Novel benzotriazole derivatives with inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase and their uses

Abstract

An objective of the present invention is to provide a novel benzotriazole derivative compound having ENPP1 inhibitory activity. [Solution] The present invention relates to novel benzotriazole derivative compounds, their tautomers, their pharma- ceutically acceptable salts, their hydrates or their stereoisomers, which are related to compounds for inhibiting ENPP1, compositions for inhibiting ENPP1 and methods for inhibiting ENPP1.

Description

[Technical Field]

[0001] The present invention relates to a compound selected from novel benzotriazole derivative compounds having ectonucleotide pyrophosphatase-phosphodiesterase (ENPP) inhibitory activity, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof, a method for producing the compound, and a pharmaceutical composition containing the compound for preventing, alleviating, or treating cancer. [Background technology]

[0002] Cancer is a group of diseases associated with uncontrolled cell proliferation, which can invade or spread to other parts of the body, reducing quality of life and ultimately leading to death. While genetic aberrations are the direct cause of uncontrolled cancer cell proliferation, failure of immune surveillance and / or the absence of an appropriate immune counterattack against cancer cells also contributes to cancer cell proliferation, leading to the formation of a tumor microenvironment (TME) in which anti-cancer immune responses are suppressed. Therapeutic agents for treating these deadly diseases have broadly been divided into two categories: first, those that directly target cancer cells themselves; and second, those that target components of the tumor microenvironment (TME) to prevent further cancer cell proliferation or survival.

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

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

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

[0006] Pattern recognition receptors (PRRs) are a group of different types of receptors primarily expressed by innate immune cells. They 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) to trigger innate immune responses. One such cytoplasmic DNA sensor, the cGAS-STING pathway (cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes), is involved in 1) the recognition of cytoplasmic DNA resulting from microbial infection or DNA damage, and 2) the production of chemical factors, primarily type 1 interferons (IFNs), via activation of the IRE3 transcription factor.

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

[0008] Systemic administration of type 1 IFN has demonstrated proven efficacy in cancer settings, with systemic injection of IFN-β resulting in tumor regression and improved survival in preclinical mouse models. However, systemic administration of type 1 IFN has the drawback of requiring high doses to reach a therapeutically effective dose for therapeutic efficacy. In this case, drug resistance issues have been reported.

[0009] A recent report published clinical results of exogenous STING agonists (modified cyclic dinucleotides) showed lower than expected disease control rates despite a clear increase in inflammatory cytokine production.

[0010] Therefore, research into new therapeutic methods that can activate the cGAS-STING pathway is needed. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] China published patent CN110575458A [Patent Document 2] International Publication WO2019 / 233300A1 [Patent Document 3] International Publication WO2018 / 119325A1 [Patent Document 4] International Publication WO2018 / 119328A1 [Patent Document 5] International Publication WO2019 / 046778A1 [Patent Document 6] International Publication WO2019 / 177971A1 [Patent Document 7] Japan Publication JP2020-15670 [Patent Document 8] International Publication WO2019 / 051269A1 [Patent Document 9] U.S. Publication US2020 / 0039979A1 [Patent Document 10] International Publication WO2019 / 023635A1 [Patent Document 11] International Publication WO2019 / 051269A1 Summary of the Invention [Problem to be solved by the invention]

[0012] To solve the above problems, the present invention aims to provide a method for increasing the activity of the cGAS-STING pathway.

[0013] Therefore, one aspect of the present invention is to provide novel benzotriazole derivative compounds that have inhibitory activity against ENPP1 and that enhance and / or regulate the production of type 1 interferons (IFNs) in the body.

[0014] Another object of the present invention is to provide a pharmaceutical composition useful for treating, preventing, and alleviating cancer diseases, which contains a novel benzotriazole derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0015] Another object of the present invention is to provide a method for preventing, alleviating, or treating cancer, which comprises administering a novel benzotriazole derivative compound or a pharmaceutical composition containing said compound to a patient or subject in need thereof.

[0016] 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 containing said compound to a patient or subject in need thereof.

[0017] 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 containing the compound to a patient or subject in need thereof.

[0018] Another object of the present invention is to provide a method for preventing, alleviating, or treating a viral disease, which comprises administering a novel benzotriazole derivative compound or a pharmaceutical composition containing said compound to a patient or subject in need thereof.

[0019] Another object of the present invention is to provide a method for preventing, alleviating or treating pathological mineralization of soft tissue, comprising administering a novel benzotriazole derivative compound or a pharmaceutical composition containing said compound to a patient or subject in need thereof.

[0020] Another object of the present invention is to provide a novel benzotriazole derivative compound, or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, as an active ingredient, embodying the following mechanism: In one aspect, the method includes priming a cancer cell with an agent that induces ICD (immunogenic cell death) before stimulating the cGAS-STING pathway. In yet another aspect, the method includes blocking the degradation of endogenous STING ligands before priming a cancer cell with an agent that induces ICD. In another aspect, the method includes using an inhibitor of 2'3'-cGAMP-degrading polypeptides together with an agent that induces ICD for cancer treatment. In one aspect, the present invention provides a method for designing inhibitors of 2'3'-cGAMP-degrading polypeptides and a detailed analytical method for evaluating the enzymatic activity of cGAMP-degrading polypeptides. [Means for solving the problem]

[0021] In order to solve the above problems, the present invention provides a compound selected from a benzotriazole derivative compound represented by the following chemical formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:

[0022] TIFF0007818010000001.tif3749

[0023] In the above Chemical Formula 1,

[0024] W1 is N or CRa;

[0025] W2 is N or CRb;

[0026] W3 is N or CRc;

[0027] W4 is N or CRd;

[0028] W5 is N or CRe;

[0029] W6 is N or CRf;

[0030] W7 is N or CRg;

[0031] 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;

[0032] R1, R2, R3, and R4 each independently represent a hydrogen atom; a hydroxy group; a halogen group; -CF3; -(O)CF3; C1-C 13 Alkyl group; C1-C6 alkoxy group; Amino group (-NR7R8); Nitro group (-N(O)2); Amide group (-(C=O)NR7R8); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); C6-C 10 Aryl group; C3-C 10 Cyclyl group; C3-C 10 Heteroaryl group; C3-C 10 heterocyclyl group; or -C(O)-(C-C 13 alkyl);

[0033] The Z may be present or absent, and when Z is present, Z is -O-, -CO-, -COO-, -C n H n+2 -, -O(C n H n+2 ) - , -(OC2H4) n -, -(C2H4O) n -, -(C n H n+2 )O-, -(C n H n+2 )CO-, -(C n H n+2 )O(C m H m+2 )-, -NR7(C n H n+2 )-, -(NR7C2H4) n -, -(C2H4NR7) n - or -(C n H n+2 )NR7-;

[0034] n is an integer from 0 to 8,

[0035] R5 is -A-(R6) y in,

[0036] The A is C3-C 10 Cyclyl group, C5-C 10 Bicyclyl group, C3-C 10 Heterocyclyl groups, C6-C 10 Aryl group, or C3-C 10 Heteroaryl groups,

[0037] R6 is hydrogen; a hydroxy group; a halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C1-C6 alkenyl group; C6-C 10 Aryl group; C3-C 10 Cyclyl group; C3-C 10 Heteroaryl group; C3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl; tert-butyloxycarbonyl group (Boc); amino group (-NR7R8); -(C m H m+2 )NR7R8; nitro group (-N(O)2); amide group (-(C=O)NR7R8); ester group (-(C m H m+2 )C(O)OR7; carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-(C m H m+2 )NHS(O)2R7); urea group; sulfamoyl group (-(C m H m+2 )NHS(O)2NHR7); sulfonamide group; sulfamoyl alkyl group (-(C m H m+2 )NHS(O)2NHR7); sulfamoyl alkyl group (-(C m H m+2 )NR7S(O)2NHR8); sulfide group (-(C m H m+2 )SR7); sulfone group (-(C m Hm+2 )S(O)2R7); phosphiryl group (-(C m H m+2 )P(O)R7R8); connected to the same carbon as connected to A to form a 3- to 7-membered saturated ring; connected to the same carbon as connected to A to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S; connected to the carbon adjacent to connected to A to form a 3- to 7-membered saturated ring; or connected to the carbon adjacent to connected to A to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S;

[0038] m is an integer from 1 to 4,

[0039] y is an integer from 1 to 4,

[0040] Said C1-C 13 Alkyl group, C1-C6 alkoxy group, C1-C6 alkenyl group or -C(O)-(C1-C 13 Alkyl) is a group consisting of hydrogen, hydroxyl, halogen, C1-C 13 Alkyl group; C1-C6 alkoxy group; Amino group (-NR7R8); Nitro group (-N(O)2); Amide group (-(C=O)NR7R8); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Urea group (-NR7(C=O)NR8-); Sulfonamide group (-NHS(O)2-); Sulfide group (-S-); Sulfone group (-S(O)2-); Phosphylyl group (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 Heteroaryl groups; and C3-C 10 heterocyclyl groups,

[0041] Said C6-C 10 Aryl groups, C3-C 10 Heteroaryl groups, C3-C 10 Cyclyl group, C3-C 10 Heterocyclyl group or C5-C 10A bicyclyl group is a group selected from the group consisting of hydrogen, hydroxyl, halogen, carbonyl (-(C=O)R7R8), halogen, or C3-C 10 The heterocyclyl group is substituted or unsubstituted C1-C3 alkyl group; halogen or C3-C 10 Heterocyclyl groups with substituted or unsubstituted C1-C3 alkoxy groups; C6-C 10 Phenoxy; Amino (-NR7R8); Nitro (-N(O)2); Amide (-(C=O)NR7R8); Carboxylic acid (-C(O)OH); Nitrile (-CN); Urea (-NR7(C=O)NR8-); Sulfonamide (-NHS(O)2-); Sulfide (-S-); Sulfone (-S(O)2-); Phosphylyl (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 Heteroaryl groups and C3-C 10 heterocyclyl groups,

[0042] R7 and R8 are each independently hydrogen; a C1-C6 alkyl group; a C1-C6 alkenyl group; a C1-C6 alkynyl group; a C6-C 10 Aryl group; C3-C 10 Heteroaryl group; C3-C 10 a heterocyclyl group; an amino group (-NH2); a nitro group (-N(O)2); -Boc; NHBoc; or R7, together with the nitrogen or carbon atom connected to R8, can optionally contain at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, and SO2, and can be hydrogen, C1-C 13 Alkyl groups, C6-C 10 Aryl groups, C3-C 10 forming a 3- to 7-membered saturated ring which may be optionally substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group, and a cyano group;

[0043] Said C3-C 10 Heteroaryl groups and C3-C 10 Heterocyclyl groups contain one or more heteroatoms selected from the group consisting of N, O, and S. [Effects of the Invention]

[0044] The compounds according to the present invention have excellent ability to inhibit the activity of ENPP1, and therefore can be used for the treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth.

[0045] The compound according to the present invention, its pharmaceutically acceptable salt, or hydrate, and a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient can effectively suppress ENPP1, activate the STING pathway, and be useful for preventing or treating cancer.

[0046] Cancer diseases that may be treated, prevented, or alleviated by treatment with the compounds of the present invention include stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, 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, etc.

[0047] The compound according to the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a composition containing the compound as an active ingredient can be used as an antiviral therapeutic agent.

[0048] In particular, the compounds according to the present invention are effective in preventing, alleviating or treating diseases in which ENPP1 is involved. DETAILED DESCRIPTION OF THE INVENTION

[0049] definition

[0050] Unless otherwise specified, all numbers, values, and / or expressions expressing ingredients, reaction conditions, and ingredient contents used herein are approximations that reflect various uncertainties in measurement that may arise in obtaining such values, even though these numbers may vary substantially, and should be understood in all cases to be modified by the term "about." Also, when ranges of numerical values ​​are disclosed herein, such ranges are continuous and include all values ​​from the minimum value to the maximum value, inclusive, unless otherwise indicated. Furthermore, when such ranges refer to integers, they include all integers from the minimum value to the maximum value, inclusive, unless otherwise indicated.

[0051] When a range is recited herein for a variable, the variable can be understood to include all values ​​within the stated range, including each of the recited endpoints of the range. For example, the range "5 to 10" can be understood to include not only the values ​​5, 6, 7, 8, 9, and 10, but also any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc., and any value between each integer within the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9. Also, for example, the range "10% to 30%" may be understood to include not only values ​​such as 10%, 11%, 12%, 13%, etc., and all integers up to and including 30%, but also any subranges such as 10% to 15%, 12% to 18%, 20% to 30%, etc., and any value between each reasonable integer within the stated range, such as 10.5%, 15.5%, 25.5%, etc.

[0052] As used herein, the terms "individual," "subject," and "patient" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. None of the terms require or are limited to situations characterized by the supervision (e.g., full-time or intermittent) of a health care professional (e.g., a physician, registered nurse, licensed practical nurse, physician assistant, handyman, or hospice worker).

[0053] "Treatment" refers to an attempt to prevent the development or alteration of a disease lesion. Therefore, "treatment" refers to both therapeutic and prophylactic treatments. The need for treatment includes not only conditions where the disease already exists, but also conditions where the disease must be prevented. In tumor treatment, a therapeutic agent may directly reduce the pathology of tumor cells or make tumor cells more susceptible to treatment with other therapeutic agents, such as radiation and / or chemotherapy and / or immunotherapy. As used herein, the term "alleviation" or "treated" refers to a sign approaching a normalized value measured by a standard statistical test. Here, a sign approaching a normalized value may be, for example, a value that shows less than a 50% difference from a value normalized to a value obtained from a healthy patient or individual, preferably a value that shows less than a 25% difference, more preferably a value that shows less than a 10% difference, and even more preferably a value that does not show a significant difference from the normalized value.

[0054] "Treatment of cancer" means any one or more of the following effects: 1) inhibition of tumor growth, including i) slowing or ii) complete cessation of growth; 2) reduction in tumor cell count; 3) maintenance of tumor size; 4) reduction in tumor size; 5) inhibition of tumor cell infiltration into peripheral organs, including i) reduction, ii) slowing, or iii) complete prevention; 6) inhibition of metastasis, including i) reduction, ii) slowing, or iii) complete prevention; 7) enhancement of the anti-tumor immune response, which may result in i) maintenance of tumor size, ii) reduction in tumor size, iii) slowing of tumor growth, or iv) reduction, slowing, or prevention of invasion.

[0055] As used herein, an "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound disclosed herein to alleviate to some extent the symptoms of the disease or condition being treated (e.g., cancer or inflammatory disease, periodontal disease, or soft tissue calcification). In some embodiments, the result is 1) a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or 2) any other favorable alteration of a biological system in a clinical setting. In some embodiments, an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.

[0056] In some embodiments, an "effective amount" refers to the amount of a disclosed compound in monotherapy or combination therapy, i.e., an amount that, when administered in one or more doses, is effective to inhibit ENPP1 by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), about 60% or more (60% inhibition), about 70% or more (70% inhibition), about 80% or more (80% inhibition), or about 90% or more (90% inhibition), when compared to ENPP1 activity in an individual not treated with the compound, or when compared to ENPP1 activity in an individual before and after treatment with the compound.

[0057] In some embodiments, a "therapeutically effective amount" refers to an amount of a disclosed compound, i.e., an amount administered in one or more doses, in monotherapy or combination therapy, that is effective to reduce a subject's tumor burden by about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more, compared to the tumor burden in a subject not treated with the compound, or compared to the tumor burden in a subject before and after treatment with the compound. As used herein, the term "tumor burden" refers to the total mass of tumor tissue in a subject with cancer.

[0058] In some embodiments, a "therapeutically effective amount" is an amount of a disclosed compound, i.e., an amount that, when administered in one or more doses, is effective in monotherapy or combination therapy to reduce the amount of radiation therapy required to observe tumor shrinkage in a subject by about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more compared to the amount of radiation therapy required to observe tumor shrinkage in a subject not treated with the compound.

[0059] The present invention will now be described in detail.

[0060] The present inventors have continued their research to solve the above problems, and as a result, have developed a compound for inhibiting ENPP1, a composition for inhibiting ENPP1, and a method for inhibiting ENPP1. In one aspect, the present inventors have developed a novel benzotriazole derivative compound for inhibiting ENPP1, its pharmaceutically acceptable salt, hydrate, and stereoisomer, or a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating cancer. In some embodiments, the method includes treating a sample with a cell-permeable ENPP1 inhibitor to inhibit cGAMP hydrolysis by ENPP1. In some embodiments, the method includes administering a therapeutically effective amount of the cell-permeable ENPP1 inhibitor to a patient or subject to treat cancer. The compounds, compositions containing the same, or the compounds and compositions according to one aspect of the present invention can be used for a variety of applications or diseases requiring ENPP1 inhibition.

[0061] cGAS-STING pathway, immunogenic cell killing, and production of type 1 IFNs

[0062] Cytoplasmic double-stranded DNA can enter the cell from the outside through microbial infection or vesicular transfer from nearby dead cells. Cytoplasmic DNA can also arise from damaged genomic or mitochondrial DNA inside the cell. Once present, cytoplasmic DNA can be detected by various DNA sensors, including RNA polymerase III, DDX41, DAI, IFI6, cGAS, LEEFIP1, DHX9, DHX36, Ku70, and AIM2.

[0063] cGAS (cyclic GMP-AMP synthase) is a dimeric cytoplasmic protein that contains two DNA-binding domains and a nucleotidyltransferase domain (which converts ATP and GTP into the cyclic dinucleotide 2'3-cGAMP with 2'5' and 3'5' phosphodiester bonds). cGAMP acts as a second messenger, binding to STING with high affinity (Kd ~ 4 nM) and inducing type 1 IFN expression.

[0064] STING (also known as TMEM173, MITA, and MPYS) is an endoplasmic reticulum (ER)-anchored protein containing four transmembrane domains at its N-terminus and a dimerization domain at its C-terminus. Upon cGAMP binding, STING forms a tetramer and translocates from the ER to the ER-Golgi intermediate compartment. In the Golgi, STING recruits and activates tank-binding kinase 1 (TBK1). Activated TBK1 phosphorylates the C-terminal domain of STING, leading to the recruitment and activation of interferon regulator factor 3 (IRF3). Activated IRF3 then translocates to the nucleus and increases the expression of immune-stimulated genes (ISGs) and type 1 IFNs. Following activation, STING terminates cGAS-STING pathway activation by being delivered to endolysosomes for degradation.

[0065] Immunogenic Cell Killing (ICD)

[0066] ICD (immunogenic cell death) is a type of cell death that triggers the activation of a regulated immune response. This cell death is characterized by apoptotic morphology and maintains the integrity of biological membranes. Furthermore, ICD is characterized by the secretion of DAMPs (e.g., calreticulin, high mobility group box 1 (HMGB1), ATP, and Hsp70 / 90 proteins) as well as the exposure of polypeptides formed by cell-specific or mutated proteins. These exposed polypeptides (acting as antigens) are recognized by dendritic cells (DCs) and subsequently prime effector T lymphocytes for the activation of adaptive immune responses.

[0067] ICD can also be further classified by different types of ICD-inducing agents, such as 1) radiation (e.g., UV radiation or gamma radiation), 2) chemotherapeutic small molecules (e.g., doxorubicin or paclitaxel), and 3) biologics (e.g., polypeptides, oligosaccharides, lipids, or nucleic acids).

[0068] radiation therapy

[0069] Radiation therapy is well known and is used to treat patients suffering from a variety of diseases. Radiation therapy is typically used to kill or inhibit the growth of undesirable tissue (e.g., cancerous tissue). Determined amounts of high-energy electromagnetic radiation and / or high-energy particles are aimed at directly damaging undesirable tissue or lesions in the path of the radiation, while minimizing unintended damage to desirable or healthy tissue.

[0070] Previous research has shown that the impact on normal tissues is greater with fraction size than with the total dose. Therefore, a 1.8-2.0-Gy fractionated dose is considered the standard for conventional radiation therapy, resulting in a longer treatment time. In practice, a small dose per fraction induces tumor effects through mitotic death of cancer cells while simultaneously allowing for recovery from sublethal damage to normal tissues after administration. Stereotactic body radiation therapy (SBRT) is an improved form of radiation therapy that uses sophisticated image guidance to accurately determine the three-dimensional location of tumors and deliver radiation more precisely to cancer cells. In addition to direct cytotoxicity, SBRT can have a substantial effect on tumor cell killing at high doses accompanied by microvascular damage, potentially adding a new mechanism for radiation-induced damage. However, recent reports have shown that high doses of radiation can induce the expression of nuclease enzymes, weakening the effects of radiation on STING-mediated innate immune activation.

[0071] Neoadjuvant therapy

[0072] Neoadjuvant therapy is a treatment in which a therapeutic agent is administered prior to the administration or operation of the main treatment, with the aim of reducing the size and progression of the tumor, facilitating the treatment and increasing the success rate of the main treatment. The therapeutic agents used in this treatment include 1) systemic therapy (chemotherapeutic agents, immunotherapy, or hormonal therapy) and 2) local therapy (radiotherapy). The toxicity of the therapeutic agents used varies depending on the patient, which affects whether the main treatment can be performed, and therefore has the disadvantage of not being applicable to all patients. A recent report showed that when a STING pathway activating agonist, an immune checkpoint inhibitor, and interleukin-2 were administered as neoadjuvant therapy in a breast cancer-bearing (syngeneic) animal model, a superior survival rate was observed compared to when a STING pathway activating agonist was not used, demonstrating the feasibility of neoadjuvant therapy using therapeutic agents that induce STING pathway activation (Lauren E. Milling, et al., can,imm,res,(2021),10.1158 / 2326-6066.CIR-21-0247).

[0073] anti-cancer vaccines

[0074] Anti-cancer vaccines are a treatment method in which selected cancer antigens are administered together with a stimulating agent to activate dendritic cells, which are antigen-targeting cells, stimulating the patient's acquired immune system to recognize and attack specific cancer antigens, thereby suppressing tumor growth and inducing tumor death. Depending on the method by which cancer antigens are administered, they are divided into specific antigen vaccines (injecting one or more selected purified antigens or antigen-producing substances) and non-specific antigen vaccines (inducing the death of cancer cells within the tumor and releasing the antigen). Depending on the form in which specific antigen vaccines are administered into the body, they are divided into DNA vaccines, RNA vaccines, and protein vaccines. Recent reports have shown that the combined administration of STING agonists and protein anti-cancer vaccines exhibits synergistic effects, increasing survival rates and preventing metastasis. It has been shown that therapeutic agents that induce STING pathway activation can be used in combination with anti-cancer vaccines (DNA vaccines, RNA vaccines, and protein vaccines) (Matteo Rossi, et al., front. In imm. (2021), 10.3389 / fimmu.2021.695056).

[0075] CAR-T treatment

[0076] CAR-T cell therapy involves isolating existing T cells from a patient's body, inducing them to express a special receptor (CAR, chimeric antigen receptor) that can recognize cancer cells, expanding them, and then injecting them back into the patient, allowing the CAR-T cells to selectively attack cancer cells that have antigens on their surface. A recent report showed that when CAR-T therapy is combined with a therapeutic agent that induces STING pathway activation, an increase in type 1 interferon increased the intratumoral penetration and cell killing ability of CAR-T cells, enhancing the efficacy of CAR-T cell therapy. This study demonstrated the feasibility of combining CAR-T cells with therapeutic agents that induce STING pathway activation in the tumor microenvironment (Feng Ji, et. al., (2021) J Hematol Oncol (2021) 14:152).

[0077] pathogen

[0078] As described above, intracellular entry of pathogen-derived nucleic acids activates the cGAS-STING pathway, increasing the immune response to the pathogen. In some cases, the pathogen is a virus, such as a DNA virus or an RNA virus. In some cases, the pathogen is a retrovirus. Exemplary viruses that activate the cGAS-STING pathway include, but are not limited to, herpes simplex virus 1 (HSV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), vaccinia virus (VACV), adenovirus, human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), influenza A virus (IAV), human immunodeficiency virus (HIV), or human cytomegalovirus (HCMV). In other 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 Neisseria gonorrhoeae.

[0079] Myocardial regeneration

[0080] Myocardial infarction is a major cause of systolic heart failure. After myocardial infarction, various types of cells infiltrate the cardiac tissue, regenerating or healing the affected tissue. This healing process depends heavily on the communication and regulatory functions between the infiltrated cells, which significantly impact the functional recovery of the myocardial tissue after healing is complete. There is a high need for drugs that can support or promote myocardial tissue regeneration. Recent reports have shown that the activity of the ENPP1 enzyme, expressed by fibrocytes in affected cardiac tissue, causes changes in adenine and purine nucleotides, increasing the death of non-cardiac myocytes and immune cells and hindering cardiac tissue regeneration. It has been reported that inhibiting ENPP1 enzyme activity may promote functional recovery of myocardial tissue (Shen Li, et al., J. Clin. Inv. (2021), 10.1172 / JCI149711).

[0081] Treatment for genetic hypophosphatasia

[0082] Hypophosphatasia is a congenital metabolic disorder characterized by impaired bone regeneration and mineralization due to a deficiency in alkaline phosphatase, an enzyme essential for cellular processes such as muscle metabolism and bone formation. Patients diagnosed with hypophosphatasia should proactively alleviate bone-related symptoms through low-impact physical activity and exercise. Expert management is essential to alleviate symptoms and prevent complications. While bone marrow transplantation has been shown to be effective in severe cases, its effectiveness remains unproven. Recent reports suggest that hypophosphatasia results from an excess of pyrophosphate in the body due to alkaline phosphatase deficiency, which is produced by ENPP1 activity. Inhibiting ENPP1 activity may improve the symptoms of hypophosphatasia (RallyBio corporate presentation (2021)).

[0083] Phosphodiesterases

[0084] Phosphodiesterases (PDEs) include cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, restriction endonucleases, and many other less well-known small molecule phosphodiesterases. An exemplary group of PDE enzymes is the important enzyme that hydrolyzes the cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) to their inactive 5'-monophosphates.

[0085] Cyclic nucleotide phosphodiesterases comprise a group of enzymes that cleave the phosphodiester bond of the cyclic nucleotide second messenger molecules cAMP and cGMP, regulating the localization, duration, and amplification of cyclic nucleotide signals within subcellular domains.

[0086] Ecto-nucleotide pyrophosphatases / phosphodiesterases

[0087] The phosphodiesterase class also includes ectonucleotide pyrophosphatases / phosphodiesterases. Ectonucleotide pyrophosphatases / phosphodiesterases (ENPPs) or nucleotide pyrophosphatases / phosphodiesterases (NPPs) are a group of ectonucleotidase enzymes that hydrolyze the pyrophosphate and phosphodiester bonds of their substrates to generate nucleotide 5'-monophosphates (or phospholipids and phosphocholines). In some embodiments, the ENPP enzyme family includes seven enzyme members (ENPP-1, ENPP-2, ENPP-3, ENPP-4, ENPP-5, ENPP-6, and ENPP-7) of ectonucleotidases that have similar protein structures and are found on the surface of cells.

[0088] Each ENPP enzyme has a modular structure containing a catalytic domain of approximately 400 amino acids. This catalytic domain is not related to phospholipases, nuclease hydrolases, or ectonucleotide triphosphate diphosphohydrolases, even if they exhibit overlapping activities. ENPP1 and 3 possess an N-terminal transmembrane domain and a C-terminal nuclease-like domain and are predicted to be type 2 single-spanning transmembrane proteins, with their catalytic domains directed to the extracellular space. ENPP2, which lacks an N- or C-terminal transmembrane domain, possesses an N-terminal signal peptide and is predicted to be secreted extracellularly. ENPP4, 5, 6, and 7, which contain a putative N-terminal signal peptide and a C-terminal transmembrane domain, are predicted to be type 1 single-spanning transmembrane proteins, with their catalytic domains directed to the extracellular space.

[0089] ENPP1, 2, and 3 are known to use nucleotides and their derivatives as substrates to generate nucleoside monophosphates (ENPP1, 2, and 3) or nucleoside diphosphates (ENPP1 and 2). Only ENPP2 is known to use lysophospholipids. ENPP6 and 7 are known to use choline phosphate esters as substrates to generate choline phosphate. ENPP4 and 5 have no known substrates.

[0090] ENPP1, also known as NPP1 or PC-1, is a type 2 transmembrane glycoprotein expressed in many tissues (pancreas, kidney, bladder, and liver). ENPP1 is important for purinergic signaling, which plays an important role in regulating cardiovascular, neuronal, immune, and hematologic functions in mammals. ENPP1 catalyzes the hydrolysis of ATP or GTP to AMP or GMP, generating inorganic pyrophosphate (PPi). Generally, inorganic pyrophosphate regulates bone and cartilage mineralization, and thus ENPP1-mediated PPi production allows ENPP1 to serve as a central regulator of bone and cartilage development. In contrast to the inhibitory effects of excess ENPP1-generated PPi in joint tissues, calcium phosphate formation from ENPP1-generated PPi is essential for bone mineralization. ENPP1 has broad specificity and hydrolyzes a variety of substrates, including phosphodiester bonds in nucleotides and nucleotide sugars, and pyrophosphate bonds in nucleotides and nucleotide sugars.

[0091] Recently, ENPP1 has been shown to play an important role in immunological responses to various external signals that activate the cGAS-STING pathway. Exploratory studies of the enzymatic activity that degrades the cGAMP molecule revealed that ENPP1 functions as the primary hydrolase of cGAMP. Consistent with these findings, it has been reported that the half-life of cGAMP is highly dependent on ENPP1, demonstrating a significantly longer half-life of cGAMP in ENPP1 knockout mice.

[0092] A bisphosphothionate analog of cGAMP that is resistant to ENPP1 hydrolysis has been shown to activate STING 10-fold more effectively than cGAMP, suggesting that delaying or reducing cGAMP hydrolysis by inhibiting ENPP1 significantly increases STING activation. ENPP1 inhibition has been reported to attenuate pseudorabies virus infection and reduce Mycobacterium tuberculosis infection by inducing sustained cGAMP and activating the STING pathway.

[0093] Therefore, one aspect of the present invention provides an inhibitor of ENPP1, a cGAMP-degrading polypeptide.

[0094] In one aspect, the ENPP1 inhibitor is a reversible inhibitor.

[0095] In one aspect, the ENPP1 inhibitor is a competitive inhibitor.

[0096] In another aspect, the ENPP1 inhibitor is an allosteric inhibitor.

[0097] In another aspect, the ENPP1 inhibitor is an irreversible inhibitor.

[0098] In one aspect, the ENPP1 inhibitor binds to a PDE (phosphodiesterase) catalytic domain to which AMP or GMP is bound.

[0099] In one aspect, the inhibitor of ENPP1 binds to the PDE catalytic domain but binds weakly when AMP is bound.

[0100] In another aspect, the ENPP1 inhibitor does not inhibit the ATP hydrolysis activity of the catalytic domain or only weakly inhibits the ATP hydrolysis activity.

[0101] How to inhibit ENPP1

[0102] As mentioned above, the present invention includes the following: 1) an ENPP1 inhibitor; 2) a method for inhibiting the ENPP1 enzyme with the ENPP1 inhibitor; 3) a method for inhibiting the hydrolase activity of ENPP1 against cGAMP; 4) a method for enhancing the signal output of STING pathway activation; and 5) a method for suppressing tumor growth in an appropriate mouse tumor model in a monotherapy or combination therapy setting.

[0103] In some embodiments, inhibiting ENPP1 means that ENPP1 activity is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more, compared to a control group not treated with the compound. In some embodiments, inhibiting ENPP1 means that ENPP1 activity is reduced by 2-fold or more, e.g., 3-fold or more, 5-fold or more, 10-fold or more, 100-fold or more, or 1000-fold or more, compared to a control group not treated with the compound.

[0104] In some embodiments, the cell-permeable ENPP1 inhibitor is an inhibitor as described herein, ie, any one of a benzotriazole derivative compound represented by Chemical Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0105] TIFF0007818010000002.tif3749

[0106] In some embodiments, the permeable ENPP1 inhibitor is one of the following compounds:

[0107] Compound No. 1: 5-methoxy-1-(piperidin-4-yl)-1H-benzo[d][1,2,3]triazole hydrochloride;

[0108] Compound No. 2: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclohexyl)methaneaniline;

[0109] Compound No. 3: 5-methoxy-1-(piperidin-4-ylmethyl)-1H-benzo[d][1,2,3]triazole;

[0110] Compound No. 4: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)aniline hydrochloride;

[0111] Compound No. 5: 4-(1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0112] Compound No. 6: 4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0113] Compound No. 7: 4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0114] Compound No. 8: 4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0115] Compound No. 9: 4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0116] Compound No. 10: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0117] Compound No. 11: 2-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

[0118] Compound No. 12: 1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)-N-methylmethanamine hydrochloride;

[0119] Compound No. 13: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)cyclopropanamine hydrochloride;

[0120] Compound No. 14: (S)-1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

[0121] Compound No. 15: 3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0122] Compound No. 16: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0123] Compound No. 17: 2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0124] Compound No. 18: 2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0125] Compound No. 19: 4-(5-ethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0126] Compound No. 20: 3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0127] Compound No. 21: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0128] Compound No. 22: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0129] Compound No. 23: 3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0130] Compound No. 24: 4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0131] Compound No. 25: 7-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0132] Compound No. 26: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0133] 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;

[0134] Compound No. 28: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,5-difluorophenyl)methanamine;

[0135] Compound No. 29: 1-(isoindolin-5-yl)-5,6-dimethoxy-1H-benzo[d][1,2,3]triazole hydrochloride;

[0136] Compound No. 30: 3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)methanamine;

[0137] Compound No. 31: 3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-5-methylthiophen-2-yl)methanamine hydrochloride;

[0138] Compound No. 32: tert-butyl ((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)sulfonyl)carbamate;

[0139] Compound No. 33: tert-butyl ((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl)carbamate;

[0140] Compound No. 34: tert-butyl (N-(1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0141] Compound No. 35: tert-butyl (N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0142] Compound No. 36: tert-butyl (N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0143] Compound No. 37: tert-butyl (N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0144] Compound No. 38: tert-butyl (N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0145] Compound No. 39: tert-butyl ((S)—N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0146] Compound No. 40: tert-butyl ((6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamoyl)carbamate;

[0147] Compound No. 41: N-((3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclopentyl)methyl)sulfamide;

[0148] Compound No. 42: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidine-1-sulfonamide;

[0149] Compound No. 43: N-((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclohexyl)methyl)sulfamide;

[0150] Compound No. 44: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonamide;

[0151] Compound No. 45: 4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)piperidine-1-sulfonamide;

[0152] Compound No. 46: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0153] Compound No. 47: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamide;

[0154] Compound No. 48: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamide hydrochloride;

[0155] Compound No. 49: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0156] Compound No. 50: N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0157] Compound No. 51: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide hydrochloride;

[0158] Compound No. 52: N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0159] Compound No. 53: N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0160] Compound No. 54: N-(4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0161] Compound No. 55: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0162] Compound No. 56: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0163] Compound No. 57: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-2,3-difluorobenzyl)sulfamide;

[0164] Compound No. 58: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-3,5-difluorobenzyl)sulfamide;

[0165] Compound No. 59: N-(3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0166] Compound No. 60: N-(2-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0167] Compound No. 61: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0168] Compound No. 62: N-(2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0169] Compound No. 63: N-(2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0170] Compound No. 64: N-(3,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)sulfamide;

[0171] Compound No. 65: N-(2,3-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)sulfamide;

[0172] Compound No. 66: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbenzyl)sulfamide;

[0173] Compound No. 67: N-(3-cyano-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-benzyl)sulfamide;

[0174] Compound No. 68: N-(3-methoxy-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0175] Compound No. 69: N-(4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0176] Compound No. 70: N-(3-fluoro-4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0177] Compound No. 71: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0178] Compound No. 72: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)sulfamide;

[0179] Compound No. 73: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)sulfamide hydrochloride;

[0180] Compound No. 74: N-(3-fluoro-4-(5-hydroxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0181] Compound No. 75: N-(3-fluoro-4-(5-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0182] Compound No. 76: N-(4-(5-ethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0183] Compound No. 77: N-(3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0184] Compound No. 78: N-(5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-2-yl)methyl)sulfamide;

[0185] Compound No. 79: (N-(6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-3-yl)methyl)sulfamide;

[0186] Compound No. 80: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-N-methyl)sulfamide;

[0187] Compound No. 81: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-N-methylsulfamide;

[0188] Compound No. 82: N-cyclopropyl-N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0189] Compound No. 83: (S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamide;

[0190] Compound No. 84: N-(4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0191] Compound No. 85: N-(3-fluoro-4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0192] Compound No. 86: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0193] Compound No. 87: N-(4-(5-dimethylamino)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0194] Compound No. 88: N-(3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0195] Compound No. 89: N-(4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0196] Compound No. 90: N-(3-fluoro-4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0197] Compound No. 91: N-(4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0198] Compound No. 92: N-(4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0199] Compound No. 93: N-(3-fluoro-4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0200] Compound No. 94: 5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)isoindoline-2-sulfonamide;

[0201] Compound No. 95: N-5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-1H-inden-2-yl)sulfamide;

[0202] Compound No. 96: 6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0203] Compound No. 97: 7-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0204] 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;

[0205] Compound No. 99: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfamide;

[0206] Compound No. 100: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfamide;

[0207] Compound No. 101: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

[0208] Compound No. 102: 5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-isoindoline-2-sulfonamide;

[0209] Compound No. 103: N-(5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-dihydro-1H-inden-2-yl)sulfamide;

[0210] Compound No. 104: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)phenyl)sulfamide hydrochloride;

[0211] Compound No. 105: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzyl)sulfamide hydrochloride;

[0212] Compound No. 106: N-((5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)thiophen-2-yl)methyl)sulfamide;

[0213] Compound No. 107: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-5-methoxythiophen-2-yl)methyl)sulfamide;

[0214] Compound No. 108: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-bicyclo[1.1.1]pentan-1-yl)sulfamide;

[0215] Compound No. 109: N-(4-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)phenyl)sulfamide hydrochloride;

[0216] Compound No. 110: N-(4-((5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)benzyl)sulfamide hydrochloride;

[0217] Compound No. 111: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

[0218] Compound No. 112: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)methanesulfonamide;

[0219] Compound No. 113: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)ethanesulfonamide;

[0220] Compound No. 114: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-4-methylbenzenesulfonamide;

[0221] Compound No. 115: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)methanesulfonimidamide;

[0222] Compound No. 116: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzoic acid;

[0223] Compound No. 117: diethyl-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)phosphoramidite;

[0224] Compound No. 118: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)phosphonic acid;

[0225] Compound No. 119: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)phosphonic acid;

[0226] Compound No. 120: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)boronic acid;

[0227] Compound No. 121: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)boronic acid;

[0228] Compound No. 122: N-(4-(5-methoxy-1H-indol-1-yl)benzyl)sulfamide;

[0229] Compound No. 123: N-(4-(5-methoxy-1H-benzo[d]imidazol-1-yl)benzyl)sulfamide; and

[0230] Compound No. 124: N-(4-(5-methoxy-1H-indazol-1-yl)benzyl)sulfamide.

[0231] In some embodiments, compounds of the invention have an ENPP1 inhibition profile that reflects activity against additional enzymes, hi some embodiments, compounds of the invention specifically inhibit ENPP1 without unintended inhibition of one or more other enzymes.

[0232] In some embodiments, compounds of the present invention are useful in inhibition assays, e.g., IC 50 or EC 50 In some embodiments, the compounds of the present invention inhibit ENPP1 as determined by assays that determine enzyme activity in a cell-free system or a cell-based system after treatment with the compounds of the present invention compared to a control by measuring the activity of the enzyme in a cell-free system or a cell-based system, respectively. In some embodiments, the compounds of the present invention inhibit ENPP1 with an IC of 10 μM or less, e.g., 3 μM or less, 1 μM or less, 500 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 30 nM or less, 10 nM or less, 5 nM or less, 3 nM or less, 1 nM or less, or even lower.50 value (or EC 50 value).

[0233] Assay procedures that can be used to determine the activity of ENPP1 can include many, but are not limited to, cell-free assay systems such as avidity assays, assays using purified enzymes, cellular assays in which the phenotype of cells is measured, such as gene expression assays, and in vivo assays associated with specific animals.

[0234] In some embodiments, the methods of the present invention are methods for reducing cancer cell proliferation, the methods comprising treating cells 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 conjunction with chemotherapy. Any available cancer cells may be used.

[0235] Treatment method

[0236] As mentioned above, the present invention includes a method for inhibiting ENPP1 activity toward cGAMP, thereby increasing cGAMP levels and / or modulating downstream factors of the STING pathway. Recent reports have shown that ENPP1 inhibition can modulate STING activity in vivo, and thus may be used in the treatment of various diseases, such as cancer immunotherapy or the treatment of infectious diseases. As described above, the method of the present invention is a method for increasing STING-mediated responses in a subject and modulating an immune response.

[0237] In some embodiments, the STING-mediated response includes increasing interferon (e.g., type 1 interferon, type 3 interferon) production in the subject. Interferons (IFNs) are a group of signaling proteins produced and released by host cells in response to the presence of one or more pathogens to enhance the defense of surrounding cells against the pathogen(s). IFNs also have a variety of other functions: 1) activating immune cells, such as NK cells and macrophages; and 2) increasing 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 IFNs 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 unique cell surface receptor complex known as the IFN-α / β receptor (IFNAR), which consists of the IFNAR1 and IFNAR2 chains.

[0238] Interferons have been investigated as cancer therapeutics due to their antitumor activity, which exhibits two distinct effects: tumor-intrinsic and / or immunomodulatory. IFNs regulate the expression of numerous genes that directly affect tumor cell growth, proliferation, differentiation, survival, migration, and other specialized functions. In some cases, in vitro treatment with type 1 IFNs has a direct antiproliferative effect due to the IFN-induced prolongation of all stages of the cell cycle. In some cases, CRKL, one of the CRK proteins activated by type 1 IFNs, interacts with the tumor-suppressor small G-protein RAP1A and inhibits RAS family GTPases, resulting in cancer cell growth arrest. IFNs are known to regulate two major apoptotic responses: the extrinsic (death receptor-mediated pathway) and the intrinsic (mitochondrial) pathway. In response to type 1 IFNs, upregulation of sensor protein activation (e.g., DR receptors) occurs, which induces apoptosis in tumor cells.

[0239] IFNs exert an external effect on tumors through the regulation of processes such as angiogenesis, osteoclastogenesis, and immunity. Both endogenous and exogenous type 1 IFNs play a key role in anti-cancer immune activity. For example, they enhance the activity of α / β T cells, γ / δ T cells, NK cells, and dendritic cells, as well as suppress the activity of immune-suppressive cells, such as regulatory T cells, bone marrow-derived suppressor cells, and tumor-associated macrophages. Furthermore, type 1 IFNs act directly on tumor cells to improve antigen expression and upregulate numerous immune-interacting molecules, such as stress ligands recognized by major histocompatibility complex class 1 (MHC I) and gonad-encoded immune receptors.

[0240] One aspect of the method includes administering a therapeutically effective amount of an ENPP1 inhibitor to a subject with cancer to treat the subject. In one embodiment, the subject may be diagnosed with or suspected of having cancer. Any suitable ENPP1 inhibitor may be administered to the subject. In one embodiment, the cancer is any one selected from adrenal, liver, kidney, bladder, breast, colon, stomach, ovary, cervix, uterus, esophagus, colorectum, prostate, pancreas, lung (small cell and non-small cell), thyroid, carcinoma, sarcoma, glioblastoma, melanoma, and various head and neck cancers. In one embodiment, the cancer is lymphoma.

[0241] In one embodiment, the effective amount of the compound may be in the range of about 10 ng to about 100 mg, e.g., about 10 ng to about 50 ng, about 50 ng to about 150 ng, about 150 ng to about 250 ng, about 250 ng to about 500 ng, about 500 ng to about 750 ng, about 750 ng to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 50 μg, about 50 μg to about 150 μg, about 150 μg to about 250 μg, about 250 μg to about 500 μg, about 500 μg to about 750 μg, about 750 μg to about 1 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, or about 50 mg to about 100 mg. The amount may be a single dose or a total daily amount. The total daily amount may range from 10 ng to 100 mg, from 100 mg to about 500 mg, or from 500 mg to about 1000 mg.

[0242] In one embodiment, a single dose of the compound is administered. In another embodiment, multiple doses are administered. When the multiple doses are administered over a period of time, the compound may be administered twice daily (bid), daily (qd), every other day (qod), every third day, three times per week (tiw), or twice per week (biw).

[0243] Combination therapy

[0244] The ENPP1 inhibitor compound of the present invention may be administered to a subject alone or in combination with an additional active agent or therapy, such as radiation therapy. The terms "agent," "compound," and "drug" are used interchangeably herein. In one embodiment, the method of the present invention further comprises administering to the subject an additional agent, such as a small molecule, a chemotherapeutic agent, an antibody, an antibody-drug conjugate, an aptamer, a protein, an immune checkpoint inhibitor, or radiation therapy, either simultaneously or sequentially.

[0245] "Co-administration" or "in combination with" includes administering two or more therapeutic agents simultaneously, concurrently, or sequentially, without specific time limitations. In some embodiments, each agent or formulation is present in a cell or a subject's body at the same time and exerts a simultaneous biological or therapeutic effect. In some embodiments, each therapeutic agent is in the same composition or unit dosage form. In some embodiments, each therapeutic agent is in a separate composition or unit dosage form. In some embodiments, the first formulation may be administered prior to (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 subsequent to (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 after) administration of the second therapeutic agent.

[0246] "Concomitant administration" of a known therapeutic agent or additional therapy with a composition comprising a disclosed compound of the present invention means administering the compound and the second agent or additional therapy such that both the known formulation and the composition of the disclosed compound have a therapeutic effect. Such concomitant administration can include simultaneous or prior administration of the drug in conjunction with administration of the compound of the present invention. While the routes of administration of the two formulations can vary, representative administration routes are described in detail below. One of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence, and dosages of the drug or therapy and the disclosed compound.

[0247] For the treatment of cancer, the ENPP1 inhibitor compounds may be administered in combination with chemotherapeutic agents selected from the group consisting of alkylating agents, antimetabolites, antitumor antibiotics, plant alkaloids, taxanes, nucleoside analogs, anthracyclines, thymidylate-targeted drugs, cell death regulators, cell cycle regulator inhibitors, colony-stimulating factor-1 receptor inhibitors, CD47 inhibitors, and others.

[0248] Combination with immunotherapy

[0249] For the treatment of cancer, the ENPP1 inhibitor compound may be administered in combination with an immunotherapeutic agent. An immunotherapeutic agent is any suitable agent used to treat cancer by inducing, enhancing, or suppressing an immune response. In some embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. Any immune checkpoint inhibitor may be used, including, but not limited to, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, scheduled death 1 (PD-1) inhibitors, and scheduled death ligand 1 (PD-L1) inhibitors. Exemplary immune checkpoint inhibitors may include, but are not limited to, ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, and the like. In some embodiments, the immunotherapeutic agent is an immune cell therapy. Any suitable cell therapy may be used, including, but not limited to, chimeric antigen receptor T cell therapy, chimeric antigen receptor NK cell therapy, and other cell therapies.

[0250] For the treatment of cancer, the ENPP1 inhibitor compound can be administered in combination with a suitable cancer vaccine therapy, such as a dendritic cell vaccine formulation that promotes Th1 / Th17 immunity. In some cases, the ENPP1 inhibitor compound is suitable for use as an adjuvant therapeutic agent in combination with Th17-inducing vaccination.

[0251] Combination with radiation therapy

[0252] In cancer treatment methods, the ENPP1 inhibitor compound may be administered in conjunction with radiation therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after radiation therapy. The combination of radiation therapy and administration of a compound of the present invention can provide a synergistic therapeutic effect. When an individual is treated with radiation (RT) at a dose and / or frequency tailored to the individual during radiation therapy (RT), cGAMP production can be induced. The induced cGAMP level can be increased, for example, compared to the level achieved with RT alone, by the ENPP1 inhibitor compound preventing the degradation of cGAMP, thereby improving the therapeutic efficacy in the subject. Thus, details of the methods of the present invention include administering a reduced dose and / or frequency / therapy of radiation therapy compared to the dose 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 present invention at a dose and / or frequency effective to reduce the risk of radiation damage to the subject, e.g., effective to reduce the risk of radiation damage expected to occur at a therapeutically effective dose.

[0253] In one embodiment, the method includes administering an ENPP1 inhibitor to a subject before administering radiation therapy. In another embodiment, the method includes administering an ENPP1 inhibitor to a subject after exposing the subject to radiation therapy. In another embodiment, the method includes sequentially administering radiation therapy, a subsequent ENPP1 inhibitor, and a subsequent immune checkpoint inhibitor to a subject in need thereof.

[0254] Combination with anti-cancer vaccines

[0255] In the case of cancer treatment methods, the ENPP1 inhibitor compound may be administered together with an anti-cancer vaccine therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after the administration of an anti-cancer vaccine therapy.

[0256] Combination with CAR-T

[0257] In the case of cancer treatment methods, the ENPP1 inhibitor compound may be administered together with CAR-T cell therapy. In some embodiments, the ENPP1 inhibitor compound may be administered before or after the administration of CAR-T cell therapy.

[0258] Monotherapy

[0259] Myocardial regeneration promotion therapy

[0260] In the case of myocardial regeneration therapy, in one aspect, the method includes administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a lesion due to myocardial infarction to treat the subject.

[0261] Hypophosphatemia Treatment

[0262] In one aspect, a method for treating hypophosphatemia includes administering a therapeutically effective amount of an ENPP1 inhibitor to a subject having a lesion caused by hereditary hypophosphatemia to treat the subject.

[0263] Pharmaceutical Composition

[0264] Pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers, or diluents, are readily available to one of ordinary skill in the art. Pharmaceutically acceptable auxiliary substances, such as pH adjusting agents, buffering agents, tonicity adjusting agents, stabilizers, wetting agents, and the like, are readily available to one of ordinary skill in the art.

[0265] In some embodiments, the compounds of the present invention are formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers with various strengths ranging from 5 mM to 1000 mM. In some embodiments, the aqueous buffer contains an agent that provides an isotonic solution. Such agents include, but are not limited to, sodium chloride, sugars such as mannitol, dextrose, and sucrose. In some embodiments, the aqueous buffer further contains a non-ionic surfactant such as polysorbate 20 or 80. Optionally, the formulation can further contain a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In other embodiments, the dosage form is stored at about 4°C. The formulation can also be lyophilized, and these typically contain a cryoprotectant such as sucrose, trehalose, lactose, maltose, or mannitol. The lyophilized formulation can be stored at room temperature for extended periods of time.

[0266] As used herein, pharmaceutical compositions may comprise or consist essentially of the compounds disclosed herein, or pharmaceutically acceptable salts, isomers, or tautomers thereof. Furthermore, pharmaceutical compositions are provided that may comprise or consist essentially of one or more additional active agents of interest. Any convenient active agent may be used in the present method together with the compounds of the present invention. In one embodiment, the compounds of the present invention and immune checkpoint inhibitors, as well as the additional therapeutic agents described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. In other embodiments, the compounds of the present invention and chemotherapeutic agents (particularly chemotherapeutic agents capable of inducing cGAMP production in vivo), and the additional therapeutic agents described herein for combination therapy may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. The compounds of the present invention and the second active agent (if present) may be administered by the same or different routes of administration. Therapeutic agents may be administered by any suitable means, including, but not limited to, oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, or intratumoral injection into the affected organ.

[0267] The compounds of the present invention can be administered in unit dosage form and can be prepared by any method well known in the art. Such methods include combining the compounds of the present invention with a pharmaceutically acceptable carrier or diluent, which constitutes one or more accessory ingredients. The pharmaceutically acceptable carrier is selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in that it is compatible with the other ingredients of the formulation and is not harmful to the subject or patient. The carrier may be solid or liquid, and the type is selected based on the type of administration commonly used.

[0268] Examples of suitable solid carriers include lactose, sucrose, gelatin, agar, and bulk powders. Examples of suitable liquid carriers include solutions and / or suspensions reconstituted from water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, such as esters, emulsions, syrups or elixirs, suspensions, and non-effervescent granules. Such liquid carriers may contain, for example, compatible solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0269] Various aspects of the present invention will now be described.

[0270] One aspect of the present invention provides a compound selected from a benzotriazole derivative compound represented by the following chemical formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:

[0271] TIFF0007818010000003.tif3749

[0272] In the above Chemical Formula 1,

[0273] W1 is N or CRa;

[0274] W2 is N or CRb;

[0275] W3 is N or CRc;

[0276] W4 is N or CRd;

[0277] W5 is N or CRe;

[0278] W6 is N or CRf;

[0279] W7 is N or CRg;

[0280] 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;

[0281] R1, R2, R3, and R4 each independently represent a hydrogen atom; a hydroxy group; a halogen group; -CF3; -(O)CF3; C1-C 13 Alkyl group; C1-C6 alkoxy group; Amino group (-NR7R8); Nitro group (-N(O)2); Amide group (-(C=O)NR7R8); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); C6-C 10 Aryl group; C3-C 10 Cyclyl group; C3-C 10 Heteroaryl group; C3-C 10 heterocyclyl group; or -C(O)-(C-C 13 alkyl);

[0282] The Z may be present or absent, and when Z is present, Z is -O-, -CO-, -COO-, -C n H n+2 -, -O(C n H n+2 ) - , -(OC2H4) n -, -(C2H4O) n -, -(C n H n+2 )O-, -(C n H n+2 )CO-, -(C n Hn+2 )O(C m H m+2 )-, -NR7(C n H n+2 )-, -(NR7C2H4) n -, -(C2H4NR7) n - or -(C n H n+2 )NR7-;

[0283] n is an integer from 0 to 8,

[0284] R5 is -A-(R6) y in,

[0285] The A is C3-C 10 Cyclyl group, C5-C 10 Bicyclyl group, C3-C 10 Heterocyclyl groups, C6-C 10 Aryl group, or C3-C 10 Heteroaryl groups,

[0286] R6 is hydrogen; a hydroxy group; a halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C1-C6 alkenyl group; C6-C 10 Aryl group; C3-C 10 Cyclyl group; C3-C 10 Heteroaryl group; C3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl; tert-butyloxycarbonyl group (Boc); amino group (-NR7R8); -(C m H m+2 )NR7R8; nitro group (-N(O)2); amide group (-(C=O)NR7R8); ester group (-(C m H m+2 )C(O)OR7; carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-(C m H m+2 )NHS(O)2R7); urea group; sulfamoyl group (-(C m H m+2)NHS(O)2NHR7); sulfonamide group; sulfamoyl alkyl group (-(C m H m+2 )NHS(O)2NHR7); sulfamoyl alkyl group (-(C m H m+2 )NR7S(O)2NHR8); sulfide group (-(C m H m+2 )SR7); sulfone group (-(C m H m+2 )S(O)2R7); phosphiryl group (-(C m H m+2 )P(O)R7R8); connected to the same carbon atom as connected to A to form a 3- to 7-membered saturated ring; connected to the same carbon atom as connected to A to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S; connected to the carbon atom adjacent to connected to A to form a 3- to 7-membered saturated ring; or connected to the carbon atom adjacent to connected to A to form a 3- to 7-membered saturated heterocyclic ring containing one or more heteroatoms selected from N, O, and S;

[0287] m is an integer from 0 to 4,

[0288] y is an integer from 0 to 4,

[0289] Said C1-C 13 Alkyl group, C1-C6 alkoxy group, C1-C6 alkenyl group or -C(O)-(C1-C 13 Alkyl) is a group consisting of hydrogen, hydroxyl, halogen, C1-C 13 Alkyl group; C1-C6 alkoxy group; Amino group (-NR7R8); Nitro group (-N(O)2); Amide group (-(C=O)NR7R8); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Urea group (-NR7(C=O)NR8-); Sulfonamide group (-NHS(O)2-); Sulfide group (-S-); Sulfone group (-S(O)2-); Phosphylyl group (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 Heteroaryl groups; and C3-C 10heterocyclyl groups,

[0290] Said C6-C 10 Aryl groups, C3-C 10 Heteroaryl groups, C3-C 10 Cyclyl group, C3-C 10 Heterocyclyl group or C5-C 10 A bicyclyl group is a group selected from the group consisting of hydrogen, hydroxyl, halogen, carbonyl (-(C=O)R7R8), halogen, or C3-C 10 The heterocyclyl group is substituted or unsubstituted C1-C3 alkyl group; halogen or C3-C 10 Heterocyclyl groups with substituted or unsubstituted C1-C3 alkoxy groups; C6-C 10 Phenoxy; Amino (-NR7R8); Nitro (-N(O)2); Amide (-(C=O)NR7R8); Carboxylic acid (-C(O)OH); Nitrile (-CN); Urea (-NR7(C=O)NR8-); Sulfonamide (-NHS(O)2-); Sulfide (-S-); Sulfone (-S(O)2-); Phosphylyl (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 containing one or more substituents selected from the group consisting of heteroaryl groups and C3-C10 heterocyclyl groups;

[0291] R7 and R8 are each independently hydrogen; a C1-C6 alkyl group; a C1-C6 alkenyl group; a C1-C6 alkynyl group; a C6-C 10 Aryl group; C3-C 10 Heteroaryl group; C3-C 10 a heterocyclyl group; an amino group (-NH2); a nitro group (-N(O)2); -Boc; NHBoc; or R7, together with the nitrogen or carbon atom connected to R8, can optionally contain at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, and SO2, and can be hydrogen, C1-C 13 Alkyl groups, C6-C 10 Aryl groups, C3-C 10forming a 3- to 7-membered saturated ring which may be optionally substituted with at least one of a heteroaryl group, a hydroxy group, a halide group, and a cyano group;

[0292] Said C3-C 10 Heteroaryl groups and C3-C 10 Heterocyclyl groups contain one or more heteroatoms selected from the group consisting of N, O, and S.

[0293] In the definitions of substituents of this invention, the term "alkyl" refers to an aliphatic hydrocarbon radical. Alkyl can be a "saturated alkyl" that does not contain an alkenyl or alkynyl moiety, or an "unsaturated alkyl" that contains at least one alkenyl or alkynyl moiety. "Alkenyl" refers to a group that contains at least one carbon-carbon double bond, and "alkynyl" refers to a group that contains at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, can be cyclic, branched, or linear, respectively.

[0294] The term "aryl," alone or in combination with other radicals, refers to a carbocyclic aromatic monocyclic group containing six carbon atoms, which may be further fused to a second five- or six-membered carbocyclic group, which may be aromatic, saturated, or unsaturated. Examples of aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and the like. An aryl may be linked to another group at any suitable position on the aromatic ring.

[0295] The term "alkoxy" refers to an alkyl group linked to another group through an oxygen atom (i.e., -O-alkyl). An alkoxy group can be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C1-C6)alkoxy groups, such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O-2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1-propyl, -O-2-methyl-1-pentyl, and 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, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

[0296] The term "phenoxy" refers to a phenyl group linked to another group through an oxygen atom (i.e., -O-aryl). The phenoxy group can be unsubstituted or substituted with one or more halogens, alkyl groups, aryl groups, and heteroaryl groups, but is not limited to these.

[0297] The term "amino group" means an alkyl group linked to another group through a nitrogen atom (i.e., -NH- or -N-alkyl). An amino group can be unsubstituted or substituted with one or more suitable substituents.Examples of amino groups include (C1-C6)amino groups, such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl-2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl, -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, and -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, - Including, but not limited to, N-propyl-N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, and -N,N-dihexyl.

[0298] The term "halogen group" means fluorine, chlorine, bromine or iodine.

[0299] The term "heterocyclyl group," unless otherwise specified, refers to a heteroaromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S. Preferably, the heterocyclyl group may include pyrrolidine, furan, morpholine, piperazine, and piperidine groups, and more preferably, may include, but is not limited to, pyrrolidine, piperidine, piperazine, and morpholine groups.

[0300] The term "heteroaryl group," unless otherwise specified, refers to a heteroaromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S. Preferably, the heteroaryl group may include, but is not limited to, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, imidazole, triazole, indole, oxadiazole, thiadiazole, quinoline, isoquinoline, isoxazole, oxazole, thiazole, and pyrrole.

[0301] In one aspect of the present invention, the compound is a compound selected from the group consisting of a compound represented by Chemical Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, wherein W1, W2, W3, and W4 are each -CH-.

[0302] In one aspect of the present invention, there is provided a compound selected from the group consisting of a compound represented by Chemical Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, wherein A is a C5-C6 cyclyl group, a C5-C7 bicyclyl group, a C5-C8 heterocyclyl group, a C6-C8 aryl group, or a C4-C7 heteroaryl group.

[0303] In one aspect of the present invention, there is provided a compound selected from the group consisting of a compound represented by Chemical Formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof, 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 benzazepine; substituted or unsubstituted piperidine; substituted or unsubstituted furan; substituted or unsubstituted naphthalene; substituted or unsubstituted anthracene; substituted or unsubstituted phenanthrene; 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 substituted or unsubstituted purine.

[0304] In one embodiment, the present invention provides a compound selected from the group consisting of a compound represented by Chemical Formula 1, 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 benzazepine; or substituted or unsubstituted piperidine, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0305] In one aspect of the present invention, R1, R2, R3, and R4 are each independently hydrogen; a hydroxy group; a halogen group; -CF3; -(O)CF3; a C1-C3 alkyl group; a C1-C6 alkoxy group; or an amino group (-NR7R8); and Z may or may not be present, and when Z is present, Z is -C n H n+2 and n is an integer from 1 to 4, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0306] In one aspect of the present invention, W1, W2, W3 and W4 are each -CH-, and 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 benzazepine; or substituted or unsubstituted piperidine; and R1, R2, R3 and R4 are each independently hydrogen; a hydroxy group; a halogen group; -CF3; -(O) CF3 a C1-C3 alkyl group; a C1-C6 alkoxy group; or an amino group (-NR7R8); wherein Z may or may not be present, and when Z is present, Z is -C n H n+2 and n is an integer from 1 to 4, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0307] In one aspect of the present invention, there is provided a compound selected from the group consisting of benzotriazole derivative compounds represented by Chemical Formula 1, tautomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof, wherein the compound is any one selected from the group consisting of Compound Nos. 1 to 124 below:

[0308] Compound No. 1: 5-methoxy-1-(piperidin-4-yl)-1H-benzo[d][1,2,3]triazole hydrochloride;

[0309] Compound No. 2: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclohexyl)methaneaniline;

[0310] Compound No. 3: 5-methoxy-1-(piperidin-4-ylmethyl)-1H-benzo[d][1,2,3]triazole;

[0311] Compound No. 4: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)aniline hydrochloride;

[0312] Compound No. 5: 4-(1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0313] Compound No. 6: 4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0314] Compound No. 7: 4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0315] Compound No. 8: 4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0316] Compound No. 9: 4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0317] Compound No. 10: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0318] Compound No. 11: 2-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

[0319] Compound No. 12: 1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)-N-methylmethanamine hydrochloride;

[0320] Compound No. 13: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)cyclopropanamine hydrochloride;

[0321] Compound No. 14: (S)-1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

[0322] Compound No. 15: 3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0323] Compound No. 16: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0324] Compound No. 17: 2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0325] Compound No. 18: 2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0326] Compound No. 19: 4-(5-ethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0327] Compound No. 20: 3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0328] Compound No. 21: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0329] Compound No. 22: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0330] Compound No. 23: 3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0331] Compound No. 24: 4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0332] Compound No. 25: 7-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0333] Compound No. 26: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0334] 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;

[0335] Compound No. 28: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,5-difluorophenyl)methanamine;

[0336] Compound No. 29: 1-(isoindolin-5-yl)-5,6-dimethoxy-1H-benzo[d][1,2,3]triazole hydrochloride;

[0337] Compound No. 30: 3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)methanamine;

[0338] Compound No. 31: 3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-5-methylthiophen-2-yl)methanamine hydrochloride;

[0339] Compound No. 32: tert-butyl ((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)sulfonyl)carbamate;

[0340] Compound No. 33: tert-butyl ((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl)carbamate;

[0341] Compound No. 34: tert-butyl (N-(1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0342] Compound No. 35: tert-butyl (N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0343] Compound No. 36: tert-butyl (N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0344] Compound No. 37: tert-butyl (N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0345] Compound No. 38: tert-butyl (N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0346] Compound No. 39: tert-butyl ((S)—N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0347] Compound No. 40: tert-butyl ((6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamoyl)carbamate;

[0348] Compound No. 41: N-((3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclopentyl)methyl)sulfamide;

[0349] Compound No. 42: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidine-1-sulfonamide;

[0350] Compound No. 43: N-((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclohexyl)methyl)sulfamide;

[0351] Compound No. 44: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonamide;

[0352] Compound No. 45: 4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)piperidine-1-sulfonamide;

[0353] Compound No. 46: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0354] Compound No. 47: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamide;

[0355] Compound No. 48: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamide hydrochloride;

[0356] Compound No. 49: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0357] Compound No. 50: N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0358] Compound No. 51: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide hydrochloride;

[0359] Compound No. 52: N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0360] Compound No. 53: N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0361] Compound No. 54: N-(4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0362] Compound No. 55: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0363] Compound No. 56: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0364] Compound No. 57: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-2,3-difluorobenzyl)sulfamide;

[0365] Compound No. 58: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-3,5-difluorobenzyl)sulfamide;

[0366] Compound No. 59: N-(3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0367] Compound No. 60: N-(2-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0368] Compound No. 61: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0369] Compound No. 62: N-(2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0370] Compound No. 63: N-(2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0371] Compound No. 64: N-(3,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)sulfamide;

[0372] Compound No. 65: N-(2,3-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)sulfamide;

[0373] Compound No. 66: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbenzyl)sulfamide;

[0374] Compound No. 67: N-(3-cyano-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-benzyl)sulfamide;

[0375] Compound No. 68: N-(3-methoxy-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0376] Compound No. 69: N-(4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0377] Compound No. 70: N-(3-fluoro-4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0378] Compound No. 71: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0379] Compound No. 72: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)sulfamide;

[0380] Compound No. 73: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)sulfamide hydrochloride;

[0381] Compound No. 74: N-(3-fluoro-4-(5-hydroxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0382] Compound No. 75: N-(3-fluoro-4-(5-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0383] Compound No. 76: N-(4-(5-ethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0384] Compound No. 77: N-(3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0385] Compound No. 78: N-(5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-2-yl)methyl)sulfamide;

[0386] Compound No. 79: (N-(6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-3-yl)methyl)sulfamide;

[0387] Compound No. 80: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-N-methyl)sulfamide;

[0388] Compound No. 81: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-N-methylsulfamide;

[0389] Compound No. 82: N-cyclopropyl-N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0390] Compound No. 83: (S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamide;

[0391] Compound No. 84: N-(4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0392] Compound No. 85: N-(3-fluoro-4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0393] Compound No. 86: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0394] Compound No. 87: N-(4-(5-dimethylamino)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0395] Compound No. 88: N-(3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0396] Compound No. 89: N-(4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0397] Compound No. 90: N-(3-fluoro-4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0398] Compound No. 91: N-(4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0399] Compound No. 92: N-(4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0400] Compound No. 93: N-(3-fluoro-4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0401] Compound No. 94: 5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)isoindoline-2-sulfonamide;

[0402] Compound No. 95: N-5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-1H-inden-2-yl)sulfamide;

[0403] Compound No. 96: 6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0404] Compound No. 97: 7-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0405] 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;

[0406] Compound No. 99: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfamide;

[0407] Compound No. 100: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfamide;

[0408] Compound No. 101: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

[0409] Compound No. 102: 5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-isoindoline-2-sulfonamide;

[0410] Compound No. 103: N-(5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-dihydro-1H-inden-2-yl)sulfamide;

[0411] Compound No. 104: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)phenyl)sulfamide hydrochloride;

[0412] Compound No. 105: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzyl)sulfamide hydrochloride;

[0413] Compound No. 106: N-((5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)thiophen-2-yl)methyl)sulfamide;

[0414] Compound No. 107: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-5-methoxythiophen-2-yl)methyl)sulfamide;

[0415] Compound No. 108: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-bicyclo[1.1.1]pentan-1-yl)sulfamide;

[0416] Compound No. 109: N-(4-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)phenyl)sulfamide hydrochloride;

[0417] Compound No. 110: N-(4-((5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)benzyl)sulfamide hydrochloride;

[0418] Compound No. 111: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

[0419] Compound No. 112: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)methanesulfonamide;

[0420] Compound No. 113: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)ethanesulfonamide;

[0421] Compound No. 114: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-4-methylbenzenesulfonamide;

[0422] Compound No. 115: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)methanesulfonimidamide;

[0423] Compound No. 116: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzoic acid;

[0424] Compound No. 117: diethyl-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)phosphoramidite;

[0425] Compound No. 118: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)phosphonic acid;

[0426] Compound No. 119: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)phosphonic acid;

[0427] Compound No. 120: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)boronic acid;

[0428] Compound No. 121: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)boronic acid;

[0429] Compound No. 122: N-(4-(5-methoxy-1H-indol-1-yl)benzyl)sulfamide;

[0430] Compound No. 123: N-(4-(5-methoxy-1H-benzo[d]imidazol-1-yl)benzyl)sulfamide; and

[0431] Compound No. 124: N-(4-(5-methoxy-1H-indazol-1-yl)benzyl)sulfamide.

[0432] The compound of Chemical Formula 1 according to the present invention can be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid, and preferred salts include at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

[0433] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may include a hydrate and a solvate. The hydrate may refer to a compound formed by combining the compound of Chemical Formula 1 with water molecules.

[0434] Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, which comprises a compound according to one aspect of the present invention as an active ingredient.

[0435] Another aspect of the present invention provides an ENPP1 inhibitor comprising a compound according to one aspect of the present invention as an active ingredient.

[0436] Another aspect of the present invention provides a STING pathway activator comprising a compound according to one aspect of the present invention as an active ingredient.

[0437] In another aspect of the present invention, there is provided a pharmaceutical composition for preventing, alleviating or treating cancer, wherein the cancer is a cancer associated with the inhibition of ENPP1.

[0438] Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, comprising, as an active ingredient, a compound selected from the compound of Chemical Formula 1 according to the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof.

[0439] The pharmaceutical composition of the present invention has an excellent ability to inhibit the activity of ENPP1.

[0440] Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treating, preventing, and alleviating cancer diseases caused by abnormal cell growth. Cancer diseases that can be prevented, treated, or alleviated by treatment with the pharmaceutical composition of the present invention may include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma, and myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, fibroadenoma, etc.

[0441] Another aspect of the present invention provides an ENPP1 inhibitor comprising any one of the above compounds as an active ingredient.

[0442] Another aspect of the present invention provides a STING pathway activator comprising any one of the above compounds as an active ingredient.

[0443] 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, and is preferably applied to primates including humans, and more preferably to humans.

[0444] As used herein, "treatment" may be used in a sense that includes alleviation or improvement of symptoms, reduction in the extent of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of the disease state, partial or complete recovery, prolongation of survival, other beneficial therapeutic results, and the like.

[0445] In addition, in this specification, the treatment of cancer means the treatment of all cancer cells, and cancer also includes the angiogenesis of endothelial cells and their mitosis (solid tumors, tumor metastases and positive tumors). For example, cancer may include, but is not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoacanthoma, 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 carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, bile duct cancer, kidney cancer, bone and marrow disease, lymphoid disease, Hodgkin's disease, hair cell carcinoma, oral cavity cancer, pharyngeal (mouth) cancer, lip cancer, tongue cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma, or pyogenic granuloma.

[0446] Depending on the mode and method of use of the pharmaceutical composition of the present invention, the content of the compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, or hydrate, which is the active ingredient, may be appropriately adjusted according to the selection of a person skilled in the art.

[0447] For example, the pharmaceutical composition may contain the compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, or hydrate 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 entire composition.

[0448] The compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, or hydrate may be contained alone in the pharmaceutical composition, or may be contained together with other pharmaceutically acceptable carriers, excipients, diluents, or accessory ingredients.

[0449] Examples of the pharmaceutically acceptable carrier, excipient, or diluent include one or more selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline, but are not limited thereto, and all common carriers, excipients, and diluents can be used. In addition, the pharmaceutical composition may further contain a conventional filler, extender, binder, disintegrant, anti-agglomerating agent, lubricant, humectant, pH adjuster, nutrient, vitamin, electrolyte, alginic acid and its salts, pectinic acid and its salts, protective colloid, glycerin, flavoring, emulsifier, preservative, etc.

[0450] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of other anticancer agents when administered in combination with the other anticancer agents for treating cancer or tumors.

[0451] Specifically, the pharmaceutical composition may further contain one or more other anticancer agents or other therapeutic agents known to be effective in the treatment or prevention of cancer in addition to the active ingredient, and may be used as a combination therapy administered simultaneously or at different times. Examples of other anticancer agents or other therapeutic agents that may be administered in the combination therapy include, but are not limited to, one or more compounds selected from the group consisting of Gleevec (Gleevec®, imatinib), Sutent (Sutent®, sunitinib), Herceptin (Herceptin®, trastuzumab), Velcade (Velcade®, bortezomib), dexamethasone, Nexavar (Nexavar®, sorafenib), aromatase inhibitors, and kinase inhibitors.

[0452] The pharmaceutical composition may be administered orally or parenterally, and may be administered via a variety of routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular. The dosage form of the composition may vary depending on the intended use, and may be formulated using methods well known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a mammal. Solid formulations for oral administration generally include tablets, lozenges, soft or hard capsules, pills, powders, and granules. These formulations may be formulated with one or more excipients, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Oral liquid preparations include suspensions, solutions, emulsions, and syrups, and in addition to the frequently used simple diluents water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. Forms for parenteral administration may be in the form of creams, lotions, ointments, plasters, liquids and solutions, aerosols, fluid extracts, elixirs, infusions, sachets, patches, or injections, and injectable dosage forms, they may preferably be in the form of an isotonic aqueous solution or suspension.

[0453] The pharmaceutical composition may further contain auxiliary agents such as a sterilizing agent, a preservative, a stabilizer, a hydrating agent or an emulsifying agent, a salt for adjusting osmotic pressure and / or a buffer, and other therapeutically useful substances, and may be formulated by a conventional mixing, granulating or coating method, or may be formulated by any other suitable method known in the art.

[0454] The dosage of the pharmaceutical composition can be determined taking into consideration the administration method, the recipient's age and sex, the severity and condition of the patient, the absorption rate of the active ingredient in the body, the inactivation rate, and concomitant drugs, and can be administered once or in divided doses. The active ingredient of the pharmaceutical composition can be administered orally or parenterally to mammals, including humans, preferably in an amount of 0.001 mg / kg to 100 mg / kg of body weight, preferably 0.01 mg / kg to 35 mg / kg of body weight per day, once or in divided doses per day.

[0455] Yet another embodiment of the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof:

[0456] Preferably, the method of treatment may further comprise the step of identifying a patient in need of prevention or treatment of cancer before the administering step.

[0457] The "therapeutically effective amount" of the present invention means the amount of an active ingredient in a mammal that is effective in preventing or treating cancer. The therapeutically effective amount can be adjusted depending on various factors, including the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of dosage form, the patient's age, body weight, general health condition, sex, diet, administration time, administration route, blood clearance rate of the composition, treatment period, and concurrently used drugs. Preferably, as described above, the therapeutically effective amount is 0.001 mg / kg to 100 mg / kg of body weight, preferably 0.01 mg / kg to 35 mg / kg of body weight per day, administered orally or parenterally once a day or in divided doses.

[0458] The present invention also relates to a method for producing a compound selected from the benzotriazole derivative compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, its hydrate, and its stereoisomer.

[0459] Meanwhile, the present invention is characterized by a method for preparing the compound represented by Chemical Formula 1. The preparation method according to the present invention will be specifically described as follows.

[0460] In one embodiment, the compound of the present invention represented by Chemical Formula 1 may be prepared by one or more of the following Preparation Methods 1 to 4.

[0461] Manufacturing Method 1

[0462] The benzotriazole derivative compound of Chemical Formula 1 according to one aspect of the present invention can be prepared by a preparation method according to the following Reaction Scheme 1.

[0463] TIFF0007818010000004.tif115137

[0464] [Reaction Scheme 1]

[0465] Manufacturing Method 2

[0466] The benzotriazole derivative compound of Chemical Formula 1 according to one aspect of the present invention can be prepared by a preparation method according to the following Reaction Scheme 2.

[0467] TIFF0007818010000005.tif104121

[0468] [Reaction Scheme 2]

[0469] Manufacturing method 3

[0470] The benzotriazole derivative compound of Chemical Formula 1 according to one aspect of the present invention can be prepared by a preparation method according to the following Reaction Scheme 2.

[0471] TIFF0007818010000006.tif63116

[0472] [Reaction Scheme 3]

[0473] Method A

[0474] After evacuating the air from an oven-dried flask and filling it with nitrogen, Pd2(dba)3 (0.05 eq.), rac-BINAP (0.1 eq.), Cs2CO3 (5 eq.), bromo-nitrobenzene (1 eq.), aniline (1.05 eq.), and degassed toluene were added. Nitrogen was purged into the reaction mixture for 15 minutes, and the mixture was heated at 110°C for 14 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, filtered through Celite, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The mixture was purified using silica column chromatography (n-hexane / ethyl acetate) using MPLC to obtain the target compound in high yield.

[0475] Method B

[0476] A solution of the nitro-intermediate (1 equivalent) in methanol is added to Pd / C (10%, 50% wet with water, 0.05 equivalent) and stirred under hydrogen gas at room temperature for 12 hours. The reaction mixture is filtered through Celite and concentrated to give the desired compound in high yield.

[0477] Method C

[0478] To a solution of the nitro-intermediate (1 equivalent) dissolved in ethanol, iron powder (5 equivalents) and an aqueous solution of ammonium chloride (10 equivalents) are added. The reaction solution is stirred at 65°C for 2 hours. The reaction solution is filtered through Celite, and then an aqueous solution of sodium bicarbonate is added and extracted three times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain the target compound in high yield.

[0479] Method D

[0480] To a solution of the nitro-intermediate (1 equivalent) dissolved in ethanol, iron powder (5 equivalents) and an aqueous solution of ammonium chloride (10 equivalents) are added. The reaction solution is stirred at 65°C for 2 hours. The reaction solution is filtered through Celite, and then an aqueous solution of sodium bicarbonate is added and extracted three times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain the target compound in high yield.

[0481] Method E

[0482] To a solution of the aniline intermediate (1 equivalent) dissolved in acetic acid, an aqueous solution of sodium nitrite (2 equivalents) is slowly added at 0°C, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is concentrated under reduced pressure, and after adding an aqueous solution of sodium bicarbonate, it is extracted three times with ethyl acetate. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica column chromatography (n-hexane / ethyl acetate) using MPLC to obtain the target compound.

[0483] Method F

[0484] To a solution of the aniline intermediate (1 equivalent) dissolved in acetic acid, an aqueous solution of sodium nitrite (2 equivalents) is slowly added at 0°C, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is concentrated under reduced pressure, and after adding an aqueous solution of sodium bicarbonate, it is extracted three times with ethyl acetate. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica column chromatography (n-hexane / ethyl acetate) using MPLC to obtain the target compound.

[0485] Method G

[0486] A solution of the Boc-protected amine or aniline intermediate dissolved in ethyl acetate is added to an excess of 4N aqueous hydrochloric acid (in dioxane) and stirred at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure and washed with dichloromethane to quantitatively obtain the target compound in the form of a hydrochloride.

[0487] Method H

[0488] The amine hydrochloride intermediate (1 equivalent) obtained in Method G was dissolved in dichloromethane and triethylamine (8 equivalents) was added at 0°C under nitrogen. 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 bicarbonate, 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 using silica column chromatography (n-hexane / ethyl acetate) using MPLC.

[0489] Method I

[0490] DMAP (2 equivalents) was added to an aqueous solution of aniline hydrochloride (1 equivalent) in acetonitrile at 0°C under nitrogen. After adding 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 bicarbonate, 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 using silica column chromatography (n-hexane / ethyl acetate) using MPLC.

[0491] Method J

[0492] tert-Butanol is slowly added to a solution of chlorosulfonyl isocyanate dissolved in anhydrous dichloromethane at 0°C. After 30 minutes, the mixture is slowly added to a solution of the amine hydrochloride intermediate dissolved in anhydrous dichloromethane in the presence of triethylamine at 0°C, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with dichloromethane and washed with 0.1N aqueous hydrochloric acid and water. The organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Purification by silica column chromatography using MPLC gives the target compound.

[0493] Method K

[0494] To a solution of the Boc-protected sulfonamide intermediate (1 equivalent) dissolved in ethyl acetate, an excess of 4N aqueous hydrochloric acid (in dioxane) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium bicarbonate, 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 was purified by silica column chromatography using MPLC to obtain the target compound.

[0495] Method L

[0496] The Boc-protected sulfonamide intermediate (1 equivalent) is added to an excess of 4N aqueous hydrochloric acid (in dioxane) and stirred at room temperature for 4 to 12 hours. The reaction mixture is concentrated under reduced pressure, washed with ethyl acetate, then with methanol, and dried to obtain the target compound in the form of a hydrochloride salt.

[0497] Method M

[0498] Nitrofluorobenzene, N-Boc-piperidin-4-ylmethanamine, and potassium carbonate are 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 is washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica column chromatography using MPLC to obtain the target compound.

[0499] Method N

[0500] Aqueous NaOH (1.1 equiv.) was 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 equiv.) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica column chromatography using MPLC (ethyl acetate, hexane) to give two structural isomers in high yields.

[0501] Method O

[0502] Sodium azide (3 equiv.) was added to a solution of the benzyl bromide intermediate (1 equiv.) in acetonitrile, and the mixture was stirred at 75°C for 16 hours. The reaction mixture was extracted with ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude azide intermediate in high yield. Triphenylphosphine (2 equiv.) was slowly added to a solution of the azide intermediate (1 equiv.) in tetrahydrofuran at 0°C. Water was added, and the solution was stirred at 70°C for 12 hours. The solvent was concentrated under reduced pressure, and hydrochloric acid in dioxane was added to give the desired compound in high yield. [Example]

[0503] The present invention will be described in detail below with reference to 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 to the following Examples.

[0504] [Production Example 1] Production of Compound No. 47

[0505] TIFF0007818010000007.tif4240

[0506] Example 1:

[0507] [Reaction Scheme 1]

[0508] TIFF0007818010000008.tif110137

[0509] tert-Butyl (3-((4-methoxy-2-nitrophenyl)amino)phenyl)carbamate (3)

[0510] TIFF0007818010000009.tif4240

[0511] A mixture of 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 Cs2CO3 (8.15 g, 25 mmol) in toluene (17 mL, 0.3 M) was purged with nitrogen for 15 minutes. The reaction mixture was heated and stirred at 110 °C under nitrogen for 14 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through Celite, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography using MPLC to obtain the desired compound (1.40 g) in 78% yield.

[0512] 1H NMR (400MHz, CDCl3) δ9.31 (brs, 1H), 7.66 (d, J=3.2Hz, 1H), 7.45 (d, J=2.2Hz, 1H), 7.36-7.2 5(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).

[0513] tert-Butyl (3-((2-amino-4-methoxyphenyl)amino)phenyl)carbamate (4)

[0514] TIFF0007818010000010.tif4240

[0515] 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), Pd / C (10%, 50% wet with water, 480 mg, 0.22 mmol) was added and stirred under hydrogen gas at room temperature for 12 hours. The reaction mixture was filtered through Celite and concentrated to give the desired compound (1.32 g) in 90% yield.

[0516]

[0517] 1 H NMR (400MHz, CDCl3) δ7.29(s, 1H), 7.15-7.05(m, 2H), 6.94-6.83(m, 1H), 6.81(br s, 1H), 6.66(brs, 1H), 6.64-6.56(m, 1H), 6.50(s, 1H), 3.66(s, 3H), 1.39(s, 9H).

[0518] tert-Butyl (3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)carbamate (5)

[0519] TIFF0007818010000011.tif3540

[0520] To a solution of tert-butyl (3-((2-amino-4-methoxyphenyl)amino)phenyl)carbamate (1.30 g, 3.95 mmol) in acetic acid (13.2 mL, 0.3 M), aqueous sodium nitrite (544 mg, 7.89 mmol) was slowly added at 0 °C and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, added with aqueous sodium bicarbonate, 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 was purified by silica column chromatography (n-hexane / ethyl acetate) using MPLC to obtain the desired compound (780 mg) in 58% yield.

[0521] 1 H NMR (400MHz, CDCl3) δ7.94(s, 1H), 7.62(d, J=9.0Hz, 1H), 7.45-7.31(m, 4H), 7.15(dd, J=2.3, 9.2Hz, 1H), 6.93(s, 1H), 3.85(s, 3H), 1.46(s, 9H).

[0522] 3-(5-Methoxy-1H-benzo[d][1,2,3]triazol-1-yl)aniline hydrochloride (6)

[0523] TIFF0007818010000012.tif3540

[0524] To a solution of tert-butyl (3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)carbamate (800 mg, 2.35 mmol) in ethyl acetate (2.35 mL, 1 M) was added an excess of 4 N aqueous hydrochloric acid (in dioxane) 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 give the target compound (645 mg) in the form of hydrochloride in 99% yield.

[0525] tert-Butyl (N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamoyl)carbamate (7)

[0526] TIFF0007818010000013.tif4340

[0527] To a solution of 3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)aniline hydrochloride (139 mg, 0.5 mmol) in acetonitrile (2.5 mL, 0.2 M) was added DMAP (123 mg, 1 mmol) at 0 °C under nitrogen atmosphere. 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 h. The solvent was concentrated under reduced pressure, diluted with aqueous sodium bicarbonate, 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 was purified by silica column chromatography (n-hexane / ethyl acetate) using MPLC to obtain the desired compound (78 mg) in 37% yield.

[0528] 1 H NMR (400MHz, Methanol-d4) δ7.81(d, J=9.1Hz, 1H), 7.78(p, J=1.0Hz, 1H), 7.67-7.60(m, 2H) , 7.49(d, J=2.3Hz, 1H), 7.42(s, 1H), 7.32(dd, J=9.1, 2.3Hz, 1H), 3.96(s, 3H), 1.39(s, 9H).

[0529] N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamide (8)

[0530] TIFF0007818010000014.tif4240

[0531] A solution of tert-butyl (N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamoyl)carbamate (70 mg, 0.17 mmol) in ethyl acetate (1.7 mL, 0.1 M) was added to an excess of 4 N aqueous hydrochloric acid (in dioxane) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium bicarbonate, 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 (n-hexane / ethyl acetate) using MPLC to obtain the target compound (33 mg) in 62% yield.

[0532] 1 H NMR (400MHz, DMSO-d6) δ9.96(s, 1H), 7.82(d, J=9.0Hz, 1H), 7.68(t, J=2.0Hz, 1H), 7.63(d , J=2.4Hz, 1H), 7.59(t, J=7.9Hz, 1H), 7.52-7.47(m, 1H), 7.41-7.23(m, 4H), 3.91(s, 3H).

[0533] The following examples were synthesized with reference to Preparation Example 1 and Reaction Schemes 1 to 4.

[0534] Example 1: 5-Methoxy-1-(piperidin-4-yl)-1H-benzo[d][1,2,3]triazole hydrochloride;

[0535] TIFF0007818010000015.tif3335

[0536] LC-MS(ESI) calculation for C 12 H 16 NO [M+H] + 232.12, found m / z 233.1

[0537] Example 2: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclohexyl)methaneaniline;

[0538] TIFF0007818010000016.tif2935

[0539] 1 H NMR (400MHz, DMSO-d6) δ7.83(m, 2H), 7.46(d, J=2. 1Hz, 1H), 7.18(dd, J=9.0, 2.2Hz, 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).

[0540] Example 3: 5-Methoxy-1-(piperidin-4-ylmethyl)-1H-benzo[d][1,2,3]triazole;

[0541] TIFF0007818010000017.tif2749

[0542] LC-MS(ESI) calculation for C 13 H 18 NO [M+H] + 246.15, found m / z 247.2

[0543] Example 4: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)aniline hydrochloride;

[0544] TIFF0007818010000018.tif3235

[0545] LC-MS(ESI) calculation for C 13 H 12 NO [M+H] + 240.10, found m / z 341.1

[0546] Example 5: 4-(1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0547] TIFF0007818010000019.tif3635

[0548] LC-MS(ESI) calculation for C 13 H 12 N4[M+H] + 224.11, found m / z 225.1

[0549] Example 6: 4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0550] TIFF0007818010000020.tif3935

[0551] LC-MS(ESI) calculation for C 14 H 14 NO [M+H] + 254.12, found m / z 255.1

[0552] Example 7: 4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0553] TIFF0007818010000021.tif2935

[0554] LC-MS(ESI) calculation for C 14 H 14 NO [M+H] + 254.12, found m / z 255.1

[0555] Example 8: 4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0556] TIFF0007818010000022.tif3535

[0557] LC-MS(ESI) calculation for C 14 H14 NO [M+H] + 254.12, found m / z 255.1

[0558] Example 9: 4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0559] TIFF0007818010000023.tif3435

[0560] LC-MS(ESI) calculation for C 15 H 16 N4O2[M+H] + 284.13, found m / z 285.1

[0561] Example 10: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0562] TIFF0007818010000024.tif2935

[0563] LC-MS(ESI) calculation for C 15 H 16 N4O2[M+H] + 284.13, found m / z 285.1

[0564] Example 11: 2-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

[0565] TIFF0007818010000025.tif4135

[0566] LC-MS(ESI) calculation for C 15 H 16 NO [M+H] + 268.13, found m / z 269.1

[0567] Example 12: 1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)-N-methylmethanamine hydrochloride;

[0568] TIFF0007818010000026.tif3135

[0569] LC-MS(ESI) calculation for C 15 H 16 NO [M+H] + 268.13, found m / z 269.1

[0570] Example 13: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)cyclopropanamine hydrochloride;

[0571] TIFF0007818010000027.tif3435

[0572] 1 H NMR (400MHz, DMSO-d6) δ9.74(d, J=4.1Hz, 2H), 7.96(d, J=8.6Hz, 2H), 7.90(d, J=8.6Hz, 2H), 7.86(d, J=9.1Hz, 1H), 7.63(d, J=2.2Hz, 1H ), 7.31(dd, J=9.1, 2.3Hz, 1H), 4.36(d, J=5.7Hz, 2H), 3.90(s, 3H), 2.71(d, J=3.6Hz, 1H), 0.97(t, J=4.4Hz, 2H), 0.76(q, J=7.0Hz, 2H).

[0573] Example 14: (S)-1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethan-1-amine hydrochloride;

[0574] TIFF0007818010000028.tif3035

[0575] LC-MS(ESI) calculation for C 15 H16 NO [M+H] + 268.13, found m / z 269.1

[0576] Example 15: 3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0577] TIFF0007818010000029.tif3035

[0578] LC-MS(ESI) calculation for C 14 H 13 ClNO [M+H] + 288.08, found m / z 289.1

[0579] Example 16: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine hydrochloride;

[0580] TIFF0007818010000030.tif2835

[0581] LC-MS(ESI) calculation for C 14 H 13 F1N4O [M+H] + 272.11, found m / z 273.1

[0582] Example 17: 2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0583] TIFF0007818010000031.tif2935

[0584] LC-MS(ESI) calculation for C 14 H 12 F2N4O [M+H] + 290.14, found m / z 291.1

[0585] Example 18: 2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0586] TIFF0007818010000032.tif2835

[0587] LC-MS(ESI) calculation for C 14 H 12 F2N4O [M+H] + 290.14, found m / z 291.1

[0588] Example 19: 4-(5-ethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0589] TIFF0007818010000033.tif2535

[0590] 1 H NMR (400MHz, DMSO-d6) δ7.75(t, J=8.0Hz, 1H), 7.64-7.58(m, 2H), 7.53-7.43(m, 2H), 7.26(d d, J=9.0, 2.3Hz, 1H), 4.16(d, J=7.0Hz, 2H), 3.87(s, 2H), 1.40(t, J=7.0Hz, 3H), 1.24(s, 2H).

[0591] Example 20: 3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0592] TIFF0007818010000034.tif2535

[0593] 1H NMR (400MHz, DMSO-d6) δ7.75(t, J=8.0Hz, 1H), 7.67-7.57(m, 2H), 7.52-7.42(m, 2H), 7.23(dd, J= 9.0, 2.2Hz, 1H), 4.82-4.74(m, 1H), 3.88(s, 2H), 1.34(s, 3H), 1.32(s, 3H), 1.18(t, J=7.1Hz, 1H).

[0594] Example 21: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0595] TIFF0007818010000035.tif3135

[0596] LC-MS(ESI) calculation for C 15 H 14 F2N4[M+H] + 288.10, found m / z 289

[0597] Example 22: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0598] TIFF0007818010000036.tif3135

[0599] LC-MS(ESI) calculation for C 15 H 13 F3N4[M+H] + 306.37, found m / z 307.1

[0600] Example 23: 3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0601] TIFF0007818010000037.tif2535

[0602] LC-MS(ESI) calculation for C 14 H 12 F2N4O [M+H] + 290.27, found m / z 291

[0603] Example 24: 4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorophenyl)methanamine;

[0604] TIFF0007818010000038.tif2535

[0605] 1 H NMR (400MHz, DMSO-d6) δ7.78(t, J=8.0Hz, 2H), 7.71(dd, J=9.0, 1.9Hz, 2H), 7.63(d, J=11.6Hz, 2H), 7.52(d, J=2.2Hz, 1H), 7.51-7.49(m, 1H), 7.38(s, 1H), 3.88(s, 2H).

[0606] Example 25: 7-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0607] TIFF0007818010000039.tif2635

[0608] 1 H NMR (400MHz, DMSO-d6) δ9.75(s, 2H), 7.89(d, J=9.1Hz, 1H), 7.79(d, J=8.5Hz, 2H), 7.62(d, J=2.2Hz, 1H), 7.54(d, J= 8.1Hz, 1H), 7.32(d, J=2.3Hz, 1H), 4.42(d, J=4.4Hz, 2H), 3.91(s, 3H), 3.44(d, J=5.6Hz, 2H), 3.15(t, J=6.1Hz, 2H).

[0609] Example 26: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0610] TIFF0007818010000040.tif3135

[0611] LC-MS(ESI) calculation for C 16 H 15 FN4O [M+H] + 298.12, found m / z 299.1

[0612] Example 27: 8-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine hydrochloride;

[0613] TIFF0007818010000041.tif2835

[0614] LC-MS(ESI) calculation for C 17 H 18 NO [M+H] + 294.15, found m / z 295.2

[0615] Example 28: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,5-difluorophenyl)methanamine;

[0616] TIFF0007818010000042.tif2935

[0617] LC-MS(ESI) calculation for C 15 H 14 F2N4O2[M+H] + 320.17, found m / z 321.1

[0618] Example 29: 1-(isoindolin-5-yl)-5,6-dimethoxy-1H-benzo[d][1,2,3]triazole hydrochloride;

[0619] TIFF0007818010000043.tif2835

[0620] 1 H NMR (400MHz, DMSO-d6) δ10.23(s, 2H), 7.93(s, 1H), 7.87(dd, J=8.2, 1.8Hz, 1H), 7.70(d , J=8.2Hz, 1H), 7.59(s, 1H), 7.24(s, 1H), 4.71-4.50(m, 4H), 3.92(s, 3H), 3.90(s, 3H).

[0621] Example 30: 3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)bicyclo[1.1.1]pentan-1-yl)methanamine;

[0622] TIFF0007818010000044.tif2635

[0623] 1 H NMR (400MHz, DMSO-d6) δ7.78(d, J=9.0Hz, 1H), 7.49(d, J=2.2Hz, 1H), 7.25-7.13 (m, 2H), 6.75 (d, J=8.6Hz, 1H), 3.85 (s, 3H), 1.24 (s, 6H), 0.85 (d, J=7.2Hz, 2H).

[0624] Example 31: 3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-5-methylthiophen-2-yl)methanamine hydrochloride;

[0625] TIFF0007818010000045.tif2937

[0626] 1H NMR (400MHz, DMSO-d6) δ8.40(s, 2H), 7.72(d, J=9.1Hz, 1H), 7.63(d, J=2.1Hz, 1H), 7.31(dd, J=8.8, 2 .5Hz, 2H), 7.16(m, 1H), 6.76(dd, J=5.9, 3.5Hz, 2H), 4.23(d, J=5.4Hz, 2H), 3.90(s, 3H), 2.57(s, 3H).

[0627] Example 32: tert-butyl ((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)sulfonyl)carbamate;

[0628] TIFF0007818010000046.tif2935

[0629] LC-MS(ESI) calculation for C 17 H 25 N5O5S [M+H] + 411.16, found m / z 412.2

[0630] Example 33: tert-butyl ((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl)carbamate;

[0631] TIFF0007818010000047.tif2549

[0632] LC-MS(ESI) calculation for C 18 H 27 N5O5S [M+H] + 425.17, found m / z 426.2

[0633] Example 34: tert-butyl (N-(1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0634] TIFF0007818010000048.tif3335

[0635] LC-MS(ESI) calculation for C 18 H 21 N5O4S [M+H] + 403.13, found m / z 404.1

[0636] Example 35: tert-butyl (N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0637] TIFF0007818010000049.tif4139

[0638] LC-MS(ESI) calculation for C 19 H 23 N5O5S [M+H] + 433.14, found m / z 434.1

[0639] Example 36: tert-butyl (N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0640] TIFF0007818010000050.tif2935

[0641] LC-MS(ESI) calculation for C 19 H 23 N5O5S [M+H] + 433.14, found m / z 434.1

[0642] Example 37: tert-butyl (N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0643] TIFF0007818010000051.tif2935

[0644] LC-MS(ESI) calculation for C19 H 23 N5O5S [M+H] + 433.14, found m / z 434.1

[0645] Example 38: tert-butyl (N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamoyl)carbamate;

[0646] TIFF0007818010000052.tif3335

[0647] LC-MS(ESI) calculation for C 19 H 23 N5O5S [M+H] + 433.14, found m / z 434.1

[0648] Example 39: tert-butyl ((S)—N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0649] TIFF0007818010000053.tif2935

[0650] LC-MS(ESI) calculation for C 20 H 25 N5O5S [M+H] + 447.16, found m / z 448.2

[0651] Example 40: tert-butyl ((6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfamoyl)carbamate;

[0652] TIFF0007818010000054.tif3035

[0653] LC-MS(ESI) calculation for C 21 H 25N5O5S [M+H] + 459.16, found m / z 460.2

[0654] Example 41: N-((3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclopentyl)methyl)sulfamide;

[0655] TIFF0007818010000055.tif3535

[0656] 1 H NMR (400MHz, DMSO-d6) δ7.79(d, J=9.0Hz, 1H), 7.45(d, J=2.1Hz, 1H), 7.18(dd , J=9.0, 2.3Hz, 1H), 6.65(t, J=6.1Hz, 1H), 6.51(s, 2H), 5.31(dd, J=15.9, 7.9H z, 1H), 3.84(s, 3H), 2.99(dd, J=10.0, 6.8Hz, 2H), 2.40-2.21(m, 2H), 2.20-2. 06(m, 1H), 1.90(dd, J=21.3, 14.1, 7.9Hz, 2H), 1.74-1.59(m, 1H), 1.24(s, 2H).

[0657] Example 42: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidine-1-sulfonamide;

[0658] TIFF0007818010000056.tif3335

[0659] 1 H NMR (400MHz, DMSO-d6) δ7.82(d, J=8.4Hz, 1H), 7.44(s, 1H), 7.18(d, J=8.2Hz, 1H), 4.97(br s, 1H), 3.86(s, 3H), 3.69(d, J=11.4Hz, 2H), 2.95(t, J=10.7Hz, 2H), 2.29-2.23(m, 4H).

[0660] Example 43: N-((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclohexyl)methyl)sulfamide;

[0661] TIFF0007818010000057.tif3235

[0662] 1 H NMR (400MHz, DMSO-d6) δ7.81 (dd, J=20.1, 9.2Hz, 1H), 7.45 (d, J=2.2Hz, 1H), 7 .17(dd, J=9.0, 2.3Hz, 1H), 6.59(t, J=6.2Hz, 1H), 6.52(d, J=11.1Hz, 1H), 4.9 1(dd, J=8.9, 4.3Hz, 1H), 3.84(s, 3H), 2.96(t, J=6.9Hz, 2H), 2.14(dt, J=15.3 , 6.5Hz, 2H), 1.91(dd, J=13.6, 4.5Hz, 0H), 1.73(d, J=4.7Hz, 3H), 1.24(s, 1H).

[0663] Example 44: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonamide;

[0664] TIFF0007818010000058.tif3135

[0665] LC-MS(ESI) calculation for C 20 H 25 N5O5S [M+H] + 447.16, found m / z 448.2

[0666] Example 45: 4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)piperidine-1-sulfonamide;

[0667] TIFF0007818010000059.tif2749

[0668] 1H NMR (400MHz, DMSO-d6) δ7.83 (d, J=9.0Hz, 1H), 7.44 (d, J=1.6Hz, 1H), 7.19 (d, J=7.2Hz, 1H), 4.60(d, J=6.9Hz, 2H), 3.85(s, 3H), 3.44(d, J=11.4Hz, 2H), 2.44(t, J=11.3Hz, 2H), 2.01(br s, 1H), 1.57(d, J=11.2Hz, 2H), 1.37-1.29(m, 2H).

[0669] Example 46: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0670] TIFF0007818010000060.tif3835

[0671] 1 H NMR (400MHz, DMSO-d6) δ8.20(d, J=8.4Hz, 1H), 7.89(dd, J=27.8, 8.4Hz, 3H), 7.68(dt, J=7.4, 2.9Hz, 3H), 7.58-7.49(m, 1H), 7.27(s, 1H), 6.73(s, 2H), 4.23(d, J=6.5Hz, 2H).

[0672] Example 47: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamide;

[0673] TIFF0007818010000061.tif3835

[0674] 1 H NMR (400MHz, DMSO-d6) δ9.96(s, 1H), 7.82(d, J=9.0Hz, 1H), 7.68(t, J=2.0Hz, 1H), 7.63(d , J=2.4Hz, 1H), 7.59(t, J=7.9Hz, 1H), 7.52-7.47(m, 1H), 7.41-7.23(m, 4H), 3.91(s, 3H).

[0675] Example 48: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)sulfamide hydrochloride;

[0676] TIFF0007818010000062.tif3135

[0677] 1 H NMR (400MHz, DMSO-d6) δ9.78 (brs, 1H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 7.42 (d, J=7.6Hz, 2H), 7.26-7.17 (m, 2H), 3.88 (s, 3H).

[0678] Example 49: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0679] TIFF0007818010000063.tif4535

[0680] 1 H NMR (400MHz, DMSO-d6) δ8.05-7.80 (m, 2H), 7.77 (d, J=8.0Hz, 1H), 7.64 (dd, J=12.0, 4.7Hz, 2H), 7. 56(d, J=7.7Hz, 1H), 7.30(td, J=8.9, 4.4Hz, 2H), 6.73(s, 2H), 4.26(d, J=6.4Hz, 2H), 3.91(s, 3H).

[0681] Example 50: N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0682] TIFF0007818010000064.tif4235

[0683] 1H NMR (400MHz, DMSO-d6) δ7.95-7.75(m, 2H), 7.66(d, J=8.6Hz, 2H), 7.63-7.51(m, 1H), 7.45-7.33(m, 1H), 7.26(t, J=6.5Hz, 1H), 6.97(d, J=7.6Hz, 1H), 6.73(s, 2H), 4.22(d, J=6.5Hz, 2H), 4.08(s, 3H).

[0684] Example 51: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide hydrochloride;

[0685] TIFF0007818010000065.tif3135

[0686] 1 H NMR (400MHz, DMSO-d6) δ7.82-7.78(m, 3H), 7.65(d, J=8.4Hz, 2H), 7.59(d, J=2.1Hz, 1H), 7.28(dd, J=9.0, 2.2Hz, 1H), 4.22(s, 2H), 3.90(s, 3H).

[0687] Example 52: N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0688] TIFF0007818010000066.tif3135

[0689] 1 H NMR (400MHz, DMSO-d6) δ8.05(d, J=9.1Hz, 1H), 7.84(d, J=8.5Hz, 2H), 7.67(d, J=8.5Hz, 2H), 7.26(s, 1H) ), 7.20(d, J=2.1Hz, 1H), 7.13(dd, J=9.1, 2.2Hz, 1H), 6.73(s, 2H), 4.22(d, J=6.5Hz, 2H), 3.90(s, 3H).

[0690] Example 53: N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0691] TIFF0007818010000067.tif3635

[0692] 1 H NMR (400MHz, DMSO-d6) δ7.71(dd, J=8.4, 0.6Hz, 1H), 7.68-7.62(m, 2H), 7.57(d, J=8.7Hz, 2H), 7.42(dd, J=8. 3, 7.8Hz, 1H), 7.24 (d, J=6.5Hz, 1H), 7.12 (d, J=7.5Hz, 1H), 6.73 (s, 2H), 4.22 (d, J=6.5Hz, 2H), 3.84 (s, 3H).

[0693] Example 54: N-(4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0694] TIFF0007818010000068.tif3535

[0695] 1 H NMR (400MHz, DMSO-d6) δ7.86-7.74(m, 2H), 7.65(d, J=8.6Hz, 2H), 7.26(t, J=6.5Hz, 1H), 6 .82-6.67(m, 3H), 6.56(d, J=1.8Hz, 1H), 4.22(d, J=6.5Hz, 2H), 4.03(s, 3H), 3.87(s, 3H).

[0696] Example 55: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0697] TIFF0007818010000069.tif3135

[0698] 1H NMR (400MHz, DMSO-d6) δ7.84(d, J=8.5Hz, 2H), 7.66(d, J=8.5Hz, 2H), 7.59(s, 1H), 7. 25(d, J=6.5Hz, 1H), 7.21(s, 1H), 6.72(s, 2H), 4.23(s, 2H), 3.92(s, 3H), 3.90(s, 3H).

[0699] Example 56: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0700] TIFF0007818010000070.tif3835

[0701] 1 H NMR (400MHz, Methanol-d4) δ8.13(d, J=8.4Hz, 1H), 7.73(t, J=7.8Hz, 1H), 7.65(d, J=7.0Hz, 1H), 7.63-7.57(m, 2H), 7.54(t, J=7.6Hz, 2H), 4.40(s, 2H).

[0702] Example 57: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-2,3-difluorobenzyl)sulfamide;

[0703] TIFF0007818010000071.tif3835

[0704] 1 H NMR (400MHz, Methanol-d4) δ8.13(d, J=8.4Hz, 1H), 7.73(t, J=7.8Hz, 1H), 7.70-7.63(m, 1H), 7.63-7.57(m, 2H), 7.57-7.52(m, 2H), 4.40(s, 2H).

[0705] Example 58: N-(4-(1H-benzo[d][1,2,3]triazol-1-yl)-3,5-difluorobenzyl)sulfamide;

[0706] TIFF0007818010000072.tif3835

[0707] 1 H NMR (400MHz, Methanol-d4) δ8.16 (d, J = 8.4Hz, 1H), 7.71-7.64 (m, 1H), 7.60-7.50 (m, 2H), 7.46 (d, J = 8.9Hz, 2H), 4.40 (s, 2H).

[0708] Example 59: N-(3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0709] TIFF0007818010000073.tif3335

[0710] 1 H NMR (400MHz, DMSO-d6) δ7.83(d, J=1.6Hz, 1H), 7.75(d, J=8.1Hz, 1H), 7.63(dd, J=6.3, 1.9Hz, 2H), 7.38 (dd, J=12.2, 7.8Hz, 2H), 7.26(dd, J=9.0, 2.3Hz, 1H), 6.78(s, 2H), 4.27(d, J=6.5Hz, 2H), 3.91(s, 3H).

[0711] Example 60: N-(2-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0712] TIFF0007818010000074.tif3135

[0713] 1 H NMR (400MHz, DMSO-d6) δ7.89(d, J=9.1Hz, 1H), 7.82-7.73(m, 3H), 7.64(d, J=2.2Hz, 1H), 7.31( dd, J=9.1, 2.4Hz, 1H), 7.26(t, J=6.5Hz, 1H), 6.76(s, 2H), 4.24(d, J=6.4Hz, 2H), 3.90(s, 3H).

[0714] Example 61: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0715] TIFF0007818010000075.tif3135

[0716] 1 H NMR (400MHz, DMSO-d6) δ7.80(t, J=7.9Hz, 1H), 7.62(dd, J=10.4, 2.0Hz, 2H), 7.54(dd, J=9.0, 2.2Hz, 1H), 7.51-7 .45(m, 1H), 7.36(t, J=6.5Hz, 1H), 7.29(dd, J=9.0, 2.3Hz, 1H), 6.77(s, 2H), 4.26(d, J=6.5Hz, 2H), 3.90(s, 3H).

[0717] Example 62: N-(2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0718] TIFF0007818010000076.tif3135

[0719] LC-MS(ESI) calculation for C 14 H 13 F2N5O3S [M+H] + 369.35, found m / z 370.1

[0720] Example 63: N-(2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0721] TIFF0007818010000077.tif3035

[0722] LC-MS(ESI) calculation for C 14 H 13 F2N5O3S [M+H] +369.35, found m / z 370.1

[0723] Example 64: N-(3,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)sulfamide;

[0724] TIFF0007818010000078.tif3235

[0725] 1 H NMR (400MHz, DMSO-d6) δ7.67(d, J=2.1Hz, 1H), 7.54(d, J=9.0Hz, 3H), 7.44(s, 1H) ), 7.31(dd, J=9.0, 2.3Hz, 1H), 6.80(s, 2H), 4.28(d, J=6.5Hz, 2H), 3.90(s, 3H).

[0726] Example 65: N-(2,3-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-benzyl)sulfamide;

[0727] TIFF0007818010000079.tif3235

[0728] 1 H NMR (400MHz, DMSO-d6) δ7.75-7.57(m, 4H), 7.36(t, J=6.2Hz, 1H), 7.31(dd, J=9.1, 2.3Hz, 1H), 6.80(s, 2H), 4.30(d, J=6.4Hz, 2H), 3.90(s, 3H).

[0729] Example 66: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-methylbenzyl)sulfamide;

[0730] TIFF0007818010000080.tif3035

[0731] 1H NMR (400MHz, DMSO-d6) δ7.62(d, J=2.1Hz, 1H), 7.55(s, 1H), 7.47(s, 2H), 7.37(d, J=9.0H) z, 1H), 7.28-7.19(m, 2H), 6.72(s, 2H), 4.21(d, J=6.5Hz, 2H), 3.90(s, 3H), 2.05(s, 3H).

[0732] Example 67: N-(3-cyano-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-benzyl)sulfamide;

[0733] TIFF0007818010000081.tif3035

[0734] LC-MS(ESI) calculation for C 15 H 14 N6O3S [M+H] + 358.08, found m / z 359.1

[0735] Example 68: N-(3-methoxy-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0736] TIFF0007818010000082.tif3035

[0737] LC-MS(ESI) calculation for C 15 H 17 N5O4S [M+H] + 363.1, found m / z 364.1

[0738] Example 69: N-(4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0739] TIFF0007818010000083.tif3135

[0740] 1H NMR (400MHz, DMSO-d6) δ7.82(d, J=8.2Hz, 2H), 7.73(s, 1H), 7.65(d, J=8.3Hz, 2H), 7.55(s , 1H), 7.25(t, J=6.4Hz, 1H), 6.72(s, 2H), 4.21(d, J=6.1Hz, 2H), 3.93(s, 3H), 2.35(s, 3H).

[0741] Example 70: N-(3-fluoro-4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0742] TIFF0007818010000084.tif3035

[0743] 1 H NMR (400MHz, DMSO-d6) δ7.77(t, J=7.9Hz, 1H), 7.61(d, J=11.4Hz, 1H), 7.57(s, 1H), 7.49(d, J=7.9Hz, 1H), 7.42(s, 1H), 7.36(t, J=6.5Hz, 1H), 6.77(s, 2H), 4.25(d, J=6.5Hz, 2H), 3.93(s, 3H), 2.31(s, 3H).

[0744] Example 71: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0745] TIFF0007818010000085.tif3135

[0746] 1 H NMR (400MHz, DMSO-d6) δ7.77(t, J=7.9Hz, 1H), 7.61(d, J=10.6Hz, 2H), 7.49(d, J=8.1Hz, 1H), 7. 36(t, J=6.5Hz, 1H), 6.97(s, 1H), 6.77(s, 2H), 4.25(d, J=6.5Hz, 2H), 3.90(s, 3H), 3.84(s, 3H).

[0747] Example 72: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)sulfamide;

[0748] TIFF0007818010000086.tif4535

[0749] 1 H NMR (400MHz, DMSO-d6) δ7.87(d, J=9.1Hz, 1H), 7.80-7.68(m, 2H), 7.67-7.58(m, 2H), 7.46(d, J=7.7Hz, 1H), 7.29(dd, J=9.1, 2.3Hz, 1H) , 6.67(t, J=5.9Hz, 1H), 6.58(s, 2H), 3.91(s, 3H), 3.34(s, 2H), 3.22(dd, J=13.5, 7.1Hz, 2H), 2.97(t, J=7.3Hz, 2H), 2.57-2.47(m, 4H).

[0750] Example 73: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)sulfamide hydrochloride;

[0751] TIFF0007818010000087.tif3735

[0752] 1 H NMR (400MHz, DMSO-d6) δ7.80(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).

[0753] Example 74: N-(3-fluoro-4-(5-hydroxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0754] TIFF0007818010000088.tif3235

[0755] 1H NMR (400MHz, DMSO-d6) δ9.92(s, 1H), 7.77(t, J=8.0Hz, 1H), 7.60(d, J=11.7Hz, 1H), 7.51-7.42(m, 2H), 7.35(dd, J=8.5, 4.3Hz, 2H), 7.17(dd, J=8.9, 2.2Hz, 1H), 6.77(s, 2H), 4.25(d, J=6.5Hz, 2H).

[0756] Example 75: N-(3-fluoro-4-(5-methyl-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0757] TIFF0007818010000089.tif3535

[0758] LC-MS(ESI) calculation for C 14 H 14 FN5O2S [M+H] + 335.09, found m / z 336.1

[0759] Example 76: N-(4-(5-ethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0760] TIFF0007818010000090.tif3138

[0761] 1 H NMR (400MHz, DMSO-d6) δ7.80(t, J=8.0Hz, 1H), 7.62(d, J=9.5Hz, 2H), 7.51(t, J=9.6Hz, 2H), 7.36(d, J=6.3Hz , 1H), 7.27(d, J=8.8Hz, 1H), 6.77(s, 2H), 4.25(d, J=6.5Hz, 2H), 4.16(d, J=6.9Hz, 2H), 1.40(t, J=6.9Hz, 3H).

[0762] Example 77: N-(3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0763] TIFF0007818010000091.tif2935

[0764] 1 H NMR (400MHz, DMSO-d6) δ7.79(t, J=8.0Hz, 1H), 7.62(t, J=7.5Hz, 2H), 7.51(dd, J=11.8, 5.0Hz, 2H), 7.36(t, J=6.5Hz , 1H), 7.24(dd, J=9.0, 2.2Hz, 1H), 6.77(s, 2H), 4.84-4.73(m, 1H), 4.25(d, J=6.5Hz, 2H), 1.34(s, 3H), 1.33(s, 3H).

[0765] Example 78: N-(5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-2-yl)methyl)sulfamide;

[0766] TIFF0007818010000092.tif3135

[0767] 1 H NMR (400MHz, DMSO-d6) δ9.03(d, J=2.4Hz, 1H), 8.36(dd, J=8.4, 2.6Hz, 1H), 7.89(d, J=9.1Hz, 1H), 7.81(d , J=8.5Hz, 1H), 7.65(d, J=2.2Hz, 1H), 7.39-7.28(m, 2H), 6.78(s, 2H), 4.34(d, J=6.5Hz, 2H), 3.90(s, 3H).

[0768] Example 79: N-(6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)pyridin-3-yl)methyl)sulfamide;

[0769] TIFF0007818010000093.tif3135

[0770] 1H NMR (400MHz, DMSO-d6) δ8.64(s, 1H), 8.45(d, J=9.2Hz, 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).

[0771] Example 80: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-N-methyl)sulfamide;

[0772] TIFF0007818010000094.tif3035

[0773] 1 H NMR (400MHz, DMSO-d6) δ7.88 (t, J=9.3Hz, 3H), 7.64 (dd, J=13.2, 5.3Hz, 3H), 7. 30(dd, J=9.1, 2.3Hz, 1H), 6.98(s, 2H), 4.23(s, 2H), 3.91(s, 3H), 2.63(s, 3H).

[0774] Example 81: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-N-methylsulfamide;

[0775] TIFF0007818010000095.tif3235

[0776] 1 H NMR (400MHz, DMSO-d6) δ7.84(t, J=7.9Hz, 1H), 7.65-7.55(m, 3H), 7.49(d, J=8.5Hz, 1 H), 7.29(dd, J=9.1, 2.3Hz, 1H), 7.03(s, 2H), 4.27(s, 2H), 3.90(s, 3H), 2.67(s, 3H).

[0777] Example 82: N-cyclopropyl-N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0778] TIFF0007818010000096.tif3035

[0779] 1 H NMR (400MHz, DMSO-d6) δ7.83(dd, J=8.8, 3.7Hz, 3H), 7.66-7.53(m, 3H), 7.29(dd, J=9.1, 2.3Hz, 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).

[0780] Example 83: (S)—N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)ethyl)sulfamide;

[0781] TIFF0007818010000097.tif3035

[0782] LC-MS(ESI) calculation for C 15 H 17 N5O3S [M+H] + 347.11, found m / z 348.1.

[0783] Example 84: N-(4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0784] TIFF0007818010000098.tif3235

[0785] LC-MS(ESI) calculation for C 14 H 12 F3N5O2S [M+H] + 371.07, found m / z 372.1.

[0786] Example 85: N-(3-fluoro-4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0787] TIFF0007818010000099.tif3135

[0788] 1 H NMR (400MHz, DMSO-d6) δ8.76(s, 1H), 7.98(dd, J=8.9, 1.3Hz, 1H), 7.88(dd, J=13.7, 5.8Hz, 2H), 7.66 (d, J=11.5Hz, 1H), 7.54(d, J=8.2Hz, 1H), 7.38(t, J=6.5Hz, 1H), 6.78(s, 2H), 4.28(d, J=6.5Hz, 2H).

[0789] Example 86: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)methanamine;

[0790] TIFF0007818010000100.tif3535

[0791] LC-MS(ESI) calculation for C 15 H 14 F2N4[M+H] + 288.10, found m / z 289

[0792] Example 87: N-(4-(5-dimethylamino)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0793] TIFF0007818010000101.tif3535

[0794] LC-MS(ESI) calculation for C 15 H 17 FN6O2S [M+H] + 364.11, found m / z 365.1

[0795] Example 88: N-(3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0796] TIFF0007818010000102.tif2935

[0797] LC-MS(ESI) calculation for C 14 H 13 F2N5O3S [M+H] + 369.35, found m / z 370.1

[0798] Example 89: N-(4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0799] TIFF0007818010000103.tif3035

[0800] 1 H NMR (400MHz, DMSO-d6) δ8.33(s, 1H), 8.04(d, J=9.0Hz, 1H), 7.87(d, J=8.5Hz, 2H ), 7.77-7.60(m, 3H), 7.27(t, J=6.5Hz, 1H), 6.73(s, 2H), 4.23(d, J=6.5Hz, 2H).

[0801] Example 90: N-(3-fluoro-4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0802] TIFF0007818010000104.tif3035

[0803] 1 H NMR (400MHz, DMSO-d6) δ8.36(s, 1H), 7.89-7.77(m, 2H), 7.72-7.61(m, 2H), 7. 52(d, J=8.2Hz, 1H), 7.37(t, J=6.5Hz, 1H), 6.77(s, 2H), 4.27(d, J=6.5Hz, 2H).

[0804] Example 91: N-(4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide;

[0805] TIFF0007818010000105.tif3035

[0806] 1 H NMR (400MHz, DMSO-d6) δ8.04(d, J=2.0Hz, 1H), 7.83(t, J=8.0Hz, 1H), 7.72(dd, J=9.0, 2.0Hz, 1H), 7.64( d, J=10.2Hz, 1H), 7.52(dd, J=8.9, 2.3Hz, 2H), 7.38(d, J=7.7Hz, 2H), 6.77(s, 2H), 4.26(d, J=6.5Hz, 2H).

[0807] Example 92: N-(4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0808] TIFF0007818010000106.tif3235

[0809] 1 H NMR (400MHz, DMSO-d6) δ7.88(dd, J=9.0, 6.0Hz, 2H), 7.84(d, J=8.5Hz, 2H), 7.65(d, J =8.5Hz, 2H), 7.26(t, J=6.5Hz, 1H), 6.72(s, 2H), 4.21(d, J=6.5Hz, 2H), 3.99(s, 3H).

[0810] Example 93: N-(3-fluoro-4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide;

[0811] TIFF0007818010000107.tif3540

[0812] 1H NMR (400MHz, DMSO-d6) δ7.89(d, J=7.6Hz, 1H), 7.80(t, J=8.0Hz, 1H), 7.69-7.57(m, 2H), 7. 49(d, J=8.1Hz, 1H), 7.37(t, J=6.5Hz, 1H), 6.76(s, 2H), 4.25(d, J=6.4Hz, 2H), 3.98(s, 3H).

[0813] Example 94: 5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)isoindoline-2-sulfonamide;

[0814] TIFF0007818010000108.tif3140

[0815] 1 H NMR (400MHz, DMSO-d6) δ7.80(s, 1H), 7.78(d, J=9.1Hz, 1H), 7.72(dd, J=8.1, 2.0Hz, 1H), 7.58- 7.53(m, 2H), 7.22(dd, J=9.1, 2.3Hz, 1H), 6.95(s, 2H), 4.57(s, 2H), 4.55(s, 2H), 3.82(s, 3H).

[0816] Example 95: N-5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-1H-inden-2-yl)sulfamide;

[0817] TIFF0007818010000109.tif2635

[0818] 1 H NMR (400MHz, DMSO-d6) δ7.80(d, J=9.0Hz, 1H), 7.68(s, 1H), 7.62-7.58(m, 2H), 7.48(d, J=3.8Hz, 1H), 7.27(dd, J=9.1, 2.3Hz, 1H) , 7.02(d, J=7.0Hz, 1H), 6.68(s, 2H), 4.17(dd, J=14.6, 7.3Hz, 1H), 3.89(s, 3H), 3.30(dd, J=10.4, 5.8Hz, 2H), 3.06-2.94(m, 2H).

[0819] Example 96: 6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0820] TIFF0007818010000110.tif3540

[0821] 1 H NMR (400MHz, DMSO-d6) δ7.84(d, J=9.1Hz, 1H), 7.68-7.67(m, 2H), 7.60(d, J=2.1Hz, 1H), 7.49(d, J=9.0Hz, 1H), 7 .28(dd, J=9.1, 2.3Hz, 1H), 7.00(s, 2H), 4.33(s, 2H), 3.89(s, 3H), 3.07(t, J=5.7Hz, 2H), 2.50(t, J=3.4Hz, 2H).

[0822] Example 97: 7-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0823] TIFF0007818010000111.tif2840

[0824] 1 H NMR (400MHz, DMSO-d6) δ7.89(d, J=9.1Hz, 1H), 7.69(dd, J=11.8, 3.6Hz, 2H), 7.61(d, J=2.1Hz, 1H), 7.48(d, J=8.2Hz, 1H), 7.29(dd, J=9.1, 2.3Hz, 1H), 6.99(s, 2H), 4.39(s, 2H), 3.91(s, 3H), 3.37(t, J=5.9Hz, 2H), 3.05(t, J=5.8Hz, 2H).

[0825] 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;

[0826] TIFF0007818010000112.tif2740

[0827] LC-MS(ESI) calculation for C 17 H 19 N5O3S [M+H] + 373.12, found m / z 374.1

[0828] Example 99: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfamide;

[0829] TIFF0007818010000113.tif3640

[0830] LC-MS(ESI) calculation for C 14 H 15 F2N5O4S [M+H] + 399.08, found m / z 400.1

[0831] Example 100: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfamide;

[0832] TIFF0007818010000114.tif3640

[0833] LC-MS(ESI) calculation for C 14 H 15 F2N5O4S [M+H] + 399.08, found m / z 400.1

[0834] Example 101: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

[0835] TIFF0007818010000115.tif3540

[0836] LC-MS(ESI) calculation for C 16 H 16 FN5O3S [M+H] + 377.1, found m / z 378.1

[0837] Example 102: 5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-isoindoline-2-sulfonamide;

[0838] TIFF0007818010000116.tif3240

[0839] 1 H NMR (400MHz, DMSO-d6) δ7.85(s, 1H), 7.79(dd, J=8.1,1.8Hz, 1H), 7.63(d, J=8.2Hz, 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).

[0840] Example 103: N-(5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-dihydro-1H-inden-2-yl)sulfamide;

[0841] TIFF0007818010000117.tif3040

[0842] 1 H NMR (400MHz, DMSO-d6) δ7.67(s, 1H), 7.61(d, J=7.9Hz, 1H), 7.57(d, J=5.6Hz, 1H), 7.49(d, J=8.2Hz, 1H), 7.17(s, 1H), 7.02( d.

[0843] Example 104: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)phenyl)sulfamide hydrochloride;

[0844] TIFF0007818010000118.tif2249

[0845] LC-MS(ESI) calculation for C 14 H 16 ClNOS [M+H] + 369.07, found m / z 370.1

[0846] Example 105: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzyl)sulfamide hydrochloride;

[0847] TIFF0007818010000119.tif2249

[0848] LC-MS(ESI) calculation for C 14 H 16 ClNOS [M+H] + 383.08, found m / z 384.1

[0849] Example 106: N-((5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)thiophen-2-yl)methyl)sulfamide;

[0850] TIFF0007818010000120.tif3440

[0851] LC-MS(ESI) calculation for C 24 H 13 N5O3S2[M+H] + 339.41, found m / z 340

[0852] Example 107: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-5-methoxythiophen-2-yl)methyl)sulfamide;

[0853] TIFF0007818010000121.tif2949

[0854] 1 H NMR (400MHz, MeOH-d4) δ6.03(d, J=9.6Hz, 1H), 5.91(s, 1H), 5.74(d, J=8.7Hz, 1H), 5.47(s, 1H), 3.08(s, 2H), 2.75(s, 2H), 2.39(s, 3H), 1.03(s, 3H).

[0855] Example 108: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-bicyclo[1.1.1]pentan-1-yl)sulfamide;

[0856] TIFF0007818010000122.tif3540

[0857] 1 H NMR (400MHz, DMSO-d6) δ7.78(d, J=9.0Hz, 1H), 7.49(d, J=2.0Hz, 1H), 7.21(dd, J=9.0, 2.2H z, 1H), 6.76(t, J=6.2Hz, 1H), 6.58(s, 2H), 3.85(s, 3H), 3.23(d, J=6.2Hz, 2H), 2.45(s, 6H).

[0858] Example 109: N-(4-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)phenyl)sulfamide hydrochloride;

[0859] TIFF0007818010000123.tif3049

[0860] LC-MS(ESI) calculation for C 14 H 15 N5O3S [M+H] +333.09, found m / z 334.1.

[0861] Example 110: N-(4-((5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)benzyl)sulfamide hydrochloride;

[0862] TIFF0007818010000124.tif3049

[0863] 1 H NMR (400MHz, DMSO-d6) δ7.90(d, J=9.0Hz, 1H), 7.33-7.31(m, 5H), 7.00(dd, J=9.1, 2.2Hz, 1H), 5.88(s, 2H), 4.03(s, 2H), 3.84(s, 3H).

[0864] Example 111: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

[0865] TIFF0007818010000125.tif4040

[0866] LC-MS(ESI) calculation for C 14 H 19 FN4O3S [M+H] + 342.12, found m / z 343.1

[0867] Example 112: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)methanesulfonamide;

[0868] TIFF0007818010000126.tif3635

[0869] 1H NMR (400MHz, DMSO-d6) δ7.82(d, J=7.9Hz, 2H), 7.63(d, J=2.1Hz, 1H), 7.60(d, J=11.6Hz, 1H), 7.57(s, 1 H), 7.50(d, J=7.3Hz, 1H), 7.28(dd, J=9.0, 2.3Hz, 1H), 4.35(d, J=6.4Hz, 2H), 3.90(s, 3H), 2.98(s, 3H).

[0870] Example 113: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)ethanesulfonamide;

[0871] TIFF0007818010000127.tif3840

[0872] 1 H NMR (400MHz, DMSO-d6) δ7.83(dd, J=9.9, 6.1Hz, 2H), 7.64-7.59(m, 1H), 7.57(d, J=6.9Hz, 1H), 7.55-7.46(m, 1H) ), 7.28(dd, J=9.1, 2.3Hz, 1H), 4.33(d, J=6.3Hz, 2H), 3.90(s, 3H), 3.07(d, J=7.4Hz, 2H), 1.24(d, J=2.6Hz, 3H).

[0873] Example 114: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)-4-methylbenzenesulfonamide;

[0874] TIFF0007818010000128.tif3849

[0875] 1H NMR (400MHz, DMSO-d6) δ8.33(t, J=6.4Hz, 1H), 7.71(dd, J=16.0, 8.1Hz, 3H), 7.62(d, J=2.1Hz, 1H), 7.51-7.4 1(m, 2H), 7.38(d, J=8.0Hz, 3H), 7.29(dd, J=9.0, 2.3Hz, 1H), 4.17(d, J=6.4Hz, 2H), 3.90(s, 3H), 2.35(s, 3H).

[0876] Example 115: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)methanesulfonimidamide;

[0877] TIFF0007818010000129.tif4040

[0878] LC-MS(ESI) calculation for C 15 H 16 FN5O2S [M+H] + 349.1, found m / z 350.1

[0879] Example 116: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzoic acid;

[0880] TIFF0007818010000130.tif3640

[0881] 1 H NMR (400MHz, DMSO-d6) δ13.86 (brs, 1H), 8.12-7.93 (m, 3H), 7.64 (dd, J=9.1, 2.5Hz, 2H), 7.31 (dd, J=9.1, 2.2Hz, 1H), 3.90 (s, 3H).

[0882] Example 117: diethyl-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)phosphoramidite;

[0883] TIFF0007818010000131.tif3540

[0884] 1 H NMR (400MHz, DMSO-d6) δ7.80(t, J=8.0Hz, 1H), 7.63(d, J=2.1Hz, 1H), 7.58(d, J=11.6Hz, 1H), 7.52(dd, J=9.0, 2.1Hz, 1H), 7.48(d, J=8.2Hz, 1H), 7.28(dd, J=9.0, 2.2Hz, 1H), 5.70(dd, J=7.3,4.6Hz, 1H), 4.16-4.09(m, 2H), 3.98-3.90(m, 4H), 3.89(s, 3H), 1.21(t, J=7.1Hz, 42.6H).

[0885] Example 118: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenyl)phosphonic acid;

[0886] TIFF0007818010000132.tif3640

[0887] 1 H NMR (400MHz, DMSO-d6) δ8.09-7.87 (m, 5H), 7.64 (d, J=2.2Hz, 1H), 7.32 (dd, J=9.1, 2.3Hz, 1H), 3.90 (s, 3H).

[0888] Example 119: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)phosphonic acid;

[0889] TIFF0007818010000133.tif3540

[0890] 1 H NMR (400MHz, DMSO-d6) δ7.79(dd, J=8.6, 6.2Hz, 3H), 7.60(d, J=2.2Hz, 1H), 7.54(dd, J=8.5, 2.2Hz, 2H), 7.28(dd, J=9.1, 2.3Hz, 1H), 3.89(s, 3H), 3.11(d, J=21.5Hz, 2H).

[0891] Example 120: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)boronic acid;

[0892] TIFF0007818010000134.tif3540

[0893] LC-MS(ESI) calculation for C 14 H 13 BFN3O3[M+H] + 301.10, found m / z 302.1

[0894] Example 121: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)boronic acid;

[0895] TIFF0007818010000135.tif3840

[0896] LC-MS(ESI) calculation for C 15 H 16 BN3O3[M+H] + 297.13, found m / z 298.1

[0897] Example 122: N-(4-(5-methoxy-1H-indol-1-yl)benzyl)sulfamide;

[0898] TIFF0007818010000136.tif3540

[0899] LC-MS(ESI) calculation for C 16 H 17 N3O3S [M+H] + 330.24, found m / z 331.1

[0900] Example 123: N-(4-(5-methoxy-1H-benzo[d]imidazol-1-yl)benzyl)sulfamide;

[0901] TIFF0007818010000137.tif3640

[0902] LC-MS(ESI) calculation for C 15 H 16 N4O3S [M+H] + 332.09, found m / z 333.1

[0903] Example 124: N-(4-(5-methoxy-1H-indazol-1-yl)benzyl)sulfamide;

[0904] TIFF0007818010000138.tif3640

[0905] LC-MS(ESI) calculation for C 15 H 16 N4O3S [M+H] + 332.09, found m / z 333.1

[0906] [Experimental Example]

[0907] The following experiments were carried out using Examples 1 to 124 prepared as above.

[0908] Experimental example 1: ENPP1 enzyme assay with cGAMP substrate

[0909] ENPP1 hydrolyzes nucleotides or nucleotide derivatives to produce nucleoside 5'-monophosphate and pyrophosphate. ENPP1 also hydrolyzes 2'3'-cGAMP to produce 5'-adenosine monophosphate (AMP) and 5'-guanosine monophosphate (GMP). The AMP produced from the reaction is measured using the AMP-Glo® kit (Promega). The AMP-Glo® kit consists of two reagents. The first reagent terminates the AMP-producing enzyme reaction, removes ATP, and converts the produced AMP to ADP. The second reagent converts ADP to ATP, which is used to generate luminescence in a luciferase reaction. The measured amount of luminescence is proportional to the amount of AMP produced by ENPP1.

[0910] The final reaction mixture for the assay system contained 50 mM Tris (pH 8.5) buffer, 250 mM NaCl, 0.5 mM CaCl2, 1 μM ZnCl2, 5% glycerol, and 1% DMSO. Serially diluted ENPP1 inhibitors (generally ranging from 10 μM to 0.5 nM) were incubated with human recombinant ENPP1 enzyme (R&D Systems) at 3 ng / reaction for 5-10 minutes at room temperature. The reaction was initiated by adding cGAMP (at a final concentration of 5 μM) and incubated at 37°C for 90 minutes. At the end of the reaction, 10 μl of AMP-Glo ​​1 Reagent was added to terminate the reaction, followed by incubation at room temperature for 1 hour. Following incubation, 20 μl of AMP detection solution (a 1:100 mixture of AMP-Glo ​​2 Reagent and Kinase-Glo) was added and incubated at room temperature for 1 hour. Luminescence signals are measured using a Victor® plate reader (Perkin Elmer). A maximum activity control (enzyme and substrate in the presence of 1% DMSO; MAX) and a minimum activity control (substrate and 1% DMSO; MIN) are evaluated simultaneously. Serially diluted reference ENPP1 inhibitors are also tested in each experiment. % residual activity: IC versus compound concentration. 50Values ​​were determined by fitting inhibition curves using the 3-parameter method in GraphPad Prism® software. Serially diluted samples of a single compound were tested in duplicate, and the mean IC for each compound was calculated. 50 values ​​were calculated.

[0911] The experimental results are shown in Tables 1 and 2 below.

[0912] [Table 1] TIFF0007818010000140.tif223152 TIFF0007818010000141.tif156145

[0913] [Table 2]

[0914] [Experimental Example 2]

[0915] Experiments were carried out using the examples prepared as above.

[0916] Experimental example 2: HCT116-dual cell Luciferase assay

[0917] HCT116-Dual TM The cells express a gene encoding secreted luciferase under the control of the interferon-stimulated gene 54 (ISG54) promoter, along with five interferon-stimulated response elements. HCT116-Dual TMThe cell line is used to measure and monitor the activity of interferon regulatory factor 3 (IRF3), which induces the formation of type I interferons and is involved in subsequent signal transduction, and Lucia secreted into the culture medium is used to generate luminescence in a luciferase reaction.

[0918] HCT116-Dual was cultured in DMEM medium containing 10% FBS and 25 mM HEPES (pH 7.2-7.5). TM 2 x 10 cells in a 96-well plate 4 The cells were cultured for 1 day at 93.4 μL / well. 3.3 μL of ENPP1 inhibitor (typically 10 μM) was added, followed by 3.3 μL of cGAMP (10 μM) to bring the final volume to 100 μL. (The final DMSO concentration was 0.1%). The ENPP1 inhibitor and cGAMP-treated cells were cultured at 37°C for 48 hours, and luciferase activity was measured in 50 μL of Quanti-Luc reaction mixture added to 20 μL of cell culture medium. The compound-induced increase in interferon regulatory factor 3 (IRF3) levels relative to cGAMP was determined as a fold increase.

[0919] The experimental results are shown in Tables 3 and 4 below.

[0920] [Table 3]

[0921] [Table 4]

[0922] [Formulation example]

[0923] Meanwhile, the novel compound represented by Chemical Formula 1 according to the present invention can be formulated into various forms according to the purpose. Several formulation methods containing the compound represented by Chemical Formula 1 according to the present invention as an active ingredient are exemplified below, but the present invention is not limited thereto.

[0924] Formulation Example 1: Tablets (direct compression)

[0925] 5.0 mg of the active ingredient was sieved, then mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate, and compressed to form tablets.

[0926] Formulation Example 2: Tablets (wet granulation)

[0927] 5.0 mg of the active ingredient was sieved and then mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added and then pulverized. After drying, the pulverized material was sieved and then mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The pulverized material was compressed to produce tablets.

[0928] Formulation Example 3: Powder and Capsules

[0929] 5.0 mg of the active ingredient was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filled into No. 5 hard gelatin capsules using suitable equipment.

[0930] Formulation Example 4: Injection

[0931] An injection was prepared by adding 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na2HPO4·12H2O, and 2974 mg of distilled water.

[0932] Although the embodiments of the present invention have been described above, those skilled in the art will understand that the present invention can be embodied in other specific forms without changing the technical concept or essential features of the present invention. Therefore, it should be understood that the embodiments described above are illustrative in all respects and are not limiting.

Claims

1. A compound represented by the following chemical formula 1, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a stereoisomer thereof: Chemical formula 1 【Chemistry 1】 In the above Chemical Formula 1, W 1 is C; W 2 is C; W 3 is C; W 4 is C; W 5 is N; W 6 is N; W 7 is N; R 1 , R 2 , R 3 and R 4 are each independently hydrogen; a hydroxy group; a halogen group; or —CF 3 -(O)CF 3 ; C 1 -C 13 Alkyl group; C 1 -C 6 Alkoxy group; amino group (—NR 7 R 8 ), nitro group (—N(O) 2 ); an amide group (—(C═O)NR 7 R 8 ); carboxylic acid group (—C(O)OH); nitrile group (—CN); C 6 -C 10 Aryl group; C 3 -C 10 Cyclyl group; C 3 -C 10 Heteroaryl group; C 3 -C 10 heterocyclyl group; or —C(O)—(C 1 -C 13 alkyl); The Z may or may not be present, and when Z is present, Z is -CH 2 and Z is W 5 Or W 7 binds to R 5 is -A-(R 6 ) y and A, R 6 and y are selected from the following combinations (a) to (d): (a) The above A is C 3 -C 10 Cyclyl group, C 5 -C 10 Bicyclyl group, C 3 -C 10 Heterocyclyl group, C 6 -C 10 an aryl group, or C 3 -C 10 A is a heteroaryl group, 6 In addition to hydrogen; halogen groups; C 1 -C 3 Alkyl group; C 1 -C 3 and a nitrile group (—CN); The R 6 is -(CH 2 ) NHS (O) 2 R 7 , -(CH 2 ) NHS (O) 2 NHR 7 , -(CH 2 ) NR 7 S (O) 2 NHR 8 , or -(CH 2 ) P(O)R 7 R 8 and y is an integer from 1 to 4; (b) A is a benzene ring and R 6 does not contain any substituents other than The R 6 is -(C m H 2m ) NHS (O) 2 R 7 , -(C m H 2m ) NHS (O) 2 NHR 7 , -(C m H 2m ) NR 7 S (O) 2 NHR 8 or -(C m H 2m ) P(O)R 7 R 8 and m is 1 or 2, and y is 1, (c) The above A is C 3 -C 10 Cyclyl group, C 5 -C 10 Bicyclyl group, C 3 -C 10 Heterocyclyl group, C 6 -C 10 an aryl group, or C 3 -C 10 Heteroaryl group, R 6 has no substituents other than The R 6 Ha-NHS(O) 2 R 7 , -NHS(O) 2 NHR 7 , -NR 7 S (O) 2 NHR 8 , or -P(O)R 7 R 8 and y is 1, and (d) A is -piperidyl or 5-, 6-, 7-, or 8-(1,2,3,4-tetrahydroisoquinolyl) and R 6 has no substituents other than The R 6 is NH 2 or a sulfonamide group (—SO 2 NH 2 ) and R 6 is attached to the N of ring A, and y is 1, and, The R 7 and R 8 are each independently hydrogen; C 1 -C 6 Alkyl group; C 1 -C 6 Alkenyl group; C 1 -C 6 Alkynyl group; C 6 -C 10 Aryl group; C 3 -C 10 Heteroaryl group; C 3 -C 10 Heterocyclyl group; amino group (-NH 2 ), nitro group (—N(O) 2 -Boc; NHBoc; or R 7 is R 8 and a nitrogen or carbon atom linked to N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O) 2 - and SO 2 and at least one of hydrogen, C 1 -C 13 Alkyl group, C 6 -C 10 Aryl group, C 3 -C 10 forming a 3- to 7-membered saturated ring substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group, and a cyano group; Said C 3 -C 10 Heteroaryl groups and C 3 -C 10 The heterocyclyl group contains one or more heteroatoms selected from the group consisting of N, O, and S.

2. A, R 6 and the combination of y is (a) or (c), and A is C 5 -C 6 Cyclyl group, C 5 -C 7 Bicyclyl group, C 5 -C 8 Heterocyclyl group, C 6 -C 8 an aryl group, or C 4 -C 7 10. The compound, tautomer, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer of claim 1, wherein: is a heteroaryl group.

3. A, R 6 and y is (a) or (c), and A is cyclopentane; cyclohexane; benzene; bicyclopentane; thiophene; pyridine; benzofuran; quinoline; indole; benzazepine; piperidine; furan; naphthalene; anthracene; phenanthrene; pyridazine; pyrazine; imidazole; pyrazole; pyrimidine; pyrrole; indole; or purine;

4. A, R 6 and y is (a) or (c), and A is cyclopentane; cyclohexane; benzene; bicyclopentane; thiophene; pyridine; benzofuran; quinoline; indole; benzazepine; or piperidine;

5. R 1 , R 2 , R 3 and R 4 are each independently hydrogen; a hydroxy group; a halogen group; or —CF 3 -(O)CF 3 ; C 1 -C 3 Alkyl group; C 1 -C 6 an alkoxy group; or an amino group (—NR 7 R 8 2. The compound, tautomer, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer of claim 1, wherein:

6. A, R 6 and the combination of y is (a) or (c), and A is cyclopentane; cyclohexane; benzene; bicyclopentane; thiophene; pyridine; benzofuran; quinoline; indole; benzazepine; or piperidine; R 1 , R 2 , R 3 and R 4 are each independently hydrogen; a hydroxy group; a halogen group; or —CF 3 -(O)CF 3 ; C 1 -C 3 Alkyl group; C 1 -C 6 an alkoxy group; or an amino group (—NR 7 R 8 2. The compound, tautomer, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer of claim 1, wherein:

7. A compound selected from the group consisting of the following compound numbers 1 to 121, a tautomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a stereoisomer thereof: Compound No. 1: 5-methoxy-1-(piperidin-4-yl)-1H-benzo[d][1,2,3]triazole hydrochloride; Compound No. 2: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)cyclohexyl)methanamine; 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-tetrahydroisoquinoline 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-(isoindolin-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)carbamate; Compound No. 33: tert-butyl((4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)methyl)piperidin-1-yl)sulfonyl)carbamate; 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-dihydroisoquinolin-2(1H)-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-(1H-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-(1H-benzo[d][1,2,3]triazol-1-yl)-3-fluorobenzyl)sulfamide; Compound No. 57: N-(4-(1H-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-1H-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-1H-benzo[d][1,2,3]triazol-1-yl)benzyl)sulfamide; Compound No. 93: N-(3-fluoro-4-(6-fluoro-5-methoxy-1H-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)isoindoline-2-sulfonamide; Compound No. 95: N-5-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,3-dihydro-1H-inden-2-yl)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-1H-benzo[d][1,2,3]triazol-1-yl)-2,5-difluorobenzyl)sulfamide; Compound No. 100: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-2,6-difluorobenzyl)sulfamide; Compound No. 101: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide; Compound No. 102: 5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-isoindoline-2-sulfonamide; Compound No. 103: N-(5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-dihydro-1H-inden-2-yl)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-methoxythiophen-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-1H-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)phosphoramidite; 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; and Compound No. 121: 4-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)phenethyl)boronic acid.

8. 10. The compound, tautomer, pharmaceutically acceptable salt, hydrate, solvate or stereoisomer of claim 1, wherein the pharmaceutically acceptable salt is a salt of an inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

9. A pharmaceutical composition for preventing, alleviating or treating cancer, comprising the compound according to any one of claims 1 to 8 as an active ingredient.

10. An ENPP1 inhibitor comprising the compound according to any one of claims 1 to 8 as an active ingredient.

11. A STING pathway activator comprising a compound according to any one of claims 1 to 8 as an active ingredient.

12. The pharmaceutical composition for preventing, alleviating or treating cancer according to claim 9, wherein the cancer is a cancer associated with the suppression of ENPP1.

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