KR20220110118A - Novel benzotriazole 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 benzotriazole derivative compound related to a method for inhibiting ENPP1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a stereoisomer thereof.

Description

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

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

Cancer is a group of diseases related to uncontrolled cell proliferation that can invade or spread to other parts of the body, reducing quality of life and eventually leading to death. Although genetic aberrations are a direct cause of uncontrolled proliferation of cancer cells, failure of immune surveillance and/or lack of an adequate immune counterattack of the immune system against cancer cells is also a cause of cancer cell proliferation, as well as anticancer immunity. This 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 the cancer cell itself, and the second is to target the components of the tumor microenvironment (TME) to prevent further proliferation or survival of cancer cells.

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

Microbial infections can cause a variety of diseases worldwide. Pathogenic microorganisms are diverse and include viruses, bacteria, fungi and protozoa. In some cases, the therapeutic agent is a chemical that directly prevents microbial growth. In other instances, the therapeutic agents are therapeutic 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). associated fibroblast), pericyte, endothelial cells, and adipocytes). On the other hand, it has been reported that the presence of tumor-infiltrating lymphocytes can lead to positive clinical outcomes in response to multiple pipelines of immunotherapy in different types of cancer. Modulation or elevation of other types of immune cells other than lymphocytes, particularly innate immune cells, has been reported in preclinical studies to modulate the responsiveness of anticancer therapies to 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) to identify and remove foreign substances (eg, bacteria, viruses) from body tissues, 2) to recruit immune cells to specific sites by producing cytokines and promoting adaptive immune responses, and 3 ) to activate the complement cascade. Such innate immunity can be achieved by recognizing molecular patterns derived from microbial pathogens (pathogen-associated molecular pattern, PAMP) or residues of destroyed cells (damage-associated molecular pattern, DAMP). is activated

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[Formula 1]

In Formula 1,

W ₁ is N or CRa;

W ₂ is N or CRb;

W ₃ is N or CRc;

W ₄ is N or CRd;

W ₅ is N or CRe;

W ₆ is N or CRf;

W ₇ is N or CRg;

Ra, Rb, Rc, Rd, Re, Rf and Rg are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. selected,

R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen; hydroxyl group; halogen group; -CF ₃ ; -(O)CF ₃ ; C1-C13 alkyl group; C1-C6 alkoxy group; amino group (-NR ₇ R ₈ ); nitro group (-N(O)2); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); C6-C10 aryl group; C3-C10 cyclyl group; C3-C10 heteroaryl group; C3-C10 heterocyclyl group; or -C(O)-(C1-C13 alkyl); is

Z is present or not, and when Z is present, Z is -O-, -CO-, -COO-, -C _n H _n+2 -, -O(C _n H _n+2 )-, -(OC ₂ H ₄ ) _n -, -(C ₂ H ₄ O) _n -, -(C _n H _n+2 )O-, -(C _n H _n+2 )CO-, -(C _n H _n+2 )O (C _m H _m+2 )-, -NR ₇ (C _n H _n+2 )-, -(NR ₇ C ₂ H ₄ ) _n -, -(C ₂ H ₄ NR ₇ ) _n -, or -( C _n H _n+2 )NR ₇ -, ; is

n is an integer from 0 to 8,

R ₅ is -A-(R ₆ ) _y ,

A is a C ₃ -C ₁₀ cyclyl group, a C ₅ -C ₁₀ bicyclyl group, a C ₃ -C ₁₀ heterocyclyl group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group,

wherein R ₆ is hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkenyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); tert-butyloxycarbonyl group (Boc); amino group (-NR ₇ R ₈ ); -(C _m H _m+2 )NR ₇ R ₈ ; nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₇ R ₈ ); ester group (-(C _m H _m+2 )C(O)OR ₇ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-(C _m H _m+2 )NHS(O) ₂ R ₇ ); urea group; sulfamoyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₇ ); sulfonamide group; sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₇ ); sulfamoylalkyl group (-(C _m H _m+2 )NR ₇ S(O) ₂ NHR ₈ ); sulfide group (-(C _m H _m+2 )SR ₇ ); sulfone group (-(C _m H _m+2 )S(O) ₂ R ₇ ); a phospyryl group (-(C _m H _m+2 )P(O)R ₇ R ₈ ); linked to the same carbon as the carbon linked to A to form a 3 to 10 membered saturated ring; It is linked to the same carbon as the carbon linked to A to form a 3 to 10 membered hetero saturated ring containing one or more heteroatoms of N, O and S; It is connected to the carbon connected to A and the carbon adjacent to it to form a 3 to 10 membered saturated ring; or connected to the carbon connected to A and the carbon adjacent to it to form a 3 to 10 membered hetero saturated ring containing one or more heteroatoms of N, O and S;

m is an integer from 0 to 4,

y is an integer from 0 to 4,

The C1-C13 alkyl group, C1-C6 alkoxy group, C1-C6 alkenyl group, or -C(O)-(C1-C13 alkyl) is hydrogen; hydroxyl group; halogen group; C1-C13 alkyl group; C1-C6 alkoxy group; amino group (-NR ₇ R ₈ ); nitro group (-N(O)2); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₇ (C=O)NR ₈ -); sulfonamide group (-NHS(O)2-); sulfide group (-S-); sulfone group (-S(O)2-); a phospyryl group (-P(O)R ₇ R ₈ ); C6-C10 aryl group; C3-C10 heteroaryl group; and one or more substituents selected from the group consisting of a C3-C10 heterocyclyl group,

The C6-C10 aryl group, C3-C10 heteroaryl group, C3-C10 cyclyl group, C3-C10 heterocyclyl group, or C5-C10 bicyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ₇ R ₈ ); a C1-C3 alkyl group unsubstituted or substituted with a halogen or C3-C10 heterocyclyl group; C1-C3 alkoxy group unsubstituted or substituted with halogen or C3-C10 heterocyclyl group; C6-C10 phenoxy; amino group (-NR ₇ R ₈ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₇ (C=O)NR ₈ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₇ R ₈ ); C6-C10 aryl group; It contains one or more substituents selected from the group consisting of a C3-C10 heteroaryl group and a C3-C10 heterocyclyl group,

The R ₇ and R ₈ are each independently hydrogen; C1-C6 alkyl group; C1-C6 alkenyl group; C1-C6 alkynyl group; C6-C10 aryl group; C3-C10 heteroaryl group; C3-C10 heterocyclyl group; amino group (-NH2); nitro group (-N(O)2); -Boc; -NHBoc; or R7 together with the nitrogen or carbon atom linked to R8 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2- , or SO2, optionally substituted with at least one of hydrogen, a C1-C13 alkyl group, a C6-C10 aryl group, a C3-C10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group Forming a 3 to 7 membered saturated ring that can be,

The C3-C10 heteroaryl group and the C3-C10 heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

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

The compound according to the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient effectively inhibits ENPP1 to activate the STING pathway, and is 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, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, adenomatosis, uterine cancer, cervical cancer , head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, or fibroadenoma, and the like.

The compound according to the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a composition comprising the same as an active ingredient may 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 ingredients, reaction conditions, and amounts of ingredients used herein refer to a variety of measures that may occur in obtaining such values, among others, in which such numbers are inherently different. Since they are approximations reflecting uncertainty, it should be understood as being modified by the term "about" in all cases. Also, where the disclosure discloses numerical ranges, such ranges are continuous and inclusive of all values from the minimum to the maximum inclusive of the range, unless otherwise indicated. Furthermore, when such ranges refer to integers, all integers inclusive from the minimum to the maximum inclusive are included, unless otherwise indicated.

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

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

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

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

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

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

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

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

Hereinafter, the present invention will be described in detail.

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

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

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

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

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

Immunogenic cell death (ICD)

ICD (immunogenic cell death, immunogenic cell death) is a form of cell death, a cellular phenomenon that induces activation of a controlled immune response. The cell death is characterized by an apoptotic morphology and maintains the integrity of the biological membrane. ICD is also characterized by exposing polypeptides formed by native or mutated proteins to cells as well as secretion of DAMPs (eg, Calreticulin, high mobility group box 1 (HMGB1), ATP and Hsp70/90 proteins). The exposed polypeptides (acting as antigens) are recognized by dendritic cells (DCs) and subsequently primed effector T-cell lymphocytes to activate an adaptive immune response.

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

radiation therapy

Radiation therapy is well known and used for the treatment of patients suffering from a variety of 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 aims to minimize unintended damage to desirable or healthy tissue while directly damaging undesirable tissues or lesions in the path through which the radiation is passed.

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

New reinforcement therapy

Neoadjuvant therapy is a treatment for the purpose of facilitating the treatment of the main treatment or increasing the success rate of the main treatment by reducing the size and progression of the tumor by administering the treatment before the administration of the main treatment or the procedure. The treatments applied include 1) systemic therapy (chemotherapy, immunotherapy, or hormone therapy) and 2) local therapy (radiotherapy). There is a disadvantage in that it cannot be applied to all patients because the toxicity that appears in the patient is different depending on the therapeutic agent used and determines whether or not this treatment is carried out. According to a recent report, in a syngeneic animal model of breast cancer, when the combined administration of a STING pathway active agonist, an immune checkpoint inhibitor, and interleukin 2 was used as a neoadjuvant therapy, it was reported that the STING pathway active agonist showed a better survival rate than the case where no STING pathway active agonist was used. It has been shown that neoadjuvant therapy of therapeutic agents that induce activation is possible (Lauren E. Milling, et al., can, imm, res, (2021), 10.1158/2326-6066.CIR-21-0247).

anti-cancer vaccine

Anticancer vaccine is a treatment that activates dendritic cells, which are antigen-marking cells, by administering a selected cancer antigen together with a reinforcing material. do it with Depending on the method in which the cancer antigen is administered, a specific antigen vaccine (in the case of injecting one or more selected purified antigens or antigen-generating substances) and a non-specific antigen vaccine (in the case of excreting the antigen by inducing the death of cancer cells in the tumor) Divide by It is divided into DNA vaccine, RNA vaccine, and protein vaccine according to the type of injection of the specific antigen vaccine into the body. According to a recent report, when a STING agonist and a protein anticancer vaccine are administered in combination, they show a synergistic effect, thereby increasing the survival rate and preventing metastasis. It has been shown that the treatment inducing STING pathway activation can be applied in combination with anticancer vaccines (DNA vaccine, RNA vaccine, protein vaccine) (Matteo Rossi, et al., front. In imm. (2021), 10.3389/fimmu. 2021.695056).

CAR-T treatment

CAR-T cell therapy separates the existing T cells from the patient's body, expresses a special receptor (CAR, chimeric antigen receptor) that can recognize cancer cells, then proliferates them and injects them back into the patient's body to make CAR-T cells It is a treatment that selectively attacks cancer cells that have antigens on their surface. According to a recent report, when a therapeutic agent that induces STING pathway activation and CAR-T treatment are used in combination, the increase in type 1 interferon increases the intratumoral infiltration and apoptosis of CAR-T cells, thereby increasing the efficacy of CAR-T cell therapy. report has been published. It has been shown that a therapeutic agent that induces STING pathway activation in the tumor microenvironment can be applied in combination with CAR-T cells (Feng Ji, et. Al., (2021) J Hematol Oncol (2021) 14:152).

pathogen

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

myocardial regeneration

Myocardial infarction is a major cause of systolic heart failure. After myocardial infarction, various types of cells flow into the heart tissue, causing the lesion to break or regenerate the heart tissue to heal. Such healing largely depends on the communication and control action between the inflowed cells, and it has a great influence on the functional recovery of the myocardial tissue after the healing is completed. There is a high need for drugs that help or promote myocardial tissue regeneration. According to a recent report, adenine and purine nucleotide changes occur due to the activity of ENPP1 enzyme expressed by fibroblasts in the lesioned heart tissue, which increases apoptosis of non-cardiomyocytes and immune cells and interferes with cardiac tissue regeneration. being. The possibility of promoting the functional recovery of myocardial tissue by inhibiting the above ENPP1 enzyme activity has been reported (Shen Li, et al., J. Clin. Inv. (2021), 10.1172/JCI149711).

Hypophosphatemia genetic disease treatment

Hypophosphatasia is a genetic disorder in which bone regeneration and mineralization are impaired due to a decrease in alkaline phosphatase, an enzyme essential for cellular processes such as muscle metabolism and bone formation, as a congenital metabolic disorder. For patients diagnosed with hypophosphatemia, it is important to alleviate the symptoms related to bones with low-impact physical activity and exercise prophylactically. There have been reports of cases in which bone marrow transplantation was effective in severe cases, but the definitive effect has not been proven yet. According to a recent report, it was announced that an increase in excessive pyrophosphate in the body due to alkaline phosphatase deficiency is a factor, and pyrophosphate is generated by ENPP1 activity, and there is a possibility of improving hypophosphatemia symptoms by inhibiting ENPP1 activity (RallyBio corporate presentation (2021) )).

Phosphodiesterases

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

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

Ecto-nucleotide pyrophosphatases/phosphodiesterase

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

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

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

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

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

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

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

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

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

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

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

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

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

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

How to Inhibit ENPP1

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

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

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

[Formula 1]

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

Compound No. 1: 5-methoxy-1-(piperidin-4-yl) -1H -benzo[ d ][1,2,3]triazolehydrochloride;

Compound No. 2: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methane aniline;

Compound No. 3: 5-methoxy-1-(piperidin-4-ylmethyl) -1H -benzo[ d ][1,2,3]triazole;

Compound No. 4: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)aniline hydrochloride;

Compound No. 5: 4-( 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 6: 4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 7: 4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 8: 4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 9: 4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 10: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 11: 2-(3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

Compound No. 12: 1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)-N-methylmethanamine hydrochloride;

Compound No. 13: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)cyclopropanamine hydrochloride;

Compound No. 14: (S)-1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

Compound No. 15: 3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 16: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 17: 2,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 18: 2,6-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 19: 4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

Compound No. 20: 3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 21: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 22: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine ;

Compound No. 23: 3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 24: 4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

Compound No. 25: 7-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

Compound No. 26: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroiso quinoline hydrochloride;

Compound No. 27: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3,4,5-tetrahydro- 1H -benzo[ c ]azepine hydrochloride;

Compound No. 28: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorophenyl)methanamine;

Compound No. 29: 1-(isoindorin-5-yl)-5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazole hydrochloride;

Compound No. 30: 3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)methanamine;

Compound No. 31: 3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methylthiophen-2-yl)methanamine hydrochloride;

Compound No. 32: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)sulfonyl)carba mate;

Compound No. 33: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl ) carbamates;

Compound No. 34: tert -butyl( N- ( 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 35: tert -butyl( N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 36: tert -butyl( N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 37: tert -butyl( N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 38: tert -butyl( N- (4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 39: tert -butyl(( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl )sulfamoyl)carbamate;

Compound No. 40: tert -butyl((6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-yl)sulfamoyl)carbamate;

Compound No. 41: N -((3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclopentyl)methyl)sulfamide;

Compound No. 42: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidine-1-sulfonamide;

Compound No. 43: N -((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methyl)sulfamide;

Compound No. 44: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonamide ;

Compound No. 45: 4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidine-1-sulfonamide;

Compound No. 46: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 47: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide;

Compound No. 48: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide hydrochloride;

Compound No. 49: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 50: N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 51: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide hydrochloride;

Compound No. 52: N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 53: N- (4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 54: N- (4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 55: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 56: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 57: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-difluorobenzyl)sulfamide;

Compound No. 58: N- (4-( 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,5-difluorobenzyl)sulfamide;

Compound No. 59: N- (3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 60: N- (2-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 61: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 62: N- (2,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 63: N- (2,6-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 64: N- (3,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;

Compound No. 65: N- (2,3-difluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;

Compound No. 66: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-methylbenzyl)sulfamide;

Compound No. 67: N- (3-cyano-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-benzyl)sulfamide;

Compound No. 68: N- (3-methoxy-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 69: N- (4-(5-methoxy-6-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 70: N- (3-fluoro-4-(5-methoxy-6-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 71: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 72: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide;

Compound No. 73: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide hydrochloride;

Compound No. 74: N- (3-fluoro-4-(5-hydroxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 75: N- (3-fluoro-4-(5-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 76: N- (4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 77: N- (3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 78: N- (5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-2-yl)methyl)sulfamide;

Compound No. 79: ( N- (6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-3-yl)methyl)sulfamide;

Compound No. 80: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methyl)sulfamide;

Compound No. 81: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methylsulfamide;

Compound No. 82: N -cyclopropyl- N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 83: ( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamide;

Compound No. 84: N- (4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 85: N- (3-fluoro-4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 86: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 87: N- (4-(5-dimethylamino) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 88: N- (3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 89: N- (4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 90: N- (3-fluoro-4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 91: N- (4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 92: N- (4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 93: N- (3-fluoro-4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide ;

Compound No. 94: 5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)isoindorin-2-sulfonamide;

Compound No. 95: N -5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-dihydro- 1H -indene-2- 1) sulfamide;

Compound No. 96: 6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;

Compound No. 97: 7-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;

Compound No. 98: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,3,4,5-tetrahydro- 2H -benzo[ c ]azepine-2-sulfonamide;

Compound No. 99: N- (4-(5,6-dimethoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfa mide;

Compound No. 100: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfa mide;

Compound No. 101: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-sulfonamide;

Compound No. 102: 5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-isoindorin-2-sulfonamide;

Compound No. 103: N- (5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-dihydro- 1H -indene-2- 1) sulfamide;

Compound No. 104: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)phenyl)sulfamide hydrochloride;

Compound No. 105: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)benzyl)sulfamide hydrochloride;

Compound No. 106: N -((5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)thiophen-2-yl)methyl)sulfamide;

Compound No. 107: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methoxylthiophen-2-yl)methyl) sulfamide;

Compound No. 108: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-bicyclo[1.1.1]pentan-1-yl) sulfamide;

Compound No. 109: N- (4-(5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)phenyl)sulfamide hydrochloride;

Compound No. 110: N- (4-((5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)benzyl)sulfamide hydrochloride;

Compound No. 111: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

Compound No. 112: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonamide;

Compound No. 113: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)ethanesulfonamide;

Compound No. 114: N- (3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)-4-methylbenzenesulfonamide ;

Compound No. 115: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonimidamide;

Compound No. 116: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzoic acid;

Compound No. 117: diethyl-(3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphoamidate;

Compound No. 118: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)phosphonic acid;

Compound No. 119: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphonic acid;

Compound No. 120: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)boronic acid;

Compound No. 121: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)boronic acid;

Compound No. 122: N- (4-(5-methoxy-1 H -indol-1-yl)benzyl)sulfamide;

Compound No. 123: N- (4-(5-methoxy- 1H -benzo[ d ]imidazol-1-yl)benzyl)sulfamide; and

Compound No. 124: N- (4-(5-methoxy-1 H -indazol-1-yl)benzyl)sulfamide.

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

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

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

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

treatment method

As mentioned above, the present invention includes methods for inhibiting ENPP1 activity against 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 of increasing the STING-mediated response in a subject and regulating the immune response.

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

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

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

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

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

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

combination therapy

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

"Co-administration" or "in combination with" includes the administration of two or more therapeutic agents simultaneously, concurrently, or sequentially, without any specific time limit. In some embodiments, agents or agents are concurrently present in the body of a cell or 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 separate compositions or unit dosage forms. In some embodiments, the first agent is administered prior to administration of the second therapeutic agent (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks before), concomitantly with, or after (eg 5 minutes, 15 weeks) minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, after 6 weeks, 8 weeks, 12 weeks).

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

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

Combination with immunotherapeutic agents

For the treatment of cancer, an ENPP1 inhibitor compound may be administered in combination with an immunotherapeutic agent. An immunotherapeutic agent is any suitable agent used in the treatment of cancer by inducing, enhancing, or inhibiting an immune response. In some embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. Any immunosuppressant may be used, including, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed death 1 (PD-1) inhibitors and programmed apoptosis ligand 1 (PD-L1) inhibitors. may be used, but is not limited thereto. Exemplary immune checkpoint inhibitors include ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, semipilimab ( cemiplimab) and the like may be included, but is not limited thereto. In some embodiments, the immunotherapeutic agent is immune cell therapy. Any suitable 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 may be administered in combination with a suitable cancer vaccine regimen, for example, a dendritic cell vaccine that promotes Th1/Th17 immunity. In some cases, the ENPP1 inhibitor compound is suitable for use as an adjuvant therapy in combination with Th-17-inducing vaccination.

Combination with radiation therapy

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

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

Combination with anticancer vaccine

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

Combination with CAR-T

In the case of a cancer treatment method, an ENPP1 inhibitor compound may be administered in combination with CAR-T cell therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after administration of CAR-T cell therapy.

monotherapy

Myocardial regeneration promotion therapy

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

Hypophosphatemia treatment regimen

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

pharmaceutical composition

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

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

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

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

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

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

One aspect of the present invention provides a compound selected from a benzotriazole derivative 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,

W ₁ is N or CRa;

W ₂ is N or CRb;

W ₃ is N or CRc;

W ₄ is N or CRd;

W ₅ is N or CRe;

W ₆ is N or CRf;

W ₇ is N or CRg;

Ra, Rb, Rc, Rd, Re, Rf and Rg are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. selected,

R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen; hydroxyl group; halogen group; -CF ₃ ; -(O)CF ₃ ; C1-C13 alkyl group; C1-C6 alkoxy group; amino group (-NR ₇ R ₈ ); nitro group (-N(O)2); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); C6-C10 aryl group; C3-C10 cyclyl group; C3-C10 heteroaryl group; C3-C10 heterocyclyl group; or -C(O)-(C1-C13 alkyl); is

Z is present or not, and when Z is present, Z is -O-, -CO-, -COO-, -C _n H _n+2 -, -O(C _n H _n+2 )-, -(OC ₂ H ₄ ) _n -, -(C ₂ H ₄ O) _n -, -(C _n H _n+2 )O-, -(C _n H _n+2 )CO-, -(C _n H _n+2 )O (C _m H _m+2 )-, -NR ₇ (C _n H _n+2 )-, -(NR ₇ C ₂ H ₄ ) _n -, -(C ₂ H ₄ NR ₇ ) _n -, or -( C _n H _n+2 )NR ₇ -, ; is

n is an integer from 0 to 8,

R ₅ is -A-(R ₆ ) _y ,

A is a C ₃ -C ₁₀ cyclyl group, a C ₅ -C ₁₀ bicyclyl group, a C ₃ -C ₁₀ heterocyclyl group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group,

wherein R ₆ is hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkenyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); tert-butyloxycarbonyl group (Boc); amino group (-NR ₇ R ₈ ); -(C _m H _m+2 )NR ₇ R ₈ ; nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₇ R ₈ ); ester group (-(C _m H _m+2 )C(O)OR ₇ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-(C _m H _m+2 )NHS(O) ₂ R ₇ ); urea group; sulfamoyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₇ ); sulfonamide group; sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₇ ); sulfamoylalkyl group (-(C _m H _m+2 )NR ₇ S(O) ₂ NHR ₈ ); sulfide group (-(C _m H _m+2 )SR ₇ ); sulfone group (-(C _m H _m+2 )S(O) ₂ R ₇ ); a phospyryl group (-(C _m H _m+2 )P(O)R ₇ R ₈ ); linked to the same carbon as the carbon linked to A to form a 3 to 10 membered saturated ring; It is linked to the same carbon as the carbon linked to A to form a 3 to 10 membered hetero saturated ring containing one or more heteroatoms of N, O and S; It is connected to the carbon connected to A and the carbon adjacent to it to form a 3 to 10 membered saturated ring; or a carbon connected to A and connected to a carbon adjacent to it to form a 3 to 10 membered hetero saturated ring containing one or more heteroatoms of N, O and S;

m is an integer from 0 to 4,

y is an integer from 0 to 4,

The C1-C13 alkyl group, C1-C6 alkoxy group, C1-C6 alkenyl group, or -C(O)-(C1-C13 alkyl) is hydrogen; hydroxyl group; halogen group; C1-C13 alkyl group; C1-C6 alkoxy group; amino group (-NR ₇ R ₈ ); nitro group (-N(O)2); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₇ (C=O)NR ₈ -); sulfonamide group (-NHS(O)2-); sulfide group (-S-); sulfone group (-S(O)2-); a phospyryl group (-P(O)R ₇ R ₈ ); C6-C10 aryl group; C3-C10 heteroaryl group; and one or more substituents selected from the group consisting of a C3-C10 heterocyclyl group,

The C6-C10 aryl group, C3-C10 heteroaryl group, C3-C10 cyclyl group, C3-C10 heterocyclyl group, or C5-C10 bicyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ₇ R ₈ ); a C1-C3 alkyl group unsubstituted or substituted with a halogen or C3-C10 heterocyclyl group; C1-C3 alkoxy group unsubstituted or substituted with halogen or C3-C10 heterocyclyl group; C6-C10 phenoxy; amino group (-NR ₇ R ₈ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₇ (C=O)NR ₈ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₇ R ₈ ); C6-C10 aryl group; It contains one or more substituents selected from the group consisting of a C3-C10 heteroaryl group and a C3-C10 heterocyclyl group,

The R ₇ and R ₈ are each independently hydrogen; C1-C6 alkyl group; C1-C6 alkenyl group; C1-C6 alkynyl group; C6-C10 aryl group; C3-C10 heteroaryl group; C3-C10 heterocyclyl group; amino group (-NH2); nitro group (-N(O)2); -Boc; -NHBoc; or R7 together with the nitrogen or carbon atom linked to R8 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2- , or SO2, optionally substituted with at least one of hydrogen, a C1-C13 alkyl group, a C6-C10 aryl group, a C3-C10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group Forming a 3 to 7 membered saturated ring that can be,

The C3-C10 heteroaryl group and the C3-C10 heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

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

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

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

The term 'phenoxy' refers to a phenyl group linked to another group through an oxygen atom (ie, -O-aryl). The phenoxy group is unsubstituted or one or more halogen; an alkyl group; It may be substituted with an aryl group and a 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 the amino group include a (C1-C6)amino group 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' refers to a heteroaromatic compound including at least one hetero atom selected from the group consisting of N, O, and S, unless otherwise stated. Preferably, the heterocyclyl group may include a pyrrolidine group, a furan group, a morpholine group, a piperazine and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, and a mol It may include a porine group, but is not limited thereto.

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

In one aspect of the present invention, the compound is a compound represented by Formula 1, wherein W1, W2, W3 and W4 are each -CH-, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoscopic thereof Compounds selected from isomers are provided.

In one aspect of the present invention, A is a C ₅ -C ₆ cyclyl group, C ₅ -C ₇ bicyclyl group, C ₅ -C ₈ heterocyclyl group, C ₆ -C ₈ aryl group, or C ₄ -C ₇ Provided is a compound selected from a compound represented by Formula 1, which is a heteroaryl group, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

In one aspect of the present invention, A is substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; substituted or unsubstituted piperidine; substituted or unsubstituted furan; substituted or unsubstituted naphthalene; substituted or unsubstituted anthracene; or substituted or unsubstituted phenathrene; substituted or unsubstituted pyridazine; substituted or unsubstituted pyrazine; substituted or unsubstituted imidazole; substituted or unsubstituted pyrazole; substituted or unsubstituted pyrimidine; substituted or unsubstituted pyrrole; substituted or unsubstituted indole; or a substituted or unsubstituted purine; Provided is 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.

In one embodiment, A is substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; or a substituted or unsubstituted piperidine; a compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

In one aspect of the present invention, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen; hydroxyl group; halogen group; -CF ₃ ; -(O)CF ₃ ; C1-C3 alkyl group; C1-C6 alkoxy group; or an amino group (-NR ₇ R ₈ ); wherein Z is present or absent, and when Z is present, Z is -C _n H _n+2 -, and n is an integer of 1 to 4, a compound represented by Formula 1, its Provided are compounds selected from tautomers, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof.

In one aspect of the present invention, W ₁ , W ₂ , W ₃ and W ₄ are each -CH-, wherein A is a substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; or substituted or unsubstituted piperidine; and R1, R2, R3 and R4 are each independently hydrogen; hydroxyl group; halogen group; -CF ₃ ; -(O)CF ₃ ; C1-C3 alkyl group; C1-C6 alkoxy group; or an amino group (-NR ₇ R ₈ ); wherein Z is present or absent, and when Z is present, Z is -C _n H _n+2 -, and n is an integer of 1 to 4, a compound represented by Formula 1, its Provided are compounds selected from tautomers, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof.

In one aspect of the present invention, the compound is a benzotriazole derivative compound represented by Formula 1, characterized in that any one selected from the group consisting of the following compound numbers 1 to 124, a tautomer thereof, and a pharmaceutical thereof Provided are compounds selected from acceptable salts, hydrates thereof and stereoisomers thereof:

Compound No. 1: 5-methoxy-1-(piperidin-4-yl) -1H -benzo[ d ][1,2,3]triazolehydrochloride;

Compound No. 2: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methane aniline;

Compound No. 3: 5-methoxy-1-(piperidin-4-ylmethyl) -1H -benzo[ d ][1,2,3]triazole;

Compound No. 4: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)aniline hydrochloride;

Compound No. 5: 4-( 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 6: 4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 7: 4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 8: 4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 9: 4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 10: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 11: 2-(3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

Compound No. 12: 1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)-N-methylmethanamine hydrochloride;

Compound No. 13: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)cyclopropanamine hydrochloride;

Compound No. 14: (S)-1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

Compound No. 15: 3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 16: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

Compound No. 17: 2,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 18: 2,6-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 19: 4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

Compound No. 20: 3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 21: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 22: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine ;

Compound No. 23: 3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 24: 4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

Compound No. 25: 7-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

Compound No. 26: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroiso quinoline hydrochloride;

Compound No. 27: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3,4,5-tetrahydro- 1H -benzo[ c ]azepine hydrochloride;

Compound No. 28: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorophenyl)methanamine;

Compound No. 29: 1-(isoindorin-5-yl)-5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazole hydrochloride;

Compound No. 30: 3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)methanamine;

Compound No. 31: 3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methylthiophen-2-yl)methanamine hydrochloride;

Compound No. 32: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)sulfonyl)carba mate;

Compound No. 33: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl ) carbamates;

Compound No. 34: tert -butyl( N- ( 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 35: tert -butyl( N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 36: tert -butyl( N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 37: tert -butyl( N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 38: tert -butyl( N- (4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

Compound No. 39: tert -butyl(( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl )sulfamoyl)carbamate;

Compound No. 40: tert -butyl((6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-yl)sulfamoyl)carbamate;

Compound No. 41: N -((3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclopentyl)methyl)sulfamide;

Compound No. 42: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidine-1-sulfonamide;

Compound No. 43: N -((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methyl)sulfamide;

Compound No. 44: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonamide ;

Compound No. 45: 4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidine-1-sulfonamide;

Compound No. 46: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 47: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide;

Compound No. 48: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide hydrochloride;

Compound No. 49: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 50: N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 51: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide hydrochloride;

Compound No. 52: N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 53: N- (4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 54: N- (4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 55: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 56: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 57: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-difluorobenzyl)sulfamide;

Compound No. 58: N- (4-( 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,5-difluorobenzyl)sulfamide;

Compound No. 59: N- (3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 60: N- (2-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 61: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 62: N- (2,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 63: N- (2,6-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 64: N- (3,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;

Compound No. 65: N- (2,3-difluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;

Compound No. 66: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-methylbenzyl)sulfamide;

Compound No. 67: N- (3-cyano-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-benzyl)sulfamide;

Compound No. 68: N- (3-methoxy-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 69: N- (4-(5-methoxy-6-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 70: N- (3-fluoro-4-(5-methoxy-6-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 71: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 72: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide;

Compound No. 73: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide hydrochloride;

Compound No. 74: N- (3-fluoro-4-(5-hydroxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 75: N- (3-fluoro-4-(5-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 76: N- (4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 77: N- (3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 78: N- (5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-2-yl)methyl)sulfamide;

Compound No. 79: ( N- (6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-3-yl)methyl)sulfamide;

Compound No. 80: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methyl)sulfamide;

Compound No. 81: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methylsulfamide;

Compound No. 82: N -cyclopropyl- N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 83: ( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamide;

Compound No. 84: N- (4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 85: N- (3-fluoro-4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 86: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

Compound No. 87: N- (4-(5-dimethylamino) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 88: N- (3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 89: N- (4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 90: N- (3-fluoro-4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 91: N- (4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

Compound No. 92: N- (4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

Compound No. 93: N- (3-fluoro-4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide ;

Compound No. 94: 5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)isoindorin-2-sulfonamide;

Compound No. 95: N -5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-dihydro- 1H -indene-2- 1) sulfamide;

Compound No. 96: 6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;

Compound No. 97: 7-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;

Compound No. 98: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,3,4,5-tetrahydro- 2H -benzo[ c ]azepine-2-sulfonamide;

Compound No. 99: N- (4-(5,6-dimethoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfa mide;

Compound No. 100: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfa mide;

Compound No. 101: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-sulfonamide;

Compound No. 102: 5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-isoindorin-2-sulfonamide;

Compound No. 103: N- (5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-dihydro- 1H -indene-2- 1) sulfamide;

Compound No. 104: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)phenyl)sulfamide hydrochloride;

Compound No. 105: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)benzyl)sulfamide hydrochloride;

Compound No. 106: N -((5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)thiophen-2-yl)methyl)sulfamide;

Compound No. 107: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methoxylthiophen-2-yl)methyl) sulfamide;

Compound No. 108: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-bicyclo[1.1.1]pentan-1-yl) sulfamide;

Compound No. 109: N- (4-(5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)phenyl)sulfamide hydrochloride;

Compound No. 110: N- (4-((5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)benzyl)sulfamide hydrochloride;

Compound No. 111: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

Compound No. 112: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonamide;

Compound No. 113: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)ethanesulfonamide;

Compound No. 114: N- (3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)-4-methylbenzenesulfonamide ;

Compound No. 115: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonimidamide;

Compound No. 116: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzoic acid;

Compound No. 117: diethyl-(3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphoamidate;

Compound No. 118: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)phosphonic acid;

Compound No. 119: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphonic acid;

Compound No. 120: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)boronic acid;

Compound No. 121: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)boronic acid;

Compound No. 122: N- (4-(5-methoxy-1 H -indol-1-yl)benzyl)sulfamide;

Compound No. 123: N- (4-(5-methoxy- 1H -benzo[ d ]imidazol-1-yl)benzyl)sulfamide; and

Compound No. 124: N- (4-(5-methoxy-1 H -indazol-1-yl)benzyl)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 acid or an organic acid. Preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, and pyruvic acid. , malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, It may be at least one selected from the group consisting of methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be administered in combination with other anticancer agents for treating cancer or tumors to enhance the therapeutic effect of the anticancer agent.

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

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

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

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

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

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

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

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

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

In one embodiment, the compound represented by Formula 1 of the present invention may be prepared by any one or more of the following Preparation Methods 1 to 3.

Manufacturing method 1

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

[Scheme 1]

Manufacturing method 2

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

[Scheme 2]

Manufacturing method 3

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

[Scheme 3]

Method A

After evacuating the oven-dried flask and filling with nitrogen gas, Pd2(dba)3 (0.05 equiv), rac-BINAP (0.1 equiv), Cs2CO3 (5 equiv), bromo-nitrobenzene (1 equiv.) ), aniline (1.05 equiv), and degassed toluene. Nitrogen gas was put into the reaction mixture for 15 minutes, and heated at 110° C. for 14 hours. After cooling the mixture to room temperature, it is diluted with ethyl acetate, filtered using celite, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The mixture is purified through silica column chromatography using MPLC (n-hexane/ethyl acetate) to obtain the target compound in high yield.

Method B

Pd/C (10%, 50% wet with water, 0.05 equivalent) was added to a nitro-intermediate (1 equivalent) solution dissolved in methanol and stirred under hydrogen gas at room temperature for 12 hours. The reaction mixture is filtered through celite and concentrated to obtain the target compound in high yield.

Method C

To a solution of the nitro-intermediate (1 equivalent) dissolved in ethanol, add iron powder (5 equivalents) and an aqueous solution of ammonium chloride (10 equivalents). The reaction solution is stirred at 65° C. for 2 hours. After the reaction solution is filtered through celite, an aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted three times using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain the target compound in high yield.

Method D

To a solution of the nitro-intermediate (1 equivalent) dissolved in ethanol, add iron powder (5 equivalents) and an aqueous solution of ammonium chloride (10 equivalents). The reaction solution is stirred at 65° C. for 2 hours. After the reaction solution is filtered through celite, an aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted three times using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain the target compound in high yield.

Method E

To a solution of the aniline intermediate (1 equivalent) dissolved in acetic acid, an aqueous solution of sodium nitrite (2 equivalents) was slowly added at 0° C., followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica column chromatography using MPLC (n-hexane/ethyl acetate) to obtain the target compound.

Method F

To a solution of the aniline intermediate (1 equivalent) dissolved in acetic acid, an aqueous solution of sodium nitrite (2 equivalents) was slowly added at 0° C., followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica column chromatography using MPLC (n-hexane/ethyl acetate) to obtain the target compound.

Method G

To a solution of the Boc-protected amine or aniline intermediate dissolved in ethyl acetate, an excess of 4 normal concentration aqueous hydrochloric acid solution (in dioxane) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure, washed with dichloromethane, and the target compound is quantitatively obtained in the form of a hydrochloride salt.

Method H

Dissolve the amine hydrochloride intermediate (1 eq) obtained in method G in dichloromethane and add triethylamine (8 eq) at 0 °C under nitrogen condition. After adding a solution of tert-butyl(chlorosulfonyl)carbamate (8 equivalents) dissolved in dichloromethane, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The target compound was obtained by purification through silica column chromatography using MPLC (n-hexane/ethyl acetate).

Method I

DMAP (2 equivalents) is added to an aqueous solution of aniline hydrochloride (1 equivalent) dissolved in acetonitrile at 0° C. under nitrogen condition. After adding a solution of tert-butyl(chlorosulfonyl)carbamate (2 equivalents) dissolved in dichloromethane, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The target compound was obtained by purification through silica column chromatography using MPLC (n-hexane/ethyl acetate).

Method J

tert-butanol is slowly added to a solution of chlorosulfonylisocyanate dissolved in anhydrous dichloromethane at 0°C. After 30 minutes, the mixture was slowly added to an amine hydrochloride intermediate solution in anhydrous dichloromethane in the presence of triethylamine at 0 °C, and the mixture was stirred at room temperature for 2 hours. After diluting the reaction mixture with dichloromethane, it was washed with an aqueous solution of hydrochloric acid with 0.1 normal concentration and water. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Purification through silica column chromatography using MPLC to obtain the target compound.

Method K

To a solution of the Boc-protected sulfondiamide intermediate (1 equivalent) in ethyl acetate was added an excess of 4 normal concentration aqueous hydrochloric acid solution (in dioxane) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica column chromatography using MPLC to obtain the target compound.

Method L

To the Boc-protected sulfondiamide intermediate (1 equivalent), an excess of 4 normal concentration aqueous hydrochloric acid solution (in dioxane) was added, and the mixture was stirred at room temperature for 4 to 12 hours. The reaction mixture was concentrated under reduced pressure, washed with ethyl acetate, washed with methanol, and dried to obtain the target compound in the form of a hydrochloride salt.

Method M

Nitrofluorobenzene, N-Boc-piperidin-4-ylmethanamine, and potassium carbonate were dissolved in DMSO and stirred at room temperature for 16 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is purified by silica column chromatography using MPLC to obtain the target compound.

Method N

An aqueous solution of NaOH (1.1 equiv) is added to a solution of 5-methoxy-1H-benzo[d][1,2,3]triazole (1 equiv) in acetonitrile. 1,4-bis(bromoethyl)benzene (1.1 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure. Two regioisomers are obtained in high yield by purifying the residue through silica column chromatography using MPLC (ethyl acetate, hexane conditions).

Method O

Sodium azide (3 equivalents) was added to a solution of benzyl brobide intermediate (1 equivalent) dissolved in acetonitrile, and the mixture was stirred at 75° C. for 16 hours. The reaction mixture was extracted with ethyl acetate and an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude azide intermediate in high yield. Triphenylphosphine (2 equivalents) is slowly added to a solution of an azide intermediate (1 equivalent) dissolved in tetrahydrofuran at 0°C. Water is added and the solution is stirred at 70° C. for 12 hours. The solvent was concentrated under reduced pressure, and hydrochloric acid contained in dioxane was added to obtain the target compound in high yield.

Hereinafter, the present invention will be described in detail by Synthesis Examples, Preparation Examples, Examples, Experimental Examples and Formulation Examples. However, the following Preparation Examples, Examples, Experimental Examples and Formulation Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following embodiments.

[Preparation Example 1] Preparation of Compound No. 47

Preparation Example 1:

[Scheme 1]

tert -Butyl(3-((4-methoxy-2-nitrophenyl)amino)phenyl)carbamate (3)

1-Bromo-4-methoxy-2-nitrobenzene (1.16 g, 5 mmol), tert-butyl(3-aminophenyl)carbamate (1.9 g, 5.25 mmol), Pd2(dba)3 (229 mg) , 0.25 mmol), rac-BINAP (311 mg, 0.5 mmol), and a mixture of Cs2CO3 (8.15 g, 25 mmol) in toluene (17 mL, 0.3 M) was replaced with nitrogen gas for 15 minutes. The reaction mixture was heated and stirred at 110° C. under nitrogen gas for 14 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, filtered using celite, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified through column chromatography using MPLC to obtain the target compound in a yield of 78% (1.40 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (brs, 1H), 7.66 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.36 - 7.25 (m, 2H) , 7.18 - 7.02 (m, 2H), 7.01 - 6.88 (m, 1H), 6.53 (s, 1H), 3.86 (s, 3H), 1.61 - 1.49 (m, 9H).

tert -Butyl (3-((2-amino-4-methoxyphenyl)amino)phenyl)carbamate (4)

To a solution of tert -butyl (3-((4-methoxy-2-nitrophenyl)amino)phenyl)carbamate (1.60 g, 4.45 mmol) in methanol (15 mL, 0.3 M) was dissolved in Pd/C (10 %, 50% wet with water, 480 mg, 0.22 mmol) and stirred for 12 hours at room temperature under hydrogen gas. The reaction mixture was filtered using celite and concentrated to obtain the target compound in a yield of 90% (1.32 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29 (s, 1H), 7.15 - 7.05 (m, 2H), 6.94 - 6.83 (m, 1H), 6.81 (brs, 1H), 6.66 (brs, 1H), 6.64 - 6.56 (m, 1H), 6.50 (s, 1H), 3.66 (s, 3H), 1.39 (s, 9H).

tert -Butyl (3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)carbamate (5)

Sodium nitrite (544 mg, 7.89 mmol) aqueous solution was slowly added at 0 °C and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica column chromatography using MPLC (n-hexane/ethyl acetate) to obtain the target compound in a yield of 58% (780 mg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.45 - 7.31 (m, 4H), 7.15 (dd, J = 2.3, 9.2 Hz, 1H), 6.93 (s, 1H), 3.85 (s, 3H), 1.46 (s, 9H).

3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)aniline hydrochloride (6)

tert -Butyl (3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)carbamate (800 mg, 2.35 mmol) was mixed with ethyl acetate (2.35 mL, 1 M), an excess of 4 n hydrochloric acid aqueous solution (in dioxane) was added to the solution at room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with dichloromethane and dried to obtain the target compound in the form of hydrochloride in a yield of 99% (645 mg).

tert -Butyl (N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamoyl)carbamate (7)

3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)aniline hydrochloride (139 mg, 0.5 mmol) was dissolved in acetonitrile (2.5 mL, 0.2 M) DMAP (123 mg, 1 mmol) was added to the dissolved solution at 0 °C under nitrogen gas. A solution of tert -butyl (chlorosulfonyl)carbamate (432 mg, 1 mmol) in acetonitrile was slowly added to the mixture and stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica column chromatography using MPLC (n-hexane/ethyl acetate) to obtain the target compound in a yield of 37% (78 mg).

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.81 (d, J = 9.1 Hz, 1H), 7.78 (p, J = 1.0 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.49 (d, J = 2.3 Hz, 1H), 7.42 (s, 1H), 7.32 (dd, J = 9.1, 2.3 Hz, 1H), 3.96 (s, 3H), 1.39 (s, 9H).

N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide (8)

tert-butyl ( N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamoyl)carbamate (70 mg, 0.17 mmol) was added to a solution of ethyl acetate (1.7 mL, 0.1 M) in an excess of 4 normal concentration aqueous hydrochloric acid solution (in dioxane) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica column chromatography using MPLC (n-hexane/ethyl acetate) to obtain the target compound in a yield of 62% (33 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.96 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.41 - 7.23 (m, 4H), 3.91 (s, 3H).

With reference to Preparation Example 1 and Schemes 1 to 4, the following Examples were synthesized.

Example 1: 5-methoxy-1-(piperidin-4-yl) -1H -benzo[ d ][1,2,3]triazolehydrochloride;

LC-MS (ESI) calcd for C ₁₂ H ₁₆ N ₄ O [M + H] ⁺ 232.12, found m/z 233.1

Example 2: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methane aniline;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.83 (m, 2H), 7.46 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 9.0, 2.2 Hz, 1H), 4.95 (s, 1H), 3.85 (s, 3H) 2.90 (d, 1H), 2.17 (S, 2H), 1.97 (s, 3H), 1.74 (s, 3H), 1.24 (s, 2H).

Example 3: 5-Methoxy-1-(piperidin-4-ylmethyl) -1H -benzo[ d ][1,2,3]triazole;

LC-MS (ESI) calcd for C ₁₃ H ₁₈ N ₄ O [M + H] ⁺ 246.15, found m/z 247.2

Example 4: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)aniline hydrochloride;

LC-MS (ESI) calcd for C ₁₃ H ₁₂ N ₄ O [M + H] ⁺ 240.10, found m/z 341.1

Example 5: 4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₃ H ₁₂ N ₄ [M + H] ⁺ 224.11, found m/z 225.1

Example 6: 4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₄ N ₄ O [M + H] ⁺ 254.12, found m/z 255.1

Example 7: 4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₄ N ₄ O [M + H] ⁺ 254.12, found m/z 255.1

Example 8: 4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₄ N ₄ O [M + H] ⁺ 254.12, found m/z 255.1

Example 9: 4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ N ₄ O ₂ [M + H] ⁺ 284.13, found m/z 285.1

Example 10: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ N ₄ O ₂ [M + H] ⁺ 284.13, found m/z 285.1

Example 11: 2-(3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ N ₄ O [M + H] ⁺ 268.13, found m/z 269.1

Example 12: 1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)-N-methylmethanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ N ₄ O [M + H] ⁺ 268.13, found m/z 269.1

Example 13: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)cyclopropanamine hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.74 (d, J = 4.1 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 9.1, 2.3 Hz, 1H), 4.36 (d, J = 5.7 Hz, 2H), 3.90 (s, 3H), 2.71 (d, J = 3.6 Hz, 1H), 0.97 (t, J = 4.4 Hz, 2H), 0.76 (q, J = 7.0 Hz, 2H).

Example 14: (S)-1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ N ₄ O [M + H] ⁺ 268.13, found m/z 269.1

Example 15: 3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₃ ClN ₄ O [M + H] ⁺ 288.08, found m/z 289.1

Example 16: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₃ F ₁ N ₄ O [M + H] ⁺ 272.11, found m/z 273.1

Example 17: 2,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

LC-MS (ESI) calcd for C ₁₄ H ₁₂ F ₂ N ₄ O [M + H] ⁺ 290.14, found m/z 291.1

Example 18: 2,6-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

LC-MS (ESI) calcd for C ₁₄ H ₁₂ F ₂ N ₄ O [M + H] ⁺ 290.14, found m/z 291.1

Example 19: 4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.75 (t, J = 8.0 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.53 - 7.43 (m, 2H), 7.26 (dd, J = 9.0) , 2.3 Hz, 1H), 4.16 (d, J = 7.0 Hz, 2H), 3.87 (s, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.24 (s, 2H).

Example 20: 3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.75 (t, J = 8.0 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.52 - 7.42 (m, 2H), 7.23 (dd, J = 9.0) , 2.2 Hz, 1H), 4.82 - 4.74 (m, 1H), 3.88 (s, 2H), 1.34 (s, 3H), 1.32 (s, 3H), 1.18 (t, J = 7.1 Hz, 1H).

Example 21: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

LC-MS (ESI) calcd for C ₁₅ H ₁₄ F ₂ N ₄ [M + H] ⁺ 288.10, found m/z 289

Example 22: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine ;

LC-MS (ESI) calcd for C ₁₅ H ₁₃ F ₃ N ₄ [M + H] ⁺ 306.37, found m/z 307.1

Example 23 3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

LC-MS (ESI) calcd for C ₁₄ H ₁₂ F ₂ N ₄ O [M + H] ⁺ 290.27, found m/z 291

Example 24: 4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (t, J = 8.0 Hz, 2H), 7.71 (dd, J = 9.0, 1.9 Hz, 2H), 7.63 (d, J = 11.6 Hz, 2H) , 7.52 (d, J = 2.2 Hz, 1H), 7.51 - 7.49 (m, 1H), 7.38 (s, 1H), 3.88 (s, 2H).

Example 25: 7-(5-Methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.75 (s, 2H), 7.89 (d, J = 9.1 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 4.42 (d, J = 4.4 Hz, 2H), 3.91 (s, 3H), 3.44 (d, J = 5.6 Hz, 2H), 3.15 (t, J = 6.1 Hz, 2H).

Example 26: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroiso quinoline hydrochloride;

LC-MS (ESI) calcd for C ₁₆ H ₁₅ FN ₄ O [M + H] ⁺ 298.12, found m/z 299.1

Example 27: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3,4,5-tetrahydro- 1H -benzo[ c ]azepine hydrochloride;

LC-MS (ESI) calcd for C ₁₇ H ₁₈ N ₄ O [M + H] ⁺ 294.15, found m/z 295.2

Example 28: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorophenyl)methanamine;

LC-MS (ESI) calcd for C ₁₅ H ₁₄ F ₂ N ₄ O ₂ [M + H] ⁺ 320.17, found m/z 321.1

Example 29: 1-(isoindorin-5-yl)-5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazole hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.23 (s, 2H), 7.93 (s, 1H), 7.87 (dd, J = 8.2, 1.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.24 (s, 1H), 4.71 - 4.50 (m, 4H), 3.92 (s, 3H), 3.90 (s, 3H).

Example 30 3-(5-Methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)methanamine;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.25 - 7.13 (m, 2H), 6.75 (d, J = 8.6 Hz, 1H), 3.85 (s, 3H), 1.24 (s, 6H), 0.85 (d, J = 7.2 Hz, 2H).

Example 31: 3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methylthiophen-2-yl)methanamine hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (s, 2H), 7.72 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.8, 2.5 Hz, 2H), 7.16 (m, 1H) 6.76 (dd, J = 5.9, 3.5 Hz, 2H), 4.23 (d, J = 5.4 Hz, 2H), 3.90 (s, 3H), 2.57 (s) , 3H).

Example 32: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)sulfonyl)carba mate;

LC-MS (ESI) calcd for C ₁₇ H ₂₅ N ₅ O ₅ S [M + H] ⁺ 411.16, found m/z 412.2

Example 33: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl ) carbamates;

LC-MS (ESI) calcd for C ₁₈ H ₂₇ N ₅ O ₅ S [M + H] ⁺ 425.17, found m/z 426.2

Example 34: tert -butyl( N- (1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

LC-MS (ESI) calcd for C ₁₈ H ₂₁ N ₅ O ₄ S [M + H] ⁺ 403.13, found m/z 404.1

Example 35: tert -Butyl( N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

LC-MS (ESI) calcd for C ₁₉ H ₂₃ N ₅ O ₅ S [M + H] ⁺ 433.14, found m/z 434.1

Example 36 tert -Butyl( N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

LC-MS (ESI) calcd for C ₁₉ H ₂₃ N ₅ O ₅ S [M + H] ⁺ 433.14, found m/z 434.1

Example 37: tert -Butyl( N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

LC-MS (ESI) calcd for C ₁₉ H ₂₃ N ₅ O ₅ S [M + H] ⁺ 433.14, found m/z 434.1

Example 38: tert -Butyl( N- (4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

LC-MS (ESI) calcd for C ₁₉ H ₂₃ N ₅ O ₅ S [M + H] ⁺ 433.14, found m/z 434.1

Example 39: tert -butyl(( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl )sulfamoyl)carbamate;

LC-MS (ESI) calcd for C ₂₀ H ₂₅ N ₅ O ₅ S [M + H] ⁺ 447.16, found m/z 448.2

Example 40: tert -butyl((6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-yl)sulfamoyl)carbamate;

LC-MS (ESI) calcd for C ₂₁ H ₂₅ N ₅ O ₅ S [M + H] ⁺ 459.16, found m/z 460.2

Example 41: N -((3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclopentyl)methyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 9.0, 2.3 Hz, 1H) , 6.65 (t, J = 6.1 Hz, 1H), 6.51 (s, 2H), 5.31 (dd, J = 15.9, 7.9 Hz, 1H), 3.84 (s, 3H), 2.99 (dd, J = 10.0, 6.8) Hz, 2H), 2.40 - 2.21 (m, 2H), 2.20 - 2.06 (m, 1H), 1.90 (dd, J = 21.3, 14.1, 7.9 Hz, 2H), 1.74 - 1.59 (m, 1H), 1.24 ( s, 2H).

Example 42: 4-(5-Methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidine-1-sulfonamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.97 (br s, 1H) ), 3.86 (s, 3H), 3.69 (d, J = 11.4 Hz, 2H), 2.95 (t, J = 10.7 Hz, 2H), 2.29-2.23 (m, 4H).

Example 43: N -((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.81 (dd, J = 20.1, 9.2 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 9.0, 2.3 Hz, 1H), 6.59 (t, J = 6.2 Hz, 1H), 6.52 (d, J = 11.1 Hz, 1H), 4.91 (dd, J = 8.9, 4.3 Hz, 1H), 3.84 (s, 3H), 2.96 ( t, J = 6.9 Hz, 2H), 2.14 (dt, J = 15.3, 6.5 Hz, 2H), 1.91 (dd, J = 13.6, 4.5 Hz, 0H), 1.73 (d, J = 4.7 Hz, 3H), 1.24 (s, 1H).

Example 44: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonamide ;

LC-MS (ESI) calcd for C ₂₀ H ₂₅ N ₅ O ₅ S [M + H] ⁺ 447.16, found m/z 448.2

Example 45: 4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidine-1-sulfonamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.83 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 4.60 (d, J = 6.9 Hz, 2H), 3.85 (s, 3H), 3.44 (d, J = 11.4 Hz, 2H), 2.44 (t, J = 11.3 Hz, 2H), 2.01 (br s, 1H), 1.57 (d, J = 11.2 Hz, 2H), 1.37-1.29 (m, 2H).

Example 46: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 27.8, 8.4 Hz, 3H), 7.68 (dt, J = 7.4, 2.9 Hz, 3H), 7.58 - 7.49 (m, 1H), 7.27 (s, 1H), 6.73 (s, 2H), 4.23 (d, J = 6.5 Hz, 2H).

Example 47: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.96 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.41 - 7.23 (m, 4H), 3.91 (s, 3H).

Example 48: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.78 (brs, 1H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 7.42 (d, J = 7.6 Hz, 2H), 7.26- 7.17 (m, 2H), 3.88 (s, 3H).

Example 49: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 - 7.80 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 12.0, 4.7 Hz, 2H), 7.56 ( d, J = 7.7 Hz, 1H), 7.30 (td, J = 8.9, 4.4 Hz, 2H), 6.73 (s, 2H), 4.26 (d, J = 6.4 Hz, 2H), 3.91 (s, 3H).

Example 50: N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.95 - 7.75 (m, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.63 - 7.51 (m, 1H), 7.45 - 7.33 (m, 1H) ), 7.26 (t, J = 6.5 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.73 (s, 2H), 4.22 (d, J = 6.5 Hz, 2H), 4.08 (s, 3H) ).

Example 51: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82-7.78 (m, 3H), 7.65 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 2.1 Hz, 1H), 7.28 (dd, J = 9.0, 2.2 Hz, 1H), 4.22 (s, 2H), 3.90 (s, 3H).

Example 52: N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.26 (s, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 9.1, 2.2 Hz, 1H), 6.73 (s, 2H), 4.22 (d, J = 6.5 Hz, 2H) , 3.90 (s, 3H).

Example 53: N- (4-(7-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (dd, J = 8.4, 0.6 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.42 ( dd, J = 8.3, 7.8 Hz, 1H), 7.24 (d, J = 6.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.73 (s, 2H), 4.22 (d, J = 6.5) Hz, 2H), 3.84 (s, 3H).

Example 54: N- (4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.86 - 7.74 (m, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.26 (t, J = 6.5 Hz, 1H), 6.82 - 6.67 ( m, 3H), 6.56 (d, J = 1.8 Hz, 1H), 4.22 (d, J = 6.5 Hz, 2H), 4.03 (s, 3H), 3.87 (s, 3H).

Example 55: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.84 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.25 (d, J = 6.5 Hz, 1H), 7.21 (s, 1H), 6.72 (s, 2H), 4.23 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H).

Example 56: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

¹ H NMR (400 MHz, Methanol- d4 ) δ 8.13 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.54 (t, J = 7.6 Hz, 2H), 4.40 (s, 2H).

Example 57: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-difluorobenzyl)sulfamide;

¹ H NMR (400 MHz, Methanol- d4 ) δ 8.13 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.70 - 7.63 (m, 1H), 7.63 - 7.57 (m , 2H), 7.57 - 7.52 (m, 2H), 4.40 (s, 2H).

Example 58: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-3,5-difluorobenzyl)sulfamide;

¹ H NMR (400 MHz, Methanol- d4 ) δ 8.16 (d, J = 8.4 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.60 - 7.50 (m, 2H), 7.46 (d, J = 8.9 Hz) , 2H), 4.40 (s, 2H).

Example 59: N- (3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.83 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 6.3, 1.9 Hz, 2H) , 7.38 (dd, J = 12.2, 7.8 Hz, 2H), 7.26 (dd, J = 9.0, 2.3 Hz, 1H), 6.78 (s, 2H), 4.27 (d, J = 6.5 Hz, 2H), 3.91 ( s, 3H).

Example 60: N- (2-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.89 (d, J = 9.1 Hz, 1H), 7.82 - 7.73 (m, 3H), 7.64 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 9.1, 2.4 Hz, 1H), 7.26 (t, J = 6.5 Hz, 1H), 6.76 (s, 2H), 4.24 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H).

Example 61: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (t, J = 7.9 Hz, 1H), 7.62 (dd, J = 10.4, 2.0 Hz, 2H), 7.54 (dd, J = 9.0, 2.2 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.36 (t, J = 6.5 Hz, 1H), 7.29 (dd, J = 9.0, 2.3 Hz, 1H), 6.77 (s, 2H), 4.26 (d, J ) = 6.5 Hz, 2H), 3.90 (s, 3H).

Example 62: N- (2,5-difluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₄ H ₁₃ F ₂ N ₅ O ₃ S [M + H] ⁺ 369.35, found m/z 370.1

Example 63: N- (2,6-difluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₄ H ₁₃ F ₂ N ₅ O ₃ S [M + H] ⁺ 369.35, found m/z 370.1

Example 64: N- (3,5-difluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.67 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 9.0 Hz, 3H), 7.44 (s, 1H), 7.31 (dd, J = 9.0, 2.3 Hz, 1H), 6.80 (s, 2H), 4.28 (d, J = 6.5 Hz, 2H), 3.90 (s, 3H).

Example 65: N- (2,3-difluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.75 - 7.57 (m, 4H), 7.36 (t, J = 6.2 Hz, 1H), 7.31 (dd, J = 9.1, 2.3 Hz, 1H), 6.80 ( s, 2H), 4.30 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H).

Example 66: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-methylbenzyl)sulfamide;

1H NMR (400 MHz, DMSO- d ₆ ) δ 7.62 (d, J = 2.1 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 2H), 7.37 (d, J = 9.0 Hz, 1H), 7.28 - 7.19 (m, 2H), 6.72 (s, 2H), 4.21 (d, J = 6.5 Hz, 2H), 3.90 (s, 3H), 2.05 (s, 3H).

Example 67: N- (3-cyano-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-3-benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₅ H ₁₄ N ₆ O ₃ S [M + H] ⁺ 358.08, found m/z 359.1

Example 68: N- (3-methoxy-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₅ H ₁₇ N ₅ O ₄ S [M + H] ⁺ 363.1, found m/z 364.1

Example 69: N- (4-(5-methoxy-6-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.55 (s, 1H) , 7.25 (t, J = 6.4 Hz, 1H), 6.72 (s, 2H), 4.21 (d, J = 6.1 Hz, 2H), 3.93 (s, 3H), 2.35 (s, 3H).

Example 70: N- (3-fluoro-4-(5-methoxy-6-methyl-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.77 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 11.4 Hz, 1H), 7.57 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.42 (s, 1H), 7.36 (t, J = 6.5 Hz, 1H), 6.77 (s, 2H), 4.25 (d, J = 6.5 Hz, 2H), 3.93 (s, 3H) , 2.31 (s, 3H).

Example 71: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.77 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 10.6 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 6.5 Hz, 1H), 6.97 (s, 1H), 6.77 (s, 2H), 4.25 (d, J = 6.5 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H) .

Example 72: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (d, J = 9.1 Hz, 1H), 7.80 - 7.68 (m, 2H), 7.67 - 7.58 (m, 2H), 7.46 (d, J = 7.7) Hz, 1H), 7.29 (dd, J = 9.1, 2.3 Hz, 1H), 6.67 (t, J = 5.9 Hz, 1H), 6.58 (s, 2H), 3.91 (s, 3H), 3.34 (s, 2H) ), 3.22 (dd, J = 13.5, 7.1 Hz, 2H), 2.97 (t, J = 7.3 Hz, 2H), 2.57 - 2.47 (m, 4H).

Example 73: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (m, 2H), 7.60-7.55 (m, 2H), 7.29-7.27 (m, 1H), 6.66-6.60 (brs, 2H), 3.89 (s) , 3H), 3.18 (brs, 2H), 2.93 (brs, 2H).

Example 74: N- (3-fluoro-4-(5-hydroxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.92 (s, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 11.7 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.35 (dd, J = 8.5, 4.3 Hz, 2H), 7.17 (dd, J = 8.9, 2.2 Hz, 1H), 6.77 (s, 2H), 4.25 (d, J = 6.5 Hz, 2H).

Example 75: N- (3-fluoro-4-(5-methyl-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₄ H ₁₄ FN ₅ O ₂ S [M + H] ⁺ 335.09, found m/z 336.1

Example 76: N- (4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 9.5 Hz, 2H), 7.51 (t, J = 9.6 Hz, 2H), 7.36 (d, J = 6.3 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.77 (s, 2H), 4.25 (d, J = 6.5 Hz, 2H), 4.16 (d, J = 6.9 Hz) , 2H), 1.40 (t, J = 6.9 Hz, 3H).

Example 77: N- (3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (t, J = 8.0 Hz, 1H), 7.62 (t, J = 7.5 Hz, 2H), 7.51 (dd, J = 11.8, 5.0 Hz, 2H) , 7.36 (t, J = 6.5 Hz, 1H), 7.24 (dd, J = 9.0, 2.2 Hz, 1H), 6.77 (s, 2H), 4.84 - 4.73 (m, 1H), 4.25 (d, J = 6.5) Hz, 2H), 1.34 (s, 3H), 1.33 (s, 3H).

Example 78: N- (5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-2-yl)methyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 2.4 Hz, 1H), 8.36 (dd, J = 8.4, 2.6 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H) , 7.81 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.39 - 7.28 (m, 2H), 6.78 (s, 2H), 4.34 (d, J = 6.5 Hz, 2H), 3.90 (s, 3H).

Example 79: N- (6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-3-yl)methyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.64 (s, 1H), 8.45 (d, J = 9.2 Hz, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.38 - 7.33 (m, 2H), 6.77 (s, 1H), 4.36 - 4.30 (m, 2H), 3.90 (s, 3H).

Example 80: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.88 (t, J = 9.3 Hz, 3H), 7.64 (dd, J = 13.2, 5.3 Hz, 3H), 7.30 (dd, J = 9.1, 2.3 Hz, 1H), 6.98 (s, 2H), 4.23 (s, 2H), 3.91 (s, 3H), 2.63 (s, 3H).

Example 81: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methylsulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.84 (t, J = 7.9 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.49 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 9.1, 2.3 Hz, 1H), 7.03 (s, 2H), 4.27 (s, 2H), 3.90 (s, 3H), 2.67 (s, 3H).

Example 82: N -cyclopropyl- N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.83 (dd, J = 8.8, 3.7 Hz, 3H), 7.66 - 7.53 (m, 3H), 7.29 (dd, J = 9.1, 2.3 Hz, 1H), 7.05 (s, 2H), 4.40 (s, 2H), 3.90 (s, 3H), 2.46 - 2.38 (m, 1H), 0.75 - 0.43 (m, 4H).

Example 83: ( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamide;

LC-MS (ESI) calcd for C ₁₅ H ₁₇ N ₅ O ₃ S [M + H] ⁺ 347.11, found m/z 348.1.

Example 84: N- (4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₄ H ₁₂ F ₃ N ₅ O ₂ S [M + H] ⁺ 371.07, found m/z 372.1.

Example 85: N- (3-fluoro-4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d6 ) δ 8.76 (s, 1H), 7.98 (dd, J = 8.9, 1.3 Hz, 1H), 7.88 (dd, J = 13.7, 5.8 Hz, 2H), 7.66 (d) , J = 11.5 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 6.5 Hz, 1H), 6.78 (s, 2H), 4.28 (d, J = 6.5 Hz, 2H) ).

Example 86: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;

LC-MS (ESI) calcd for C ₁₅ H ₁₄ F ₂ N ₄ [M + H] ⁺ 288.10, found m/z 289

Example 87: N- (4-(5-dimethylamino) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₅ H ₁₇ FN ₆ O ₂ S [M + H] ⁺ 364.11, found m/z 365.1

Example 88: N- (3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₄ H ₁₃ F ₂ N ₅ O ₃ S [M + H] ⁺ 369.35, found m/z 370.1

Example 89: N- (4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d6 ) δ 8.33 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.77 - 7.60 (m, 3H) ), 7.27 (t, J = 6.5 Hz, 1H), 6.73 (s, 2H), 4.23 (d, J = 6.5 Hz, 2H).

Example 90: N- (3-fluoro-4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.36 (s, 1H), 7.89 - 7.77 (m, 2H), 7.72 - 7.61 (m, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.37 (t, J = 6.5 Hz, 1H), 6.77 (s, 2H), 4.27 (d, J = 6.5 Hz, 2H).

Example 91: N- (4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.04 (d, J = 2.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.72 (dd, J = 9.0, 2.0 Hz, 1H) , 7.64 (d, J = 10.2 Hz, 1H), 7.52 (dd, J = 8.9, 2.3 Hz, 2H), 7.38 (d, J = 7.7 Hz, 2H), 6.77 (s, 2H), 4.26 (d, J = 6.5 Hz, 2H).

Example 92: N- (4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.88 (dd, J = 9.0, 6.0 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 6.5 Hz, 1H), 6.72 (s, 2H), 4.21 (d, J = 6.5 Hz, 2H), 3.99 (s, 3H).

Example 93: N- (3-fluoro-4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide ;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.89 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.49 (d, J ) = 8.1 Hz, 1H), 7.37 (t, J = 6.5 Hz, 1H), 6.76 (s, 2H), 4.25 (d, J = 6.4 Hz, 2H), 3.98 (s, 3H).

Example 94: 5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)isoindorin-2-sulfonamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (s, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.72 (dd, J = 8.1, 2.0 Hz, 1H), 7.58 - 7.53 ( m, 2H), 7.22 (dd, J = 9.1, 2.3 Hz, 1H), 6.95 (s, 2H), 4.57 (s, 2H), 4.55 (s, 2H), 3.82 (s, 3H).

Example 95: N -5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-dihydro- 1H -indene-2- 1) sulfamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (d, J = 9.0 Hz, 1H), 7.68 (s, 1H), 7.62 - 7.58 (m, 2H), 7.48 (d, J = 3.8 Hz, 1H), 7.27 (dd, J = 9.1, 2.3 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.68 (s, 2H), 4.17 (dd, J = 14.6, 7.3 Hz, 1H), 3.89 (s, 3H), 3.30 (dd, J = 10.4, 5.8 Hz, 2H), 3.06 - 2.94 (m, 2H).

Example 96: 6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.84 (d, J = 9.1 Hz, 1H), 7.68-7.67 (m, 2H), 7.60 (d, J = 2.1 Hz, 1H), 7.49 (d, J ) = 9.0 Hz, 1H), 7.28 (dd, J = 9.1, 2.3 Hz, 1H), 7.00 (s, 2H), 4.33 (s, 2H), 3.89 (s, 3H), 3.07 (t, J = 5.7 Hz) , 2H), 2.50 (t, J = 3.4 Hz, 2H).

Example 97: 7-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.89 (d, J = 9.1 Hz, 1H), 7.69 (dd, J = 11.8, 3.6 Hz, 2H), 7.61 (d, J = 2.1 Hz, 1H) , 7.48 (d, J = 8.2 Hz, 1H), 7.29 (dd, J = 9.1, 2.3 Hz, 1H), 6.99 (s, 2H), 4.39 (s, 2H), 3.91 (s, 3H), 3.37 ( t, J = 5.9 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H).

Example 98: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,3,4,5-tetrahydro- 2H -benzo[ c ]azepine-2-sulfonamide;

LC-MS (ESI) calcd for C ₁₇ H ₁₉ N ₅ O ₃ S [M + H] ⁺ 373.12, found m/z 374.1

Example 99: N- (4-(5,6-dimethoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfa mide;

LC-MS (ESI) calcd for C ₁₄ H ₁₅ F ₂ N ₅ O ₄ S [M + H] ⁺ 399.08, found m/z 400.1

Example 100: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfa mide;

LC-MS (ESI) calcd for C ₁₄ H ₁₅ F ₂ N ₅ O ₄ S [M + H] ⁺ 399.08, found m/z 400.1

Example 101: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-sulfonamide;

LC-MS (ESI) calcd for C ₁₆ H ₁₆ FN ₅ O ₃ S [M + H] ⁺ 377.1, found m/z 378.1

Example 102: 5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-isoindorin-2-sulfonamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.85 (s, 1H), 7.79 (dd, J = 8.1, 1.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.58 (s, 1H), 7.23 (s, 1H), 7.03 (s, 2H), 4.66 (s, 2H), 4.63 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H).

Example 103: N- (5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-dihydro- 1H -indene-2- 1) sulfamide;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.67 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.49 (d, J = 8.2) Hz, 1H), 7.17 (s, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.68 (s, 2H), 4.17 (dd, J = 14.7, 7.3 Hz, 1H), 3.90 (s, 3H) ), 3.89 (s, 3H), 3.34 - 3.25 (m, 2H), 3.06 - 2.97 (m, 2H).

Example 104: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)phenyl)sulfamide hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₆ ClN ₅ O ₃ S [M + H] ⁺ 369.07, found m/z 370.1

Example 105: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)benzyl)sulfamide hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₆ ClN ₅ O ₃ S [M + H] ⁺ 383.08, found m/z 384.1

Example 106: N -((5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)thiophen-2-yl)methyl)sulfamide;

LC-MS (ESI) calcd for C ₂₄ H ₁₃ N ₅ O ₃ S ₂ [M + H]+ 339.41, found m/z 340

Example 107: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methoxylthiophen-2-yl)methyl) sulfamide;

¹ H NMR (400 MHz, MeOH- d ₄ ) δ 6.03 (d, J = 9.6 Hz, 1H), 5.91 (s, 1H), 5.74 (d, J = 8.7 Hz, 1H), 5.47 (s, 1H) , 3.08 (s, 2H), 2.75 (s, 2H), 2.39 (s, 3H), 1.03 (s, 3H).

Example 108: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-bicyclo[1.1.1]pentan-1-yl) sulfamide;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.78 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 9.0, 2.2 Hz, 1H), 6.76 (t, J = 6.2 Hz, 1H), 6.58 (s, 2H), 3.85 (s, 3H), 3.23 (d, J = 6.2 Hz, 2H), 2.45 (s, 6H).

Example 109: N- (4-(5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)phenyl)sulfamide hydrochloride;

LC-MS (ESI) calcd for C ₁₄ H ₁₅ N ₅ O ₃ S [M + H] ⁺ 333.09, found m/z 334.1.

Example 110: N- (4-((5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)benzyl)sulfamide hydrochloride;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.90 (d, J = 9.0 Hz, 1H), 7.33-7.31 (m, 5H), 7.00 (dd, J = 9.1, 2.2 Hz, 1H), 5.88 ( s, 2H), 4.03 (s, 2H), 3.84 (s, 3H).

Example 111: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

LC-MS (ESI) calcd for C ₁₄ H ₁₉ FN ₄ O ₃ S [M + H] ⁺ 342.12, found m/z 343.1

Example 112: N- (3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 11.6 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.28 (dd, J = 9.0, 2.3 Hz, 1H), 4.35 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H) , 2.98 (s, 3H).

Example 113: N- (3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)ethanesulfonamide;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.83 (dd, J = 9.9, 6.1 Hz, 2H), 7.64 - 7.59 (m, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.55 - 7.46 (m, 1H), 7.28 (dd, J = 9.1, 2.3 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.07 (d, J = 7.4 Hz, 2H) ), 1.24 (d, J = 2.6 Hz, 3H).

Example 114: N- (3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)-4-methylbenzenesulfonamide ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.33 (t, J = 6.4 Hz, 1H), 7.71 (dd, J = 16.0, 8.1 Hz, 3H), 7.62 (d, J = 2.1 Hz, 1H) , 7.51 - 7.41 (m, 2H), 7.38 (d, J = 8.0 Hz, 3H), 7.29 (dd, J = 9.0, 2.3 Hz, 1H), 4.17 (d, J = 6.4 Hz, 2H), 3.90 ( s, 3H), 2.35 (s, 3H).

Example 115: N- (3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonimidamide;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ FN ₅ O ₂ S [M + H] ⁺ 349.1, found m/z 350.1

Example 116: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzoic acid;

¹ H NMR (400 MHz, DMSO- d6 ) δ 13.86 (brs, 1H), 8.12 - 7.93 (m, 3H), 7.64 (dd, J = 9.1, 2.5 Hz, 2H), 7.31 (dd, J = 9.1, 2.2 Hz, 1H), 3.90 (s, 3H).

Example 117: diethyl-(3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphoamidate;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.80 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 11.6 Hz, 1H), 7.52 ( dd, J = 9.0, 2.1 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.28 (dd, J = 9.0, 2.2 Hz, 1H), 5.70 (dd, J = 7.3, 4.6 Hz, 1H) ), 4.16 - 4.09 (m, 2H), 3.98 - 3.90 (m, 4H), 3.89 (s, 3H), 1.21 (t, J = 7.1 Hz, 42.6H).

Example 118: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)phosphonic acid;

¹ H NMR (400 MHz, DMSO- d6 ) δ 8.09 - 7.87 (m, 5H), 7.64 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 9.1, 2.3 Hz, 1H), 3.90 (s) , 3H).

Example 119: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphonic acid;

¹ H NMR (400 MHz, DMSO- d6 ) δ 7.79 (dd, J = 8.6, 6.2 Hz, 3H), 7.60 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.5, 2.2 Hz, 2H) ), 7.28 (dd, J = 9.1, 2.3 Hz, 1H), 3.89 (s, 3H), 3.11 (d, J = 21.5 Hz, 2H).

Example 120: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)boronic acid;

LC-MS (ESI) calcd for C ₁₄ H ₁₃ BFN ₃ O ₃ [M + H] ⁺ 301.10, found m/z 302.1

Example 121: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)boronic acid;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ BN ₃ O ₃ [M + H] ⁺ 297.13, found m/z 298.1

Example 122: N- (4-(5-methoxy-1 H -indol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₆ H ₁₇ N ₃ O ₃ S [M + H] ⁺ 330.24, found m/z 331.1

Example 123: N- (4-(5-methoxy- 1H -benzo[ d ]imidazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ N ₄ O ₃ S [M + H] ⁺ 332.09, found m/z 333.1

Example 124: N- (4-(5-methoxy-1 H -indazol-1-yl)benzyl)sulfamide;

LC-MS (ESI) calcd for C ₁₅ H ₁₆ N ₄ O ₃ S [M + H] ⁺ 332.09, found m/z 333.1

[Experimental example]

The following experiment was performed on Examples 1-124 prepared as described above.

Experimental Example 1: ENPP1 enzyme assay with cGAMP substrate

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

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

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

Example Enzyme activity One C 2 C 3 B 4 B 5 A 6 C 7 C 8 C 9 B 10 B 11 C 12 C 13 C 14 A 15 A 17 C 18 C 19 C 20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 C 31 C 41 A 42 C 43 A 44 A 45 A 46 B 47 B 48 A 49 B 50 A 51 A 52 A 53 C 54 B 55 A 56 A 57 A 58 A 59 A 60 A 61 A 64 A 65 A 66 A 68 B 69 B 70 A 71 A 72 A 73 A 74 A 75 C 76 C 77 C 78 A 79 C 80 A 81 A 82 A 83 A 84 C 85 C 86 C 88 C 89 C 90 C 91 A 92 A 93 A 92 A 93 A 94 A 95 A 96 A 97 A 98 C 101 A 102 A 103 A 104 B 105 C 106 C 107 C 108 B 109 B 110 B 111 C 112 C 113 C 114 C 116 C 117 C 118 C 119 A 122 C

Enzyme activity A B C IC50 (uM) Activity < 1 1 ≤ activity < 10 10 ≤ activity

[Experimental Example 2]

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

Experimental Example 2: HCT116-dual cell Luciferase assay

HCT116-Dual ^TM cells express a gene encoding a secreted luciferase under the control of an interferon-stimulated gene 54 (ISG54) promoter with five interferon-stimulated response elements. The HCT116-Dual ^TM cell line was used to measure and monitor the activity of interferon regulatory factor 3 (IRF3), a type I interferon induction and subsequent signaling, and lucia secreted from the culture medium is used to generate luminescence in a luciferase reaction. .

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

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

Example cell activity 55 B 60 A 61 A 64 A 65 A 71 B 81 A 83 B 92 A 93 A 94 A 100 B

cell activity A B Drainage 1.5 < cell activity Cell activity < 1.5

[Formulation example]

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

Formulation Example 1: Tablet (Direct Pressurization)

After sieving 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 pressurized to make tablets.

Formulation Example 2: Tablet (wet granulation)

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

Formulation Example 3: Powder and Capsule

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

Formulation Example 4: Injection

An injection was prepared by containing 100 mg as an active ingredient, in addition to 180 mg of mannitol, 26 mg of Na2HPO4·12H2O, and 2974 mg of distilled water.

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

Claims (13)

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

In Formula 1,
W ₁ is N or CRa;
W ₂ is N or CRb;
W ₃ is N or CRc;
W ₄ is N or CRd;
W ₅ is N or CRe;
W ₆ is N or CRf;
W ₇ is N or CRg;
Ra, Rb, Rc, Rd, Re, Rf and Rg are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. selected,
R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen; hydroxyl group; halogen group; -CF ₃ ; -(O)CF ₃ ; C1-C13 alkyl group; C1-C6 alkoxy group; amino group (-NR ₇ R ₈ ); nitro group (-N(O)2); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); C6-C10 aryl group; C3-C10 cyclyl group; C3-C10 heteroaryl group; C3-C10 heterocyclyl group; or -C(O)-(C1-C13 alkyl); is
Z is present or not, and when Z is present, Z is -O-, -CO-, -COO-, -C _n H _n+2 -, -O(C _n H _n+2 )-, -(OC ₂ H ₄ ) _n -, -(C ₂ H ₄ O) _n -, -(C _n H _n+2 )O-, -(C _n H _n+2 )CO-, -(C _n H _n+2 )O (C _m H _m+2 )-, -NR ₇ (C _n H _n+2 )-, -(NR ₇ C ₂ H ₄ ) _n -, -(C ₂ H ₄ NR ₇ ) _n -, or -( C _n H _n+2 )NR ₇ -, ; is
n is an integer from 0 to 8,
R ₅ is -A-(R ₆ ) _y ,
A is a C ₃ -C ₁₀ cyclyl group, a C ₅ -C ₁₀ bicyclyl group, a C ₃ -C ₁₀ heterocyclyl group, a C ₆ -C ₁₀ aryl group, or a C ₃ -C ₁₀ heteroaryl group,
wherein R ₆ is hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkenyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); tert-butyloxycarbonyl group (Boc); amino group (-NR ₇ R ₈ ); -(C _m H _m+2 )NR ₇ R ₈ ; nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₇ R ₈ ); ester group (-(C _m H _m+2 )C(O)OR ₇ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-(C _m H _m+2 )NHS(O) ₂ R ₇ ); urea group; sulfamoyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₇ ); sulfonamide group; sulfamoylalkyl group (-(C _m H _m+2 )NHS(O) ₂ NHR ₇ ); sulfamoylalkyl group (-(C _m H _m+2 )NR ₇ S(O) ₂ NHR ₈ ); sulfide group (-(C _m H _m+2 )SR ₇ ); sulfone group (-(C _m H _m+2 )S(O) ₂ R ₇ ); a phospyryl group (-(C _m H _m+2 )P(O)R ₇ R ₈ ); linked to the same carbon as the carbon linked to A to form a 3 to 10 membered saturated ring; It is linked to the same carbon as the carbon linked to A to form a 3 to 10 membered hetero saturated ring containing one or more heteroatoms of N, O and S; It is connected to the carbon connected to A and the carbon adjacent to it to form a 3 to 10 membered saturated ring; or connected to the carbon connected to A and the carbon adjacent to it to form a 3 to 10 membered hetero saturated ring containing one or more heteroatoms of N, O and S;
m is an integer from 0 to 4,
y is an integer from 0 to 4,
The C1-C13 alkyl group, C1-C6 alkoxy group, C1-C6 alkenyl group, or -C(O)-(C1-C13 alkyl) is hydrogen; hydroxyl group; halogen group; C1-C13 alkyl group; C1-C6 alkoxy group; amino group (-NR ₇ R ₈ ); nitro group (-N(O)2); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₇ (C=O)NR ₈ -); sulfonamide group (-NHS(O)2-); sulfide group (-S-); sulfone group (-S(O)2-); a phospyryl group (-P(O)R ₇ R ₈ ); C6-C10 aryl group; C3-C10 heteroaryl group; and one or more substituents selected from the group consisting of a C3-C10 heterocyclyl group,
The C6-C10 aryl group, C3-C10 heteroaryl group, C3-C10 cyclyl group, C3-C10 heterocyclyl group, or C5-C10 bicyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ₇ R ₈ ); a C1-C3 alkyl group unsubstituted or substituted with a halogen or C3-C10 heterocyclyl group; C1-C3 alkoxy group unsubstituted or substituted with halogen or C3-C10 heterocyclyl group; C6-C10 phenoxy; amino group (-NR ₇ R ₈ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₇ R ₈ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₇ (C=O)NR ₈ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₇ R ₈ ); C6-C10 aryl group; It contains one or more substituents selected from the group consisting of a C3-C10 heteroaryl group and a C3-C10 heterocyclyl group,
The R ₇ and R ₈ are each independently hydrogen; C1-C6 alkyl group; C1-C6 alkenyl group; C1-C6 alkynyl group; C6-C10 aryl group; C3-C10 heteroaryl group; C3-C10 heterocyclyl group; amino group (-NH2); nitro group (-N(O)2); -Boc; -NHBoc; or R7 together with the nitrogen or carbon atom linked to R8 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2- , or SO2, optionally substituted with at least one of hydrogen, a C1-C13 alkyl group, a C6-C10 aryl group, a C3-C10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group Forming a 3 to 7 membered saturated ring that can be,
The C3-C10 heteroaryl group and the C3-C10 heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.
The method of claim 1,
W ₁ , W ₂ , W ₃ and W ₄ are each -CH-;
A compound selected from the compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
3. The method of claim 2,
A is a C ₅ -C ₆ cyclyl group, a C ₅ -C ₇ bicyclyl group, a C ₅ -C ₈ heterocyclyl group, a C ₆ -C ₈ aryl group, or a C ₄ -C ₇ heteroaryl group,
A compound selected from the compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
3. The method of claim 2,
wherein A is substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; substituted or unsubstituted piperidine; substituted or unsubstituted furan; substituted or unsubstituted naphthalene; substituted or unsubstituted anthracene; or substituted or unsubstituted phenathrene; substituted or unsubstituted pyridazine; substituted or unsubstituted pyrazine; substituted or unsubstituted imidazole; substituted or unsubstituted pyrazole; substituted or unsubstituted pyrimidine; substituted or unsubstituted pyrrole; substituted or unsubstituted indole; or a substituted or unsubstituted purine; sign,
A compound selected from the compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
5. The method of claim 4,
wherein A is substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; or a substituted or unsubstituted piperidine;
A compound selected from the compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen; hydroxyl group; halogen group; -CF ₃ ; -(O)CF ₃ ; C1-C3 alkyl group; C1-C6 alkoxy group; or an amino group (-NR ₇ R ₈ );
The Z is present or absent, and when Z is present, Z is -C _n H _n+2 -, and n is an integer from 1 to 4,
A compound selected from the compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
W ₁ , W ₂ , W ₃ and W ₄ are each -CH-,
wherein A is substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; Or a substituted or unsubstituted piperidine;
R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen; hydroxyl group; halogen group; -CF ₃ ; -(O)CF ₃ ; C1-C3 alkyl group; C1-C6 alkoxy group; or an amino group (-NR ₇ R ₈ );
The Z is present or absent, and when Z is present, Z is -C _n H _n+2 -, and n is an integer from 1 to 4,
A compound selected from the compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The method of claim 1,
The compound is from the compound represented by Formula 1, tautomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof, characterized in that any one selected from the group consisting of the following compound numbers 1 to 124 Selected compounds:
Compound No. 1: 5-methoxy-1-(piperidin-4-yl) -1H -benzo[ d ][1,2,3]triazolehydrochloride;
Compound No. 2: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methane aniline;
Compound No. 3: 5-methoxy-1-(piperidin-4-ylmethyl) -1H -benzo[ d ][1,2,3]triazole;
Compound No. 4: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)aniline hydrochloride;
Compound No. 5: 4-( 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 6: 4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 7: 4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 8: 4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 9: 4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 10: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 11: 2-(3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;
Compound No. 12: 1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)-N-methylmethanamine hydrochloride;
Compound No. 13: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)cyclopropanamine hydrochloride;
Compound No. 14: (S)-1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;
Compound No. 15: 3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 16: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;
Compound No. 17: 2,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;
Compound No. 18: 2,6-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;
Compound No. 19: 4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;
Compound No. 20: 3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;
Compound No. 21: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;
Compound No. 22: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine ;
Compound No. 23: 3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;
Compound No. 24: 4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;
Compound No. 25: 7-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;
Compound No. 26: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroiso quinoline hydrochloride;
Compound No. 27: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3,4,5-tetrahydro- 1H -benzo[ c ]azepine hydrochloride;
Compound No. 28: 4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorophenyl)methanamine;
Compound No. 29: 1-(isoindorin-5-yl)-5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazole hydrochloride;
Compound No. 30: 3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)methanamine;
Compound No. 31: 3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methylthiophen-2-yl)methanamine hydrochloride;
Compound No. 32: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)sulfonyl)carba mate;
Compound No. 33: tert -butyl((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl ) carbamates;
Compound No. 34: tert -butyl( N- ( 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;
Compound No. 35: tert -butyl( N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;
Compound No. 36: tert -butyl( N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;
Compound No. 37: tert -butyl( N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;
Compound No. 38: tert -butyl( N- (4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;
Compound No. 39: tert -butyl(( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl )sulfamoyl)carbamate;
Compound No. 40: tert -butyl((6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-yl)sulfamoyl)carbamate;
Compound No. 41: N -((3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclopentyl)methyl)sulfamide;
Compound No. 42: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidine-1-sulfonamide;
Compound No. 43: N -((4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)cyclohexyl)methyl)sulfamide;
Compound No. 44: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonamide ;
Compound No. 45: 4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)piperidine-1-sulfonamide;
Compound No. 46: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 47: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide;
Compound No. 48: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)sulfamide hydrochloride;
Compound No. 49: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 50: N- (4-(4-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 51: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide hydrochloride;
Compound No. 52: N- (4-(6-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 53: N- (4-(7-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 54: N- (4-(4,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 55: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 56: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;
Compound No. 57: N- (4-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-difluorobenzyl)sulfamide;
Compound No. 58: N- (4-( 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,5-difluorobenzyl)sulfamide;
Compound No. 59: N- (3-chloro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 60: N- (2-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 61: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;
Compound No. 62: N- (2,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 63: N- (2,6-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 64: N- (3,5-difluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;
Compound No. 65: N- (2,3-difluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-benzyl)sulfamide;
Compound No. 66: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-methylbenzyl)sulfamide;
Compound No. 67: N- (3-cyano-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-benzyl)sulfamide;
Compound No. 68: N- (3-methoxy-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 69: N- (4-(5-methoxy-6-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 70: N- (3-fluoro-4-(5-methoxy-6-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 71: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;
Compound No. 72: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide;
Compound No. 73: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)sulfamide hydrochloride;
Compound No. 74: N- (3-fluoro-4-(5-hydroxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 75: N- (3-fluoro-4-(5-methyl- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 76: N- (4-(5-ethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;
Compound No. 77: N- (3-fluoro-4-(5-isopropoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 78: N- (5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-2-yl)methyl)sulfamide;
Compound No. 79: ( N- (6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)pyridin-3-yl)methyl)sulfamide;
Compound No. 80: N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methyl)sulfamide;
Compound No. 81: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl) -N -methylsulfamide;
Compound No. 82: N -cyclopropyl- N- (4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 83: ( S )-N-(1-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamide;
Compound No. 84: N- (4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 85: N- (3-fluoro-4-(5-trifluoromethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 86: 4-(5-(1,1-difluoroethyl) -1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)methanamine;
Compound No. 87: N- (4-(5-dimethylamino) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;
Compound No. 88: N- (3-fluoro-4-(5-fluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 89: N- (4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 90: N- (3-fluoro-4-(5-trifluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 91: N- (4-(5-difluoromethoxy) -1H -benzo[ d ][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;
Compound No. 92: N- (4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide;
Compound No. 93: N- (3-fluoro-4-(6-fluoro-5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)sulfamide ;
Compound No. 94: 5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)isoindorin-2-sulfonamide;
Compound No. 95: N -5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,3-dihydro- 1H -indene-2- 1) sulfamide;
Compound No. 96: 6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;
Compound No. 97: 7-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1H )sulfonamide ;
Compound No. 98: 8-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-1,3,4,5-tetrahydro- 2H -benzo[ c ]azepine-2-sulfonamide;
Compound No. 99: N- (4-(5,6-dimethoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfa mide;
Compound No. 100: N- (4-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfa mide;
Compound No. 101: 7-fluoro-6-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2( 1 H )-sulfonamide;
Compound No. 102: 5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-isoindorin-2-sulfonamide;
Compound No. 103: N- (5-(5,6-dimethoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-dihydro- 1H -indene-2- 1) sulfamide;
Compound No. 104: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)phenyl)sulfamide hydrochloride;
Compound No. 105: N- (4-((5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)methyl)benzyl)sulfamide hydrochloride;
Compound No. 106: N -((5-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)thiophen-2-yl)methyl)sulfamide;
Compound No. 107: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-5-methoxylthiophen-2-yl)methyl) sulfamide;
Compound No. 108: N- (3-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)-bicyclo[1.1.1]pentan-1-yl) sulfamide;
Compound No. 109: N- (4-(5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)phenyl)sulfamide hydrochloride;
Compound No. 110: N- (4-((5-methoxy- 2H -benzo[ d ][1,2,3]triazol-2-yl)benzyl)sulfamide hydrochloride;
Compound No. 111: 2-(4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;
Compound No. 112: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonamide;
Compound No. 113: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)ethanesulfonamide;
Compound No. 114: N- (3-fluoro-4-(5-methoxy-1 H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)-4-methylbenzenesulfonamide ;
Compound No. 115: N- (3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)methanesulfonimidamide;
Compound No. 116: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzoic acid;
Compound No. 117: diethyl-(3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphoamidate;
Compound No. 118: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenyl)phosphonic acid;
Compound No. 119: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)phosphonic acid;
Compound No. 120: 3-fluoro-4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)benzyl)boronic acid;
Compound No. 121: 4-(5-methoxy- 1H -benzo[ d ][1,2,3]triazol-1-yl)phenethyl)boronic acid;
Compound No. 122: N- (4-(5-methoxy-1 H -indol-1-yl)benzyl)sulfamide;
Compound No. 123: N- (4-(5-methoxy- 1H -benzo[ d ]imidazol-1-yl)benzyl)sulfamide; and
Compound No. 124: N- (4-(5-methoxy-1 H -indazol-1-yl)benzyl)sulfamide.
According to claim 1,
The pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, a salt of an inorganic or organic acid selected from the group consisting of ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid;
A compound selected from the compound represented by Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
The pharmaceutical composition for preventing, alleviating or treating cancer, wherein the compound of any one of claims 1 to 9 is included as an active ingredient.
[10] The compound of any one of claims 1 to 9 as an active ingredient, an ENPP 1 inhibitor.
10. The compound of any one of claims 1 to 9 as an active ingredient, a STING pathway activator.
11. The method of claim 10,
The cancer is a cancer associated with inhibiting ENPP1, a pharmaceutical composition for preventing, alleviating or treating cancer.