100]: tert -butyl (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl)piperidin-4-yl)ethyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 4.28 (s, 2H), 3.71 (d, J = 13.0 Hz, 2H), 3.31 (s, 3H), 3.11 (t, J = 7.1 Hz, 2H), 3.02 (s, 3H), 2.91 (t, J = 12.6 Hz, 2H), 1.81 (d, J = 12.9 Hz, 2H), 1.66 - 1.53 (m, 1H), 1.46 (s, 11H) ), 1.38 - 1.26 (m, 2H).

[Example 101]: tert -butyl (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)carbamate

¹ H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 4.37 (s, 2H), 3.49 (dt, J = 14.0, 3.8 Hz, 2H), 3.27 - 3.19 (m, 2H), 3.00 (s , 3H), 2.16 (d, J = 14.0 Hz, 2H), 1.67 - 1.57 (m, 2H), 1.44 (s, 9H), 1.34 (s, 3H).

[Example 102]: tert -butyl ((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl)piperidin-4-yl)methyl)carbamate

^1H NMR (600 MHz, DMSO) δ 9.31 (s, 1H), 7.83 (s, 1H), 6.52 (t, J = 6.5 Hz, 1H), 3.90 (s, 2H), 2.80 (dd, J = 12.9 , 9.1 Hz, 2H), 2.53 - 2.50 (m, 2H), 2.14 (s, 5H), 1.11 - 1.05 (m, 2H), 1.02 (s, 9H), 0.94 - 0.88 (m, 2H), 0.52 ( s, 3H).

[Example 103]: tert -butyl (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine- 4-yl)piperidin-4-yl)ethyl)carbamate

¹ H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 4.36 (s, 2H), 3.51 - 3.40 (m, 2H), 3.30 - 3.26 (m, 2H), 3.15 - 3.06 (m, 2H) , 3.00 (s, 3H), 1.63 - 1.46 (m, 6H), 1.44 (s, 9H), 1.06 (s, 3H).

[Example 104]: tert -butyl 8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-2-carboxylate

¹ H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 4.38 (s, 2H), 3.73 (p, J = 6.7 Hz, 1H), 3.45 - 3.38 (m, 4H), 3.24 - 3.19 (m , 2H), 3.00 (s, 3H), 1.90 - 1.81 (m, 2H), 1.80 - 1.75 (m, 1H), 1.68 (t, J = 5.7 Hz, 4H), 1.46 (d, J = 1.7 Hz, 9H).

Step 2 : Put 3 (1.0 equivalent) in a round bottom flask and dissolve by adding dichloromethane (0.04 M). Thereafter, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) was added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 4 (70-90% yield).

[Example 105]: 5-(4-aminopiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

¹ H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 4.51 (s, 2H), 4.16 (d, J = 13.8 Hz, 2H), 3.53 - 3.42 (m, 1H), 3.29 - 3.23 (m , 2H), 3.03 (s, 3H), 2.16 (d, J = 12.8 Hz, 2H), 1.75 (qd, J = 12.4, 4.1 Hz, 2H).

[Example 106]: 5-(4-(aminomethyl)piperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2(1 H ) -one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 4.52 (s, 2H), 4.13 (d, J = 13.5 Hz, 2H), 3.29 - 3.21 (m, 2H), 3.03 (s, 3H) ), 2.11 - 1.89 (m, 5H), 1.51 - 1.43 (m, 2H).

[Example 107]: 5-(4-(2-aminoethyl)piperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 4.51 (s, 2H), 4.09 (d, J = 13.4 Hz, 2H), 3.24 (t, J = 12.9 Hz, 2H), 3.02 ( s, 5H), 1.92 (d, J = 13.3 Hz, 2H), 1.84 - 1.73 (m, 1H), 1.67 (q, J = 7.3 Hz, 2H), 1.48 - 1.33 (m, 2H).

[Example 108]: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,3-dimethyl-3,4-dihydropyrimido[4,5- d ]pyrimidine -2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 4.40 (s, 2H), 3.88 (d, J = 12.9 Hz, 2H), 3.37 (s, 3H), 3.19 (t, J = 12.7 Hz, 2H), 3.05 (s, 3H), 3.06 - 2.98 (m, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.82 - 1.72 (m, 1H), 1.67 (q, J = 7.3, 6.9 Hz, 2H), 1.49 - 1.36 (m, 2H).

[Example 109]: 5-(4-amino-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2(1 H ) -one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.39 (s, 1H), 4.52 (s, 2H), 3.95 (dt, J = 13.8, 4.3 Hz, 2H), 3.60 - 3.47 (m, 2H), 3.03 (s , 3H), 1.99 - 1.94 (m, 4H), 1.52 (s, 3H).

[Example 110]: 5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine- 2(1 H )-one hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.38 (s, 1H), 4.56 (s, 2H), 3.87 (dt, J = 13.4, 4.8 Hz, 2H), 3.60 (ddd, J = 13.8, 10.0, 3.1 Hz , 2H), 3.03 (s, 3H), 2.95 (s, 2H), 1.75 (ddd, J = 13.9, 10.0, 3.8 Hz, 2H), 1.66 (d, J = 14.1 Hz, 2H), 1.22 (s, 3H).

[Example 111]: 5-(4-(2-aminoethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyr Midin-2(1 H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 4.55 (s, 2H), 3.79 (dt, J = 13.7, 5.0 Hz, 2H), 3.64 - 3.57 (m, 2H), 3.03 (s , 3H), 3.02 - 2.97 (m, 2H), 1.77 - 1.57 (m, 6H), 1.13 (s, 3H).

[Example 112]: 3-methyl-5-(2,8-diazaspiro[4.5]decane-8-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidine- 2(1 H )-one hydrochloride

¹ H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 4.55 (s, 2H), 3.80 - 3.64 (m, 2H), 3.48 - 3.41 (m, 2H), 3.27 - 3.24 (m, 2H) , 3.03 (s, 3H), 2.09 - 2.03 (m, 2H), 1.94 - 1.81 (m, 4H), 1.40 - 1.35 (m, 2H).

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

Step 3 : Add a solution of 4 (1.0 equiv.) and triethylamine (2.5 equiv.) in dichloromethane (0.1 M) to a round bottom flask. Then add 6 (1.1 eq.). Stir at room temperature for one day. After the reaction was completed, the mixture was concentrated under reduced pressure and dried, and the resulting residue was extracted with dichloromethane and water. 7 (50-60% yield) was obtained from the obtained residue through column chromatography (1:20 MeOH:CH ₂ Cl ₂ ).

[Example 113]: tert -butyl ( N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) Piperidin-4-yl)sulfamoyl)carbamate

¹ H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 4.37 (s, 2H), 3.76 (d, J = 13.6 Hz, 2H), 3.54 - 3.41 (m, 1H), 3.10 - 3.01 (m , 2H), 3.00 (s, 3H), 2.05 - 1.97 (m, 2H), 1.72 - 1.60 (m, 2H), 1.50 (s, 9H).

[Example 114]: tert -butyl ( N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)methyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 4.36 (s, 2H), 3.82 (d, J = 13.1 Hz, 2H), 3.00 (s, 3H), 2.97 - 2.88 (m, 4H) ), 1.89 - 1.73 (m, 3H), 1.48 (s, 9H), 1.40 - 1.27 (m, 2H).

[Example 115]: tert -butyl ( N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 4.36 (s, 2H), 3.80 (d, J = 13.3 Hz, 2H), 3.07 (t, J = 7.1 Hz, 2H), 3.00 ( s, 3H), 2.99 - 2.88 (m, 2H), 1.82 (d, J = 13.0 Hz, 2H), 1.76 - 1.63 (m, 1H), 1.54 (q, J = 7.0 Hz, 2H), 1.48 (s , 9H), 1.36 - 1.24 (m, 2H).

[Example 116]: tert -butyl ( N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyridine midin-4-yl) piperidin-4-yl) ethyl) sulfamoyl) carbamate

^1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 4.28 (s, 2H), 3.72 (d, J = 13.1 Hz, 2H), 3.31 (s, 3H), 3.07 (t, J = 7.1 Hz, 2H), 3.02 (s, 3H), 2.93 (t, J = 12.3 Hz, 2H), 1.82 (d, J = 12.9 Hz, 2H), 1.75 - 1.63 (m, 1H), 1.55 (q, J = 7.0 Hz, 2H), 1.49 (s, 9H), 1.38 - 1.25 (m, 2H).

[Example 117]: tert -butyl ( N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine- 4-yl)piperidin-4-yl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 4.39 (s, 2H), 3.57 - 3.49 (m, 2H), 3.44 (dd, J = 10.4, 2.9 Hz, 2H), 3.02 (s , 3H), 2.11 (d, J = 13.7 Hz, 2H), 1.69 (ddd, J = 14.1, 10.4, 4.0 Hz, 2H), 1.50 (s, 9H), 1.43 (s, 3H).

[Example 118]: tert -butyl ( N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine -4-yl) piperidin-4-yl) methyl) sulfamoyl) carbamate

¹ H NMR (600 MHz, MeOD) δ 8.20 (s, 1H), 4.37 (s, 2H), 3.50 - 3.44 (m, 2H), 3.30 - 3.26 (m, 2H), 3.00 (s, 3H), 2.93 (s, 2H), 1.65 (ddd, J = 13.3, 9.3, 3.8 Hz, 2H), 1.50 (s, 9H), 1.48 - 1.43 (m, 2H), 1.05 (s, 3H).

[Example 119]: tert -butyl ( N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ] Pyrimidin-4-yl) piperidin-4-yl) ethyl) sulfamoyl) carbamate

¹ H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 4.36 (s, 2H), 3.50 - 3.42 (m, 2H), 3.12 - 3.03 (m, 4H), 3.00 (s, 3H), 1.67 - 1.55 (m, 4H), 1.48 (s, 11H), 1.05 (s, 3H).

[Example 120]: tert -butyl ((8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2 ,8-diazaspiro[4.5]decane-2-yl)sulfonyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 4.37 (s, 2H), 3.56 (t, J = 7.0 Hz, 2H), 3.49 - 3.41 (m, 4H), 3.39 - 3.34 (m , 2H), 3.00 (s, 3H), 1.89 (t, J = 7.1 Hz, 2H), 1.76 - 1.67 (m, 4H), 1.49 (s, 9H).

Step 4 : Put 7 (1.0 equiv.) in a round bottom flask and dissolve by adding dichloromethane (0.04 M). Thereafter, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) was added and stirred at room temperature for 16 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 8 (60-80% yield).

[Example 121]: N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin- 4-day) sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 4.51 (s, 2H), 4.00 (d, J = 13.6 Hz, 2H), 3.62 - 3.53 (m, 1H), 3.43 - 3.34 (m , 2H), 3.03 (s, 3H), 2.21 - 2.13 (m, 2H), 1.76 - 1.63 (m, 2H).

[Example 122]: N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidine -4-yl) methyl) sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 4.50 (s, 2H), 4.05 (d, J = 13.4 Hz, 2H), 3.25 - 3.16 (m, 2H), 3.02 (s, 3H) ), 2.98 (d, J = 6.4 Hz, 2H), 2.01 - 1.87 (m, 3H), 1.46 - 1.33 (m, 2H).

[Example 123]: N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p Peridin-4-yl)ethyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.31 (s, 1H), 4.48 (s, 2H), 4.01 (d, J = 13.3 Hz, 2H), 3.18 (t, J = 12.8 Hz, 2H), 3.11 ( t, J = 7.1 Hz, 2H), 3.02 (s, 3H), 1.92 (d, J = 13.4 Hz, 2H), 1.88 - 1.77 (m, 1H), 1.56 (q, J = 6.9 Hz, 2H), 1.43 - 1.28 (m, 2H).

[Example 124]: N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl)piperidin-4-yl)ethyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 4.41 (s, 2H), 3.86 (d, J = 13.2 Hz, 2H), 3.38 (s, 3H), 3.21 (t, J = 12.5 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H), 3.05 (s, 3H), 1.93 (d, J = 13.1 Hz, 2H), 1.87 - 1.75 (m, 1H), 1.57 (q, J = 7.1 Hz, 2H), 1.44 - 1.31 (m, 2H).

[Example 125]: N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) Piperidin-4-yl)sulfamide hydrochloride

¹ H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 4.52 (s, 2H), 3.80 (d, J = 13.6 Hz, 2H), 3.73 - 3.64 (m, 2H), 3.02 (s, 3H) ), 2.21 (d, J = 14.0 Hz, 2H), 1.70 (ddd, J = 15.1, 11.4, 4.1 Hz, 3H), 1.49 (s, 3H).

[Example 126]: N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)methyl)sulfamide hydrochloride

^1H NMR (600 MHz, MeOD) δ 8.33 (s, 1H), 4.52 (s, 2H), 3.78 - 3.69 (m, 2H), 3.58 (ddd, J = 13.2, 9.1, 3.4 Hz, 2H), 3.02 (s, 3H), 2.97 (s, 2H), 1.76 (ddd, J = 13.3, 8.9, 3.8 Hz, 2H), 1.53 (ddd, J = 13.9, 6.8, 3.4 Hz, 2H), 1.08 (s, 3H) ).

[Example 127]: N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl)piperidin-4-yl)ethyl)sulfamide hydrochloride

¹ H NMR (400 MHz, MeOD) δ 8.32 (s, 1H), 4.51 (s, 2H), 3.74 - 3.65 (m, 2H), 3.60 - 3.52 (m, 2H), 3.14 - 3.07 (m, 2H) , 3.02 (d, J = 0.8 Hz, 3H), 1.73 - 1.63 (m, 4H), 1.62 - 1.53 (m, 2H), 1.11 (s, 3H).

[Example 128]: 3-methyl-5-(2-(sulfamile)-2,8-diazaspiro[4.5]decane-8-yl)-3,4-dihydropyrimido[4, 5- d ]pyrimidin-2(1 H )-one hydrochloride

¹ H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 4.53 (s, 2H), 3.76 - 3.60 (m, 4H), 3.39 - 3.33 (m, 4H), 3.03 (s, 3H), 1.92 (t, J = 7.2 Hz, 2H), 1.88 - 1.74 (m, 4H).

<S _N Ar reaction II>

Step 1 : In a round bottom flask, add 1 (1.0 equiv.) and 2 (1.3 equivalents), and N,N -diisopropylethylamine (3.0 equivalents) were dissolved in n -butanol (0.1 M) and refluxed for 16 hours. After the reaction was completed, after cooling to room temperature, the settled solid was filtered to obtain 3 , or water was poured into the mixture and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 3 (75% yield).

[Example 129]: tert -butyl (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino )methyl)phenyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.11 (s, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 4.64 (s, 2H), 4.30 ( s, 2H), 3.02 (s, 3H), 1.53 (s, 9H).

Step 2 : Put 3 (1.0 equivalent) in a round bottom flask and dissolve by adding dichloromethane (0.04 M). Thereafter, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.2 M) was added and stirred at room temperature for 4 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 4 (90% yield).

[Example 130]: 5-((4-aminobenzyl)amino)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 4.82 (s, 2H), 4.36 ( s, 2H), 3.04 (s, 3H).

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

Step 3 : Add a solution of 4 (1.0 equiv.) and triethylamine (2.5 equiv.) in dichloromethane (0.1 M) to a round bottom flask. Then add 6 (1.1 eq.). Stir at room temperature for one day. After the reaction was completed, the mixture was concentrated under reduced pressure and dried, and the resulting residue was extracted with dichloromethane and water. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 7 (25% yield).

[Example 131]: tert -butyl ( N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl)amino)methyl)phenyl)sulfamoyl)carbamate

^1H NMR (400 MHz, MeOD) δ 8.06 (s, 1H), 7.23 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 4.60 (s, 2H), 4.26 ( s, 2H), 3.00 (s, 3H), 1.35 (s, 9H).

Step 4 : Put 7 (1.0 equiv.) in a round bottom flask and dissolve by adding dichloromethane (0.04 M). Thereafter, a hydrochloride solution (4.0 M in 1,4-dioxane, 0.20 M) was added and stirred at room temperature for 16 hours. After the reaction was completed, the residue obtained by concentration under reduced pressure was washed with diethyl ether, filtered and dried to obtain 8 (60% yield).

[Example 132]: tert -butyl N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )amino)methyl)phenyl)sulfamide hydrochloride

^1H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 4.68 (s, 2H), 4.32 ( s, 2H), 3.02 (s, 3H).

Step 1 : In a round bottom flask, add 1 (1.0 equiv.) and 2 (1.3 equivalents) was dissolved in dimethylformamide (0.10 M), and then 0.10 M potassium carbonate aqueous solution (2.1 equivalents) was added and stirred at 100 °C for 16 hours. After the reaction was completed, water was poured into the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (1:20 MeOH:CH ₂ Cl ₂ ) to obtain 3 (10% yield).

[Example 133]: tert -butyl N- (4-((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) amino) phenyl) sulfamide

^1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 4.37 (s, 2H), 3.03 ( s, 3H).

[Experimental example]

The following experiment was conducted on the Example 1-133 prepared as described above.

Experimental Example 1: ENPP1 enzyme assay with cGAMP substrate

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

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

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

Example number
(compound code) Enzyme activity 15 C 16 C 69 A 70 A 71 A 72 A 73 NA 74 A 75 B 76 NA 77 NA 78 NA 79 NA 80 NA 81 NA 82 NA 83 A 84 NA 85 NA 86 NA 87 A 88 A 89 A 90 A 91 NA 92 NA 93 NA 94 NA 95 NA 96 NA 121 A 122 A 123 A 124 B 125 A 126 A 127 A 128 A 132 A 133 NA

Enzyme activity A B C NA IC50 (uM) activity<1 uM 1 uM ≤ activity < 10 uM 10uM≤activity Not available

[Formulation example]

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

Formulation Example 1: Tablet (direct pressurization)

After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed into tablets.

Formulation Example 2: Tablet (wet granulation)

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

Formulation Example 3: Powder and Capsule

After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture is hardened to No. 10 using a suitable device. Filled in 5 gelatin capsules.

Formulation Example 4: Injection

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

Although the embodiments of the present invention have been described above, those skilled in the art will understand that the present invention can be implemented in other specific forms without changing its technical spirit or essential features. . Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (12)

A compound selected from a pyridopyrimidine compound represented by Formula 1 below, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:
[Formula 1]

In Formula 1,
X is N or CR ^a ;
R ^a is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R ₁ and R ₂ are hydrogen; hydroxy group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; or -C(O)-(C ₁ -C ₁₃ alkyl); is
R ₄ and R ₅ are each independently hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); ester group (-C(O)OR ₆ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); a sulfonamide group (-NHS(O) ₂ R ₆ ); sulfide group (-SR ₆ ); A sulfone group (-S(O) ₂ R ₆ ); or a phosphoryl group (-P(O)R ₆ R ₇ );
R ₃ is -ZAY;
Z is present or absent, and when Z is present, Z is -O-, -CO-, -COO-, -C _n H _n+2 -, -O(C _n H _n+2 )-, -(OC ₂ H ₄ ) _n -, -(C ₂ H ₄ O) _n -, -(C _n H _n+2 )O-, -(C _n H _n+2 )CO-, -(C _n H _n+2 )O (C _m H _m+2 )-, -NR ₆ (C _n H _n+2 )-, -(NR ₆ C ₂ H ₄ ) _n -, -(C ₂ H ₄ NR ₆ ) _n -, -(C _n H _n+2 )NR ₆ -, -C ₃ -C ₁₀ Cyclyl group-; or -C ₃ -C ₁₀ heterocyclyl group-; is
n is an integer from 0 to 8;
A is a C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; or a C ₃ -C ₁₀ heterocyclyl group;
wherein Y is hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); tert-butyloxycarbonyl group (Boc); amino group (-NR ₆ R ₇ ); -(C _m H _m+2 )NR ₆ R ₇ ; nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); ester group (-C(O)OR ₆ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); a sulfonamide group (-NHS(O) ₂ R ₆ ); sulfamoyl group (-NHS(O) ₂ NHR ₆ ); a sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₆ ); a sulfamoylalkyl group (-(C _m H _m+2 )NR ₆ S(O) ₂ NHR ₇ ); sulfide group (-SR ₆ ); A sulfone group (-S(O) ₂ R ₆ ); or a phosphoryl group (-P(O)R ₆ R ₇ );
m is an integer from 0 to 8;
The C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group may be hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₆ (C=O)NR ₇ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₆ R ₇ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group;
The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may be hydrogen; hydroxy group; halogen group; a carbonyl group (-(C=O)R ₆ R ₇ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; A C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₆ R ₇ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₆ R ₇ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₆ (C=O)NR ₇ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₆ R ₇ ); C ₆ -C ₁₀ aryl group; It contains one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group;
The R ₆ and R ₇ are each independently hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -NH ₂ ; tert-butyloxycarbonyl group (Boc); or R ₆ together with the nitrogen or carbon atom connected to R ₇ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group and Forming a 3- to 7-membered saturated ring that may be optionally substituted with at least one of the cyano groups;
The C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.
According to claim 1,
R ₄ and R ₅ are each independently hydrogen; or a C ₁ -C ₁₃ alkyl group;
X is CH or N;
A compound selected from a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
According to claim 2,
R ₁ is hydrogen; C ₁ -C ₆ alkyl group; C ₃ -C ₁₀ cyclyl group; benzyl group; methoxybenzyl group; hydroxyethyl group; or a methoxyethyl group;
R ₂ is hydrogen; C ₁ -C ₆ alkyl group; or a benzyl group;
A compound selected from a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
According to claim 3,
A is substituted or unsubstituted benzene; substituted or unsubstituted furan; A substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; A substituted or unsubstituted benzofuran; Substituted or unsubstituted naphthalene; A substituted or unsubstituted anthracene; or substituted or unsubstituted phenathrene; A substituted or unsubstituted pyridazine; A substituted or unsubstituted pyrazine; substituted or unsubstituted imidazole; substituted or unsubstituted pyrazole; Substituted or unsubstituted quinoline; A substituted or unsubstituted pyrimidine; A substituted or unsubstituted pyrrole; A substituted or unsubstituted indole; Or a substituted or unsubstituted purine; substituted or unsubstituted piperidine; substituted or unsubstituted morpholine; substituted or unsubstituted pyrrolidine; A substituted or unsubstituted cyclopropane; Or a substituted or unsubstituted cyclobutane,
A compound selected from a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
According to claim 4,
A is substituted or unsubstituted benzene; or a substituted or unsubstituted piperidine; person
A compound selected from a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
According to claim 5,
Y is hydrogen, halogen, methyl group, ethyl group, -NH ₂ , tert-butyloxycarbonyl group (Boc),

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

person,
A compound selected from a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
According to claim 1,
The compound is a pyridopyrimidine compound represented by Formula 1, characterized in that it is any one selected from the group consisting of Compound Nos. 1 to 133, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and Compounds selected from stereoisomers thereof:
Compound No. 1: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl)carbamate
Compound No. 2: tert -butyl (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate
Compound No. 3: tert -butyl (4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate
Compound No. 4: tert -butyl methyl (4- (3-methyl-2-oxo-1,2,3,4-tetrahydro [2,3- d ] pyrimidin-5-yl) benzyl) carbamate
Compound No. 5: tert -butyl (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)phenyl)propan- 2-day) carbamate
Compound No. 6: tert -butyl (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl) carbamate
Compound No. 7: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-4-yl)phenyl)carbamate
Compound No. 8: tert -butyl (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate
Compound No. 9: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)carbamate
Compound No. 10: tert -butyl (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) (methyl ) carbamate
Compound No. 11: tert -butyl (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate
Compound No. 12: tert -butyl (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)carbamate
Compound No. 13: tert -butyl (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl ) carbamate
Compound No. 14: tert -butyl (3-(3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)carbamate
Compound No. 15: N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide
Compound No. 16: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide
Compound No. 17: tert -butyl (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carbamate
Compound No. 18: tert -butyl (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydro[2,3- d ]pyrimidin-5-yl)benzyl)carba mate
Compound No. 19: tert -butyl (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) carbamate
Compound No. 20: tert -butyl (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) carbamate
Compound No. 21: tert -butyl (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carbamate
Compound No. 22: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)carbamate
Compound No. 23: tert -butyl (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)carbamate
Compound No. 24: tert -butyl (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) benzyl) carbamate
Compound No. 25: 5-(3-aminophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 26: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 27: 5-(4-((aminomethyl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H -one hydrochloride
Compound No. 28: 3-methyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 29: 5-(4-((aminopropan-2-yl)phenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 30: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one hydrochloride
Compound No. 31: 5-(3-aminophenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 32: 5-(3-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 33: 5-(4-(aminomethyl)phenyl)-3-cyclopropyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 34: 3-cyclopropyl-5-(4-((methylamino)methyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride
Compound No. 35: 5-(4-(aminomethyl)phenyl)-3-benzyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 36: 5-(3-(aminomethyl)phenyl)-3-(2-hydroxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride
Compound No. 37: 5-(4-(aminomethyl)phenyl)-3-(2-methoxyethyl)-3,4-dihydropyrido[2,3- d ]pyrimidine-2( 1H )- on hydrochloride
Compound No. 38: 5-(4-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 39: 5-(4-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride
Compound No. 40: 5-(3-(aminomethyl)phenyl)-1,3-dimethyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 41: 5-(3-(aminomethyl)phenyl)-1-benzyl-3-methyl-3,4-dihydropyrido[2,3- d ]pyrimidin-2( 1H )-one hydro chloride
Compound No. 42: 5-(4-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 43: 5-(3-(aminomethyl)phenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 44: 5-(3-(aminophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride
Compound No. 45: 5-(4-(aminomethyl)-3-fluorophenyl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2(1 H )-one hydrochloride
Compound No. 46: 5-(3-(aminomethyl)phenyl)-3,4-dihydropyrido[2,3- d ]pyrimidin-2(1 H )-one trifluoroacetic acid
Compound No. 47: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl) sulfamoyl) carbamate
Compound No. 48: tert -butyl ( N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamoyl) carbamate
Compound No. 49: tert -butyl ( N- (4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate
Compound No. 50: tert -butyl ( N -methyl- N -(4-(3-methyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate
Compound No. 51: tert -butyl ( N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )phenyl)propan-2-yl)sulfamoyl)carbamate
Compound No. 52: tert -butyl ( N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5 -yl) benzyl) sulfamoyl) carbamate
Compound No. 53: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl ) sulfamoyl) carbamate
Compound No. 54: tert -butyl ( N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate
Compound No. 55: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate
Compound No. 56: tert -butyl ( N- (4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) -N -methylsulfamoyl)carbamate
Compound No. 57: tert -butyl ( N- (4-(3-benzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl ) sulfamoyl) carbamate
Compound No. 58: tert -butyl ( N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate
Compound No. 59: tert -butyl ( N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine- 5-yl)benzyl)sulfamoyl)carbamate
Compound No. 60: tert -butyl ( N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamoyl)carba mate
Compound No. 61: tert -butyl ( N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate
Compound No. 62: tert -butyl ( N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) benzyl) sulfamoyl) carbamate
Compound No. 63: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl)sulfamoyl)carbamate
Compound No. 64: tert -butyl ( N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5- 1) benzyl) sulfamoyl) carbamate
Compound No. 65: tert -butyl ( N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) sulfamoyl) carbamate
Compound No. 66: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) sulfamoyl) carbamate
Compound No. 67: tert -butyl ( N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl) sulfamoyl) carbamate
Compound No. 68: tert -butyl ( N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl) benzyl) sulfamoyl) carbamate
Compound No. 69: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide hydrochloride
Compound No. 70: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride
Compound No. 71: N- (4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride
Compound No. 72: N -methyl- N -(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride
Compound No. 73: N- (2-(4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)propane -2-day) sulfamide hydrochloride
Compound No. 74: N- (2-fluoro-4-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl )sulfamide hydrochloride
Compound No. 75: N- (3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)phenyl)sulfamide hydro chloride
Compound No. 76: N-(3-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)sulfamide hydro chloride
Compound No. 77: N-(4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)sulfamide hydro chloride
Compound No. 78: N-(4-(3-cyclopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)benzyl)-N- Methylsulfamide Hydrochloride
Compound No. 79: N- (4-(3-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methylsulfamide hydro chloride
Compound No. 80: N- (3-(3-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)sulfamide hydrochloride
Compound No. 81: N- (4-(3-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl) Benzyl)methylsulfamide hydrochloride
Compound No. 82: N- (3-(2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfamide hydrochloride
Compound No. 83: N- (4-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)sulfa amide hydrochloride
Compound No. 84: N- (4-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride
Compound No. 85: tert -butyl ( N- (3-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl )benzyl) sulfamide hydrochloride
Compound No. 86: N- (3-(1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) sulfamide hydrochloride
Compound No. 87: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride
Compound No. 88: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)sulfamide hydrochloride
Compound No. 89: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)phenyl)sulfamide hydrochloride
Compound No. 90: N- (2-fluoro-4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl )sulfamide hydrochloride
Compound No. 91: N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl)methanesulfonamide
Compound No. 92: 4-methyl- N- (3-(3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidin-5-yl)benzyl) Benzenesulfonamide
Compound No. 93: 4-methyl- N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) Benzenesulfonamide
Compound No. 94: N- (4-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesulfonamide
Compound No. 95: 4-methyl- N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl) Benzenesulfonamide
Compound No. 96: N- (3-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)benzyl)methanesulfonamide
Compound No. 97: tert -butyl (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4 -day) carbamate
Compound No. 98: tert -butyl ((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin- 4-yl)methyl)carbamate
Compound No. 99: tert -butyl (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl)ethyl)carbamate
Compound No. 100: tert -butyl (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)carbamate
Compound No. 101: tert -butyl (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)carbamate;
Compound No. 102: tert -butyl ((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) piperidin-4-yl)methyl)carbamate;
Compound No. 103: tert -butyl (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl)piperidin-4-yl)ethyl)carbamate;
Compound No. 104: tert -butyl 8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2,8-dia jaspiro[4.5]decane-2-carboxylate;
Compound No. 105: 5-(4-aminopiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride ;
Compound No. 106: 5-(4-(aminomethyl)piperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H )- on hydrochloride;
Compound No. 107: 5- (4- (2-aminoethyl) piperidin-1-yl) -3-methyl-3,4-dihydropyrimido [4,5- d ] pyrimidine-2 (1 H )-one hydrochloride;
Compound No. 108: 5-(4-(2-aminoethyl)piperidin-1-yl)-1,3-dimethyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2 (1 H )-one hydrochloride;
Compound No. 109: 5-(4-amino-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H ) -on hydrochloride;
Compound No. 110: 5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1 H )-one hydrochloride;
Compound No. 111: 5-(4-(2-aminoethyl)-4-methylpiperidin-1-yl)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidine- 2(1 H )-one hydrochloride;
Compound No. 112: 3-methyl-5- (2,8-diazaspiro [4.5] decane-8-yl) -3,4-dihydropyrimido [4,5- d ] pyrimidine-2 ( 1 H )-one hydrochloride;
Compound No. 113: tert -butyl ( N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl) sulfamoyl) carbamate;
Compound No. 114: tert -butyl ( N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)methyl)sulfamoyl)carbamate;
Compound No. 115: tert -butyl ( N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)sulfamoyl)carbamate;
Compound No. 116: tert -butyl ( N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine- 4-yl)piperidin-4-yl)ethyl)sulfamoyl)carbamate;
Compound No. 117: tert -butyl ( N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4- yl) piperidin-4-yl) sulfamoyl) carbamate;
Compound No. 118: tert -butyl ( N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine-4 -yl)piperidin-4-yl)methyl)sulfamoyl)carbamate;
Compound No. 119: tert -butyl ( N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidine -4-yl) piperidin-4-yl) ethyl) sulfamoyl) carbamate;
Compound No. 120: tert -butyl ((8-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)-2,8 -diazaspiro[4.5]decane-2-yl)sulfonyl)carbamate;
Compound No. 121: N- (1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4- 1) sulfamide hydrochloride;
Compound No. 122: N -((1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidin-4 -yl)methyl)sulfamide hydrochloride;
Compound No. 123: N- (2-(1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperidine -4-yl)ethyl)sulfamide hydrochloride;
Compound No. 124: N- (2-(1-(6,8-dimethyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) piperidin-4-yl)ethyl)sulfamide hydrochloride;
Compound No. 125: N- (4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)piperi din-4-yl)sulfamide hydrochloride;
Compound No. 126: N -((4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)p peridin-4-yl)methyl)sulfamide hydrochloride;
Compound No. 127: N- (2-(4-methyl-1-(6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl )piperidin-4-yl)ethyl)sulfamide hydrochloride;
Compound No. 128: 3-methyl-5-(2-(sulfamile)-2,8-diazaspiro[4.5]decane-8-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2(1 H )-one hydrochloride;
Compound No. 129: tert -butyl (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino)methyl )phenyl)carbamate;
Compound No. 130: 5-((4-aminobenzyl)amino)-3-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride;
Compound No. 131: tert -butyl ( N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl) amino)methyl)phenyl)sulfamoyl)carbamate;
Compound No. 132: tert -butyl N- (4-(((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino )methyl)phenyl)sulfamide hydrochloride; and
Compound No. 133: tert -butyl N- (4-((6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-4-yl)amino) phenyl) sulfamide.
According to claim 1,
The pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, A salt of an inorganic or organic acid selected from the group consisting of ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid,
A compound selected from a pyridopyrimidine compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
A pharmaceutical composition for the prevention, reduction or treatment of cancer, comprising the compound of any one of claims 1 to 8 as an active ingredient.
An ENPP 1 inhibitor comprising the compound of any one of claims 1 to 8 as an active ingredient.
A STING pathway activator comprising the compound of any one of claims 1 to 8 as an active ingredient.
According to claim 9,
The cancer is cancer associated with inhibition of ENPP1, a pharmaceutical composition for preventing, reducing or treating cancer.