Pharmaceutical composition for preventing, ameliorating, or treating calcium pyrophosphate deposition disease and hypophosphatasia, comprising a benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase

Abstract

The present invention relates to a pharmaceutical composition for preventing, ameliorating, or treating calcium pyrophosphate deposition disease and hypophosphatasia, comprising a benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase.

Description

Pharmaceutical composition for the prevention, alleviation, or treatment of calcium pyrophosphate accumulation disease and hypophosphatasia comprising a benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase.

[0001] The present invention relates to a pharmaceutical composition for the prevention, alleviation, or treatment of calcium pyrophosphate accumulation disease and hypophosphatasia comprising a benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase.

[0002] Calcium Pyrophosphate Deposition (CPPD) disease occurs due to the accumulation of calcium pyrophosphate (CPP) crystals in joint tissues. In CPPD, the formation of CPP crystals in the joint cartilage and synovial membranes causes inflammation, joint pain, and destruction.

[0003] CPPD is a heterogeneous nodular arthritis that can cause acute or chronic joint symptoms and is known as the most common inflammatory arthritis in people over 60 years of age.

[0004] Acute calcium pyrophosphate crystalline arthritis, historically known as 'pseudoarthritis,' is the most widely known form of CPPD. It occurs when CPP crystals activate the NLRP3 inflammasome, inducing IL-1β secretion and causing acute inflammatory arthritis.

[0005] Chondrocalcinosis is a radiological finding caused by CPPD (much less commonly, basic calcium phosphate), commonly found in the elderly, with prevalence increasing every 10 years after age 60. In Europe and North America, the prevalence of imaging evidence of CPPD in middle-aged adults is estimated at about 10% depending on the joint location, and increases to about 30% in adults over 80 years of age. Additionally, CPPD is associated with cartilage degradation and osteoarthritis.

[0006] There is no effective treatment for the prevention or dissolution of CPP crystals, similar to the use of uric acid-lowering therapy for gout, a common inflammatory arthritis caused by the accumulation of crystals (sodium urate) in the joints. Although the pathogenesis of CPPD is not yet fully understood, an increase in inorganic pyrophosphate (PPi) is key to the formation of CPP crystals inside and outside the cartilage. Treatment for CPPD mostly focuses on alleviating inflammation with non-steroidal anti-inflammatory drugs such as colchicine or prednisone. Biological agents that inhibit IL-1β and IL-6 have been shown to be effective in patients with recurrent acute or chronic inflammatory CPP crystal arthritis.

[0007] The Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) in the United States recognized that there is a significant unmet need for CPPD. However, there are currently no disease-changing treatments available.

[0008] Hypophosphatasia (HPP) is a hereditary metabolic disorder caused by a deficiency in the activity of tissue non-specific alkaline phosphatase (TNAP). The main function of TNAP is to hydrolyze pyrophosphate, a tissue mineralization inhibitor.

[0009] The major biochemical defect of HPP is the elevated blood concentration of substrates, particularly PPi, a potent calcification inhibitor, due to a deficiency in TNAP activity. Decreased alkaline phosphatase activity leads to the accumulation of three major metabolites: pyridoxal 5'-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine. Impaired PLP dephosphorylation triggers seizures, and PPi accumulation impairs bone mineralization. Clinical symptoms of HPP include rickets-like bone changes, bone mineralization, brittle fractures, muscle weakness, thoracic deformity, pulmonary hypoplasia, kidney stones, nephrocalcinosis, and chondrocalcinosis.

[0010] Currently, TNAP enzyme replacement therapy alleviates skeletal, motor, and cognitive impairments in pediatric patients with hypophosphatemia, but it does not completely eliminate craniosynostosis.

[0011] As a result of continuing research to solve the above problems, the inventors discovered that a substance having ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1) inhibitory activity can reduce the accumulation of PPi and the burden of CPP crystallization by blocking the production of extracellular pyrophosphate.

[0012] Accordingly, the problem that the present invention aims to solve is to provide a pharmaceutical composition for the prevention, alleviation, or treatment of one or more of CPPD and HPP, comprising a benzotriazole derivative having inhibitory activity on ENPP1.

[0013] Another problem that the present invention aims to solve is to provide a method for the prevention, alleviation, or treatment of one or more of CPPD and HPP, comprising the step of administering a benzotriazole derivative having inhibitory activity on ENPP1 or a pharmaceutical composition containing the same to a patient or subject who requires it.

[0014] The problems of the present invention are not limited to the technical problems mentioned above, and other unmentioned technical problems will be clearly understood by those skilled in the art from the description below.

[0015] A pharmaceutical composition for the prevention, alleviation, or treatment of one or more of Calcium Pyrophosphate Deposition (CPPD) disease and Hypophosphatasia (HPP) according to one embodiment of the present invention for solving the above problem comprises a benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1).

[0016] Benzotriazole derivatives having inhibitory activity on ENPP1 include compounds represented by the following chemical formula 1, pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, or isomers thereof. The isomers may be tautomers or stereoisomers.

[0017] [Chemical Formula 1]

[0018]

[0019] In the above chemical formula 1,

[0020] W1 is N or C;

[0021] W2 is N or C;

[0022] W3 is N or C;

[0023] W4 is N or C;

[0024] W5 is N or CR a And;

[0025] W6 is N or CR b And;

[0026] W7 is N or CR c And;

[0027] R a , R b and R c Each is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, and heteroaryl, and

[0028] R1, R2, R3, and R4 are each independently hydrogen; hydroxyl group; halogen group; -CF3; -CF2CH3; -CF(CH3)CH3; -(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 Cyclic reel; C3-C 10 Heteroaryl group; C3-C 10 Heterocyclyl group; or -C(O)-(C1-C 13 alkyl); and,

[0029] The above Z may or may not be present, and if Z is present, Z is -O-, -CO-, -COO-, -C n H 2n -, -O(C n H 2n)-, -(OC2H4) n -, -(C2H4O) n -, -(C n H 2n )O-, -(C n H 2n )CO-, -(C n H 2n )O(C m H 2m )-, -NR7(C n H 2n )-, -(NR7C2H4) n -, -(C2H4NR7) n -, or -(C n H 2n )NR7-; and,

[0030] n is an integer from 0 to 8, and

[0031] R5 is -A-(R6) y is,

[0032] The above A is C3-C 10 Cycle reel, C5-C 10 Bicyclil, C3-C 10 Heterocyclyl group, C6-C 10 aryl group, or C3-C 10 It is a heteroaryl group, and

[0033] The above R6 is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C1-C6 alkenyl group; C6-C 10 Aryl group; C3-C 10 Cyclic reel; 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 2m )NR7R8; nitro group(-N(O)2); amide group(-(C=O)NR7R8); ester group(-(C m H 2m )C(O)OR7); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-(C m H2m )NHS(O)2R7); Ureagenesis; Sulfamodialysis(-(C m H 2m )NHS(O)2NHR7); -(C m H 2m )NR7S(O)2NHR8; sulfide group(-(C m H 2m )SR7); Sulfoni(-( C m H 2m )S(O)2R7); phosphiryl group(-(C m H 2m )P(O)R7R8); or connected to the same carbon as the carbon connected to A or an adjacent carbon to form a 3 to 10-membered saturated ring or a heterosaturated ring comprising one or more heteroatoms of N, O, and S,

[0034] The above A may include one or more substituents selected from halogens, independently of R6, and

[0035] m is an integer from 0 to 4, and

[0036] y is an integer from 0 to 4, and

[0037] The above C1-C 13 Alkyl group, C1-C6 alkoxy group, C1-C6 alkenyl group, or -C(O)-(C1-C 13 Alkyl) is hydrogen; hydroxyl group; halogen group; 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)2R7); sulfide group (-SR7); sulfonate group (-S(O)2R7); phosphyryl group (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 heteroaryl group; and C3-C 10 It comprises one or more substituents selected from the group consisting of heterocyclil groups, and

[0038] The above C6-C10 Aryl group, C3-C 10 Heteroaryl group, C3-C 10 Cyclic reel, C3-C 10 heterocyclyl group or C5-C 10 The bicyclil group is hydrogen; a hydroxyl group; a halogen group; a carbonyl group (-(C=O)R7R8); a halogen or C3-C 10 C1-C3 alkyl groups substituted or unsubstituted with heterocyclyl groups; halogen or C3-C 10 C1-C3 alkoxy groups substituted or unsubstituted with heterocyclyl groups; C6-C 10 Phenoxy; 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)2R7); sulfide group (-SR7); sulfon group (-S(O)2R7); phosphyryl group (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 heteroaryl group and C3-C 10 It comprises one or more substituents selected from the group consisting of heterocyclil groups, and

[0039] The above R7 and R8 are each independently hydrogen; C1-C6 alkyl group; C1-C6 alkenyl group; C1-C6 alkynyl group; C3-C 10 Cyclic reel; C6-C 10 Aryl group; C3-C 10 Heterocyclyl group; C3-C 10 Heteroaryl group; amino group (-NH2); nitro group (-N(O)2); -Boc; -NHBoc; or R7 may optionally include at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, or SO2 together with the nitrogen or carbon atom connected to R8, and hydrogen, C1-C 13 Alkyl group, C6-C 10 Aryl group, C3-C 10Forming a 3 to 7-membered saturated ring that can be optionally substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group, and a cyano group, and

[0040] The above C3-C 10 heteroaryl group and C3-C 10 The heterocyclyl group comprises one or more heteroatoms selected from the group consisting of N, O, and S.

[0041] According to one embodiment, W1, W2, W3 and W4 may each be C.

[0042] According to one embodiment, A may be 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.

[0043] According to one embodiment, A may be substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; substituted or unsubstituted piperidine; substituted or unsubstituted furan; substituted or unsubstituted naphthalene; substituted or unsubstituted anthracene; or substituted or unsubstituted phenatrene; substituted or unsubstituted pyridazine; substituted or unsubstituted pyrazine; substituted or unsubstituted imidazole; substituted or unsubstituted pyrazol; substituted or unsubstituted pyrimidine; substituted or unsubstituted pyrrole; substituted or unsubstituted indole; or substituted or unsubstituted purine.

[0044] In one embodiment, A may be substituted or unsubstituted cyclopentane; substituted or unsubstituted cyclohexane; substituted or unsubstituted benzene; substituted or unsubstituted bicyclopentane; substituted or unsubstituted thiophene; substituted or unsubstituted pyridine; substituted or unsubstituted benzofuran; substituted or unsubstituted quinoline; substituted or unsubstituted indole; substituted or unsubstituted benzoazepine; or substituted or unsubstituted piperidine.

[0045] In one embodiment, R1, R2, R3, and R4 are each independently hydrogen; a hydroxyl group; a halogen group; -CF3; -(O)CF3; C1-C3 alkyl group; C1-C6 alkoxy group; or amino group (-NR7R8), wherein Z may or may not be present, and if Z is present, Z is -C n H 2n - and n can be an integer from 1 to 4.

[0046] In one embodiment, W1, W2, W3, and W4 are each C, 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 benzoazepine; or substituted or unsubstituted piperidine, and R1, R2, R3, and R4 are each independently hydrogen; hydroxyl group; halogen group; -CF3; -(O)CF3; C1-C3 alkyl group; C1-C6 alkoxy group; or amino group (-NR7R8), wherein Z may or may not be present, and if Z is present, Z is -C n H 2n - and n can be an integer from 1 to 4.

[0047] In one embodiment, the R6 is a sulfonamide group (-(C m H 2m )NHS(O)2R7); Sulfamo Diary(-(Cm H 2m )NHS(O)2NHR7); -(C m H 2m )NR7S(O)2NHR8; sulfide group(-(C m H 2m )SR7) or sulfonate(-( C m H 2m )S(O)2R7) may be.

[0048] The alkyl group may be an aliphatic hydrocarbon radical. The alkyl group may be a saturated alkyl group that does not contain an alkenyl or alkynyl group, or an unsaturated alkyl group that contains at least one alkenyl or alkynyl group. The alkenyl group may be a group containing at least one carbon-carbon double bond, and the alkynyl group may be a group containing at least one carbon-carbon triple bond. When used alone or in combination, the alkyl group may be cyclic, branched, or straight-chain, respectively.

[0049] The aryl may be a carbocyclic aromatic monocyclic group comprising six carbon atoms that can be additionally fused to a second 5- or 6-membered carbocyclic group, which may be aromatic, saturated, or unsaturated, either alone or in combination with other radicals. The aryl may include, but is not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tephrahyadronapthyl, etc., for example. The aryl may be connected to another group at an appropriate position on the aromatic ring.

[0050] The alkoxy group can be an alkyl group (i.e., -O-alkyl) connected to another group through an oxygen atom. The alkoxy group may be unsubstituted or substituted with one or more suitable substituents. The alkoxy group is, for example, a (C1-C6)alkoxy group, e.g., -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O―2-methyl-2-propyl, -O―2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1-propyl, -O―2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O-3-methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl-1-butyl, -O-butyl, -O-isobutyl, -Ot-butyl, It may include one or more from the group consisting of -O-pentyl, -O-isopentyl, -O-neopentyl, and -O-hexyl, but is not limited thereto.

[0051] The phenoxy group may be a phenyl group (i.e., -O-aryl) connected to another group through an oxygen atom. The phenoxy group may be unsubstituted or substituted with one or more selected from the group consisting of halogens; alkyl groups; aryl groups and heteroaryl groups, but is not limited thereto.

[0052] The amino group may be an alkyl group (i.e., -NH- or -N-alkyl) connected to another group through a nitrogen atom. The amino group may be unsubstituted or substituted with one or more suitable substituents. The amino group is, for example, a (C1-C6)amino group, e.g. -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH―2-methyl-2-propyl, -NH―2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl, -NH―2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2-methyl-2-pentyl, -NH-3-methyl-2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2-ethyl-1-butyl, -NH-butyl, -NH-isobutyl, -NH-t-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N,N-dimethyl, -N-methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl-N-butyl, -N-methyl-N-isobutyl, -N-methyl-N-pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N-propyl, -N-ethyl-N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N-hexyl, , It includes, but is not limited to, one or more selected from the group consisting of -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N-propyl-N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, and -N,N-dihexyl.

[0053] The halogen group can be fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), and specifically, it can be fluorine.

[0054] The cyclic group or heterocyclic group may specifically be a saturated or unsaturated non-aromatic (hetero)cyclic compound. More specifically, the cyclic group or heterocyclic group may be a saturated non-aromatic (hetero)cyclic compound.

[0055] Unless otherwise noted, the heterocyclic group may be a saturated or unsaturated hetero-aromatic compound comprising one or more hetero atoms selected from the group consisting of N, O, and S. Preferably, the heterocyclic group may comprise one or more selected from the group consisting of pyrrolidine, furan group, morpholine group, piperazine, and piperidine group, and more preferably may comprise one or more of pyrrolidine group, piperidine group, piperazine group, and morpholine group, but is not limited thereto.

[0056] Unless otherwise noted, the heteroaryl group may be a heteroaromatic compound comprising 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, one or more selected from the group consisting of pyridine, pyrazine, pyrimidine, pyridazine, pyrazol, imidazole, triazole, indole, oxadiazole, thiadiazole, quinoline, isoquinoline, isoxazole, oxazole, thiazole, and pyrrole groups.

[0057] In one embodiment, a benzotriazole derivative having inhibitory activity of ENPP1 may be any one of the following compound numbers 1 to 124, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, or an isomer thereof.

[0058] Compound No. 1: 5-methoxy-1-(piperidin-4-yl)-1H-benzo[d][1,2,3]triazole hydrochloride;

[0059] Compound No. 2: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclohexyl)methaneaniline;

[0060] Compound No. 3: 5-methoxy-1-(piperidine-4-ylmethyl)-1H-benzo[d][1,2,3]triazole;

[0061] Compound No. 4: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)aniline hydrochloride;

[0062] Compound No. 5: 4-(1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0063] Compound No. 6: 4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0064] Compound No. 7: 4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0065] Compound No. 8: 4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0066] Compound No. 9: 4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0067] Compound No. 10: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0068] Compound No. 11: 2-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethane-1-amine hydrochloride;

[0069] Compound No. 12: 1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)-N-methylmethaneamine hydrochloride;

[0070] Compound No. 13: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)cyclopropanamine hydrochloride;

[0071] Compound No. 14: (S)-1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethane-1-amine hydrochloride;

[0072] Compound No. 15: 3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0073] Compound No. 16: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0074] Compound No. 17: 2,5-Difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0075] Compound No. 18: 2,6-Difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0076] Compound No. 19: 4-(5-ethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine;

[0077] Compound No. 20: 3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0078] Compound No. 21: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0079] Compound No. 22: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine;

[0080] Compound No. 23: 3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0081] Compound No. 24: 4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine;

[0082] Compound No. 25: 7-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0083] Compound No. 26: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0084] Compound No. 27: 8-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine hydrochloride;

[0085] Compound No. 28: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,5-difluorophenyl)methaneamine;

[0086] Compound No. 29: 1-(isoindorin-5-yl)-5,6-dimethoxy-1H-benzo[d][1,2,3]triazole hydrochloride;

[0087] Compound No. 30: 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)bicyclo[1.1.1]pentane-1-yl)methaneamine;

[0088] Compound No. 31: 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-5-methylthiophene-2-yl)methaneamine hydrochloride;

[0089] Compound No. 32: tert-butyl((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidine-1-yl)sulfonyl)carbamate;

[0090] Compound No. 33: tert-butyl((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)piperidine-1-yl)sulfonyl)carbamate;

[0091] Compound No. 34: tert-butyl(N-(1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0092] Compound No. 35: tert-butyl(N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0093] Compound No. 36: tert-butyl(N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0094] Compound No. 37: tert-butyl(N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0095] Compound No. 38: tert-butyl(N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0096] Compound No. 39: tert-butyl((S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0097] Compound No. 40: tert-butyl((6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfamoyl)carbamate;

[0098] Compound No. 41: N-((3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclopentyl)methyl)sulfamide;

[0099] Compound No. 42: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidine-1-sulfonamide;

[0100] Compound No. 43: N-((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclohexyl)methyl)sulfamide;

[0101] Compound No. 44: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidin-1-yl)ethane-1-sulfonamide;

[0102] Compound No. 45: 4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)piperidine-1-sulfonamide;

[0103] Compound No. 46: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0104] Compound No. 47: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamide;

[0105] Compound No. 48: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamide hydrochloride;

[0106] Compound No. 49: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0107] Compound No. 50: N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0108] Compound No. 51: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide hydrochloride;

[0109] Compound No. 52: N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0110] Compound No. 53: N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0111] Compound No. 54: N-(4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0112] Compound No. 55: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0113] Compound No. 56: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0114] Compound No. 57: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-2,3-difluorobenzyl)sulfamide;

[0115] Compound No. 58: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-3,5-difluorobenzyl)sulfamide;

[0116] Compound No. 59: N-(3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0117] Compound No. 60: N-(2-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0118] Compound No. 61: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0119] Compound No. 62: N-(2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0120] Compound No. 63: N-(2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0121] Compound No. 64: N-(3,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)sulfamide;

[0122] Compound No. 65: N-(2,3-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)sulfamide;

[0123] Compound No. 66: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-methylbenzyl)sulfamide;

[0124] Compound No. 67: N-(3-cyano-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-benzyl)sulfamide;

[0125] Compound No. 68: N-(3-methoxy-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0126] Compound No. 69: N-(4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0127] Compound No. 70: N-(3-fluoro-4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0128] Compound No. 71: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0129] Compound No. 72: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)sulfamide;

[0130] Compound No. 73: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)sulfamide hydrochloride;

[0131] Compound No. 74: N-(3-fluoro-4-(5-hydroxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0132] Compound No. 75: N-(3-fluoro-4-(5-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0133] Compound No. 76: N-(4-(5-ethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0134] Compound No. 77: N-(3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0135] Compound No. 78: N-(5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)pyridine-2-yl)methyl)sulfamide;

[0136] Compound No. 79: (N-(6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)pyridine-3-yl)methyl)sulfamide;

[0137] Compound No. 80: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-N-methyl)sulfamide;

[0138] Compound No. 81: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-N-methylsulfamide;

[0139] Compound No. 82: N-cyclopropyl-N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0140] Compound No. 83: (S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethyl)sulfamide;

[0141] Compound No. 84: N-(4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0142] Compound No. 85: N-(3-fluoro-4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0143] Compound No. 86: N-(4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0144] Compound No. 87: N-(4-(5-dimethylamino)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0145] Compound No. 88: N-(3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0146] Compound No. 89: N-(4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0147] Compound No. 90: N-(3-fluoro-4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0148] Compound No. 91: N-(4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0149] Compound No. 92: N-(4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0150] Compound No. 93: N-(3-fluoro-4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0151] Compound No. 94: 5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)isoindorin-2-sulfonamide;

[0152] Compound No. 95: N-5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,3-dihydro-1H-indene-2-yl)sulfamide;

[0153] Compound No. 96: 6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0154] Compound No. 97: 7-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0155] Compound No. 98: 8-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-sulfonamide;

[0156] Compound No. 99: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,5-difluorobenzyl)sulfamide;

[0157] Compound No. 100: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,6-difluorobenzyl)sulfamide;

[0158] Compound No. 101: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

[0159] Compound No. 102: 5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-isoindorin-2-sulfonamide;

[0160] Compound No. 103: N-(5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-dihydro-1H-indene-2-yl)sulfamide;

[0161] Compound No. 104: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)phenyl)sulfamide hydrochloride;

[0162] Compound No. 105: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)benzyl)sulfamide hydrochloride;

[0163] Compound No. 106: N-((5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)thiophene-2-yl)methyl)sulfamide;

[0164] Compound No. 107: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-5-methoxythiophen-2-yl)methyl)sulfamide;

[0165] Compound No. 108: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-bicyclo[1,1.1]pentane-1-yl)sulfamide;

[0166] Compound No. 109: N-(4-(5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)phenyl)sulfamide hydrochloride;

[0167] Compound No. 110: N-(4-((5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)benzyl)sulfamide hydrochloride;

[0168] Compound No. 111: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

[0169] Compound No. 112: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)methanesulfonamide;

[0170] Compound No. 113: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)ethanesulfonamide;

[0171] Compound No. 114: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-4-methylbenzenesulfonamide;

[0172] Compound No. 115: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)methanesulfonimide;

[0173] Compound No. 116: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzoic acid;

[0174] Compound No. 117: Diethyl-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)phosphoamidate;

[0175] Compound No. 118: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)phosphonic acid;

[0176] Compound No. 119: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)phosphonic acid;

[0177] Compound No. 120: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)boronic acid;

[0178] Compound No. 121: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)boronic acid;

[0179] Compound No. 122: N-(4-(5-methoxy-1H-indole-1-yl)benzyl)sulfamide;

[0180] Compound No. 123: N-(4-(5-methoxy-1H-benzo[d]imidazole-1-yl)benzyl)sulfamide; and

[0181] Compound No. 124: N-(4-(5-methoxy-1H-indazole-1-yl)benzyl)sulfamide.

[0182] In one embodiment, the compound of Formula 1 may be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, and preferred salts may be one or more selected from the group consisting of hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvate, 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.

[0183] In one embodiment, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may include a hydrate and a solvate. The hydrate may mean that the compound of Formula 1 is formed by combining with a water molecule.

[0184] CPPD disease may refer to any disease resulting from the accumulation of calcium pyrophosphate (CPP) crystals, specifically any disease associated with inflammation, joint pain, or destruction caused by the formation of CPP crystals in articular cartilage and synovial membranes. More specifically, it may include one or more of acute inflammatory arthritis and chronic inflammatory arthritis associated with the accumulation of CPP crystals. CPPD disease may also include inflammation induced by the activation of the NLRP3 inflammasome due to an increase in the extracellular pyrophosphate concentration in the cartilage.

[0185] In the present invention, CPPD disease can be understood in a broad sense that includes underlying diseases or complications. For example, it may include metabolic diseases such as hyperparathyroidism, hemochromatosis, hypomagnesemia, and hypophosphatemia that cause or follow CPPD disease, as well as mutations in genes such as ANKH and osteoprotegerin.

[0186] In an exemplary embodiment, CPPD disease is pathological mineralization of soft tissue,

[0187] HPP may refer to any disease resulting from a decrease in the activity of tissue non-specific alkaline phosphatase (TNAP), and may include perinatal HPP, infantile HPP, childhood HPP, and adult HPP. Specifically, HPP may be a disease in which one or more metabolites selected from the group consisting of pyridoxal 5'-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine accumulate.

[0188] ENPP1 is a major enzyme that produces pyrophosphate, and inhibiting ENPP1 can be expected to restore hypomineralization of the skull, spine, and long bones—symptoms of HPP—to varying degrees in subjects with TNAP deficiency. However, the effects of the present invention are not limited thereto.

[0189] CPPD and HPP are diseases associated with TNAP deficiency or reduction (or activity deficiency / reduction), and the pharmaceutical composition of the present invention may be used for the prevention, alleviation, or treatment of diseases associated with TNAP deficiency or reduction (or activity deficiency / reduction).

[0190] In one embodiment, the pharmaceutical composition of the present invention may include a benzotriazole derivative represented by Formula 1 in an amount of 0.1 to 10 weight%, more preferably 0.5 to 5 weight%, based on the total weight of the composition.

[0191] The above 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 preferably may be applied to primates including humans, more preferably to humans.

[0192] In one embodiment, the pharmaceutical composition of the present invention may comprise a benzotriazole derivative represented by Formula 1 alone, or may further comprise one or more selected from the group consisting of pharmaceutically acceptable carriers, excipients, diluents, and auxiliary components. Additionally, it may further comprise pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers, isotonic adjusters, stabilizers, wetting agents, etc.

[0193] The above pharmaceutically acceptable carriers, excipients, or diluents may be any conventional carriers, excipients, or diluents. Additionally, the pharmaceutical composition may further include conventional fillers, extenders, binders, disintegrants, anticoagulants, lubricants, wetting agents, pH adjusters, nutrients, electrolytes, protective colloids, flavors, emulsifiers, or preservatives.

[0194] In one embodiment, the pharmaceutical composition of the present invention may be formulated as an aqueous buffer. In one embodiment, the aqueous buffer comprises a reagent that provides an isotonic solution. In one embodiment, the aqueous buffer may further comprise a nonionic surfactant. Optionally, the formulation may further comprise a preservative. The formulation may be freeze-dried, and these may generally comprise an antifreeze agent. The freeze-dried formulation may be stored for a long period at room temperature.

[0195] The pharmaceutical composition of the present invention may include or essentially consist of a benzotriazole derivative having inhibitory activity of ENPP1, and additionally may include or essentially consist of one or more additional activators of interest. In one embodiment, the pharmaceutical composition of the present invention, as well as additional therapeutic agents as described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. In another embodiment, the pharmaceutical composition of the present invention and additional therapeutic agents for combination therapy may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. The pharmaceutical composition of the present invention and a second activator (if present) may be administered by the same route or by different routes. The therapeutic agents may be administered to the affected organ by any suitable means, including but not limited to oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, and intratumoral injections.

[0196] In one embodiment, the pharmaceutical composition of the present invention may additionally include one or more convenient active agents, either optionally or essentially.

[0197] A method for preventing, alleviating, or treating one or more of CPPD and HPP according to one embodiment of the present invention for solving the above problem comprises the step of administering a benzotriazole derivative of Formula 1 or a pharmaceutical composition containing the same to a patient or subject who requires it. The benzotriazole derivative may be administered as an active ingredient.

[0198] In one embodiment, the effective amount of the benzotriazole derivative of the present invention may be in the range of about 10 ng to about 100 mg. The amount may be a single dose or a total daily amount. The total daily amount may be in the range of 10 ng to 100 mg, or in the range of 100 mg to about 500 mg, or in the range of 500 mg to about 1000 mg.

[0199] "Therapeutic effective dose" may refer to an amount of an active ingredient for mammals that is effective for the prevention or treatment of cancer, and the therapeutic effective dose may be adjusted according to 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 formulation, the patient's age, body weight, general health condition, gender and diet, the time of administration, the route of administration, the blood clearance rate of the composition, the duration of treatment, drugs used concurrently, the absorption rate and inactivation rate of the active ingredient in the body, etc., and may be administered once or in divided doses. Preferably, it may be administered to mammals, including humans, in an amount of 0.001 to 100 mg / kg body weight, preferably 0.01 to 35 mg / kg body weight on a daily basis, once a day or in divided doses via an oral or parenteral route.

[0200] In one embodiment, a single dose of the compound may be administered. In another embodiment, multiple doses may be administered. When the multiple doses are administered over a period of time, the compound of the present invention may be administered twice a day (bid), daily (qd), every other day (qod), every three days, three times a week (tiw), or twice a week (biw).

[0201] The method of administration of the above pharmaceutical composition may be either oral or parenteral, and may be administered via various routes including, for example, oral, transdermal, subcutaneous, intravenous, or intramuscular. In addition, the formulation of the above pharmaceutical composition may vary depending on the method of use and may be formulated using methods well known in the art to which the present invention belongs so as to provide rapid, sustained, or delayed release of the active ingredient after administration to mammals. Generally, solid formulations for oral administration include tablets, pills, soft or hard capsules, pills, powders, and granules, and these formulations may be prepared by mixing one or more excipients. Liquid formulations for oral administration include suspensions, oral liquids, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as humectants, sweeteners, flavorings, and preservatives may be included. Forms for parenteral administration may be in the form of creams, lotions, ointments, plasters, liquids and soultions, aerosols, fluid extracts, elixirs, infusions, sachets, patches, or injections. If an injectable formulation is used, it may preferably be in the form of an isotonic aqueous solution or a suspension.

[0202] The above pharmaceutical composition may further contain adjuvants such as sterilizing agents, preservatives, stabilizers, hydrating agents or emulsifying promoters, salts and / or buffers for osmotic pressure regulation, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation, or coating methods, and may also be formulated using appropriate methods known in the art.

[0203] The pharmaceutical composition of the present invention may be administered in a unit dosage form and may be prepared by any method well known in the art. Such methods include the step of combining the pharmaceutical composition of the present invention with a pharmaceutically acceptable carrier or diluent constituting one or more auxiliary components. The pharmaceutically acceptable carrier is selected based on the selected route of administration and standard pharmaceutical practice. Each carrier must be pharmaceutically acceptable in that it is compatible with other components of the formulation and does not cause harm to the object or patient. The carrier may be solid or liquid, and the type is selected according to the type of administration commonly used.

[0204] In addition, the dosage of the above pharmaceutical composition may be determined by considering the method of administration, the age and gender of the user, the severity and condition of the patient, the absorption and inactivation rate of the active ingredient in the body, and concomitant drugs, and may be administered once or in divided doses. The active ingredient of the above pharmaceutical composition may preferably be administered to mammals, including humans, via an oral or parenteral route in an amount of 0.001 to 100 mg / kg body weight, preferably 0.01 to 35 mg / kg body weight, on a daily basis, once a day or in divided doses.

[0205] In one embodiment, the method may include the step of treating a subject having one or more of CPPD disease and HPP by administering a therapeutically effective amount of a benzotriazole derivative of the present invention, which is an ENPP1 inhibitor, to the subject. In one embodiment, the subject may be a subject diagnosed with CPPD disease and / or HPP, or a subject suspected of having CPPD disease and / or HPP. Any suitable ENPP1 inhibitor may be used on the subject.

[0206] The above method for the prevention, alleviation, or treatment of CPPD disease and / or HPP may further include a step of identifying a patient requiring prevention, alleviation, or treatment of CPPD disease and / or HPP prior to the administration step.

[0207] In one embodiment, the step of identifying a patient requiring prevention, relief, or treatment of CPPD disease and / or HPP may include one or more of the steps of detecting CPP crystals in synovial fluid and imaging CPPD in the joint through radiography or ultrasound examination.

[0208] A method for preventing, alleviating, or treating one or more of CPPD disease and HPP according to one embodiment of the present invention for solving the above problem may include the step of administering the ENPP1 inhibitor compound, which is the benzotriazole derivative, to a subject alone or together with an additional activator or additional therapy.

[0209] The terms "agent," "compound," and "drug" are used interchangeably herein. In one embodiment, the method of the present invention may further include the step of administering to the object an additional agent, e.g., a small molecule, a chemotherapy agent, an antibody, an antibody-drug conjugate, an aptamer, a protein, an immune checkpoint inhibitor, or a radiotherapy agent in combination or sequentially.

[0210] "Co-administration" or "in combination with" involves the administration of two or more therapeutic agents simultaneously, concurrently, or sequentially without specific time limitations. In some embodiments, the agents or formulations are simultaneously present in the body of a cell or object or exert biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are the same composition or unit dosage form. In one embodiment, the therapeutic agents are separate compositions or unit dosage forms. In one embodiment, the first formulation may be administered prior to, incidentally together with, or subsequently to the administration of the second therapeutic agent.

[0211] "Concomitant administration" of an additional therapy with a composition comprising a known therapeutic agent or a benzotriazole derivative of the present invention may mean administering the compound and the second agent or additional therapy so that both compositions of the known agent and the disclosed compound have a therapeutic effect. Such concomitant administration may include the simultaneous or prior administration of a drug in connection with the administration of the benzotriazole derivative of the present invention. The routes of administration of the two agents may vary, and representative routes of administration are described in detail herein.

[0212] To solve the other problems mentioned above, the present invention provides 1) an ENPP1 inhibitor; 2) a STING pathway activator; 3) a method of inhibiting the ENPP1 enzyme with the ENPP1 inhibitor; 4) a method of inhibiting the hydrolase activity of ENPP1 against cGAMP; 5) a method of increasing the level of cGAMP and / or regulating downstream factors of the STING pathway; 6) a method of enhancing the signal output of STING pathway activation; and 7) a method of inhibiting tumor growth in a suitable mouse tumor model in a monotherapy or combination therapy setting.

[0213] In one embodiment, the benzotriazole compound having inhibitory activity on ENPP1 may be an ENPP1 inhibitor. In an exemplary embodiment, the benzotriazole compound having inhibitory activity on ENPP1 may be a cell-permeable ENPP1 inhibitor.

[0214] The above ENPP1 inhibitor may be one or more of a reversible inhibitor, a competitive inhibitor, an allosteric inhibitor, and an irreversible inhibitor.

[0215] In one embodiment, the inhibitor of ENPP1 can bind to a PDE (phosphodiesterase) catalytic domain to which AMP or GMP is bound.

[0216] In one embodiment, the inhibitor of ENPP1 binds to the PDE catalyst domain, but may bind weakly when AMP is bound.

[0217] In one embodiment, the inhibitor of ENPP1 may not inhibit the ATP hydrolysis activity of the catalytic domain or may weakly inhibit the ATP hydrolysis activity.

[0218] In one embodiment, inhibition of ENPP1 may mean that the activity of ENPP1 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 another embodiment, inhibition of ENPP1 may mean that the activity of ENPP1 is reduced by 2 times or more, 3 times or more, 5 times or more, 10 times or more, 100 times or more, or 1000 times or more compared to a control group not treated with the compound.

[0219] In one embodiment, the benzotriazole compound having inhibitory activity on ENPP1 may have an ENPP1 inhibition profile that reflects activity toward additional enzymes. In another embodiment, the benzotriazole compound having inhibitory activity on ENPP1 may specifically inhibit ENPP1 without unintended inhibition of one or more other enzymes.

[0220] In one embodiment, the benzotriazole compound having inhibitory activity of ENPP1 is subjected to inhibition analysis, e.g., IC 50 or EC 50 ENPP1 can be inhibited, as determined by an analysis determining the enzyme activity in a cell-free system or a cell system after treatment with the compound compared to a control group, by measuring each of the above values. In an exemplary embodiment, the benzotriazole compound having inhibitory activity against ENPP1 has an IC50 value of 10 µM or less, 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 a lower value. 50 Value (or EC) 50 It can have a value.

[0221] Analytical procedures that can be used to determine the activity of ENPP1 may include cell-free analytical systems, e.g., binding affinity analysis, analysis using purified enzymes, cell analysis in which the cell phenotype is measured, e.g., gene expression analysis, and in vivo analysis related to specific animals, but are not limited thereto.

[0222] (Manufacturing Method 1) In one embodiment, the benzotriazole derivative compound of Formula 1 can be manufactured according to the manufacturing method according to the following Reaction Scheme 1.

[0223] [Reaction Equation 1]

[0224]

[0225] (Manufacturing Method 2) In one embodiment, the benzotriazole derivative compound of Formula 1 can be manufactured according to the manufacturing method according to the following reaction scheme 2.

[0226] [Reaction Equation 2]

[0227]

[0228] (Manufacturing Method 3) In one embodiment, the benzotriazole derivative compound of Formula 1 can be manufactured according to the manufacturing method according to the following reaction scheme 3.

[0229] [Reaction Equation 3]

[0230]

[0231] (Method A) Remove air from a flask dried in an oven and fill it with nitrogen gas, then add Pd2(dba)3 (0.05 equivalents), rac-BINAP (0.1 equivalents), Cs2CO3 (5 equivalents), bromonitrobenzene (1 equivalent), aniline (1.05 equivalents), and degassed toluene. Introduce nitrogen gas into the reaction mixture for 15 minutes and heat at 110 °C for 14 hours. After cooling the mixture to room temperature, dilute it with ethyl acetate, filter it using Celite, and wash it with salt water. Dry the organic layer with anhydrous magnesium sulfate, filter it, and then evaporate it under reduced pressure. Purify the mixture using silica column chromatography (n-hexane / ethyl acetate) with MPLC to obtain the target compound in high yield.

[0232] (Method B) Add Pd / C (10%, 50% wet with water, 0.05 equivalents) to a solution of nitro-intermediate (1 equivalent) dissolved in methanol and stir at room temperature under hydrogen gas for 12 hours. Filter the reaction mixture through celite and concentrate to obtain the target compound in high yield.

[0233] (Method C) Add iron powder (5 equivalents) and an aqueous solution of ammonium chloride (10 equivalents) to a solution of nitro-intermediate (1 equivalent) dissolved in ethanol. Stir the reaction solution at 65 °C for 2 hours. Filter the reaction solution through celite, add an aqueous solution of sodium bicarbonate, and extract three times using ethyl acetate. Dry the organic layer with anhydrous magnesium sulfate and evaporate under reduced pressure to obtain the target compound with a high yield.

[0234] (Method D) Add iron powder (5 equivalents) and an aqueous solution of ammonium chloride (10 equivalents) to a solution of nitro-intermediate (1 equivalent) dissolved in ethanol. Stir the reaction solution at 65 °C for 2 hours. Filter the reaction solution through celite, add an aqueous solution of sodium bicarbonate, and extract three times using ethyl acetate. Dry the organic layer with anhydrous magnesium sulfate and evaporate under reduced pressure to obtain the target compound with a high yield.

[0235] (Method E) An aqueous solution of sodium nitrite (2 equivalents) is slowly added to a solution of aniline intermediate (1 equivalent) dissolved in acetic acid at 0 °C, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is concentrated under reduced pressure, an aqueous solution of sodium bicarbonate is added, and the mixture is extracted three times with ethyl acetate. The organic layer is washed with salt water, dried with 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.

[0236] (Method F) An aqueous solution of sodium nitrite (2 equivalents) is slowly added to a solution of aniline intermediate (1 equivalent) dissolved in acetic acid at 0 °C, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is concentrated under reduced pressure, an aqueous solution of sodium bicarbonate is added, and the mixture is extracted three times with ethyl acetate. The organic layer is washed with salt water, dried with 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.

[0237] (Method G) Add an excess of 4 normal concentration aqueous hydrochloric acid solution (in dioxane) to a solution of Boc-protected amine or aniline intermediate dissolved in ethyl acetate and stir at room temperature for 4 hours. Concentrate the reaction mixture under reduced pressure and wash with dichloromethane to obtain the target compound in quantitative form in the hydrochloride salt form.

[0238] (Method H) The amine hydrochloride intermediate (1 equivalent) obtained by Method G was dissolved in dichloromethane, and triethylamine (8 equivalents) was added at 0 °C under nitrogen conditions. After adding the 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 an aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and evaporated under reduced pressure. The target compound was obtained by purification using silica column chromatography (n-hexane / ethyl acetate) with MPLC.

[0239] (Method I) DMAP (2 equivalents) was added to an aqueous solution of aniline hydrochloride (1 equivalent) dissolved in acetonitrile at 0 °C under nitrogen conditions. After adding a solution of tert-butyl(chlorosulfonyl)carbamate (2 equivalents) dissolved in dichloromethane, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with an aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and evaporated under reduced pressure. The target compound was obtained by purification using silica column chromatography (n-hexane / ethyl acetate) with MPLC.

[0240] (Method J) Tert-butanol is slowly added to a chlorosulfonyl isocyanate solution dissolved in anhydrous dichloromethane at 0 °C. After 30 minutes, the mixture is slowly added to an amine hydrochloride intermediate solution 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 a 0.1 normal concentration aqueous hydrochloric acid solution and water. The organic layer is dried with anhydrous magnesium sulfate and evaporated under reduced pressure. The target compound is obtained by purification using silica column chromatography with MPLC.

[0241] (Method K) An excess amount of 4-normal concentration aqueous hydrochloric acid solution (in dioxane) is added to a solution of Boc-protected sulfonidiamide intermediate (1 equivalent) dissolved in ethyl acetate, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure, diluted with an aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layer is washed with brine, dried with anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica column chromatography using MPLC to obtain the target compound.

[0242] (Method L) Add an excess of 4-normal concentration aqueous hydrochloric acid solution (in dioxane) to 1 equivalent of Boc-protected sulfonidiamide intermediate and stir at room temperature for 4 to 12 hours. Concentrate the reaction mixture under reduced pressure, wash with ethyl acetate, then wash with methanol and dry to obtain the target compound in the form of a hydrochloride salt.

[0243] (Method M) Nitrofluorobenzene, N-Boc-piperidine-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 with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica column chromatography using MPLC to obtain the target compound.

[0244] (Method N) An aqueous solution of NaOH (1.1 equivalents) is added to a solution of 5-methoxy-1H-benzo[d][1,2,3]triazole (1 equivalent) dissolved in acetonitrile. 1,4-bis(bromoethyl)benzene (1.1 equivalents) is added to the mixture, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is dried with anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure. The residue is purified by silica column chromatography using MPLC (under ethyl acetate, hexane conditions) to obtain two structural isomers in high yield.

[0245] (Method O) Sodium azide (3 equivalents) was added to a solution of benzyl brovide intermediate (1 equivalent) dissolved in acetonitrile, and the mixture was stirred at 75 °C for 16 hours. The reaction mixture was extracted with an aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude azide intermediate with a high yield. Triphenylphosphine (2 equivalents) was slowly added at 0 °C to a solution of the azide intermediate (1 equivalent) dissolved in tetrahydrofuran. Water was added, and the solution was stirred at 70 °C for 12 hours. The solvent was concentrated under reduced pressure, and hydrochloric acid contained in dioxane was added to obtain the target compound with a high yield.

[0246] In another embodiment of the present invention, a pharmaceutical composition for the prevention, alleviation, or treatment of cancer, infectious diseases, periodontal diseases, or viral diseases is provided, comprising a benzotriazole derivative having inhibitory activity of ENPP1. The cancer, infectious disease, periodontal disease, or viral disease may be a complication or associated disease of CPPD disease and / or HPP, and may be manifested simultaneously with or at the same time as CPPD disease and / or HPP.

[0247] Cancer diseases may include angiogenesis and mitosis of endothelial cells (solid tumors, tumor metastases, and benign tumors), specifically may be cancers associated with ENPP1 inhibition, and more specifically may be RAS variant cancers.

[0248] In one embodiment, the cancer may be a cancer caused by a KRAS mutation, and more specifically, may include gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, 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, non-Hodgkin's lymphoma), psoriasis or fibroadenoma, etc.

[0249] Or, cancer may be, 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, keratosquamous cell carcinoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary duct cancer, kidney cancer, myeloid disease, lymphoid disease, Hodgkin's disease, hair cell carcinoma, oral cancer, pharyngeal (oral) cancer, lip cancer, tongue cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma or pyogenic sarcoma.

[0250] In one embodiment, the cancer may be any one selected from the adrenal gland, liver, kidney, bladder, breast, colon, stomach, ovary, cervical gland, uterus, esophagus, colorectal gland, prostate gland, pancreas, lung (small cell and non-small cell), thyroid gland, carcinoma, sarcoma, glioblastoma, melanoma, and various head and neck cancers. In an exemplary embodiment, the cancer is lymphoma.

[0251] In one embodiment, the method of the present invention is a method for reducing cancer cell proliferation, said method comprising treating cells with an effective amount of the compound of the present invention to reduce cancer cell proliferation. In one embodiment, said method may be performed in conjunction with chemotherapy. Any available cancer cells may be used.

[0252] The viral disease may be a DNA viral or RNA viral disease. In exemplary embodiments, the virus may be a retrovirus. Examples include herpes simplex virus 1 (HSV-1), Kaposi 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).

[0253] Infectious diseases may be diseases caused by bacterial infection. In exemplary embodiments, bacteria include Listeria monocytogenes, Mycobacterium tuberculousis, Francisella novicida, Legionella pneumophila, Chlamydia trachomatis, Streptococcus pneumoniae, or Neisseria gonorrhea. However, they are not limited thereto.

[0254] In an exemplary embodiment, the benzotriazole derivative of the present invention may be administered in combination with one or more targeted anticancer agents selected from the group consisting of PDEd inhibitors, SHP2 inhibitors, STK19 inhibitors, BRAF inhibitors, MEK inhibitors, pERK inhibitors, PI3K inhibitors, AKT inhibitors, and others for the treatment of cancer.

[0255] In one embodiment, the benzotriazole derivative of the present invention may be administered in combination with one or more chemotherapy agents selected from the group consisting of alkylating agents, antimetabolites, antitumor antibiotics, plant alkaloids, taxanes, nucleoside analogs, anthracyclines, thymidylates-targeted drugs, apoptosis regulators, cell cycle regulators, colony-stimulating factor-1 receptor inhibitors, CD47 inhibitors, and others for the treatment of cancer.

[0256] In one embodiment, the benzotriazole derivative of the present invention may be administered in combination with an immunotherapeutic agent for the treatment of cancer. The immunotherapeutic agent is any suitable agent used for the treatment of cancer by inducing, enhancing, or suppressing an immune response. In one embodiment, the immunotherapeutic agent is an immune checkpoint inhibitor. Any immune checkpoint inhibitor may be used, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed death 1 (PD-1) inhibitors, and programmed death ligand 1 (PD-L1) inhibitors may be used, but are not limited thereto. Exemplary immune checkpoint inhibitors may be, but are not limited to, ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, etc.

[0257] In exemplary embodiments, the pharmaceutical composition of the present invention may be used as a combination therapy applied simultaneously or separately by further including one or more other anticancer agents or other therapeutic agents known to be effective for the treatment or prevention of cancer, and the other anticancer agents or other therapeutic agents that may be applied in the combination therapy may include, for example, one or more compounds selected from the group consisting of Gleevec (imatinib), Sutent (sunitinib), Herceptin (Trastuzumab), Vulcade (Bortezomib), dexamethasone, Nexavar (Sorafenib), aromatase inhibitors or kinase inhibitors, but are not limited thereto.

[0258] The benzotriazole derivative of the present invention may be administered in conjunction with radiation therapy. In one embodiment, the benzotriazole derivative may be administered before or after the administration of radiation therapy. The combination of radiation therapy and the benzotriazole derivative of the present invention may provide a synergistic therapeutic effect. When an individual is treated with radiation at a dose and / or frequency appropriate for the individual during radiation therapy (RT), activation of the autophagy signaling pathway may be induced in the individual. By downregulating the activated autophagy signaling pathway, the therapeutic efficacy in the subject may be enhanced, for example, by improving it compared to the level achieved by RT alone. Thus, details of the method of the present invention include the administration of 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 one embodiment, radiation therapy is administered in combination with the compound of the present invention at a dosage and / or frequency effective for reducing the risk of radiation damage to a subject, for example, effective for reducing the risk of radiation damage expected to occur under a therapeutically effective dosage.

[0259] In one embodiment, the method may include the step of administering a benzotriazole derivative of the present invention to a subject before radiation therapy. In one embodiment, the method may include the step of administering a benzotriazole derivative of the present invention to a subject after exposing the subject to radiation therapy. In another embodiment, the method may include a method of sequentially administering radiation therapy, followed by a benzotriazole derivative, followed by an immune checkpoint inhibitor to a subject requiring radiation therapy.

[0260] In one embodiment, for combination therapy, the benzotriazole derivative and immune checkpoint inhibitor of the present invention, as well as additional therapeutic agents as described in the present invention, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. In another embodiment, the benzotriazole derivative and chemotherapy agent of the present invention (particularly a chemotherapy agent capable of inducing activation of the autophagy signaling pathway in vivo) and additional therapeutic agents described in the present invention for combination therapy may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes. The benzotriazole derivative and second activator of the present invention (if present) may be administered by the same route of administration or by different routes of administration. The therapeutic agent may be administered to the affected organ by any suitable means, including but not limited to oral, rectal, nasal, topical, vaginal, parenterally, intravenously, intranasally, and intratumoral injection.

[0261] In one embodiment, the immunotherapeutic agent is an immune cell therapy. Any suitable cell therapy may be used and may include, but is not limited to, chimeric antigen receptor T cell therapy, chimeric antigen receptor NK cell therapy, and other cell therapies.

[0262] For the treatment of cancer, ENPP1 inhibitor compounds may be administered in combination with suitable cancer vaccine regimens, for example, dendritic cell vaccines that promote Th1 / Th17 immunity. In some cases, ENPP1 inhibitor compounds may be used as adjuvant therapies in combination with Th-17-induced vaccination.

[0263] In the case of cancer treatment methods, ENPP1 inhibitor compounds may be administered in combination with radiation therapy. In some embodiments, ENPP1 inhibitor compounds may be administered before or after the administration of radiation therapy. The combination of radiation therapy and the administration of the compounds of the present invention may provide a synergistic therapeutic effect. When treated with radiation at a dose and / or frequency appropriate for the subject during radiation therapy (RT), the production of cGAMP in the subject may be induced. The induced cGAMP levels may enhance therapeutic efficacy for the subject by preventing the degradation of cGAMP with the ENPP1 inhibitor compounds, thereby improving them compared to levels achieved, for example, by RT alone. As such, details of the method of the present invention include the administration of a reduced dose and / or frequency / reduction 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 the compound of the present invention at a dose and / or frequency effective for reducing the risk of radiation damage to a subject, for example, effective for reducing the risk of radiation damage expected to occur under a therapeutically effective dose.

[0264] In one embodiment, the method comprises the step of administering an ENPP1 inhibitor to a subject before radiation therapy. In one embodiment, the method comprises the step of administering an ENPP1 inhibitor to a subject after exposing the subject to radiation therapy. In another embodiment, the method comprises a method of sequentially administering radiation therapy, followed by an ENPP1 inhibitor, followed by an immune checkpoint inhibitor to a subject requiring radiation therapy.

[0265] In the case of a cancer treatment method, an ENPP1 inhibitor compound may be administered in combination with anticancer vaccine therapy and / or CAR-T cell therapy. In some embodiments, an ENPP1 inhibitor compound may be administered before or after the administration of anticancer vaccine therapy or CAR-T cell therapy.

[0266] In the case of myocardial regeneration therapy, one aspect includes the step of treating a subject having a lesion due to myocardial infarction by administering a therapeutically effective amount of an ENPP1 inhibitor to said subject.

[0267] In one aspect, a method for treating hypophosphatemia includes the step of treating an object having a lesion caused by a hypophosphatemia genetic disease by administering a therapeutically effective amount of an ENPP1 inhibitor to said object.

[0268] Specific details of other embodiments are included in the detailed description.

[0269] The pharmaceutical composition according to the embodiments of the present invention may be usefully used for the prevention, alleviation, or treatment of one or more of CPPD and HPP.

[0270] The effects according to the embodiments of the present invention are not limited to those exemplified above, and a wider variety of effects are included in this specification.

[0271] Figure 1 is a graph evaluating the ENPP1 ATP hydrolysis inhibitory ability according to an experimental example of the present invention.

[0272] Figure 2 is a graph showing the measurement of PPi in patient serum according to an experimental example of the present invention.

[0273] Figure 3 is a graph evaluating the inhibitory effect compared to DMSO on the degree of mineral deposition according to an experimental example of the present invention.

[0274] Figure 4 is a graph showing the plasma PPi concentration of a mouse after a single oral administration according to an experimental example of the present invention.

[0275] Figure 5 is a graph showing the plasma PPi concentration of mice after repeated oral administration according to an experimental example of the present invention.

[0276] Unless otherwise specified, all numbers, values, and / or expressions used herein to denote ingredients, reaction conditions, and the content of ingredients shall be understood to be modified by the term “approximately” in all cases, as these numbers are essentially approximations reflecting the various uncertainties of measurement that occur in obtaining these values ​​among other things. Furthermore, where a numerical range is disclosed herein, such range is continuous and, unless otherwise indicated, includes all values ​​from the minimum value of such range to the maximum value including the maximum value. Moreover, where such range refers to an integer, it includes all integers from the minimum value to the maximum value including the maximum value, unless otherwise indicated.

[0277] In this specification, where a range is described for a variable, it will be understood that the variable includes all values ​​within the described range, including the described endpoints of the range. For example, the range “5 to 10” will be understood to include not only the values ​​5, 6, 7, 8, 9, and 10, but also any sub-ranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc., and any values ​​between integers valid for the category of the described 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%” will be understood to include all integers including values ​​such as 10%, 11%, 12%, 13%, etc. and up to 30%, as well as any sub-range such as 10% to 15%, 12% to 18%, 20% to 30%, etc., and any value between valid integers within the stated range category such as 10.5%, 15.5%, 25.5%, etc.

[0278] As used herein, the terms “individual(s),” “object(s),” and “patient(s)” refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. None of the terms require, or are limited to, a situation characterized (e.g., constant or intermittent) by a healthcare worker (e.g., physician, licensed nurse, nurse apprentice, physician assistant, janitor, or hospice worker).

[0279] "Treatment" may be used to include all of the following: relief or improvement of symptoms, reduction of the extent of the disease, delay or alleviation of disease progression, improvement of the disease state, alleviation or stabilization, partial or complete recovery, extension of survival, and other beneficial treatment outcomes. "Treatment" is an attempt made with the intention of preventing the development or alteration of a disease lesion. Therefore, "Treatment" refers to both therapeutic and preventive aspects. Those requiring treatment include not only conditions where the disease is already present but also conditions where the disease must be prevented. In the treatment of tumors, a therapeutic agent may mean directly reducing the pathology of tumor cells or making tumor cells more sensitive to treatment by other therapeutic agents, e.g., radiation and / or chemotherapy and / or immunotherapy. As used herein, the terms "alleviation" or "treated" refer to signs of approaching a normalized value measured by conventional statistical tests. Here, indications of approaching the normalized value may be, for example, a value obtained from a healthy patient or individual that differs from the normalized value by less than 50%, preferably by less than 25%, more preferably by less than 10%, and even more preferably by no significant difference from the normalized value.

[0280] "Treatment of cancer" means one or more of the following effects: 1) inhibition of tumor growth, including i) slowing or ii) complete arrest of growth; 2) reduction in the number of tumor cells; 3) maintenance of tumor size; 4) reduction in tumor size; 5) inhibition of tumor cell invasion into peripheral organs, including i) reduction or ii) slowing or iii) complete prevention; 6) inhibition of metastasis, including i) reduction or ii) slowing or iii) complete prevention; 7) enhancement of an anti-tumor immune response, which may result in i) maintenance of tumor size or ii) reduction in tumor size or iii) slowing of tumor growth or iv) reduction, slowing or prevention of invasion.

[0281] As used herein, “effective dose” or “therapeutic effective dose” means a sufficient amount of the compound disclosed herein that alleviates to some degree the symptoms of a disease or condition to be 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 desirable alteration of the biological system in a clinical setting. In some embodiments, the appropriate “effective” dose for any individual case is determined using techniques such as dose-escalation studies.

[0282] In some embodiments, "effective amount" is an amount of the compound initiated in monotherapy or combination therapy, that is, when administered in one or more doses, 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 subjects not treated with the compound, or before or after treatment with the compound.

[0283] In some embodiments, “therapeutic effective amount” is an amount of compound disclosed in monotherapy or combination therapy that is effective in reducing the tumor burden of 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 when administered in one or more doses compared to the tumor burden of a subject not treated with the compound, or compared to the tumor burden of a subject before or after treatment with the compound. As used herein, the term “tumor burden” is the total mass of tumor tissue possessed by a subject with cancer.

[0284] In some embodiments, the “therapeutic effective amount” is an amount effective for reducing the amount of replacement therapy required to observe disease improvement 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 the compound initiated in monotherapy or combination therapy, that is, when administered in one or more doses, the amount of replacement therapy required to observe disease improvement in a subject not treated with the compound.

[0285] In this specification, "hydrate" means a compound or its salt containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0286] In this specification, "solvate" means a compound or its salt comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. As a preferred solvent, a volatile, non-toxic, and / or suitable solvent for administration to humans may be used.

[0287] In this specification, "isomer" means a compound or its salt that has the same chemical formula or molecular formula but is structurally or stereochemically different. These isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers).

[0288] Phosphodiesterases (PDEs) include cyclic nucleotide phosphodiesterases, phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNase, RNase, restriction endonucleases, and many types of small molecule phosphodiesterases that are not well known. An exemplary group of PDE enzymes is an important group of enzymes that hydrolyzes cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) into their inactive 5' monophosphates.

[0289] Cyclic nucleotide phosphodiesterases include a group of enzymes that degrade the phosphodiester bonds of cyclic nucleotide secondary messenger molecules, cAMP and cGMP. They regulate the localization, persistence, and amplification of cyclic nucleotide signals within subcellular domains.

[0290] The class of phosphodiesterases also includes "ecto-nucleotide pyrophosphatases / phosphodiesterases." Ecto-nucleotide pyrophosphatases / phosphodiesterases (ENPP) or nucleotide pyrophosphatases / phosphodiesterases (NPP) are a group of ectonucleotides that hydrolyze the pyrophosphate and phosphodiester bonds of their substrates to produce nucleotide 5'-monophosphate (or phospholipids and phosphocholine). In some embodiments, the ENPP group comprises seven enzyme members as ectonucleotides with similar protein structures on the cell surface (ENPP-1, ENPP-2, ENPP-3, ENPP-4, ENPP-5, ENPP-6, and ENPP-7).

[0291] ENPP enzymes generally possess a modular structure containing a catalytic domain of 400 amino acids. This catalytic domain is not related to phospholipase, nudix hydrolaise, or ectonucleotide triphosphate diphosphohydrolaise, even though they exhibit partially overlapping activities. ENPP1 and 3 have a transmembrane domain at the N-terminus and a nuclease-like domain at the C-terminus, and are predicted to be Type 2 single-spanning transmembrane proteins with a catalytic domain directed toward the extracellular space. ENPP 2, which lacks a transmembrane domain at either the N-terminus or C-terminus, carries a signal peptide at the N-terminus and is expected to be secreted extracellularly. ENPP 4, 5, 6, and 7, which contain a putative N-terminal signal peptide and a C-terminal transmembrane domain, are predicted to be Type 1 single-spanning transmembrane proteins with a catalytic domain also directed toward the extracellular space.

[0292] ENPP1, 2, and 3 are known to use nucleotides and their derivatives as substrates to produce nucleoside monophosphate (ENPP1,2,3) or nucleoside diphosphate (ENPP1,2). Only ENPP2 is known to utilize lysophospholipids. ENPP6 and 7 are known to use choline phosphate esters as substrates to produce choline phosphate. For ENPP4 and 5, there are no known substrates.

[0293] ENPP1, also known as NPP1 or PC-1, is a type II transmembrane glycoprotein expressed in many tissues (pancreas, kidney, bladder, and liver). ENPP1 is important for purinergic signaling, which plays a crucial role in the regulation of cardiovascular, neurological, immune, and blood functions in mammals. ENPP1 catalyzes the hydrolysis of ATP or GTP into AMP or GMP to produce inorganic pyrophosphate (PPi). Generally, because inorganic pyrophosphate regulates the mineralization of bone and cartilage, the production of PPi by ENPP1 makes ENPP1 a central regulator of bone and cartilage development. In contrast to the inhibitory effect of excess PPi produced by ENPP1 in joint tissue, the formation of calcium phosphate from PPi produced by ENPP1 is essential for the mineralization of bone tissue. ENPP1 has broad specificity and hydrolyzes various substrates including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars.

[0294] ENPP1 has been identified as playing a crucial role in immunological responses to various exogenous signals that activate the cGAS-STING pathway. Exploratory studies on the enzymatic activity of cGAMP degradation revealed that ENPP1 functions as a major hydrolase of cGAMP. Consistent with these findings, the half-life of cGAMP was found to be highly dependent on ENPP1, as demonstrated by a significantly longer half-life in ENPP1 knockout mice.

[0295] Bisphosphothioneate analogs of cGAMP resistant to ENPP1 hydrolysis were shown to activate STING more than 10 times compared to cGAMP, suggesting that the delay or reduction of cGAMP hydrolysis caused by the inhibition of ENPP1 would significantly increase STING activation. Inhibition of ENPP1 was found to attenuate Pseudo-Leavis virus infection and reduce Mycobacterium tuberculouse infection by inducing the sustained presence of cGAMP and activating the STING pathway.

[0296] The present invention will be explained in detail below through synthesis examples, manufacturing examples, embodiments, experimental examples, and formulation examples. However, the following manufacturing examples, embodiments, experimental examples, and formulation examples are merely illustrative of the present invention, and the scope of the present invention is not limited by the following embodiments.

[0297] [Preparation Example 1] Preparation of Compound No. 47

[0298]

[0299] Preparation Example 1 :

[0300] [Reaction Equation 1]

[0301]

[0302] tert-butyl(3-((4-methoxy-2-nitrophenyl)amino)phenyl)carbamate (3)

[0303]

[0304] 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) dissolved in toluene (17 mL, 0.3 M) was purged with nitrogen gas for 15 minutes. The reaction mixture was heated and stirred under nitrogen gas at 110 °C for 14 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered using Celite, and washed with salt water. The organic layer was dried and concentrated with anhydrous magnesium sulfate, and purified by column chromatography using MPLC to obtain the target compound with a yield of 78% (1.40 g).

[0305] 1 H NMR (400 MHz, CDCl3) δ 9.31 (brs, 1H), 7.66 (d,J= 3.2 Hz, 1H), 7.45 (d,J= 2.2 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.18 - 7.02 (m, 2H), 7.01 - 6.88 (m, 1H), 6.53 (s, 1H), 3.86 (s, 3H), 1.61 - 1.49 (m, 9H).

[0306] tert-butyl (3-((2-amino-4-methoxyphenyl)amino)phenyl)carbamate (4)

[0307]

[0308] Pd / C (10%, 50% wet with water, 480 mg, 0.22 mmol) was added to a solution of tert-butyl (3-((4-methoxy-2-nitrophenyl)amino)phenyl)carbamate (1.60 g, 4.45 mmol) dissolved in methanol (15 mL, 0.3 M), and the mixture was stirred at room temperature under hydrogen gas for 12 hours. The reaction mixture was filtered using Celite and concentrated to obtain the target compound with a yield of 90% (1.32 g).

[0309] 1 H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.15 - 7.05 (m, 2H), 6.94 - 6.83 (m, 1H), 6.81 (brs, 1H), 6.66 (brs, 1H), 6.64 - 6.56 (m, 1H), 6.50 (s, 1H), 3.66 (s, 3H), 1.39 (s, 9H).

[0310] tert-butyl (3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)carbamate (5)

[0311]

[0312] An aqueous solution of sodium nitrite (544 mg, 7.89 mmol) was slowly added at 0 °C to a solution of tert-butyl (3-((2-amino-4-methoxyphenyl)amino)phenyl)carbamate (1.30 g, 3.95 mmol) dissolved in acetic acid (13.2 mL, 0.3 M), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, an aqueous solution of sodium bicarbonate was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with salt water, dried with anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica column chromatography using MPLC (n-hexane / ethyl acetate) to obtain the target compound with a yield of 58% (780 mg).

[0313] 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.62 (d,J= 9.0 Hz, 1H), 7.45 - 7.31 (m, 4H), 7.15 (dd,J= 2.3, 9.2 Hz, 1H), 6.93 (s, 1H), 3.85 (s, 3H), 1.46 (s, 9H).

[0314] 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)aniline hydrochloride (6)

[0315]

[0316] An excess amount of 4-normal aqueous hydrochloric acid solution (in dioxane) was added at room temperature to a solution of tert-butyl (3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)carbamate (800 mg, 2.35 mmol) dissolved in ethyl acetate (2.35 mL, 1 M), and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was washed with dichloromethane, and then dried to obtain the target compound in the hydrochloride form with a yield of 99% (645 mg).

[0317] tert-butyl (N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamoyl)carbamate (7)

[0318]

[0319] DMAP (123 mg, 1 mmol) is added to a solution of 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)aniline hydrochloride (139 mg, 0.5 mmol) dissolved in acetonitrile (2.5 mL, 0.2 M) at 0 °C under nitrogen gas. A solution of tert-butyl (chlorosulfonyl)carbamate (432 mg, 1 mmol) dissolved in acetonitrile is slowly added to the mixture and stirred at room temperature for 3 hours. The solvent is concentrated under reduced pressure, diluted with an aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layer is washed with brine, dried with anhydrous magnesium sulfate, and then the solvent is evaporated under reduced pressure. The residue was purified by silica column chromatography (n-hexane / ethyl acetate) using MPLC to obtain the target compound with a yield of 37% (78 mg).

[0320] 1 H NMR (400 MHz, Methanol-d4) δ 7.81 (d,J= 9.1 Hz, 1H), 7.78 (p,J= 1.0 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.49 (d,J= 2.3 Hz, 1H), 7.42 (s, 1H), 7.32 (dd,J= 9.1, 2.3 Hz, 1H), 3.96 (s, 3H), 1.39 (s, 9H).

[0321] N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamide (8)

[0322]

[0323] An excess of 4-normal aqueous hydrochloric acid solution (in dioxane) was added to a solution of tert-butyl (N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamoyl)carbamate (70 mg, 0.17 mmol) dissolved in ethyl acetate (1.7 mL, 0.1 M), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with an aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with salt water, dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica column chromatography using MPLC (n-hexane / ethyl acetate) to obtain the target compound with a yield of 62% (33 mg).

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.82 (d,J= 9.0 Hz, 1H), 7.68 (t,J= 2.0 Hz, 1H), 7.63 (d,J= 2.4 Hz, 1H), 7.59 (t,J= 7.9 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.41 - 7.23 (m, 4H), 3.91 (s, 3H).

[0325] The following examples were synthesized with reference to the above Preparation Example 1 and Reaction Schemes 1 to 4.

[0326] Example 1: 5-methoxy-1-(piperidin-4-yl)-1H-benzo[d][1,2,3]triazole hydrochloride;

[0327]

[0328] LC-MS (ESI) calcd for C 12 H 16 N4O [M + H] + 232.12, found m / z 233.1

[0329] Example 2: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclohexyl)methaneaniline;

[0330]

[0331] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (m, 2H), 7.46 (d,J= 2.1 Hz, 1H), 7.18 (dd,J= 9.0, 2.2 Hz, 1H), 4.95 (s, 1H), 3.85 (s, 3H) 2.90 (d, 1H), 2.17 (S, 2H), 1.97 (s, 3H), 1.74 (s, 3H), 1.24 (s, 2H).

[0332] Example 3: 5-methoxy-1-(piperidine-4-ylmethyl)-1H-benzo[d][1,2,3]triazole;

[0333]

[0334] LC-MS (ESI) calcd for C 13 H 18 N4O [M + H] + 246.15, found m / z 247.2

[0335] Example 4: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)aniline hydrochloride;

[0336]

[0337] LC-MS (ESI) calcd for C 13 H 12 N4O [M + H] + 240.10, found m / z 341.1

[0338] Example 5: 4-(1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0339]

[0340]

[0341] LC-MS (ESI) calcd for C 13 H 12 N4[M + H] + 224.11, found m / z 225.1

[0342] Example 6: 4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0343]

[0344] LC-MS (ESI) calcd for C 14 H 14 N4O [M + H] + 254.12, found m / z 255.1

[0345] Example 7: 4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0346]

[0347] LC-MS (ESI) calcd for C 14 H 14 N4O [M + H] + 254.12, found m / z 255.1

[0348] Example 8: 4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0349]

[0350] LC-MS (ESI) calcd for C 14 H 14 N4O [M + H] + 254.12, found m / z 255.1

[0351] Example 9: 4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0352]

[0353] LC-MS (ESI) calcd for C 15 H 16 N4O2[M + H] + 284.13, found m / z 285.1

[0354] Example 10: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0355]

[0356] LC-MS (ESI) calcd for C 15 H 16 N4O2[M + H] + 284.13, found m / z 285.1

[0357] Example 11: 2-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethane-1-amine hydrochloride;

[0358]

[0359] LC-MS (ESI) calcd for C 15 H 16 N4O [M + H] + 268.13, found m / z 269.1

[0360] Example 12: 1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)-N-methylmethaneamine hydrochloride;

[0361]

[0362] LC-MS (ESI) calcd for C 15 H 16 N4O [M + H] + 268.13, found m / z 269.1

[0363] Example 13: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)cyclopropanamine hydrochloride;

[0364]

[0365] 1H NMR (400 MHz, DMSO-d6) δ 9.74 (d,J= 4.1 Hz, 2H), 7.96 (d,J= 8.6 Hz, 2H), 7.90 (d,J= 8.6 Hz, 2H), 7.86 (d,J= 9.1 Hz, 1H), 7.63 (d,J= 2.2 Hz, 1H), 7.31 (dd,J= 9.1, 2.3 Hz, 1H), 4.36 (d,J= 5.7 Hz, 2H), 3.90 (s, 3H), 2.71 (d,J= 3.6 Hz, 1H), 0.97 (t,J= 4.4 Hz, 2H), 0.76 (q,J= 7.0 Hz, 2H).

[0366] Example 14: (S)-1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethane-1-amine hydrochloride;

[0367]

[0368] LC-MS (ESI) calcd for C 15 H 16 N4O [M + H] + 268.13, found m / z 269.1

[0369] Example 15: 3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0370]

[0371] LC-MS (ESI) calcd for C 14 H 13 ClN4O [M + H] + 288.08, found m / z 289.1

[0372] Example 16: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride;

[0373]

[0374] LC-MS (ESI) calcd for C 14 H13 F1N4O [M + H] + 272.11, found m / z 273.1

[0375] Example 17: 2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0376]

[0377] LC-MS (ESI) calcd for C 14 H 12 F2N4O [M + H] + 290.14, found m / z 291.1

[0378] Example 18: 2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0379]

[0380] LC-MS (ESI) calcd for C 14 H 12 F2N4O [M + H] + 290.14, found m / z 291.1

[0381] Example 19: 4-(5-ethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine;

[0382]

[0383] 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (t,J= 8.0 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.53 - 7.43 (m, 2H), 7.26 (dd,J= 9.0, 2.3 Hz, 1H), 4.16 (d,J= 7.0 Hz, 2H), 3.87 (s, 2H), 1.40 (t,J= 7.0 Hz, 3H), 1.24 (s, 2H).

[0384] Example 20: 3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0385]

[0386] 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (t,J= 8.0 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.52 - 7.42 (m, 2H), 7.23 (dd,J= 9.0, 2.2 Hz, 1H), 4.82 - 4.74 (m, 1H), 3.88 (s, 2H), 1.34 (s, 3H), 1.32 (s, 3H), 1.18 (t,J= 7.1 Hz, 1H).

[0387] Example 21: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0388]

[0389] LC-MS (ESI) calcd for C 15 H 14 F2N4[M + H] + 288.10, found m / z 289

[0390] Example 22: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine;

[0391]

[0392] LC-MS (ESI) calcd for C 15 H 13 F3N4[M + H] + 306.37, found m / z 307.1

[0393] Example 23: 3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine;

[0394]

[0395] LC-MS (ESI) calcd for C 14 H 12 F2N4O [M + H] + 290.27, found m / z 291

[0396] Example 24: 4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine;

[0397]

[0398] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (t,J= 8.0 Hz, 2H), 7.71 (dd,J= 9.0, 1.9 Hz, 2H), 7.63 (d,J= 11.6 Hz, 2H), 7.52 (d,J= 2.2 Hz, 1H), 7.51 - 7.49 (m, 1H), 7.38 (s, 1H), 3.88 (s, 2H).

[0399] Example 25: 7-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0400]

[0401] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 2H), 7.89 (d,J= 9.1 Hz, 1H), 7.79 (d,J= 8.5 Hz, 2H), 7.62 (d,J= 2.2 Hz, 1H), 7.54 (d,J= 8.1 Hz, 1H), 7.32 (d,J= 2.3 Hz, 1H), 4.42 (d,J= 4.4 Hz, 2H), 3.91 (s, 3H), 3.44 (d,J= 5.6 Hz, 2H), 3.15 (t,J= 6.1 Hz, 2H).

[0402] Example 26: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride;

[0403]

[0404] LC-MS (ESI) calcd for C 16 H 15 FN4O [M + H] + 298.12, found m / z 299.1

[0405] Example 27: 8-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine hydrochloride;

[0406]

[0407] LC-MS (ESI) calcd for C 17 H 18 N4O [M + H] + 294.15, found m / z 295.2

[0408] Example 28: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,5-difluorophenyl)methaneamine;

[0409]

[0410] LC-MS (ESI) calcd for C 15 H 14 F2N4O2[M + H] + 320.17, found m / z 321.1

[0411] Example 29: 1-(isoindorin-5-yl)-5,6-dimethoxy-1H-benzo[d][1,2,3]triazole hydrochloride;

[0412]

[0413] 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 2H), 7.93 (s, 1H), 7.87 (dd,J= 8.2, 1.8 Hz, 1H), 7.70 (d,J= 8.2 Hz, 1H), 7.59 (s, 1H), 7.24 (s, 1H), 4.71 - 4.50 (m, 4H), 3.92 (s, 3H), 3.90 (s, 3H).

[0414] Example 30: 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)bicyclo[1.1.1]pentane-1-yl)methaneamine;

[0415]

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d,J= 9.0 Hz, 1H), 7.49 (d,J= 2.2 Hz, 1H), 7.25 - 7.13 (m, 2H), 6.75 (d,J= 8.6 Hz, 1H), 3.85 (s, 3H), 1.24 (s, 6H), 0.85 (d,J= 7.2 Hz, 2H).

[0417] Example 31: 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-5-methylthiophene-2-yl)methaneamine hydrochloride;

[0418]

[0419] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 2H), 7.72 (d,J= 9.1 Hz, 1H), 7.63 (d,J= 2.1 Hz, 1H), 7.31 (dd,J= 8.8, 2.5 Hz, 2H), 7.16 (m, 1H) 6.76 (dd,J= 5.9, 3.5 Hz, 2H), 4.23 (d,J= 5.4 Hz, 2H), 3.90 (s, 3H), 2.57 (s, 3H).

[0420] Example 32: tert-butyl((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidin-1-yl)sulfonyl)carbamate;

[0421]

[0422] LC-MS (ESI) calcd for C 17 H 25 N5O5S [M + H] + 411.16, found m / z 412.2

[0423] Example 33: tert-butyl((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)piperidine-1-yl)sulfonyl)carbamate;

[0424]

[0425] LC-MS (ESI) calcd for C 18 H 27 N5O5S [M + H] + 425.17, found m / z 426.2

[0426] Example 34: tert-butyl(N-(1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0427]

[0428] LC-MS (ESI) calcd for C 18 H 21 N5O4S [M + H] + 403.13, found m / z 404.1

[0429] Example 35: tert-butyl(N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0430]

[0431] LC-MS (ESI) calcd for C 19 H 23 N5O5S [M + H] +433.14, found m / z 434.1

[0432] Example 36: tert-butyl(N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0433]

[0434] LC-MS (ESI) calcd for C 19 H 23 N5O5S [M + H] + 433.14, found m / z 434.1

[0435] Example 37: tert-butyl(N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0436]

[0437] LC-MS (ESI) calcd for C 19 H 23 N5O5S [M + H] + 433.14, found m / z 434.1

[0438] Example 38: tert-butyl(N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate;

[0439]

[0440] LC-MS (ESI) calcd for C 19 H 23 N5O5S [M + H] + 433.14, found m / z 434.1

[0441] Example 39: tert-butyl((S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethyl)sulfamoyl)carbamate;

[0442]

[0443] LC-MS (ESI) calcd for C 20 H25 N5O5S [M + H] + 447.16, found m / z 448.2

[0444] Example 40: tert-butyl((6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfamoyl)carbamate;

[0445]

[0446] LC-MS (ESI) calcd for C 21 H 25 N5O5S [M + H] + 459.16, found m / z 460.2

[0447] Example 41 : N-((3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclopentyl)methyl)sulfamide;

[0448]

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d,J= 9.0 Hz, 1H), 7.45 (d,J= 2.1 Hz, 1H), 7.18 (dd,J= 9.0, 2.3 Hz, 1H), 6.65 (t,J= 6.1 Hz, 1H), 6.51 (s, 2H), 5.31 (dd,J= 15.9, 7.9 Hz, 1H), 3.84 (s, 3H), 2.99 (dd,J= 10.0, 6.8 Hz, 2H), 2.40 - 2.21 (m, 2H), 2.20 - 2.06 (m, 1H), 1.90 (dd,J= 21.3, 14.1, 7.9 Hz, 2H), 1.74 - 1.59 (m, 1H), 1.24 (s, 2H).

[0450] Example 42: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidine-1-sulfonamide;

[0451]

[0452] 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d,J= 8.4 Hz, 1H), 7.44 (s, 1H), 7.18 (d,J= 8.2 Hz, 1H), 4.97 (br s, 1H), 3.86 (s, 3H), 3.69 (d,J= 11.4 Hz, 2H), 2.95 (t,J= 10.7 Hz, 2H), 2.29-2.23 (m, 4H).

[0453] Example 43 :N-((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclohexyl)methyl)sulfamide;

[0454]

[0455] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd,J= 20.1, 9.2 Hz, 1H), 7.45 (d,J= 2.2 Hz, 1H), 7.17 (dd,J= 9.0, 2.3 Hz, 1H), 6.59 (t,J= 6.2 Hz, 1H), 6.52 (d,J= 11.1 Hz, 1H), 4.91 (dd,J= 8.9, 4.3 Hz, 1H), 3.84 (s, 3H), 2.96 (t,J= 6.9 Hz, 2H), 2.14 (dt,J= 15.3, 6.5 Hz, 2H), 1.91 (dd,J=13.6, 4.5 Hz, 0H), 1.73 (d,J= 4.7 Hz, 3H), 1.24 (s, 1H).

[0456] Example 44: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidin-1-yl)ethane-1-sulfonamide;

[0457]

[0458] LC-MS (ESI) calcd for C 20 H 25 N5O5S [M + H] + 447.16, found m / z 448.2

[0459] Example 45: 4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)piperidine-1-sulfonamide;

[0460]

[0461] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d,J= 9.0 Hz, 1H), 7.44 (d,J= 1.6 Hz, 1H), 7.19 (d,J= 7.2 Hz, 1H), 4.60 (d,J= 6.9 Hz, 2H), 3.85 (s, 3H), 3.44 (d,J= 11.4 Hz, 2H), 2.44 (t,J= 11.3 Hz, 2H), 2.01 (br s, 1H), 1.57 (d,J= 11.2 Hz, 2H), 1.37-1.29 (m, 2H).

[0462] Example 46 :N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0463]

[0464] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d,J= 8.4 Hz, 1H), 7.89 (dd,J= 27.8, 8.4 Hz, 3H), 7.68 (dt,J= 7.4, 2.9 Hz, 3H), 7.58 - 7.49 (m, 1H), 7.27 (s, 1H), 6.73 (s, 2H), 4.23 (d,J= 6.5 Hz, 2H).

[0465] Example 47 : N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamide;

[0466]

[0467] 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.82 (d,J= 9.0 Hz, 1H), 7.68 (t,J= 2.0 Hz, 1H), 7.63 (d,J= 2.4 Hz, 1H), 7.59 (t,J= 7.9 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.41 - 7.23 (m, 4H), 3.91 (s, 3H).

[0468] Example 48 : N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamide hydrochloride;

[0469]

[0470] 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (brs, 1H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 7.42 (d, J= 7.6 Hz, 2H), 7.26-7.17 (m, 2H), 3.88 (s, 3H).

[0471] Example 49 :N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0472]

[0473] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.80 (m, 2H), 7.77 (d,J= 8.0 Hz, 1H), 7.64 (dd,J= 12.0, 4.7 Hz, 2H), 7.56 (d,J= 7.7 Hz, 1H), 7.30 (td,J= 8.9, 4.4 Hz, 2H), 6.73 (s, 2H), 4.26 (d,J= 6.4 Hz, 2H), 3.91 (s, 3H).

[0474] Example 50: N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0475]

[0476] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.75 (m, 2H), 7.66 (d,J= 8.6 Hz, 2H), 7.63 - 7.51 (m, 1H), 7.45 - 7.33 (m, 1H), 7.26 (t,J= 6.5 Hz, 1H), 6.97 (d,J= 7.6 Hz, 1H), 6.73 (s, 2H), 4.22 (d,J= 6.5 Hz, 2H), 4.08 (s, 3H).

[0477] Example 51: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide hydrochloride;

[0478]

[0479] 1 H NMR (400 MHz, DMSO-d6) δ 7.82-7.78 (m, 3H), 7.65 (d,J= 8.4 Hz, 2H), 7.59 (d,J= 2.1 Hz, 1H), 7.28(dd,J= 9.0, 2.2 Hz, 1H), 4.22(s, 2H), 3.90 (s, 3H).

[0480] Example 52: N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0481]

[0482] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d,J= 9.1 Hz, 1H), 7.84 (d,J= 8.5 Hz, 2H), 7.67 (d,J= 8.5 Hz, 2H), 7.26 (s, 1H), 7.20 (d,J= 2.1 Hz, 1H), 7.13 (dd,J= 9.1, 2.2 Hz, 1H), 6.73 (s, 2H), 4.22 (d,J= 6.5 Hz, 2H), 3.90 (s, 3H).

[0483] Example 53 : N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0484]

[0485] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (dd,J= 8.4, 0.6 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.57 (d,J= 8.7 Hz, 2H), 7.42 (dd,J= 8.3, 7.8 Hz, 1H), 7.24 (d,J= 6.5 Hz, 1H), 7.12 (d,J= 7.5 Hz, 1H), 6.73 (s, 2H), 4.22 (d,J= 6.5 Hz, 2H), 3.84 (s, 3H).

[0486] Example 54 :N-(4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0487]

[0488] 1 H NMR (400 MHz, DMSO-d6) δ 7.86 - 7.74 (m, 2H), 7.65 (d,J= 8.6 Hz, 2H), 7.26 (t,J= 6.5 Hz, 1H), 6.82 - 6.67 (m, 3H), 6.56 (d,J= 1.8 Hz, 1H), 4.22 (d,J= 6.5 Hz, 2H), 4.03 (s, 3H), 3.87 (s, 3H).

[0489] Example 55 : N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0490]

[0491] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d,J= 8.5 Hz, 2H), 7.66 (d,J= 8.5 Hz, 2H), 7.59 (s, 1H), 7.25 (d,J= 6.5 Hz, 1H), 7.21 (s, 1H), 6.72 (s, 2H), 4.23 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H).

[0492] Example 56 :N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0493]

[0494] 1 H NMR (400 MHz, Methanol-d4) δ 8.13 (d,J= 8.4 Hz, 1H), 7.73 (t,J= 7.8 Hz, 1H), 7.65 (d,J= 7.0 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.54 (t,J= 7.6) Hz, 2H), 4.40 (s, 2H).

[0495] Example 57 : N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-2,3-difluorobenzyl)sulfamide;

[0496]

[0497] 1 H NMR (400 MHz, Methanol-d4) δ 8.13 (d,J= 8.4 Hz, 1H), 7.73 (t,J= 7.8 Hz, 1H), 7.70 - 7.63 (m, 1H), 7.63 - 7.57 (m, 2H), 7.57 - 7.52 (m, 2H), 4.40 (s, 2H).

[0498] Example 58 :N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-3,5-difluorobenzyl)sulfamide;

[0499]

[0500] 1H NMR (400 MHz, Methanol-d4) δ 8.16 (d,J= 8.4 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.60 - 7.50 (m, 2H), 7.46 (d,J= 8.9 Hz, 2H), 4.40 (s, 2H).

[0501] Example 59 :N-(3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0502]

[0503] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d,J= 1.6 Hz, 1H), 7.75 (d,J= 8.1 Hz, 1H), 7.63 (dd,J= 6.3, 1.9 Hz, 2H), 7.38 (dd,J= 12.2, 7.8 Hz, 2H), 7.26 (dd,J= 9.0, 2.3 Hz, 1H), 6.78 (s, 2H), 4.27 (d,J= 6.5 Hz, 2H), 3.91 (s, 3H).

[0504] Example 60: N-(2-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0505]

[0506] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d,J= 9.1 Hz, 1H), 7.82 - 7.73 (m, 3H), 7.64 (d,J= 2.2 Hz, 1H), 7.31 (dd,J= 9.1, 2.4 Hz, 1H), 7.26 (t,J= 6.5 Hz, 1H), 6.76 (s, 2H), 4.24 (d,J= 6.4 Hz, 2H), 3.90 (s, 3H).

[0507] Example 61: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0508]

[0509] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (t,J= 7.9 Hz, 1H), 7.62 (dd,J= 10.4, 2.0 Hz, 2H), 7.54 (dd,J= 9.0, 2.2 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.36 (t,J= 6.5 Hz, 1H), 7.29 (dd,J= 9.0, 2.3 Hz, 1H), 6.77 (s, 2H), 4.26 (d,J= 6.5 Hz, 2H), 3.90 (s, 3H).

[0510] Example 62: N-(2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0511]

[0512] LC-MS (ESI) calcd for C 14 H 13 F2N5O3S [M + H] + 369.35, found m / z 370.1

[0513] Example 63: N-(2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0514]

[0515] LC-MS (ESI) calcd for C 14 H 13 F2N5O3S [M + H] + 369.35, found m / z 370.1

[0516] Example 64: N-(3,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)sulfamide;

[0517]

[0518] 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d,J= 2.1 Hz, 1H), 7.54 (d,J= 9.0 Hz, 3H), 7.44 (s, 1H), 7.31 (dd,J= 9.0, 2.3 Hz, 1H), 6.80 (s, 2H), 4.28 (d,J= 6.5 Hz, 2H), 3.90 (s, 3H).

[0519] Example 65: N-(2,3-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)sulfamide;

[0520]

[0521] 1 H NMR (400 MHz, DMSO-d6) δ 7.75 - 7.57 (m, 4H), 7.36 (t,J= 6.2 Hz, 1H), 7.31 (dd,J= 9.1, 2.3 Hz, 1H), 6.80 (s, 2H), 4.30 (d,J= 6.4 Hz, 2H), 3.90 (s, 3H).

[0522] Example 66 :N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-methylbenzyl)sulfamide;

[0523]

[0524] 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 2.1 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 2H), 7.37 (d, J = 9.0 Hz, 1H), 7.28 - 7.19 (m, 2H), 6.72 (s, 2H), 4.21 (d, J = 6.5 Hz, 2H), 3.90 (s, 3H), 2.05 (s, 3H).

[0525] Example 67: N-(3-cyano-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-benzyl)sulfamide;

[0526]

[0527] LC-MS (ESI) calcd for C 15 H 14 N6O3S [M + H] + 358.08, found m / z 359.1

[0528] Example 68: N-(3-methoxy-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0529]

[0530] LC-MS (ESI) calcd for C 15 H 17 N5O4S [M + H] + 363.1, found m / z 364.1

[0531] Example 69 :N-(4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0532]

[0533] 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d,J= 8.2 Hz, 2H), 7.73 (s, 1H), 7.65 (d,J= 8.3 Hz, 2H), 7.55 (s, 1H), 7.25 (t,J= 6.4 Hz, 1H), 6.72 (s, 2H), 4.21 (d,J= 6.1 Hz, 2H), 3.93 (s, 3H), 2.35 (s, 3H).

[0534] Example 70: N-(3-fluoro-4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0535]

[0536] 1H NMR (400 MHz, DMSO-d6) δ 7.77 (t,J= 7.9 Hz, 1H), 7.61 (d,J= 11.4 Hz, 1H), 7.57 (s, 1H), 7.49 (d,J= 7.9 Hz, 1H), 7.42 (s, 1H), 7.36 (t,J= 6.5 Hz, 1H), 6.77 (s, 2H), 4.25 (d,J= 6.5 Hz, 2H), 3.93 (s, 3H), 2.31 (s, 3H).

[0537] Example 71: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0538]

[0539] 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (t,J= 7.9 Hz, 1H), 7.61 (d,J= 10.6 Hz, 2H), 7.49 (d,J= 8.1 Hz, 1H), 7.36 (t,J= 6.5 Hz, 1H), 6.97 (s, 1H), 6.77 (s, 2H), 4.25 (d,J= 6.5 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H).

[0540] Example 72 : N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)sulfamide;

[0541]

[0542] 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d,J= 9.1 Hz, 1H), 7.80 - 7.68 (m, 2H), 7.67 - 7.58 (m, 2H), 7.46 (d,J= 7.7 Hz, 1H), 7.29 (dd,J= 9.1, 2.3 Hz, 1H), 6.67 (t,J= 5.9 Hz, 1H), 6.58 (s, 2H), 3.91 (s, 3H), 3.34 (s, 2H), 3.22 (dd,J= 13.5, 7.1 Hz, 2H), 2.97 (t,J= 7.3 Hz, 2H), 2.57 - 2.47 (m, 4H).

[0543] Example 73 : N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)sulfamide hydrochloride;

[0544]

[0545] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (m, 2H), 7.60-7.55 (m, 2H), 7.29-7.27 (m, 1H), 6.66-6.60 (brs, 2H), 3.89 (s, 3H), 3.18 (brs, 2H), 2.93 (brs, 2H).

[0546] Example 74: N-(3-fluoro-4-(5-hydroxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0547]

[0548] 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.77 (t,J= 8.0 Hz, 1H), 7.60 (d,J= 11.7 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.35 (dd,J= 8.5, 4.3 Hz, 2H), 7.17 (dd,J= 8.9, 2.2 Hz, 1H), 6.77 (s, 2H), 4.25 (d,J= 6.5 Hz, 2H).

[0549] Example 75 :N-(3-fluoro-4-(5-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0550]

[0551] LC-MS (ESI) calcd for C 14 H 14 FN5O2S [M + H] + 335.09, found m / z 336.1

[0552] Example 76 :N-(4-(5-ethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0553]

[0554] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (t,J= 8.0 Hz, 1H), 7.62 (d,J= 9.5 Hz, 2H), 7.51 (t,J= 9.6 Hz, 2H), 7.36 (d,J= 6.3 Hz, 1H), 7.27 (d,J= 8.8 Hz, 1H), 6.77 (s, 2H), 4.25 (d,J= 6.5 Hz, 2H), 4.16 (d,J= 6.9 Hz, 2H), 1.40 (t,J= 6.9 Hz, 3H).

[0555] Example 77: N-(3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0556]

[0557] 1H NMR (400 MHz, DMSO-d6) δ 7.79 (t,J= 8.0 Hz, 1H), 7.62 (t,J= 7.5 Hz, 2H), 7.51 (dd,J= 11.8, 5.0 Hz, 2H), 7.36 (t,J= 6.5 Hz, 1H), 7.24 (dd,J= 9.0, 2.2 Hz, 1H), 6.77 (s, 2H), 4.84 - 4.73 (m, 1H), 4.25 (d,J= 6.5 Hz, 2H), 1.34 (s, 3H), 1.33 (s, 3H).

[0558] Example 78 :N-(5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)pyridine-2-yl)methyl)sulfamide;

[0559]

[0560] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d,J= 2.4 Hz, 1H), 8.36 (dd,J= 8.4, 2.6 Hz, 1H), 7.89 (d,J= 9.1 Hz, 1H), 7.81 (d,J= 8.5 Hz, 1H), 7.65 (d,J= 2.2 Hz, 1H), 7.39 - 7.28 (m, 2H), 6.78 (s, 2H), 4.34 (d,J= 6.5 Hz, 2H), 3.90 (s, 3H).

[0561] Example 79 :N-(6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)pyridine-3-yl)methyl)sulfamide;

[0562]

[0563] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.45 (d,J= 9.2 Hz, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.38 - 7.33 (m, 2H), 6.77 (s, 1H), 4.36 - 4.30 (m, 2H), 3.90 (s, 3H).

[0564] Example 80: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-N-methyl)sulfamide;

[0565]

[0566] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (t,J= 9.3 Hz, 3H), 7.64 (dd,J= 13.2, 5.3 Hz, 3H), 7.30 (dd,J= 9.1, 2.3 Hz, 1H), 6.98 (s, 2H), 4.23 (s, 2H), 3.91 (s, 3H), 2.63 (s, 3H).

[0567] Example 81: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-N-methylsulfamide;

[0568]

[0569] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (t,J= 7.9 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.49 (d,J= 8.5 Hz, 1H), 7.29 (dd,J= 9.1, 2.3 Hz, 1H), 7.03 (s, 2H), 4.27 (s, 2H), 3.90 (s, 3H), 2.67 (s, 3H).

[0570] Example 82: N-cyclopropyl-N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0571]

[0572] 1H NMR (400 MHz, DMSO-d6) δ 7.83 (dd,J= 8.8, 3.7 Hz, 3H), 7.66 - 7.53 (m, 3H), 7.29 (dd,J= 9.1, 2.3 Hz, 1H), 7.05 (s, 2H), 4.40 (s, 2H), 3.90 (s, 3H), 2.46 - 2.38 (m, 1H), 0.75 - 0.43 (m, 4H).

[0573] Example 83: (S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethyl)sulfamide;

[0574]

[0575] LC-MS (ESI) calcd for C 15 H 17 N5O3S [M + H] + 347.11, found m / z 348.1.

[0576] Example 84: N-(4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0577]

[0578] LC-MS (ESI) calcd for C 14 H 12 F3N5O2S [M + H] + 371.07, found m / z 372.1.

[0579] Example 85: N-(3-fluoro-4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0580]

[0581] 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.98 (dd,J= 8.9, 1.3 Hz, 1H), 7.88 (dd,J= 13.7, 5.8 Hz, 2H), 7.66 (d,J= 11.5 Hz, 1H), 7.54 (d,J= 8.2 Hz, 1H), 7.38 (t,J= 6.5 Hz, 1H), 6.78 (s, 2H), 4.28 (d,J= 6.5 Hz, 2H).

[0582] Example 86 :N-(4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0583]

[0584] LC-MS (ESI) calcd for C 15 H 14 F2N4[M + H] + 288.10, found m / z 289

[0585] Example 87: N-(4-(5-dimethylamino)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0586]

[0587] LC-MS (ESI) calcd for C 15 H 17 FN6O2S [M + H] + 364.11, found m / z 365.1

[0588] Example 88 :N-(3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0589]

[0590] LC-MS (ESI) calcd for C 14 H 13 F2N5O3S [M + H] + 369.35, found m / z 370.1

[0591] Example 89 :N-(4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0592]

[0593] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.04 (d,J= 9.0 Hz, 1H), 7.87 (d,J= 8.5 Hz, 2H), 7.77 - 7.60 (m, 3H), 7.27 (t,J= 6.5 Hz, 1H), 6.73 (s, 2H), 4.23 (d,J= 6.5 Hz, 2H).

[0594] Example 90: N-(3-fluoro-4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0595]

[0596] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.89 - 7.77 (m, 2H), 7.72 - 7.61 (m, 2H), 7.52 (d,J= 8.2 Hz, 1H), 7.37 (t,J= 6.5 Hz, 1H), 6.77 (s, 2H), 4.27 (d,J= 6.5 Hz, 2H).

[0597] Example 91: N-(4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide;

[0598]

[0599] 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d,J= 2.0 Hz, 1H), 7.83 (t,J= 8.0 Hz, 1H), 7.72 (dd,J= 9.0, 2.0 Hz, 1H), 7.64 (d,J= 10.2 Hz, 1H), 7.52 (dd,J= 8.9, 2.3 Hz, 2H), 7.38 (d,J= 7.7 Hz, 2H), 6.77 (s, 2H), 4.26 (d,J= 6.5 Hz, 2H).

[0600] Example 92: N-(4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0601]

[0602] 1 H NMR (400 MHz, DMSO-d6) δ7.88 (dd,J= 9.0, 6.0 Hz, 2H), 7.84 (d,J= 8.5 Hz, 2H), 7.65 (d,J= 8.5 Hz, 2H), 7.26 (t,J= 6.5 Hz, 1H), 6.72 (s, 2H), 4.21 (d,J= 6.5 Hz, 2H), 3.99 (s, 3H).

[0603] Example 93: N-(3-fluoro-4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide;

[0604]

[0605] 1 H NMR (400 MHz, DMSO-d6) δ7.89 (d,J= 7.6 Hz, 1H), 7.80 (t,J= 8.0 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.49 (d,J= 8.1 Hz, 1H), 7.37 (t,J= 6.5 Hz, 1H), 6.76 (s, 2H), 4.25 (d,J= 6.4 Hz, 2H), 3.98 (s, 3H).

[0606] Example 94: 5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)isoindorin-2-sulfonamide;

[0607]

[0608] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.78 (d,J= 9.1 Hz, 1H), 7.72 (dd,J= 8.1, 2.0 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.22 (dd,J= 9.1, 2.3 Hz, 1H), 6.95 (s, 2H), 4.57 (s, 2H), 4.55 (s, 2H), 3.82 (s, 3H).

[0609] Example 95: N-5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,3-dihydro-1H-indene-2-yl)sulfamide;

[0610]

[0611] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d,J= 9.0 Hz, 1H), 7.68 (s, 1H), 7.62 - 7.58 (m, 2H), 7.48 (d,J= 3.8 Hz, 1H), 7.27 (dd,J= 9.1, 2.3 Hz, 1H), 7.02 (d,J= 7.0 Hz, 1H), 6.68 (s, 2H), 4.17 (dd,J= 14.6, 7.3 Hz, 1H), 3.89 (s, 3H), 3.30 (dd,J= 10.4, 5.8 Hz, 2H), 3.06 - 2.94 (m, 2H).

[0612] Example 96: 6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0613]

[0614] 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d,J= 9.1 Hz, 1H), 7.68-7.67 (m, 2H), 7.60 (d,J= 2.1 Hz, 1H), 7.49 (d,J= 9.0 Hz, 1H), 7.28 (dd,J= 9.1, 2.3 Hz, 1H), 7.00 (s, 2H), 4.33 (s, 2H), 3.89 (s, 3H), 3.07 (t,J= 5.7 Hz, 2H), 2.50 (t,J= 3.4 Hz, 2H).

[0615] Example 97: 7-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide;

[0616]

[0617] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d,J= 9.1 Hz, 1H), 7.69 (dd,J= 11.8, 3.6 Hz, 2H), 7.61 (d,J= 2.1 Hz, 1H), 7.48 (d,J= 8.2 Hz, 1H), 7.29 (dd,J= 9.1, 2.3 Hz, 1H), 6.99 (s, 2H), 4.39 (s, 2H), 3.91 (s, 3H), 3.37 (t,J= 5.9 Hz, 2H), 3.05 (t,J= 5.8 Hz, 2H).

[0618] Example 98: 8-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-sulfonamide;

[0619]

[0620] LC-MS (ESI) calcd for C 17 H 19 N5O3S [M + H] + 373.12, found m / z 374.1

[0621] Example 99 : N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,5-difluorobenzyl)sulfamide;

[0622]

[0623] LC-MS (ESI) calcd for C 14 H 15 F2N5O4S [M + H] + 399.08, found m / z 400.1

[0624] Example 100: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,6-difluorobenzyl)sulfamide;

[0625]

[0626] LC-MS (ESI) calcd for C 14 H 15 F2N5O4S [M + H] + 399.08, found m / z 400.1

[0627] Example 101: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

[0628]

[0629] LC-MS (ESI) calcd for C 16 H 16 FN5O3S [M + H] + 377.1, found m / z 378.1

[0630] Example 102: 5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-isoindorin-2-sulfonamide;

[0631]

[0632] 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.79 (dd,J= 8.1, 1.8 Hz, 1H), 7.63 (d,J= 8.2 Hz, 1H), 7.58 (s, 1H), 7.23 (s, 1H), 7.03 (s, 2H), 4.66 (s, 2H), 4.63 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H).

[0633] Example 103: N-(5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-dihydro-1H-indene-2-yl)sulfamide;

[0634]

[0635] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.61 (d,J= 7.9 Hz, 1H), 7.57 (d,J= 5.6 Hz, 1H), 7.49 (d,J= 8.2 Hz, 1H), 7.17 (s, 1H), 7.02 (d,J= 7.0 Hz, 1H), 6.68 (s, 2H), 4.17 (dd,J= 14.7, 7.3 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.34 - 3.25 (m, 2H), 3.06 - 2.97 (m, 2H).

[0636] Example 104 :N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)phenyl)sulfamide hydrochloride;

[0637]

[0638] LC-MS (ESI) calcd for C 14 H 16 ClN5O3S [M + H] + 369.07, found m / z 370.1

[0639] Example 105 :N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)benzyl)sulfamide hydrochloride;

[0640]

[0641] LC-MS (ESI) calcd for C 14 H 16 ClN5O3S [M + H] + 383.08, found m / z 384.1

[0642] Example 106 :N-((5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)thiophene-2-yl)methyl)sulfamide;

[0643]

[0644] LC-MS (ESI) calcd for C 24 H 13 N5O3S2[M + H]+ 339.41, found m / z 340

[0645] Example 107 :N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-5-methoxythiophen-2-yl)methyl)sulfamide;

[0646]

[0647] 1 H NMR (400 MHz, MeOH-d4) δ 6.03 (d,J= 9.6 Hz, 1H), 5.91 (s, 1H), 5.74 (d,J= 8.7 Hz, 1H), 5.47 (s, 1H), 3.08 (s, 2H), 2.75 (s, 2H), 2.39 (s, 3H), 1.03 (s, 3H).

[0648] Example 108: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-bicyclo[1,1.1]pentane-1-yl)sulfamide;

[0649]

[0650] 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d,J= 9.0 Hz, 1H), 7.49 (d,J= 2.0 Hz, 1H), 7.21 (dd,J= 9.0, 2.2 Hz, 1H), 6.76 (t,J= 6.2 Hz, 1H), 6.58 (s, 2H), 3.85 (s, 3H), 3.23 (d,J= 6.2 Hz, 2H), 2.45 (s, 6H).

[0651] Example 109 :N-(4-(5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)phenyl)sulfamide hydrochloride;

[0652]

[0653] LC-MS (ESI) calcd for C 14 H 15 N5O3S [M + H] + 333.09, found m / z 334.1.

[0654] Example 110 :N-(4-((5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)benzyl)sulfamide hydrochloride;

[0655]

[0656] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d,J= 9.0 Hz, 1H), 7.33-7.31 (m, 5H), 7.00 (dd,J= 9.1, 2.2 Hz, 1H), 5.88 (s, 2H), 4.03 (s, 2H), 3.84 (s, 3H).

[0657] Example 111: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride;

[0658]

[0659] LC-MS (ESI) calcd for C 14 H 19 FN4O3S [M + H] +342.12, found m / z 343.1

[0660] Example 112: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)methanesulfonamide;

[0661]

[0662] 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d,J= 7.9 Hz, 2H), 7.63 (d,J= 2.1 Hz, 1H), 7.60 (d,J= 11.6 Hz, 1H), 7.57 (s, 1H), 7.50 (d,J= 7.3 Hz, 1H), 7.28 (dd,J= 9.0, 2.3 Hz, 1H), 4.35 (d,J= 6.4 Hz, 2H), 3.90 (s, 3H), 2.98 (s, 3H).

[0663] Example 113: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)ethanesulfonamide;

[0664]

[0665] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (dd,J= 9.9, 6.1 Hz, 2H), 7.64 - 7.59 (m, 1H), 7.57 (d,J= 6.9 Hz, 1H), 7.55 - 7.46 (m, 1H), 7.28 (dd,J= 9.1, 2.3 Hz, 1H), 4.33 (d,J= 6.3 Hz, 2H), 3.90 (s, 3H), 3.07 (d,J= 7.4 Hz, 2H), 1.24 (d,J= 2.6 Hz, 3H).

[0666] Example 114: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-4-methylbenzenesulfonamide;

[0667]

[0668] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (t,J= 6.4 Hz, 1H), 7.71 (dd,J= 16.0, 8.1 Hz, 3H), 7.62 (d,J= 2.1 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.38 (d,J= 8.0 Hz, 3H), 7.29 (dd,J= 9.0, 2.3 Hz, 1H), 4.17 (d,J= 6.4 Hz, 2H), 3.90 (s, 3H), 2.35 (s, 3H).

[0669] Example 115: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)methanesulfonimide;

[0670]

[0671] LC-MS (ESI) calcd for C 15 H 16 FN5O2S [M + H] + 349. 1, found m / z 350.1

[0672] Example 116: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzoic acid;

[0673]

[0674] 1 H NMR (400 MHz, DMSO-d6) δ13.86 (brs, 1H), 8.12 - 7.93 (m, 3H), 7.64 (dd,J= 9.1, 2.5 Hz, 2H), 7.31 (dd,J= 9.1, 2.2 Hz, 1H), 3.90 (s, 3H).

[0675] Example 117: Diethyl-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)phosphoamidate;

[0676]

[0677] 1H NMR (400 MHz, DMSO-d6) δ 7.80 (t,J= 8.0 Hz, 1H), 7.63 (d,J= 2.1 Hz, 1H), 7.58 (d,J= 11.6 Hz, 1H), 7.52 (dd,J= 9.0, 2.1 Hz, 1H), 7.48 (d,J= 8.2 Hz, 1H), 7.28 (dd,J= 9.0, 2.2 Hz, 1H), 5.70 (dd,J= 7.3, 4.6 Hz, 1H), 4.16 - 4.09 (m, 2H), 3.98 - 3.90 (m, 4H), 3.89 (s, 3H), 1.21 (t,J= 7.1 Hz, 42.6H).

[0678] Example 118: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)phosphonic acid;

[0679]

[0680] 1 H NMR (400 MHz, DMSO-d6) δ8.09 - 7.87 (m, 5H), 7.64 (d,J= 2.2 Hz, 1H), 7.32 (dd,J= 9.1, 2.3 Hz, 1H), 3.90 (s, 3H).

[0681] Example 119: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)phosphonic acid;

[0682]

[0683] 1 H NMR (400 MHz, DMSO-d6) δ7.79 (dd,J= 8.6, 6.2 Hz, 3H), 7.60 (d,J= 2.2 Hz, 1H), 7.54 (dd,J= 8.5, 2.2 Hz, 2H), 7.28 (dd,J= 9.1, 2.3 Hz, 1H), 3.89 (s, 3H), 3.11 (d,J= 21.5 Hz, 2H).

[0684] Example 120: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)boronic acid;

[0685]

[0686] LC-MS (ESI) calcd for C 14 H 13 BFN3O3[M + H] + 301.10, found m / z 302.1

[0687] Example 121: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)boronic acid;

[0688]

[0689] LC-MS (ESI) calcd for C 15 H 16 BN3O3[M + H] + 297.13, found m / z 298.1

[0690] Example 122: N-(4-(5-methoxy-1H-indole-1-yl)benzyl)sulfamide;

[0691]

[0692] LC-MS (ESI) calcd for C 16 H 17 N3O3S [M + H] + 330.24, found m / z 331.1

[0693] Example 123 :N-(4-(5-methoxy-1H-benzo[d]imidazole-1-yl)benzyl)sulfamide;

[0694]

[0695] LC-MS (ESI) calcd for C 15 H 16 N4O3S [M + H] + 332.09, found m / z 333.1

[0696] Example 124 :N-(4-(5-methoxy-1H-indazole-1-yl)benzyl)sulfamide;

[0697]

[0698] LC-MS (ESI) calcd for C 15 H 16 N4O3S [M + H] + 332.09, found m / z 333.1

[0699] [Experimental Example]

[0700] The following experiment was conducted on Example 1-124 manufactured as described above.

[0701] Experimental Example 1: ENPP1 enzyme assay with cGAMP substrate

[0702] ENPP1 hydrolyzes nucleotides or nucleotide derivatives to produce nucleoside-5'-monophosphate and pyrophosphate. Additionally, ENPP1 hydrolyzes 2'3'-cGAMP to produce 5'-adenosine monophosphate (AMP) and 5'-guanosine monophosphate (GMP). The AMP produced from the above reaction is measured using the AMP-Glo® kit (Promega). The AMP-Glo® kit consists of two reagents. The first reagent terminates the AMP-generating enzyme reaction, removes ATP, and converts the generated AMP into ADP. The second reagent converts ADP into ATP, which is used to generate luminescence in the luciferase reaction. The amount of luminescence measured above is proportional to the amount of AMP produced by ENPP1.

[0703] The final reaction mixture of the evaluation system contains 50 mM Tris (pH 8.5) buffer, 250 mM NaCl, 0.5 mM CaCl2, 1 μM ZnCl2, 5% glycerol, and 1% DMSO. Serially diluted ENPP1 inhibitors (typically in the range of 10 μM to 0.5 nM) are pre-stored with human recombinant ENPP1 enzyme (R&D systems) at 3 ng / reaction for 5–10 minutes under room temperature (RT) conditions. The reaction is initiated by the addition of cGAMP (at a final concentration of 5 μM) and reacted for 90 minutes at 37 °C. At the end of the reaction, 10 μL of AMP-Glo ​​reagent 1 is added to stop the reaction, followed by storage at room temperature for 1 hour. After the above storage, 20 µl of AMP detection solution (a mixture of AMP-Glo ​​II reagent and Kinase-Glo in a 1:100 ratio) was added, and the sample was stored at room temperature for 1 hour. The luminescence signal was measured using a Victor® plate reader (Perkin Elmer). The maximum activity control (containing enzyme and substrate in the presence of 1% DMSO; MAX) and the minimum activity control (containing substrate and 1% DMSO; MIN) were evaluated simultaneously. In each experiment, serially diluted reference ENPP1 inhibitors were tested concurrently. The IC50 values ​​for residual activity % versus compound concentration were determined by fitting inhibition curves using the 3-parameter method of GraphPad Prism® software. Serially diluted samples of a single compound were tested at least twice, and the average IC50 for each compound was calculated. 50 The value was calculated.

[0704] The experimental results were as shown in Tables 1 and 2 below.

[0705] Example Enzyme Activity 1C2C3B4B5A6C7C8C9B10B11C12C13C14A15A17C18C19C20C21C22C23C24C25C26C27C28C29C30C31C41A42C43A44A45A46B47B48A49B50A51A52A53C54B55A56A57A58A59A60A61A64A65A66A68B69B70 A71A72A73A74A75C76C77C78A79C80A81A82A83A84C85C86C88C89C90C91A92A93A92A93A94A95A96A 97A98C101A102A103A104B105C106C107C108B109B110B111C112C113C114C116C117C118C119A122C

[0706] Enzyme activityABCIC50 (uM)Activity < 11 ≤ activity < 1010 ≤ activity

[0707] [Experimental Example 2]

[0708] The following experiment was conducted on the example manufactured as described above.

[0709] Experimental Example 2: HCT116-dual cell Luciferase assay

[0710] HCT116-Dual TM 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 TM Cell lines were used to monitor the activity of interferon regulatory factor 3 (IRF3), a type I interferon induction and subsequent signaling, and Lucia secreted in the culture medium was used to generate luminescence in the luciferase reaction.

[0711] HCT116-Dual in DMEM culture medium containing 10% FBS and 25mM HEPES (pH 7.2 - 7.5) TM 2 x 10 cells in a 96-well plate 4Incubate for one day at wells (93.4 µL). Add 3.3 µL of ENPP1 inhibitor (typically 10 µM) and 3.3 µL of cGAMP (10 µM) to set the final dose to 100 µL. (The final fraction of DMSO is 0.1%.) Incubate cells treated with ENPP1 inhibitor and cGAMP at 37 ℃ for 48 hours, and add 50 µL of Quanti-Luc reaction solution to 20 µL of cell culture medium to measure Lucia luciferase activity. The increase in interferon regulatory factor 3 (IRF3) induced by the compounds relative to cGAMP was determined as a multiple.

[0712] The experimental results were as shown in Tables 3 and 4 below.

[0713] Example Cell Activation 55B60A61A64A65A71B81A83B92A93A94A100B

[0714] Cell activity AB multiple 1.5 < Cell activity Cell activity < 1.5

[0715] [Preparation]

[0716] Meanwhile, the novel compound represented by Chemical Formula 1 according to the present invention can be formulated into various forms depending on the purpose. The following are examples of several formulation methods containing the compound represented by Chemical Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

[0717] Formulation Example 1: Tablet (Direct Pressurization)

[0718] After sieving 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form tablets.

[0719] Formulation Example 2: Tablet (Wet Granulation)

[0720] 5.0 mg of the active ingredient was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water, an appropriate amount of this solution was added, and the mixture was micronized. After drying, the micron was sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The micron was pressurized to form tablets.

[0721] Formulation Example 3: Powder and capsule

[0722] After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filled into hard No. 5 gelatin capsules using a suitable device.

[0723] Formulation Example 4: Injectable

[0724] An injectable drug was prepared by containing 100 mg as an active ingredient, and also containing 180 mg of mannitol, 26 mg of Na2HPO4·12H2O, and 2974 mg of distilled water.

[0725] Experimental Example 3: Evaluation of In Vitro ATP Hydrolysis Activity Inhibitory Ability of Benzotriazole Derivatives Having ENPP1 Inhibitory Activity

[0726] When ATP is hydrolyzed by the ENPP1 enzyme, AMP and Ppi are produced. In this experiment, to evaluate the inhibitory effect of ENPP1 inhibitory compounds on PPi production, the amount of AMP generated during the ATP hydrolysis reaction by ENPP1 was quantified to compare enzyme inhibitory capabilities. For the evaluation of ATP hydrolysis activity inhibition, test compounds were prepared by serially diluting up to 10 μM of the compound in a buffer solution composed of 50 mM Tris-HCl (pH 8.5), 250 mM NaCl, 0.5 mM CaCl₂, 1 μM ZnCl₂, 5% Glycerol, and 1% DMSO in triplicate. The diluted test compounds were incubated with ENPP1 enzyme (0.3 ng / μL) and ATP (2 μM) at 37°C for 2 hours. After the reaction was complete, the generated AMP was converted to ATP, and the luminescence amount was measured using a CLARIOstar Plus plate reader (BMG LABTECH) for luciferase-based luminescence analysis. Activity inhibition curve analysis was performed using the 3-parameter fits method with GraphPad Prism 9 software, and the IC50 was calculated after plotting the enzyme activity inhibition curve according to compound concentration 50 The ENPP1 ATP hydrolysis inhibitory ability was evaluated using the value.

[0727] As a result of the evaluation, MV-658, used as a control compound as shown in Fig. 1, IC 50 187 nM, the compound of Example 61 is IC 50 The inhibitory effect of 128 nM on ENPP1 ATP hydrolysis was confirmed. In addition, the inhibitory effect of various compounds of the examples on ENPP1 ATP hydrolysis was confirmed as shown in Table 5 below.

[0728] Example ENPP1 IC 50 MV-658++51+61+++80+60+64+65+55+93+++92++94++81+115++62+++“+++” < 1 μM, 1 μM ≤”++”<3 μM, and “+≥3 μM

[0729] Experimental Example 4: Evaluation of the inhibitory activity of a benzotriazole derivative having ENPP1 inhibitory activity against PPi (Inorganic pyrophosphate) in human serum

[0730] The luminescence analysis in this test is based on the principle that enzyme-bound antibodies generate chemiluminescence by reacting with specific substrates. Commonly used enzymes include luciferase and alkaline phosphatase (AP). The method utilizes the Chemiluminescent Immunoassay (CLIA) technique, which determines the concentration of a substance within a sample by detecting the light emitted when these enzymes react with substrates. ATP is generated through the luciferase reaction of the target substance in the sample, and this ATP further participates in the luciferase reaction to induce luminescence. Since the intensity of the luminescence is proportional to the amount of the generated target substance, the concentration of the substance can be quantified by measuring the amount of luminescence. Luminescence occurs when an electron in the ground state absorbs energy, transitions to a higher-energy excited state, and then returns to the ground state. During this process, light equivalent to the energy difference is emitted, occurring in the form of photons. These photons are detected using a luminescent signal instrument.

[0731] As a result of measuring PPi in the serum of patients administered the compound of Example 61, a decreasing trend was confirmed when comparing the pre- and post-administration periods as shown in Figure 2.

[0732] Experimental Example 5: Evaluation of Mineralization After Osteogenesis Induction

[0733] In this experiment, the effect of the compounds of the present invention on mineral deposition in human bone-associated cells (Saos-2, ATCC HTB-85) was evaluated. Saos-2 cells were placed in a 24-well plate at a rate of 3.5 × 10⁴ per well. 5 Canine cells were inoculated and cultured for 1–2 days until a density of 100% was reached. Once the cell density was fully increased, the medium was replaced with fresh medium containing 50 μg / mL ascorbic acid (Sigma, A4554), 10 mM β-glycerophosphate (MCE, D4902), and 30 μM ENPP1 inhibitor. The date on which the mineralization component was first added was considered Day 1. On Day 3, the existing medium was removed, and the mineralization component and 30 μM ENPP1 inhibitor were added to the fresh medium. On Day 5, the existing medium was removed, and the cells were washed twice with PBS. The cells were treated with 4% formaldehyde and fixed at room temperature for 15 minutes. After fixation, the cells were washed three times with PBS, and stained with 40 mM Alizarin Red solution by gently rotating at room temperature for 30 minutes. After staining was complete, the cells were washed three times with distilled water, and imaging was performed. Dye extraction reagent was added to the cells in each stained well and reacted at room temperature for 30 minutes, after which the extracted reagent was transferred to a 96-well plate. The absorbance of Alizarin Red was measured at a wavelength of 405 nm using a CLARIOstar Plus reader (BMG LABTECH).

[0734] As a result of the evaluation, it was confirmed that various embodiments of the present invention, as shown in Fig. 3, exhibit an inhibitory effect compared to DMSO in the range of 20 to 30 percent.

[0735] Experimental Example 6: Measurement of plasma PPi concentration after oral administration

[0736] The compound of Example 61 was administered orally to normal mice at a single dose and repeated doses of 200 mg / kg for 5 days. After reaching room temperature, 20 μL of the plasma sample was mixed with 100 μL of 0.9% sodium chloride solution to dilute it 5-fold. 100 μL of the diluted plasma sample was injected into a 10 kDa cutoff column (Abcam, ab93349) and centrifuged at 10,000 × g for 20 minutes at room temperature. After centrifugation, the column was removed, and 10 μL of the filtrate was dispensed into 384-well plates (each sample was replicated 3 times). Inorganic pyrophosphate (PPi) quantification was performed using PPiLight TM The procedure was performed using an inorganic pyrophosphate kit (Lonza, LT07-610) according to the manufacturer's recommended protocol. 5 μL of converting reagent was added to each well of a 384-well plate and reacted at room temperature for 30 minutes. Subsequently, 5 μL of detection reagent was added and reacted at room temperature for an additional 30 minutes. Luminescence values ​​were obtained from wells where the reaction was complete by measuring them with a CLARIOstar reader (BMG LABTECH, 430-2518). The obtained luminescence values ​​were applied to the PPi standard curve to calculate the PPi concentration of the plasma sample, and the final concentration was calculated by multiplying by the sample dilution factor (× 5).

[0737] As a result of measurement, it was confirmed that PPi decreased after administration, as shown in Figure 4 (single dose, compound 200 mg / kg, PO Once, Time: 1, 4, 8, 24 hr) and Figure 5 (repeated dose, compound 200 mg / kg, PO QDx5, Time: 1 hr & 4 hr).

[0738] Although embodiments of the present invention have been described above, those skilled in the art will understand that the present invention may be implemented in other specific forms without changing its technical concept or essential features. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0739] This research was conducted with funding from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare, and with support from the National Drug Development Project of the National Drug Development Agency (RS-2023-00282830).

[0740] This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2023-00282830, Republic of Korea).

Claims

1. A pharmaceutical composition for the prevention, alleviation, or treatment of one or more of calcium pyrophosphate deposition (CPPD) disease and hypophosphatasia (HPP), comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, or an isomer thereof. [Chemical Formula 1] (In the above chemical formula 1, W1 is N or C; W2 is N or C; W3 is N or C; W4 is N or C; W5 is N or CR a And; W6 is N or CR b And; W7 is N or CR c And; R a , R b and R c Each is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, and heteroaryl, and R1, R2, R3, and R4 are each independently hydrogen; hydroxyl group; halogen group; -CF3; -CF2CH3; -CF(CH3)CH3; -(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 Cyclic reel; C3-C 10 Heteroaryl group; C3-C 10 Heterocyclyl group; or -C(O)-(C1-C 13 alkyl); and, The above Z may or may not be present, and if Z is present, Z is -O-, -CO-, -COO-, -C n H 2n -, -O(C n H 2n )-, -(OC2H4) n -, -(C2H4O) n -, -(C n H 2n )O-, -(C n H 2n )CO-, -(C n H 2n )O(C m H 2m )-, -NR7(C n H 2n )-, -(NR7C2H4) n -, -(C2H4NR7) n -, or -(C n H 2n )NR7-; and, n is an integer from 0 to 8, and R5 is -A-(R6) y is, The above A is C3-C 10 Cyclic reel, C5-C 10 Bicyclil, C3-C 10 Heterocyclyl group, C6-C 10 aryl group, or C3-C 10 It is a heteroaryl group, and The above R6 is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C1-C6 alkenyl group; C6-C 10 Aryl group; C3-C 10 Cyclic reel; 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 2m )NR7R8; nitro group(-N(O)2); amide group(-(C=O)NR7R8); ester group(-(C m H 2m )C(O)OR7); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-(C m H 2m )NHS(O)2R7); Ureagenesis; Sulfamodialysis(-(C m H 2m )NHS(O)2NHR7); -(C m H 2m )NR7S(O)2NHR8; sulfide group(-(C m H 2m )SR7); Sulfoni(-( C m H 2m )S(O)2R7); phosphiryl group(-(C m H 2m )P(O)R7R8); or connected to the same carbon as the carbon connected to A or an adjacent carbon to form a 3 to 10-membered saturated ring or a heterosaturated ring comprising one or more heteroatoms of N, O, and S, The above A may include one or more substituents selected from halogens, independently of R6, and m is an integer from 0 to 4, and y is an integer from 0 to 4, and The above C1-C 13 Alkyl group, C1-C6 alkoxy group, C1-C6 alkenyl group, or -C(O)-(C1-C 13 Alkyl) is hydrogen; hydroxyl group; halogen group; 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)2R7); sulfide group (-SR7); sulfon group (-S(O)2R7); phosphyryl group (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 heteroaryl group; and C3-C 10 It comprises one or more substituents selected from the group consisting of heterocyclil groups, and The above C6-C 10 Aryl group, C3-C 10 Heteroaryl group, C3-C 10 Cyclic reel, C3-C 10 heterocyclyl group or C5-C 10 The bicyclil group is hydrogen; a hydroxyl group; a halogen group; a carbonyl group (-(C=O)R7R8); a halogen or C3-C 10 C1-C3 alkyl groups substituted or unsubstituted with heterocyclyl groups; halogen or C3-C 10 C1-C3 alkoxy groups substituted or unsubstituted with heterocyclyl groups; C6-C 10 Phenoxy; 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)2R7); sulfide group (-SR7); sulfon group (-S(O)2R7); phosphyryl group (-P(O)R7R8); C6-C 10 Aryl group; C3-C 10 heteroaryl group and C3-C 10 It comprises one or more substituents selected from the group consisting of heterocyclil groups, and The above R7 and R8 are each independently hydrogen; C1-C6 alkyl group; C1-C6 alkenyl group; C1-C6 alkynyl group; C3-C 10 Cyclic reel; C6-C 10 Aryl group; C3-C 10 Heterocyclyl group; C3-C 10 Heteroaryl group; amino group (-NH2); nitro group (-N(O)2); -Boc; -NHBoc; or R7 may optionally include at least one of N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, or SO2 together with the nitrogen or carbon atom connected to R8, and hydrogen, C1-C 13 Alkyl group, C6-C 10 Aryl group, C3-C 10 Forming a 3 to 7-membered saturated ring that can be optionally substituted with at least one of a heteroaryl group, a hydroxyl group, a halide group, and a cyano group, and The above C3-C 10 heteroaryl group and C3-C 10 A heterocyclile group comprises one or more heteroatoms selected from the group consisting of N, O, and S.

2. In Claim 1, The above W1, W2, W3, and W4 are each C, and The above R1, R2, R3, and R4 are each independently hydrogen; a hydroxyl group; a halogen group; -CF3; -(O)CF3; C1-C3 alkyl group; C1-C6 alkoxy group; or amino group (-NR7R8), and The above Z may or may not exist, and if Z is present, Z is -C n H 2n -is, n is an integer from 1 to 4, and The above A is cyclopentane; cyclohexane; benzene; bicyclopentane; thiophene; pyridine; benzofuran; quinoline; indole; benzoazepine; or piperidine, The above R6 is a sulfonamide group (-(C m H 2m )NHS(O)2R7); Sulfamo Diary(-(C m H 2m )NHS(O)2NHR7); -(C m H 2m )NR7S(O)2NHR8; sulfide group(-(C m H 2m )SR7) or sulfonate(-( C m H 2m )S(O)2R7) Pharmaceutical composition.

3. In Claim 2, A pharmaceutical composition in which the compound represented by the above chemical formula 1 is any one of the following compound numbers 1 to 124. 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]triazole-1-yl)cyclohexyl)methaneaniline; Compound No. 3: 5-methoxy-1-(piperidine-4-ylmethyl)-1H-benzo[d][1,2,3]triazole; Compound No. 4: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)aniline hydrochloride; Compound No. 5: 4-(1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 6: 4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 7: 4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 8: 4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 9: 4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 10: 4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 11: 2-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethane-1-amine hydrochloride; Compound No. 12: 1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)-N-methylmethaneamine hydrochloride; Compound No. 13: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)cyclopropanamine hydrochloride; Compound No. 14: (S)-1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethane-1-amine hydrochloride; Compound No. 15: 3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 16: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine hydrochloride; Compound No. 17: 2,5-Difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine; Compound No. 18: 2,6-Difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine; Compound No. 19: 4-(5-ethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine; Compound No. 20: 3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine; Compound No. 21: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine; Compound No. 22: 4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine; Compound No. 23: 3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)methaneamine; Compound No. 24: 4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorophenyl)methaneamine; Compound No. 25: 7-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; Compound No. 26: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; Compound No. 27: 8-(5-methoxy-1H-benzo[d][1,2,3]triazole-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]triazole-1-yl)-2,5-difluorophenyl)methaneamine; Compound No. 29: 1-(isoindorin-5-yl)-5,6-dimethoxy-1H-benzo[d][1,2,3]triazole hydrochloride; Compound No. 30: 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)bicyclo[1.1.1]pentane-1-yl)methaneamine; Compound No. 31: 3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-5-methylthiophene-2-yl)methaneamine hydrochloride; Compound No. 32: tert-butyl((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidine-1-yl)sulfonyl)carbamate; Compound No. 33: tert-butyl((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)piperidine-1-yl)sulfonyl)carbamate; Compound No. 34: tert-butyl(N-(1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 35: tert-butyl(N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 36: tert-butyl(N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 37: tert-butyl(N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 38: tert-butyl(N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamoyl)carbamate; Compound No. 39: tert-butyl((S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethyl)sulfamoyl)carbamate; Compound No. 40: tert-butyl((6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfamoyl)carbamate; Compound No. 41: N-((3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclopentyl)methyl)sulfamide; Compound No. 42: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidine-1-sulfonamide; Compound No. 43: N-((4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)cyclohexyl)methyl)sulfamide; Compound No. 44: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidin-1-yl)ethane-1-sulfonamide; Compound No. 45: 4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)piperidine-1-sulfonamide; Compound No. 46: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 47: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamide; Compound No. 48: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)sulfamide hydrochloride; Compound No. 49: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 50: N-(4-(4-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 51: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide hydrochloride; Compound No. 52: N-(4-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 53: N-(4-(7-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 54: N-(4-(4,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 55: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 56: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide; Compound No. 57: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-2,3-difluorobenzyl)sulfamide; Compound No. 58: N-(4-(1H-benzo[d][1,2,3]triazole-1-yl)-3,5-difluorobenzyl)sulfamide; Compound No. 59: N-(3-chloro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 60: N-(2-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 61: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide; Compound No. 62: N-(2,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 63: N-(2,6-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 64: N-(3,5-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)sulfamide; Compound No. 65: N-(2,3-difluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-benzyl)sulfamide; Compound No. 66: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-methylbenzyl)sulfamide; Compound No. 67: N-(3-cyano-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-benzyl)sulfamide; Compound No. 68: N-(3-methoxy-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 69: N-(4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 70: N-(3-fluoro-4-(5-methoxy-6-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 71: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide; Compound No. 72: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)sulfamide; Compound No. 73: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)sulfamide hydrochloride; Compound No. 74: N-(3-fluoro-4-(5-hydroxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 75: N-(3-fluoro-4-(5-methyl-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 76: N-(4-(5-ethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide; Compound No. 77: N-(3-fluoro-4-(5-isopropoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 78: N-(5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)pyridine-2-yl)methyl)sulfamide; Compound No. 79: (N-(6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)pyridine-3-yl)methyl)sulfamide; Compound No. 80: N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-N-methyl)sulfamide; Compound No. 81: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-N-methylsulfamide; Compound No. 82: N-cyclopropyl-N-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 83: (S)-N-(1-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)ethyl)sulfamide; Compound No. 84: N-(4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 85: N-(3-fluoro-4-(5-trifluoromethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 86: N-(4-(5-(1,1-difluoroethyl)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 87: N-(4-(5-dimethylamino)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide; Compound No. 88: N-(3-fluoro-4-(5-fluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 89: N-(4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 90: N-(3-fluoro-4-(5-trifluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 91: N-(4-(5-difluoromethoxy)-1H-benzo[d][1,2,3]triazole-1-yl)-3-fluorobenzyl)sulfamide; Compound No. 92: N-(4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 93: N-(3-fluoro-4-(6-fluoro-5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)sulfamide; Compound No. 94: 5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)isoindorin-2-sulfonamide; Compound No. 95: N-5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,3-dihydro-1H-indene-2-yl)sulfamide; Compound No. 96: 6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide; Compound No. 97: 7-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)sulfonamide; Compound No. 98: 8-(5-methoxy-1H-benzo[d][1,2,3]triazole-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]triazole-1-yl)-2,5-difluorobenzyl)sulfamide; Compound No. 100: N-(4-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-2,6-difluorobenzyl)sulfamide; Compound No. 101: 7-fluoro-6-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide; Compound No. 102: 5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-isoindorin-2-sulfonamide; Compound No. 103: N-(5-(5,6-dimethoxy-1H-benzo[d][1,2,3]triazole-1-yl)-dihydro-1H-indene-2-yl)sulfamide; Compound No. 104: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)phenyl)sulfamide hydrochloride; Compound No. 105: N-(4-((5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)methyl)benzyl)sulfamide hydrochloride; Compound No. 106: N-((5-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)thiophene-2-yl)methyl)sulfamide; Compound No. 107: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-5-methoxythiophen-2-yl)methyl)sulfamide; Compound No. 108: N-(3-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)-bicyclo[1,1.1]pentane-1-yl)sulfamide; Compound No. 109: N-(4-(5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)phenyl)sulfamide hydrochloride; Compound No. 110: N-(4-((5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)benzyl)sulfamide hydrochloride; Compound No. 111: 2-(4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)piperidin-1-yl)ethane-1-sulfonyl fluoride; Compound No. 112: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)methanesulfonamide; Compound No. 113: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)ethanesulfonamide; Compound No. 114: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)-4-methylbenzenesulfonamide; Compound No. 115: N-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)methanesulfonimide; Compound No. 116: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzoic acid; Compound No. 117: Diethyl-(3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)phosphoamidate; Compound No. 118: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenyl)phosphonic acid; Compound No. 119: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)phosphonic acid; Compound No. 120: 3-fluoro-4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)benzyl)boronic acid; Compound No. 121: 4-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)phenethyl)boronic acid; Compound No. 122: N-(4-(5-methoxy-1H-indole-1-yl)benzyl)sulfamide; Compound No. 123: N-(4-(5-methoxy-1H-benzo[d]imidazole-1-yl)benzyl)sulfamide; and Compound No. 124: N-(4-(5-methoxy-1H-indazole-1-yl)benzyl)sulfamide.

4. A benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1). A pharmaceutical composition for the prevention, alleviation, or treatment of one or more of calcium pyrophosphate deposition (CPPD) disease and hypophosphatasia (HPP).

5. A step comprising administering a benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1). A method for the prevention, alleviation, or treatment of one or more of the diseases of calcium pyrophosphate deposition (CPPD) and hypophosphatasia (HPP).

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