TNAP inhibitory compound and use thereof

Abstract

The present invention relates to a tissue-nonspecific alkaline phosphatase (TNAP) inhibitory compound and a use thereof in relation to the prevention or treatment of diseases associated with TNAP over-expression or over-activation. The compound is a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

Description

TNAP inhibitory compounds and uses thereof

[0001] The present invention relates to compounds that inhibit tissue-nonspecific alkaline phosphatase (TNAP) and uses thereof.

[0002] The research on the present invention was conducted with the support of the National New Drug Development Project of the National Drug Development Agency with funds from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare (Project Number: RS-2023-00217370).

[0003] Among alkaline phosphatases (ALPs), tissue-nonspecific alkaline phosphatase (TNAP) has been shown to hydrolyze extracellular pyrophosphate (ePPi) during bone mineralization. This reduces the amount of ePPi, an inhibitor of hydroxyapatite formation, and provides phosphate (Pi) for hydroxyapatite formation. Therefore, since the balance between ePPi and Pi is crucial for mineralization, TNAP plays a crucial role in osteogenesis.

[0004] TNAP is expressed in bone, liver, and kidney, and is particularly highly expressed in the matrix vesicles of chondrocytes and osteoblasts. This enzyme is known to play a crucial role in in vivo calcification through the degradation of pyrophosphate, an endogenous anti-calcification factor. Calcification in unwanted sites, known as ectopic calcification, can lead to various diseases.

[0005] Increased expression or activity of TNAP was observed at the lesion site of ectopic calcification. Therefore, inhibition of TNAP is expected to increase pyrophosphate concentrations in blood and tissues and suppress ectopic calcification, leading to the development of TNAP inhibitors.

[0006] Various diseases in which ectopic calcification is found include pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), craniometaphyseal dysplasia (CMD), ossification of the yellow ligament (OYL), arterial calcification, calcification of joints, arthrosis deformans, osteoarthritis, ankylosis of the joint, idiopathic infantile arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC), and progressive osseous heteroplasia (PHE).POH), Keutel syndrome, vascular calcification associated with chronic renal failure (chronic renal failure includes glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic calcification, calciphylaxis, calcific tendinitis of the longus colli muscle, fibrodysplasia ossificans progressive (FOP), calcific aortic stenosis, pericarditis calculosa, atherosclerotic vascular calcification, calcific uremic arteriopathy uremic arteriopathy (CUA), Kawasaki disease, calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget's disease, idiopathic basal ganglia calcification (IBGC), heterotopic ossification (HO), calcific aortic valve disease (CAVD).These include aortic valve stenosis (AVS), calcific tendinitis, ossification of the posterior longitudinal ligament (OPLL), ossification of the anterior longitudinal ligament (OALL), diffuse idiopathic skeletal hyperostosis (DISH), meniscal calcification, and peritoneal calcification.

[0007] Several patents relating to TNAP inhibitors, including benzene sulfonamides, have been disclosed. Examples include WO 2013 / 126608 and WO 2017 / 007943.

[0008] The present inventors have completed the present invention by developing a TNAP inhibitory compound having a novel structure based on benzene sulfonamide but including a fused pyridine compound.

[0009] An object of the present invention is to provide a novel TNAP inhibitory compound.

[0010] Another object of the present invention is to provide a preventive or therapeutic agent for diseases caused by TNAP overexpression or overactivation.

[0011] Another object of the present invention is to provide a preventive or therapeutic agent for isotopic calcification and / or various diseases related thereto.

[0012] In one aspect, the present invention

[0013] A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] R 1 is hydrogen, halogen, unsubstituted or substituted phenyl, or C 1-10 It is alkoxy;

[0018] R 2 is hydrogen;

[0019] R 3 is hydrogen or halogen;

[0020] R 4 is hydrogen, halogen, unsubstituted or substituted phenyl, unsubstituted or substituted 5-9 membered heteroaryl, unsubstituted or substituted 6-membered cycloalkenyl substituted with one or more halogens, unsubstituted or substituted 6-membered heterocycloalkenyl, or C 1-10 It is alkoxy;

[0021] R 5 is hydrogen or halogen;

[0022] or

[0023] R 1 Inland R 5 The two adjacent substituents in the group together form -(CH2)mO-, -O-(CH2)mO-, or -O-(CH2)m-CO-NH-, while the remaining three substituents are as described above;

[0024] The above substituted phenyl is C 1-10 Alkoxy, carboxyl, unsubstituted or substituted C 1-10 Substituted with 1 to 3 substituents selected from 3-6 membered cycloalkyl substituted with alkyl, carboxyl, halogen and hydroxyl, or substituted at two adjacent positions to form -O-(CH2)mO-, wherein the substituted C 1-10 Alkyl is carboxyl, C 1-10 Alkoxycarbonyl, amino or C 1-10 Substituted with alkylaminocarbonyl;

[0025] The above substituted 5-9 membered heteroaryl is halogen, amino, unsubstituted C1-10 Alkyl, substituted C 1-10 Alkyl, NH2CO-, unsubstituted or substituted 4-6 membered heterocycloalkyl, C 1-10 Substituted with 1 to 3 substituents selected from alkylsulfonyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl and phenyl, wherein the substituted C 1-10 Alkyl is carboxyl, C 1-10 Alkoxycarbonyl, C 1-10 Alkylaminocarbonyl, C 1-10 A 5-6 membered heteroaryl substituted with alkyl or phenyl substituted with one or more halogens, a 4-6 membered heterocycloalkyl substituted with one or more halogens or hydroxyl, is C 1-10 Alkyl or C 1-10 substituted with alkoxycarbonyl;

[0026] The above substituted 6-membered heterocycloalkenyl is C 1-10 Alkoxycarbonyl or C 1-10 substituted with alkylcarbonyl;

[0027] R 6a and R 6b are all hydrogen or together are oxo;

[0028] R 7 Silver hydrogen, 5-6 membered heteroaryl, -CO x -R 8a , -CONR 8b R 8c , or C 1-10 alkyl, where x is 1 or 2,

[0029] R 8a and R 8b are each independently unsubstituted or substituted C 1-10 Alkyl, or C 6-10 Aryl, where the substituted C 1-10 Alkyl is substituted with one or more halogens, or 3-6 cycloalkyl,

[0030] R 8c is hydrogen or R 8b and these together with the substituted nitrogen atom form a 5-6 membered heterocycloalkyl;

[0031] wherein m is an integer from 1 to 4;

[0032] The above n is an integer from 1 to 3.

[0033] Another aspect of the present invention provides a use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of a TNAP-related disease.

[0034] Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a TNAP-related disease, which contains the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0035] Another aspect of the present invention provides a use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of diseases associated with ectopic calcification.

[0036] Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a disease related to ectopic calcification, which contains the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0037] In addition, the present invention provides a method for preventing or treating a TNAP-related disease or an ectopic calcification-related disease, comprising a step of administering the pharmaceutical composition in a pharmaceutically effective amount to a subject in need thereof.

[0038] The compound according to the present invention effectively inhibits the activity of TNAP and inhibits calcification. Therefore, it can effectively prevent or treat diseases caused by TNAP overexpression or overactivation or diseases associated with ectopic calcification.

[0039] Figure 1 shows that the example compound inhibits inflammation and calcification in a warfarin-induced animal model.

[0040] Figure 2 shows that the example compound inhibits inflammation and calcification in a vitamin D-induced animal model.

[0041] Hereinafter, the present invention will be described in detail.

[0042] Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, the embodiments of the present invention are provided to more fully explain the present invention to those with average knowledge in the relevant technical field.

[0043] Furthermore, reference to an element "including" throughout the specification does not exclude other elements, but rather includes other elements, unless specifically stated otherwise.

[0044] As used herein, “alkoxy” means a radical in which alkyl is substituted through an oxygen atom. Here, alkyl means a saturated hydrocarbon, including both straight and branched chains. For example, “C 1-6 "Alkyl" means an alkyl group having a skeleton of 1 to 6 carbons. Specifically, C 1-6 Alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc. C6 alkyl is a fully saturated hydrocarbon with 6 carbons, and includes all structural isomers that can be formed as a saturated hydrocarbon with 6 carbons. C 1-10 Alkoxy is C 1-6 Alkoxy, C 1-3 Contains alkoxy or methoxy.

[0045] As used herein, “alkyl” includes straight or branched chain saturated hydrocarbon residues, unless otherwise specified. For example, “C 1-6 "Alkyl" means an alkyl group having a skeleton of 1 to 6 carbons. Specifically, C 1-6Alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc.

[0046] In this specification, unless otherwise specified, “cycloalkyl” means a cyclic hydrocarbon residue forming a ring as a saturated hydrocarbon residue, and “3-6 membered cycloalkyl” means a cyclic hydrocarbon residue containing 3 to 6 carbon atoms as ring atoms.

[0047] As used herein, “heterocycloalkyl” means a monovalent saturated moiety consisting of 1 to 3 rings containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S, unless otherwise specified. It may be bicyclic or tricyclic containing 2 or 3 rings, and in this case, these 2 or 3 rings may be bridged, fused or spiro-shaped heterocycloalkyl. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.

[0048] In this specification, “aryl” means an aromatic radical having a single ring or two or three hydrocarbon aromatic rings fused together, C 6-10 Aryl refers to an aromatic ring compound containing 6-10 carbons, including phenyl or naphthyl.

[0049] As used herein, “heteroaryl” means, unless otherwise specified, a single ring or an aromatic radical having one or more aromatic rings (the remaining ring atoms being C) containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S as ring atoms, or two or three rings fused together. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.

[0050] In this specification, “halogen” means a halogen atom such as F, Cl, Br, or I, and when it is said to be substituted with a halogen, it means that it is substituted with one or more halogen atoms. In this case, the halogen atoms to be substituted can be selected within the range of 1 to 5.

[0051] As used herein, “cycloalkenyl” means a monovalent monocyclic group having at least one unsaturated double bond in the ring and having no aromacity.

[0052] As used herein, “heterocycloalkenyl” is a monocyclic group containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S as ring atoms, and having at least one unsaturated double bond within the ring.

[0053] In this specification, “substituted with a plurality of substituents selected from” may include substitution with a plurality of different substituents, and also includes substitution with a plurality of identical substituents selected.

[0054]

[0055] In the first embodiment of the present invention,

[0056] The compound according to the present invention may be a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0057] [Chemical Formula 1]

[0058]

[0059] In the above chemical formula 1,

[0060] R 1 is hydrogen, halogen, unsubstituted or substituted phenyl, or C 1-10 It is alkoxy;

[0061] R 2 is hydrogen;

[0062] R 3 is hydrogen or halogen;

[0063] R 4 is hydrogen, halogen, unsubstituted or substituted phenyl, unsubstituted or substituted 5-9 membered heteroaryl, unsubstituted or substituted 6-membered cycloalkenyl substituted with one or more halogens, unsubstituted or substituted 6-membered heterocycloalkenyl, or C 1-10 It is alkoxy;

[0064] R 5 is hydrogen or halogen;

[0065] or

[0066] R 1 Inland R 5 In R 1 Inland R 5 wherein two adjacent substituents together form -(CH2)mO-, -O-(CH2)mO-, or -O-(CH2)m-CO-NH-, while the remaining three substituents are as described above;

[0067] The above substituted phenyl is C 1-10 Alkoxy, carboxyl, unsubstituted or substituted C 1-10 Substituted with 1 to 3 substituents selected from 3-6 membered cycloalkyl substituted with alkyl, carboxyl, halogen and hydroxyl, or substituted at two adjacent positions to form -O-(CH2)mO-, wherein the substituted C 1-10 Alkyl is carboxyl, C 1-10 Alkoxycarbonyl, amino or C 1-10 Substituted with alkylaminocarbonyl;

[0068] The above substituted 5-9 membered heteroaryl is halogen, amino, unsubstituted C 1-10 Alkyl, substituted C 1-10 Alkyl, NH2CO-, unsubstituted or substituted 4-6 membered heterocycloalkyl, C 1-10 Substituted with 1 to 3 substituents selected from alkylsulfonyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl and phenyl, wherein the substituted C 1-10 Alkyl is carboxyl, C 1-10 Alkoxycarbonyl, C 1-10 Alkylaminocarbonyl, C 1-10 A 5-6 membered heteroaryl substituted with alkyl or phenyl substituted with one or more halogens, a 4-6 membered heterocycloalkyl substituted with one or more halogens or hydroxyl, is C 1-10 Alkyl or C 1-10 substituted with alkoxycarbonyl;

[0069] The above substituted 6-membered heterocycloalkenyl is C 1-10 Alkoxycarbonyl or C 1-10 substituted with alkylcarbonyl;

[0070] R 6a and R 6b are all hydrogen or together are oxo;

[0071] R 7 Silver hydrogen, 5-6 membered heteroaryl, -CO x -R 8a , -CONR 8b R 8c , or C 1-10 alkyl, where x is 1 or 2,

[0072] R 8a and R 8b are each independently unsubstituted or substituted C 1-10 Alkyl, or C 6-10 Aryl, where the substituted C 1-10 Alkyl is substituted with one or more halogens, or 3-6 cycloalkyl,

[0073] R 8c is hydrogen or R8b and these together with the substituted nitrogen atom form a 5-6 membered heterocycloalkyl;

[0074] wherein m is an integer from 1 to 4;

[0075] The above n is an integer from 1 to 3.

[0076]

[0077] The second embodiment is in accordance with the first embodiment,

[0078] The above R 1 is hydrogen, halogen, unsubstituted or substituted phenyl, or C 1-5 Alkoxy, and the substituted phenyl is cyclopropyl substituted with carboxyl, or unsubstituted or substituted C 1-5 Alkyl, where C is substituted 1-5 Alkyl may be substituted with carboxyl or amino.

[0079]

[0080] The third embodiment is, in each of the preceding embodiments,

[0081] The above R 4 is hydrogen, halogen, unsubstituted or substituted phenyl, 9-membered bicyclic heteroaryl, unsubstituted or substituted 5-6-membered heteroaryl, 6-membered cycloalkenyl unsubstituted or substituted with one or more halogens, or 6-membered heterocycloalkenyl containing one heteroatom among unsubstituted or substituted O, N, or C 1-5 It is alkoxy,

[0082] The above substituted phenyl is C 1-5 Alkoxy, carboxyl, unsubstituted or substituted C 1-5 Substituted with 1 to 3 substituents selected from alkyl, carboxyl-substituted cyclopropyl, halogen and hydroxyl, or substituted at two adjacent positions to form -O-(CH2)mO-, wherein the substituted C 1-5 Alkyl is carboxyl, C 1-5 Alkoxycarbonyl, amino or C 1-5 Substituted with alkylaminocarbonyl;

[0083] The above substituted 5-6 membered heteroaryl is halogen, amino, unsubstituted C 1-5 Alkyl, substituted C 1-5 Substituted with 1 to 3 substituents selected from alkyl, NH2CO-, unsubstituted or substituted 4-6 membered heterocycloalkyl, methylsulfonyl, cyclopropyl, 6 membered heteroaryl and phenyl, wherein the substituted C 1-5 Alkyl is carboxyl, C 1-5 Alkoxycarbonyl, C 1-5 Alkylaminocarbonyl, C 1-5 A 5-membered heteroaryl substituted with alkyl or phenyl substituted with one or more halogens, a 4-6-membered heterocycloalkyl substituted with one or more halogens or hydroxyl, is C 1-5 Alkyl or C 1-5 substituted with alkoxycarbonyl;

[0084] The above substituted 6-membered heterocycloalkenyl is C 1-5 Alkoxycarbonyl or C 1-5 substituted with alkylcarbonyl;

[0085] The above m can be an integer from 1 to 3.

[0086]

[0087] The fourth embodiment is, in each of the preceding embodiments,

[0088] The above R 1 Inland R 5 The two adjacent substituents are R 1 and R 2 or R 2 and R 3 It could be.

[0089]

[0090] The fifth embodiment is, in each of the preceding embodiments,

[0091] The above R 1 Inland R 5 Two adjacent substituents in the group are -(CH2)mO-, -O-(CH2)mO-, or -O-(CH2) mIn the case of forming -CO-NH-,

[0092] The remaining three substituents are each independently hydrogen, halogen, or substituted phenyl,

[0093] The above substituted phenyl is a 3-6 membered cycloalkyl substituted with carboxyl, or an amino substituted C 1-10 Substituted with alkyl,

[0094] The above m can be an integer from 1 to 3.

[0095]

[0096] The sixth embodiment is, in each of the preceding embodiments,

[0097] The above R 1 Inland R 5 The two adjacent substituents are R 1 and R 2 And,

[0098] R 1 and R 2 together with -(CH2)mO-, -O-(CH2)mO-, or -O-(CH 2)m When forming -CO-NH-,

[0099] The remaining three substituents are each independently hydrogen, halogen, or substituted phenyl,

[0100] The above substituted phenyl is cyclopropyl substituted with carboxyl, or amino substituted C 1-5 substituted with alkyl;

[0101] or

[0102] The above R 1 Inland R 5 The two adjacent substituents are R 2 and R 3 And,

[0103] R 2 and R 3 together form -O-(CH2)mO- or -O-(CH2)m-CO-NH-, and the remaining three substituents are all hydrogen;

[0104] The above m can be an integer from 1 to 2.

[0105]

[0106] The seventh embodiment is, in each of the preceding embodiments,

[0107] The above R 7 Silver hydrogen, 6-membered heteroaryl, -CO x -R 8a , -CONR 8b R 8c or C 1-5 alkyl, where x is 1 or 2,

[0108] R 8a is unsubstituted or substituted with 1 halogen C 1-6 It is alkyl,

[0109] R 8b is unsubstituted or substituted C 1-6 alkyl, or phenyl,

[0110] C substituted here 1-6 Alkyl is substituted with 1 or 2 halogens, or cyclopropyl,

[0111] R 8c is hydrogen or R 8b And these can form a 6-membered heterocycloalkyl together with the substituted nitrogen atom.

[0112]

[0113] The eighth embodiment is, in each of the preceding embodiments,

[0114] R 1 Silver C 1-5 alkoxy, halogen, hydrogen, unsubstituted or substituted phenyl;

[0115] R 2 is hydrogen;

[0116] R 3 is hydrogen or halogen;

[0117] R 4is hydrogen, halogen, unsubstituted or substituted phenyl, pyrazolopyridine, unsubstituted or substituted 5-6 membered heteroaryl, unsubstituted or substituted 6 membered cycloalkenyl substituted with one or more halogens, unsubstituted or substituted heterocycloalkenyl containing one heteroatom among O, N, or C 1-5 It is alkoxy;

[0118] R 5 is hydrogen or halogen;

[0119] or

[0120] R 1 Inland R 5 Two adjacent substituents in the group are together -(CH2)mO-, -O-(CH2)mO-, or -O-(CH 2)m -CO-NH-, the remaining three substituents are each independently hydrogen, halogen, or substituted phenyl, wherein the substituted phenyl is cyclopropyl substituted with carboxyl, or amino substituted C 1-3 substituted with alkyl;

[0121] The above substituted phenyl is C 1-5 Alkoxy, carboxyl, unsubstituted or substituted C 1-5 substituted with cyclopropyl substituted with alkyl, carboxyl, or substituted with 1 to 3 substituents selected from halogen and hydroxyl, or substituted at two adjacent positions to form -O-(CH2)mO-, wherein the substituted C 1-5 Alkyl is carboxyl, C 1-5 Alkoxycarbonyl, amino or C 1-5 Substituted with alkylaminocarbonyl;

[0122] The above substituted 5-6 membered heteroaryl is halogen, amino, unsubstituted C 1-5 Alkyl, substituted C 1-5 Substituted with 1 to 3 substituents selected from alkyl, NH2CO-, unsubstituted or substituted 4-6 membered heterocycloalkyl, methylsulfonyl, cyclopropyl, 6 membered heteroaryl and phenyl, wherein the substituted C 1-5 Alkyl is carboxyl, C1-5 Alkoxycarbonyl, C 1-5 Alkylaminocarbonyl, C 1-5 A 5-membered heteroaryl substituted with alkyl or 1 halogen substituted phenyl, substituted with one or more halogens, or hydroxyl, and substituted 4-6 membered heterocycloalkyl is C 1-5 Alkyl or C 1-5 substituted with alkoxycarbonyl;

[0123] The above substituted 6-membered heterocycloalkenyl is C 1-5 Alkoxycarbonyl or C 1-5 substituted with alkylcarbonyl;

[0124] R 6a and R 6b are all hydrogen or together are oxo;

[0125] R 7 Silver hydrogen, pyrimidinyl, -CO x -R 8a , -CONR 8b R 8c , or C 1-5 alkyl, where x is 1 or 2,

[0126] R 8a is unsubstituted or substituted with one halogen C 1-6 It is alkyl,

[0127] R 8b is unsubstituted or substituted C 1-6 alkyl, or phenyl,

[0128] C substituted here 1-6 Alkyl is substituted with 1 or 2 halogens, or cyclopropyl,

[0129] R 8c is hydrogen or R 8b and these together with the substituted nitrogen atom form morpholinyl;

[0130] wherein m is an integer of 1 or 2;

[0131] The above n can be an integer from 1 to 3.

[0132]

[0133] The ninth embodiment is in accordance with the eighth embodiment,

[0134] The above R 1 Inland R 5 The two adjacent substituents are R 1 and R 2 or R 2 and R 3 It could be.

[0135]

[0136] The 10th embodiment is in accordance with the 8th embodiment,

[0137] The above R 1 Inland R 5 The two adjacent substituents are R 1 and R 2 And,

[0138] R 1 and R 2 together with -(CH2)mO-, -O-(CH2)mO-, or -O-(CH2) m When forming -CO-NH-,

[0139] The remaining three substituents are each independently hydrogen, halogen, or substituted phenyl,

[0140] The above substituted phenyl is cyclopropyl substituted with carboxyl, or amino substituted C 1-5 substituted with alkyl;

[0141] or

[0142] The above R 1 Inland R 5 The two adjacent substituents are R 2 and R 3 And,

[0143] R 2 and R 3 together form -O-(CH2)mO- or -O-(CH2)m-CO-NH-, and the remaining three are all hydrogen;

[0144] The above m can be an integer from 1 to 2.

[0145]

[0146] The eleventh embodiment is, in each of the preceding embodiments,

[0147] R 1 Silver hydrogen, halogen, or methoxy;

[0148] R 2 is hydrogen;

[0149] R 3 is hydrogen or halogen;

[0150] R 4 is hydrogen, halogen,

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] or methoxy;

[0160] R 5 is hydrogen or halogen;

[0161] or

[0162] R 1 Inland R 5 Two adjacent substituents in the middle are together , , or The remaining three substituents are each independently hydrogen, halogen, or substituted phenyl, wherein the substituted phenyl is cyclopropyl substituted with carboxyl, or amino substituted C 1-3 substituted with alkyl;

[0163] R 6aand R 6b are all hydrogen or together are oxo;

[0164] R 7 Silver hydrogen,

[0165]

[0166] or C 1-3 It is alkyl;

[0167] The above n can be an integer from 1 to 3.

[0168]

[0169] In the 12th embodiment, in each of the preceding embodiments, the compound or a pharmaceutically acceptable salt thereof may be any one selected from the following.

[0170] <1> 5-Chloro-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide;

[0171] <2> 5-Bromo-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide;

[0172] <3> 2,5-Dimethoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide;

[0173] <4> 5-Fluoro-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide;

[0174] <5> 5-Bromo-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0175] <6> 5-chloro-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0176] <7> 2,5-Dimethoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0177] <8> 5-Fluoro-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0178] <9> 5-Bromo-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0179] <10> 5-Bromo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0180] <11> 2-Bromo-5-fluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide;

[0181] <12> 2-Bromo-4,6-difluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide;

[0182] <13> 5-Chloro-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide;

[0183] <14> 5-Bromo-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide;

[0184] <15> 5-Fluoro-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide;

[0185] <16> 2,5-Dimethoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide;

[0186] <17> 5-Bromo-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0187] <18> N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0188] <19> N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0189] <20> 5-Chloro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0190] <21> 5-Fluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0191] <22> 5-Chloro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0192] <23> 5-Fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0193] <24> N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide;

[0194] <25> 3-Oxo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide;

[0195] <26> 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0196] <27> Methyl 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate;

[0197] <28> 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid;

[0198] <29> 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0199] <30> 4,4'-Dimethoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-3-sulfonamide;

[0200] <31> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(pyridin-4-yl)benzenesulfonamide;

[0201] <32> 1-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid;

[0202] <33> 2-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid;

[0203] <34> 4'-Methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-carboxylic acid;

[0204] <35> 2-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid;

[0205] <36> 1-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid;

[0206] <37> 1-(3',5'-difluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid;

[0207] <38> 1-(4-(7-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-2,3-dihydrobenzofuran-5-yl)phenyl)cyclopropane-1-carboxylic acid;

[0208] <39> 4'-(Aminomethyl)-4-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride;

[0209] <40> 4'-(Aminomethyl)-3,5-difluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride;

[0210] <41> 5-(4-(aminomethyl)phenyl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide;

[0211] <42> Ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)propanoate;

[0212] <43> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)propanoic acid;

[0213] <44> 5-(2-aminopyrimidin-5-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0214] <45> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)benzenesulfonamide;

[0215] <46> 3',5'-Difluoro-4'-hydroxy-4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-3-sulfonamide;

[0216] <47> tert-Butyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetate;

[0217] <48> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetic acid;

[0218] <49> Ethyl 3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanoate;

[0219] <50> 3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanoic acid;

[0220] <51> 5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0221] <52> tert-Butyl 4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate;

[0222] <53> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzenesulfonamide hydrochloride;

[0223] <54> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzenesulfonamide;

[0224] <55> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1H-pyrazol-4-yl)benzenesulfonamide;

[0225] <56> 2-Bromo-5-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0226] <57> 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0227] <58> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanamide;

[0228] <59> Ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanoate;

[0229] <60> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid;

[0230] <61> 5-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0231] <62> 5-(5,6-dihydro-2H-pyran-3-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0232] <63> 4-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-sulfonamide;

[0233] <64> 4',4'-Difluoro-4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-sulfonamide;

[0234] <65> 2-Methoxy-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0235] <66> N-Ethyl-2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetamide;

[0236] <67> N-Ethyl-3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanamide;

[0237] <68> Ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetate;

[0238] <69> 5-(1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0239] <70> 2-Methoxy-5-(1-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0240] <71> 5-(1-(1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0241] <72> 5-(1-Isopropyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0242] <73> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzenesulfonamide;

[0243] <74> 5-(1-Cyclopropyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0244] <75> 2-Methoxy-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0245] <76> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide;

[0246] <77> 5-(6-Fluoropyridin-3-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0247] <78> 5-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0248] <79> 2-Methoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0249] <80> 5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0250] <81> 5-(1-Isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0251] <82> 5-(1-Ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0252] <83> 5-(Isoxazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0253] <84> 5-(3,5-dimethylisoxazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0254] <85> tert-Butyl 4-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;

[0255] <86> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide hydrochloride;

[0256] <87> 5-Bromo-2-methoxy-N-(6-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0257] <88> tert-Butyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0258] <89> tert-Butyl 3-((2,5-dimethoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0259] <90> 5-Fluoro-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride;

[0260] <91> 5-Fluoro-2-bromo-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride;

[0261] <92> 5-chloro-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride;

[0262] <93> 5-Bromo-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride;

[0263] <94> 2,5-Dimethoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride;

[0264] <95> Ethyl 3-((5-fluoro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0265] <96> Ethyl 3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0266] <97> Ethyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0267] <98> Neopentyl 3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0268] <99> Neopentyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0269] <100> Neopentyl 3-((5-methoxy-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0270] <101> 2-Fluoroethyl-3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0271] <102> 2-Fluoroethyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0272] <103> 2-Fluoroethyl-3-((5-methoxy-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate;

[0273] <104> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0274] <105> 3-((5-Fluoro-2-methoxyphenyl)sulfonamido)-N-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0275] <106> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0276] <107> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0277] <108> 3-((5-Bromo-2-methoxyphenyl)sulfonamido)-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0278] <109> 5-chloro-2-methoxy-N-(6-(morpholine-4-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0279] <110> 5-Bromo-2-methoxy-N-(6-(morpholine-4-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0280] <111> 3-((5-Bromo-2-methoxyphenyl)sulfonamido)-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0281] <112> 5-chloro-N-(6-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide;

[0282] <113> 5-Bromo-N-(6-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide;

[0283] <114> 3-5-chloro-2-methoxy-N-(6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0284] <115> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-phenyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0285] <116> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(cyclopropylmethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0286] <117> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(2-fluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide;

[0287] <118> 5-Chloro-N-(6-(3,3-dimethylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide;

[0288] <119> 5-Bromo-N-(6-(3,3-dimethylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide;

[0289] <120> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide;

[0290] <121> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide;

[0291] <122> 5-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0292] <123> 5-(1-Butyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide;

[0293] <124> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-phenyl-1H-pyrazol-4-yl)benzenesulfonamide.

[0294] The compound of the above chemical formula 1 of the present invention can be provided in the form of a pharmaceutically acceptable salt, and “pharmaceutically acceptable salt” means a salt formed by ionic bonding when the compound contains a carboxylic acid or amine functional group, which is pharmaceutically acceptable.

[0295] The compound of the above chemical formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is preferably useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Includes phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0296] The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.

[0297] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. Among the metal salts, sodium, potassium, or calcium salts are pharmaceutically suitable. Furthermore, the corresponding salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable anion salt (e.g., silver nitrate).

[0298]

[0299] The use of the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof is described.

[0300] In one aspect, the present invention provides that the compound of formula 1 or a pharmaceutically acceptable salt thereof inhibits TNAP.

[0301] In another aspect of the present invention, the compound of formula 1 or a pharmaceutically acceptable salt thereof can improve or treat a disease associated with overexpression or overactivation of TNAP by inhibiting TNAP.

[0302] In another aspect of the present invention, the compound of formula 1 or a pharmaceutically acceptable salt thereof can improve or treat a disease associated with ectopic calcification by inhibiting TNAP.

[0303] A specific example of the present invention relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease associated with TNAP overexpression or overactivation.

[0304] Another specific example of the present invention relates to a pharmaceutical composition for preventing or treating a disease associated with TNAP overexpression or overactivation, comprising the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient or active component.

[0305] Another specific embodiment of the present invention relates to a pharmaceutical composition for use in the prevention or treatment of a disease associated with TNAP overexpression or overactivation, comprising the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an effective ingredient or active component.

[0306] Another specific example of the present invention relates to a method for treating a disease associated with TNAP overexpression or overactivation by administering a pharmaceutically effective amount of a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0307] Another specific embodiment of the present invention relates to the use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease associated with TNAP overexpression or overactivation.

[0308] In the present invention, diseases associated with TNAP overexpression or hyperactivation include diseases involving ectopic calcification. Diseases associated with TNAP overexpression or hyperactivation include, but are not limited to, the following diseases.

[0309] Pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), craniometaphyseal dysplasia (CMD), ossification of the yellow ligament (OYL), arterial calcification, calcification of joints, arthrosis deformans, osteoarthritis, ankylosis of the joint, idiopathic infantile arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC), progressive osseous heteroplasia (POH), Keutel syndrome, vascular calcification associated with chronic renal failure (vascular calcification associated with chronic renal failure) (chronic renal failure includes glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic calcification, calciphylaxis, calcific tendinitis of the longus colli muscle, fibrodysplasia ossificans progressive;FOP), calcific aortic stenosis, pericarditis calculosa, atherosclerotic vascular calcification, calcific uremic arteriopathy (CUA), Kawasaki disease, calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget's disease, idiopathic basal ganglia calcification (IBGC), heterotopic ossification (HO), calcific aortic valve disease (CAVD), aortic valve stenosis (AVS), Calcific tendinitis, ossification of the posterior longitudinal ligament (OPLL), ossification of the anterior longitudinal ligament (OALL), diffuse idiopathic skeletal hyperostosis (DISH), meniscal calcification, and peritoneal calcification.;

[0310]

[0311] The above pharmaceutical composition may be formulated further including a pharmaceutically acceptable additive.

[0312] The compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof can be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, fragrances, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0313]

[0314] A pharmaceutical composition containing the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0315] At this time, in order to formulate a dosage form for parenteral administration, the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and / or contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for osmotic pressure control and / or buffers, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation or coating methods.

[0316] Oral dosage forms include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, and troches, which contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine), lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and, if desired, disintegrating agents or effervescent mixtures such as starch, agar, alginic acid or its sodium salt, and / or absorbents, coloring agents, flavoring agents, and sweetening agents.

[0317] In the present invention, the term “pharmaceutically effective amount” means containing in a dosage range that brings about a preventive, improving, or therapeutic effect, and the dosage range may vary depending on the severity and formulation, and the number of applications may also vary depending on the age, weight, and constitution of the subject. In one specific embodiment of the present invention, the compound of formula 1 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention is contained in an amount of, for example, 0.001 mg / kg or more, preferably 0.1 mg / kg or more, 1 mg / kg or more, 10 mg / kg or more, 100 mg / kg or more, or 250 mg / kg or more, and may be contained within an amount that does not cause fatal toxicity. For example, it may be selected from the range of 10 g / kg or less, or 1 g / kg or less. The quantitative upper limit of the compound of formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention can be selected and implemented within an appropriate range by those skilled in the art.

[0318] In the present invention, the term “prevention” means preventing the occurrence of symptoms of a disease related to TNAP overexpression or overactivation in advance by administering, ingesting, or applying the pharmaceutical composition of the present invention to a subject not suffering from a disease related to TNAP overexpression or overactivation, thereby suppressing or blocking symptoms of a disease related to TNAP overexpression or overactivation.

[0319] In the present invention, the term “treatment” includes complete cure of symptoms of a disease associated with TNAP overexpression or overactivation as well as partial cure, improvement and alleviation of symptoms of a disease associated with TNAP overexpression or overactivation as a result of administering the pharmaceutical composition of the present invention to a subject suffering from kidney disease.

[0320]

[0321] The compound of chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be prepared according to the following reaction scheme.

[0322] [Reaction Formula 1]

[0323]

[0324] In the above reaction scheme 1, R 1 Inland R 7 and n are defined in Chemical Formula 1 of this specification. Y may be a halogen, specifically Cl.

[0325] The above reaction can be carried out in the presence of a base, preferably an amine base, and the base preferably includes a tertiary amine such as triethylamine or pyridine. The reaction temperature is not particularly limited, but may be carried out, for example, at 5 to 40°C or at room temperature. However, when the reactants are first mixed, the temperature may be raised after mixing at a low temperature, for example, 0°C or lower, or at -30 to 0°C. The above reaction can be carried out in an organic solvent, for example, dichloromethane, THF, diethyl ether, or chloroform.

[0326] Hereinafter, specific examples of compounds according to the present invention and their preparation are presented. The following examples are provided solely for the purpose of understanding the invention and should not be construed as limiting the invention.

[0327]

[0328] <Intermediate Manufacturing Example>

[0329] The synthesis method of the intermediate used in the present invention is as follows.

[0330] Intermediate 1. Preparation of 3-amino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0331]

[0332] Step 1. Preparation of ethyl 5-bromo-2-(bromomethyl)nicotinate

[0333] 5-Bromo-2-methylnicotinate (9.70 g, 39.75 mmol, 1.0 eq) was dissolved in 100 mL of carbon tetrachloride, and N-bromo succinimide (7.07 g, 39.75 mmol, 1.0 eq) and azobisisobutyronitrile (1.95 g, 11.92 mmol, 0.3 eq) were slowly added while stirring at room temperature. The reaction temperature was increased to 90 °C and stirred for 16 hours. The progress of the reaction was monitored using TLC. After the reaction was completed, the temperature was cooled to room temperature. The mixture at room temperature was filtered and washed with ethyl acetate and petroleum ether. The filtrate was extracted with water and ethyl acetate (3 x 30 ml). The organic layer was washed with brine, treated with sodium hydroxide, and the filtrate was concentrated. The concentrated mixture was purified using silica gel column chromatography under the conditions of ethyl acetate / pet ether 5% developing solvent to obtain the title compound (11.10 g, yield: mixture) as a red solid.

[0334] LCMS (m / z): 322.06 (M+H).

[0335] Step 2.3 Preparation of Bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0336] In a sealed reaction vessel, 110 mL of ammonia isopropyl alcohol solution (2 M in IPA) was placed, and 5-bromo-2-(bromomethyl)nicotinate (5.60 g, 17.44 mmol, 1.0 eq) was added at 0 degrees, the mixture was warmed to room temperature, and stirred for 16 hours. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was filtered and washed with 80% ethyl acetate / pet ether. The washed solid was dried to obtain the title compound (2.70 g, yield: 64% (result of the second reaction step)).

[0337] 1H-NMR (400MHz, DMSO-d6): δ4.41 (s,2H), 8.30 (d,J= 2.20 Hz, 1H), 8.89 (d,J= 2.20 Hz, 1H), 8.94 (brs, 1H).

[0338] LCMS (m / z): 215.06 (M+H).

[0339] Step 3. Preparation of 3-amino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0340] 3-Bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (3.80 g, 17.92 mmol, 1.0 eq) was dissolved in 45 mL of deoxygenated dimethyl sulfoxide solution. 25% aqueous ammonia solution (6.09 mL, 89.62 mmol, 5.0 eq), copper(I) iodide (1.36 g, 7.17 mmol, 0.4 eq), potassium carbonate (12.36 g, 89.62 mmol, 5.0 eq), and L-proline (1.64 g, 14.34 mmol, 0.8 eq) were added to the mixture at room temperature. The mixture was stirred at 120°C for 16 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the temperature was lowered to room temperature. The room temperature mixture was filtered through a Celite pad and washed with a 10% methanol / dichloromethane solution. The filtrate was concentrated under reduced pressure. The concentrated mixture was purified using silica gel column chromatography using 2% methanol / ethyl acetate as a developing solvent to obtain the title compound (1.50 g, yield: 56%) as a yellow solid.

[0341] 1 H-NMR (400MHz, DMSO-d6) δ 4.20 (s, 2H), 5.53 (s, 2H), 7.12 (d,J= 2.75 Hz, 1H), 8.10 (d,J= 2.50 Hz, 1H), 8.52 (brs, 1H).

[0342] LCMS (m / z): 150.15 (M+H).

[0343]

[0344] Intermediate 2. Preparation of 3-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0345]

[0346] Step 1. Preparation of 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0347] tert-Butyl 4-oxopiperidine-1-carboxylate (0.70 g, 3.51 mmol, 1.0 eq) and 1-methyl-3,5-dinitropyridin-2(1H)-one (0.70 g, 3.51 mmol, 1.0 eq) were added to 10 mL of ammonia solution (2 M in MeOH) at room temperature. The mixture was stirred in a microwave reactor at 120 °C for 30 min. The progress of the reaction was monitored using TLC. After the reaction was completed, the temperature was cooled to room temperature. The mixture was concentrated under reduced pressure. The concentrated mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium hydroxide, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography using 28% ethyl acetate / pet ether as a developing solvent to obtain the title compound as a solid (0.8 g, yield: 82%).

[0348] 1 H-NMR (400 MHz, CDCl3) δ 1.51 (s, 9H), 3.12 (t,J= 5.88 Hz, 2H), 3.80 (t,J= 6.00 Hz, 2H), 4.72 (s, 2H), 8.23 ​​(d,J= 2.40 Hz, 1H), 9.25 (d,J= 2.25 Hz, 1H).

[0349] LCMS (m / z): 280.20 (M+H).

[0350] Step 2. Preparation of tert-butyl 3-nitro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0351] To a solution of tert-butyl 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (6.50 g, 23.29 mmol, 1.0 eq) mixed with 95 mL of carbon tetrachloride and 12 mL of acetonitrile, 40 mL of aqueous sodium periodate (14.88 g, 69.89 mmol, 3.0 eq) and 20 mL of aqueous ruthenium chloride (1.44 g, 6.98 mmol, 0.3 eq) were added while stirring at room temperature. The mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was filtered through a pad of Celite. The filtered solution was extracted with water and dichloromethane. The organic layer was washed with brine, treated with sodium hydroxide, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography using 25% ethyl acetate / pet ether as a developing solvent to obtain the title compound as a solid (3.60 g, yield: 53%).

[0352] 1 H-NMR (400 MHz, CDCl3) δ 1.60 (s, 9H), 3.35 (t,J= 6.48 Hz, 2H), 4.14 (t,J= 6.36 Hz, 2H), 9.17 (d,J= 2.69 Hz, 1H), 9.47 (d,J= 2.45 Hz, 1H).

[0353] LCMS (m / z): 294.25 (M+H).

[0354] Step 3. Preparation of 3-amino-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0355] To a solution of tert-butyl 3-nitro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (3.60 g, 12.28 mmol, 1.0 eq) in 100 mL of ethanol and 30 mL of water was added ammonium chloride (3.25 g, 61.43 mmol, 5.0 eq) and iron (2.75 g, 49.14 mmol, 4.0 eq) at room temperature while stirring. The mixture was stirred at 80°C for 3 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the temperature was lowered to room temperature, the mixture was filtered through a Celite pad, and concentrated under reduced pressure. The concentrated mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium hydroxide, and the filtrate was concentrated. The concentrated mixture was purified using silica gel column chromatography under the condition of 80% ethyl acetate / pet ether developing solvent to obtain the title compound (1.70 g, yield: 53%).

[0356] LCMS (m / z): 264.22 (M+H).

[0357] Step 4.3 Preparation of amino-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0358] To a solution of tert-butyl 3-amino-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.70 g, 6.46 mmol, 1.0 eq) in 20 mL of dichloromethane, trifluoroacetic acid (4.97 ml, 64.63 mmol, 10.0 eq) was slowly added at 0°C while stirring. The mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was concentrated and basified using 2 M ammonia solution (2 M in MeOH). The basified mixture was concentrated under reduced pressure. The concentrated mixture was purified using silica gel column chromatography under the condition of 95% ethyl acetate / pet ether developing solvent to obtain the title compound as a solid (1.04 g, yield: 99%).

[0359] 1 H-NMR (400 MHz, DMSO-d6) δ 2.82 (t,J= 6.75 Hz, 2H), 3.36 (td,J= 6.75, 2.75 Hz, 2H), 5.36 (s, 2H), 7.34 (d,J= 2.75 Hz, 1H), 7.90 (brs, 1H), 7.95 (d,J= 2.75 Hz, 1H).

[0360] LCMS (m / z): 164.08 (M+H).

[0361]

[0362] Intermediate 3. Preparation of 3-amino-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one

[0363]

[0364] Step 1.3 - Preparation of aminocyclohex-2-en-1-one hydrobromide

[0365] To a solution of 3-aminocyclohex-2-en-1-one (25.0 g, 225.22 mmol, 1.0 eq.) dissolved in 500 mL of ethanol was added 47% Aq. HBr solution (38.77 mL, 225.22 mmol, 1.0 eq.) at room temperature, and the reaction mixture was stirred at the same temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was evaporated under reduced pressure to obtain a residue. The residue was co-distilled with toluene to obtain 3-aminocyclohex-2-en-1-one hydrobromide (40.0 g).

[0366] Step 2.3 - Preparation of bromo-7,8-dihydroquinolin-5(6H)-one

[0367] To a stirred solution of 3-aminocyclohex-2-en-1-one hydrobromide (40.0 g, 208.33 mmol, 1.0 eq.) dissolved in 600 ml of ethanol was added 2-bromomalonaldehyde (34.60 g, 229.16 mmol, 1.1 eq.) at room temperature. The reaction mixture was heated to 80°C and stirred at the same temperature for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature and evaporated under reduced pressure to obtain a residue. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to obtain a mixture. The mixture was purified by silica gel column chromatography and eluted with 30% ethyl acetate / pet ether to obtain 3-bromo-7,8-dihydroquinolin-5(6H)-one (28.0 g).

[0368] LC-MS(M+H): 225.99.

[0369] Step 3. Preparation of (E)-3-bromo-7,8-dihydroquinoline-5(6H)-one oxime

[0370] To a stirred solution of 3-bromo-7,8-dihydroquinolin-5(6H)-one (26.0 g, 115.55 mmol, 1.0 eq.) in a mixture of methanol and water (325.0 mL, 4:1), hydroxylamine hydrochloride (24.26 g, 346.66 mmol, 3.0 eq.) and sodium acetate (28.42 g, 346.66 mmol, 3.0 eq.) were added at room temperature. The reaction mixture was heated to 85°C and stirred at the same temperature for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature and evaporated under reduced pressure to obtain a residue. The residue was diluted with water to precipitate a solid. The precipitated solid was filtered, washed with n-pentane, and dried under vacuum to obtain (E)-3-bromo-7,8-dihydroquinoline-5(6H)-one oxime (16.0 g).

[0371] 1 H-NMR (500 MHz, DMSO-d6) δ 1.80-1.86 (m, 2H), 2.63-2.68 (m, 2H), 2.81-2.84 (m, 2H), 8.20-8.24 (m, 1H), 8.55-8.61 (m, 1H), 11.57(s, 1H).

[0372] LC-MS(M+H): 241.17.

[0373] Step 4.3 Preparation of Bromo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one

[0374] (E)-3-Bromo-7,8-dihydroquinoline-5(6H)-one oxime (16.0 g, 66.66 mmol, 1.0 eq.) was dissolved in phosphate chloride (128 mL). To a stirred solution, phosphorus pentoxide (13.43 g, 93.33 mmol, 1.4 eq.) and N,N-dimethylformamide (2.60 mL, 33.33 mmol, 0.5 eq.) were added at 0°C. The reaction mixture was heated to 100°C and stirred at the same temperature for 3 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature and evaporated under reduced pressure to obtain a residue. The residue was basified with 3N NaOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to obtain a mixture. The mixture was purified by silica gel column chromatography and eluted with 80% ethyl acetate / pet ether to obtain 3-bromo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one (2.20 g).

[0375] 1 H NMR (400MHz, DMSO-d6) δ 1.96-2.00 (m, 2H), 2.88-2.91 (m, 2H), 2.96-3.02 (m, 2H), 8.03 (d, J = 2.45Hz, 1H), 8.37 (brs, 1H), 8.70 (d, J = 2.20Hz, 1H).

[0376] LC-MS((M+2) +H, isotopic mass): 242.92.

[0377] Step 5.3 Preparation of amino-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one

[0378] To a stirred solution of 3-bromo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one (2.20 g, 9.16 mmol, 1.0 eq.) in dimethyl sulfoxide (33.0 mL) were added L-proline (0.843 g, 7.33 mmol, 0.8 eq.), copper(I) iodide (0.696 g, 3.66 mmol, 0.4 eq.), and potassium carbonate (6.32 g, 45.83 mmol, 5.0 eq.), followed by addition of 25% aqueous ammonia solution (3.11 mL, 45.83 mmol, 5.0 eq.) in a sealed tube at room temperature. The reaction mixture was heated to 120°C and stirred at that temperature for 16 h. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to obtain a residue. The residue was diluted with 10% methanol in dichloromethane, filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure to obtain a mixture. The mixture was purified by -NH silica gel column chromatography, eluted with 2% methanol / dichloromethane, and recrystallized from acetonitrile to obtain 3-amino-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-5-one (0.34 g, 21%).

[0379] 1 H-NMR (400 MHz, DMSO-d6) δ 1.87 (quin, J = 6.82 Hz, 2H), 2.73 (t, J = 7.25 Hz, 2H), 2.93 (q, J = 6.42 Hz, 2H), 5.31 (s, 2H), 7.05 (d, J = 2.75 Hz, 1H), 7.89(d, J = 2.75Hz, 1H), 8.02(t, J = 5.50Hz, 1H).

[0380] LC-MS(M+H): 178.12.

[0381]

[0382] Intermediate 4. Preparation of neopentyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0383]

[0384] Step 1. Preparation of neopentyl-3-nitro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0385] To a solution of 3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (192 mg, 1.074 mmol, 1.0 eq) and triethylamine (0.6 mL, 4.296 mmol, 4 eq) in 6 mL of dichloromethane was slowly added neopentyl carbonochloroformate (0.24 mL, 1.611 mmol, 1.5 eq) at 0 degrees with stirring. The mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored using TLC. The mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography using ethyl acetate / hexane as a developing solvent to obtain the title compound (0.304 g, yield: 96%) as a solid.

[0386] LCMS (m / z): 294.1 (M+H).

[0387] Step 2. Preparation of neopentyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0388] To a solution of neopentyl-3-nitro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate (304 mg, 1.038 mmol, 1.0 eq) and tetrahydroxydiboron (279 mg, 3.113 mmol, 3.0 eq) in 2 mL of dimethylformamide was slowly added 4,4'-bipyridine (32 mg, 0.208 mmol, 0.2 eq) at 0 degrees while stirring. After stirring for an additional 30 minutes, the mixture was warmed to room temperature and stirred for more than 1 hour. The progress of the reaction was monitored using TLC. The mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified using silica gel column chromatography under methanol / dichloromethane as a developing solvent to obtain the title compound (158 mg, yield: 58%) as a solid.

[0389] LCMS (m / z): 264.1 (M+H).

[0390]

[0391] Intermediate 5. Preparation of 2-fluoroethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0392]

[0393] Step 1.2 Preparation of fluoroethyl-3-nitro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0394] To a solution of 3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (192 mg, 1.074 mmol, 1.0 eq) and triethylamine (0.6 mL, 4.296 mmol, 4 eq) in 6 mL of dichloromethane was slowly added 2-fluoroethyl carbonochloroformate (0.15 mL, 1.611 mmol, 1.5 eq) at 0°C while stirring. The mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored using TLC. The mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified using silica gel column chromatography under ethyl acetate / hexane developing solvent conditions to obtain the title compound (0.280 g, yield: 97%) as a solid.

[0395] LCMS (m / z): 270.2 (M+H).

[0396] Step 2.2 Preparation of fluoroethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0397] 2-Fluoroethyl-3-nitro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate was reacted according to the method for preparing step 2 of intermediate 4 to obtain the title compound as a solid (179 mg, yield: 72%).

[0398] LCMS (m / z): 240.2 (M+H).

[0399]

[0400] Intermediate 6. Preparation of 3-amino-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0401]

[0402] Step 1.3 Preparation of Nitro-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0403] The title compound (181 mg, yield: 86%) was obtained by reacting according to the manufacturing method of step 1 of Example 104 using 1-pentylamine as the amine substituent.

[0404] LCMS (m / z): 293.1 (M+H).

[0405] Step 2.3 Preparation of amino-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0406] The title compound (153 mg, yield: 94%) was obtained from 3-nitro-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide using the precursor 4-2 step preparation method.

[0407] LCMS (m / z): 263.1 (M+H).

[0408]

[0409] Intermediate 7. Preparation of 3-amino-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0410]

[0411] Step 1. Preparation of N-(2,2-difluoroethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0412] The title compound (69 mg, yield: 21%) was obtained by reacting according to the manufacturing method of step 1 of Example 104 using 2,2-difluoroethane-1-amine hydrochloride as the amine substituent.

[0413] LCMS (m / z): 287.1 (M+H).

[0414] Step 2.3 Preparation of amino-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0415] The title compound (59 mg, yield: 96%) was obtained from N-(2,2-difluoroethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide by the method of step 2 of intermediate 4.

[0416] LCMS (m / z): 257.1 (M+H).

[0417]

[0418] Intermediate 8. Preparation of (3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(morpholino)methanone

[0419]

[0420] Step 1. Preparation of N-morpholino(3-nitro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

[0421] The title compound (72 mg, yield: 44%) was obtained by reacting according to the manufacturing method of step 1 of Example 104 using morpholine as the amine substituent.

[0422] LCMS (m / z): 293.1 (M+H).

[0423] Step 2. Preparation of (3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(morpholino)methanone

[0424] N-morpholino(3-nitro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone was reacted according to the preparation method of step 2 of intermediate 4 to obtain the title compound (63 mg, yield: 97%).

[0425] LCMS (m / z): 263.1 (M+H).

[0426]

[0427] <Example: Preparation of TNAP inhibitor compound>

[0428] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to the following examples.

[0429]

[0430] Example 1. Preparation of 5-chloro-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide

[0431]

[0432] To a solution of 5-chloro-2-methoxybenzenesulfonyl chloride (30 mg, 0.124 mmol, 1.0 eq) and intermediate 1 (3-amino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one) (20.42 mg, 0.137 mmol, 1.1 eq) in 20 mL of dichloromethane was added triethylamine (0.03 mL, 0.249 mmol, 2.0 eq) at 0 degrees. The mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was concentrated. The concentrated mixture was purified by silica gel column chromatography using methanol / dichloromethane as a developing solvent to obtain the title compound (22 mg, yield: 50%) as a solid.

[0433] 1 H-NMR (400 MHz, DMSO-d6) δ10.67 (s, 1H), 8.80 (s, 1H), 8.44 (d,J= 2.8 Hz, 1H), 7.69 (dd,J= 2.9, 1.2 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.20 (dd,J= 8.2, 1.7 Hz, 1H), 4.28 (s, 2H), 3.82 (s, 3H).

[0434] LCMS (m / z): 345.1 (M+H).

[0435]

[0436] Example 2. Preparation of 5-bromo-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide

[0437] 5-Bromo-2-methoxybenzenesulfonyl chloride and the compound of intermediate 1 were reacted according to the manufacturing method of Example 1 to obtain the title compound (17 mg, yield: 41%).

[0438] 1 H-NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.80 (s, 1H), 8.47-8.40 (m,1H), 7.82-7.75 (m,1H), 7.74 (dq,J= 8.9, 1.9 Hz, 1H), 7.64 (q,J= 1.9 Hz, 1H), 7.14 (dt,J= 8.9, 1.7 Hz, 1H), 4.28 (s, 2H), 3.81 (s, 3H).

[0439] LCMS (m / z): 398.1 (M+H).

[0440]

[0441] Example 3. Preparation of 2,5-dimethoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide

[0442] 2,5-Dimethoxybenzenesulfonyl chloride and the compound of intermediate 1 were reacted according to the manufacturing method of Example 1 to obtain the title compound (20 mg, yield: 45%).

[0443] 1 H-NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.77 (s, 1H), 8.44 (t,J= 2.2 Hz, 1H), 7.65 (t,J= 2.1 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.17 - 7.05 (m, 2H), 4.27 (s, 2H), 3.75 (s, 3H), 3.68 (s, 3H).

[0444] LCMS (m / z): 350.2 (M+H).

[0445]

[0446] Example 4. Preparation of 5-fluoro-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide

[0447] 5-Fluoro-2-methoxybenzenesulfonyl chloride and the compound of intermediate 1 were reacted according to the preparation method of Example 1 to obtain the title compound (24 mg, yield: 32%).

[0448] 1 H-NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.80 (s, 1H), 8.48-8.39 (m, 1H), 7.70-7.61 (m, 1H), 7.59-7.51 (m, 1H), 7.51-7.40 (m, 1H), 7.24-7.15 (m, 1H), 4.27 (s, 2H), 3.80 (s, 3H).

[0449] LCMS (m / z): 338.1 (M+H).

[0450]

[0451] Example 5. Preparation of 5-bromo-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0452] 5-Bromo-2,3-dihydrobenzofuran-7-sulfonyl chloride and the compound of intermediate 1 were reacted according to the manufacturing method of Example 1 to obtain the title compound (32 mg, yield: 46%).

[0453] 1 H-NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.79 (s, 1H), 8.46-8.42 (m, 1H), 7.67-7.61 (m, 2H), 7.52-7.48 (m, 1H), 4.61 (td,J= 8.9, 3.4 Hz, 2H), 4.29 (d,J= 3.4 Hz, 2H), 3.23-3.15 (m, 2H).

[0454] LCMS (m / z): 409.9 (M+H).

[0455]

[0456] Example 6. Preparation of 5-chloro-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0457] 5-Chloro-2-methoxybenzenesulfonyl chloride and the compound of intermediate 2 (3-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-one) were reacted according to the preparation method of Example 1 to obtain the title compound (28 mg, yield: 37%).

[0458] 1 H-NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.35-8.27 (m, 1H), 8.12-8.06 (m, 1H), 7.89-7.81 (m, 1H), 7.71-7.58 (m, 2H), 7.26-7.17 (m, 1H), 3.82 (s, 3H), 3.41-3.26 (m, 2H), 2.95-2.84 (m, 2H).

[0459] LCMS (m / z): 368.1 (M+H).

[0460]

[0461] Example 7. Preparation of 2,5-dimethoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0462] 2,5-Dimethoxybenzenesulfonyl chloride and the compound of intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain the title compound (24 mg, yield: 31%).

[0463] 1 H-NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.34-8.27 (m, 1H), 8.07 (s, 1H), 7.89-7.83 (m, 1H), 7.26-7.19 (m, 1H), 7.18-7.05 (m, 2H), 3.76 (s, 3H), 3.69 (s, 3H), 3.37-3.31 (m, 2H), 2.92-2.83 (m, 2H).

[0464] LCMS (m / z): 364.2 (M+H).

[0465]

[0466] Example 8. Preparation of 5-fluoro-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0467] The compound of intermediate 2 was reacted with 5-fluoro-2-methoxybenzenesulfonyl chloride according to the manufacturing method of Example 1 to obtain the title compound (25 mg, yield: 32%).

[0468] 1 H-NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.30 (d,J= 2.7 Hz, 1H), 8.07 (s, 1H), 7.85 (d,J= 2.7 Hz, 1H), 7.54 - 7.40 (m, 2H), 7.19 (dd,J= 9.2, 4.0 Hz, 1H), 3.80 (s, 3H), 3.34 (q,J= 5.8, 5.3 Hz, 2H), 2.88 (t,J= 6.7 Hz, 2H).

[0469] LCMS (m / z): 352.2 (M+H).

[0470]

[0471] Example 9. Preparation of 5-bromo-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0472] 5-Bromo-2-methoxybenzenesulfonyl chloride and the compound of intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain the title compound (42 mg, yield: 36%).

[0473] 1H-NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.30 (d,J= 2.6 Hz, 1H), 8.07 (s, 1H), 7.85 (d,J= 2.7 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.15 (d,J= 8.8 Hz, 1H), 3.81 (s, 3H), 3.35 (td,J= 6.7, 2.8 Hz, 2H), 2.89 (t,J= 6.7 Hz, 2H).

[0474] LCMS (m / z): 412.1 (M+H).

[0475]

[0476] Example 10. Preparation of 5-bromo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0477] The compound of intermediate 2 was reacted with 5-bromo-2,3-dihydrobenzofuran-7-sulfonyl chloride according to the manufacturing method of Example 1 to obtain the title compound (29 mg, yield: 41%).

[0478] 1 H-NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.34-8.25 (m, 1H), 8.12-8.04 (m, 1H), 7.88-7.78 (m, 1H), 7.67-7.58 (m, 1H), 7.52-7.43 (m, 1H), 4.68-4.57 (m, 2H), 3.41-3.31 (m, 2H), 3.23-3.07 (m, 2H), 2.94-2.85 (m, 2H).

[0479] LCMS (m / z): 425.0 (M+H).

[0480]

[0481] Example 11. Preparation of 2-bromo-5-fluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide

[0482] The compound of 2-bromo-5-fluorobenzenesulfonyl chloride and intermediate 1 were reacted according to the manufacturing method of Example 1 to obtain the title compound (110 mg, yield: 80%).

[0483] 1 H-NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.80 (s, 1H), 8.48 (dt, J = 4.4, 2.2 Hz, 1H), 8.00 - 7.79 (m, 2H), 7.63 (dt, J = 4.4, 2.2 Hz, 1H), 7.50 - 7.41 (m, 1H), 4.29 (s, 2H).

[0484] LCMS (m / z): 387.2 (M+H).

[0485]

[0486] Example 12. Preparation of 2-bromo-4,6-difluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide

[0487] The compound of 2-bromo-4,6-difluorobenzenesulfonyl chloride and intermediate 1 were reacted according to the manufacturing method of Example 1 to obtain the title compound (55 mg, yield: 49%).

[0488] 1 H-NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.80 (s, 1H), 8.53 - 8.43 (m, 1H), 7.78 - 7.64 (m, 2H), 7.64 - 7.50 (m, 1H), 4.30 (s, 2H).

[0489] LCMS (m / z): 405.1 (M+H).

[0490]

[0491] Example 13. Preparation of 5-chloro-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide

[0492] The compound of 5-chloro-2-methoxybenzenesulfonyl chloride and intermediate 3 were reacted according to the manufacturing method of Example 1 to obtain the title compound (23 mg, yield: 29%).

[0493] 1 H-NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.34 - 8.08 (m, 2H), 7.74 - 7.45 (m, 3H), 7.31 - 7.09 (m, 1H), 3.80 (s, 3H), 2.92 - 2.64 (m, 4H), 1.96 - 1.75 (m, 2H).

[0494] LCMS (m / z): 382 (M+H).

[0495]

[0496] Example 14. Preparation of 5-bromo-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide

[0497] The compound of 5-bromo-2-methoxybenzenesulfonyl chloride and intermediate 3 were reacted according to the manufacturing method of Example 1 to obtain the title compound (25 mg, yield: 33%).

[0498] 1 H-NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.33 - 8.08 (m, 2H), 7.83 - 7.65 (m, 2H), 7.62 - 7.47 (m, 1H), 7.19 - 6.99 (m, 1H), 3.79 (s, 3H), 2.92 - 2.64 (m, 4H), 1.98 - 1.75 (m, 2H).

[0499] LCMS (m / z): 427 (M+H).

[0500]

[0501] Example 15. Preparation of 5-fluoro-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide

[0502] The compound of intermediate 3 was reacted with 5-fluoro-2-methoxybenzenesulfonyl chloride according to the manufacturing method of Example 1 to obtain the title compound (21 mg, yield: 25%).

[0503] 1 H-NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.32 - 8.10 (m, 2H), 7.61 - 7.38 (m, 3H), 7.26 - 7.13 (m, 1H), 3.80 (s, 3H), 2.92 - 2.68 (m, 4H), 1.99 - 1.75 (m, 2H).

[0504] LCMS (m / z): 366 (M+H).

[0505]

[0506] Example 16. Preparation of 2,5-dimethoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide

[0507] 2,5-Dimethoxybenzenesulfonyl chloride and the compound of intermediate 3 were reacted according to the manufacturing method of Example 1 to obtain the title compound (15 mg, yield: 19%).

[0508] 1 H-NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.30 - 8.13 (m, 2H), 7.56 (t, J = 2.1 Hz, 1H), 7.22 (dd, J = 3.1, 1.5 Hz, 1H), 7.19 - 7.06 (m, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 2.91 - 2.69 (m, 4H), 1.94 - 1.76 (m, 2H).

[0509] LCMS (m / z): 378 (M+H).

[0510]

[0511] Example 17. Preparation of 5-bromo-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0512] The compound of intermediate 3 was reacted with 5-bromo-2,3-dihydrobenzofuran-7-sulfonyl chloride according to the manufacturing method of Example 1 to obtain the title compound (18 mg, yield: 24%).

[0513] 1 H-NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.35 - 8.15 (m, 2H), 7.63 (s, 1H), 7.54 (d, J = 3.1 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 4.61 (t, J = 8.7 Hz, 2H), 3.19 (t, J = 8.7 Hz, 2H), 2.82 (dt, J = 30.9, 6.8 Hz, 4H), 1.95 - 1.81 (m, 2H).

[0514] LCMS (m / z): 439 (M+H).

[0515]

[0516] Example 18. Preparation of N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0517] 2,3-Dihydrobenzofuran-7-sulfonyl chloride and the compound of intermediate 1 were reacted according to the manufacturing method of Example 1 to obtain the title compound (13 mg, yield: 20%).

[0518] 1H-NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.77 (s, 1H), 8.44 - 8.37 (m, 1H), 7.65 - 7.56 (m, 2H), 7.48 (d, J = 8.2 Hz, 1H), 6.83 (dt, J = 8.5, 1.7 Hz, 1H), 4.62 - 4.52 (m, 2H), 4.28 (s, 2H), 3.19 - 3.13 (m, 2H).

[0519] LCMS (m / z): 332 (M+H).

[0520]

[0521] Example 19. Preparation of N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0522] The compound of 2,3-dihydrobenzofuran-7-sulfonyl chloride and intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain the title compound (9 mg, yield: 14%).

[0523] 1 H-NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.35 - 8.21 (m, 1H), 8.10 (s, 1H), 7.81 (dt, J = 4.6, 2.6 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.47 (t, J = 6.1 Hz, 1H), 6.90 - 6.75 (m, 1H), 4.65 - 4.49 (m, 2H), 3.34 (d, J = 8.2 Hz, 2H), 3.16 (d, J = 20.1 Hz, 2H), 2.95 - 2.82 (m, 2H).

[0524] LCMS (m / z): 346 (M+H).

[0525]

[0526] Example 20. Preparation of 5-chloro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0527] The title compound (17 mg, yield: 23%) was obtained from 5-chloro-2,3-dihydrobenzofuran-7-sulfonyl chloride and the compound of intermediate 1 according to the manufacturing method of Example 1.

[0528] 1 H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.79 (s, 1H), 8.52 - 8.37 (m, 1H), 7.73 - 7.59 (m, 1H), 7.53 (dd, J = 4.9, 2.4 Hz, 1H), 7.39 (q, J = 2.7 Hz, 1H), 4.70 - 4.52 (m, 2H), 4.29 (q, J = 3.5, 2.8 Hz, 2H), 3.19 (d, J = 8.5 Hz, 2H).

[0529] LCMS (m / z): 366 (M+H).

[0530]

[0531] Example 21. Preparation of 5-fluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0532] The compound of intermediate 1 was reacted with 5-fluoro-2,3-dihydrobenzofuran-7-sulfonyl chloride according to the manufacturing method of Example 1 to obtain the title compound (11 mg, yield: 16%).

[0533] 1 H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.78 (s, 1H), 8.44 (dt, J = 7.0, 3.3 Hz, 1H), 7.65 (dt, J = 6.7, 3.3 Hz, 1H), 7.47 - 7.30 (m, 1H), 7.28 - 7.12 (m, 1H), 4.70 - 4.48 (m, 2H), 4.29 (q, J = 3.8 Hz, 2H), 3.23-3.10 (m, 2H).

[0534] LCMS (m / z): 350 (M+H).

[0535]

[0536] Example 22. Preparation of 5-chloro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0537] The compound of intermediate 2 was reacted with 5-chloro-2,3-dihydrobenzofuran-7-sulfonyl chloride according to the manufacturing method of Example 1 to obtain the title compound (13 mg, yield: 18%).

[0538] 1 H-NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.35 - 8.25 (m, 1H), 8.16 - 8.02 (m, 1H), 7.88 - 7.79 (m, 1H), 7.52 (q, J = 3.7, 2.7 Hz, 1H), 7.37 (q, J = 2.9 Hz, 1H), 4.70 - 4.54 (m, 2H), 3.41 - 3.32 (m, 2H), 3.18 (t, J = 8.5 Hz, 2H), 2.89 (tt, J = 6.3, 2.8 Hz, 2H).

[0539] LCMS (m / z): 380 (M+H).

[0540]

[0541] Example 23. Preparation of 5-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0542] The title compound (9 mg, yield: 14%) was obtained by mixing 5-fluoro-2,3-dihydrobenzofuran-7-sulfonyl chloride with intermediate 2 according to the manufacturing method of Example 1.

[0543] 1H-NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.36 - 8.26 (m, 1H), 8.17 - 8.02 (m, 1H), 7.89 - 7.78 (m, 1H), 7.38 (dt, J = 7.9, 3.0 Hz, 1H), 7.22 - 7.10 (m, 1H), 4.70 - 4.54 (m, 2H), 3.41 - 3.31 (m, 2H), 3.18 (t, J = 8.6 Hz, 2H), 2.89 (td, J = 6.7, 2.8 Hz, 2H).

[0544] LCMS (m / z): 364 (M+H).

[0545]

[0546] Example 24. Preparation of N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide

[0547] 2,3-Dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride and the compound of intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain the title compound (3 mg, yield: 3%).

[0548] 1 H-NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 2.7 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.23 (tt, J = 4.4, 2.3 Hz, 2H), 6.95 - 6.83 (m, 1H), 4.29 - 4.18 (m, 4H), 3.52 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H).

[0549] LCMS (m / z): 362 (M+H).

[0550]

[0551] Example 25. Preparation of 3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide

[0552] The compound of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride and intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain the title compound (15 mg, yield: 13%).

[0553] 1 H-NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.32 - 7.27 (m, 3H), 7.18 - 7.13 (m, 2H), 3.49 - 3.44 (m, 2H), 3.12 - 3.02 (m, 4H).

[0554] LCMS (m / z): 375 (M+H).

[0555]

[0556] Example 26. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0557] 2-Methoxybenzenesulfonyl chloride and the compound of intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain the title compound (10 mg, yield: 41%).

[0558] 1 H-NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.29 (t, J = 4.3 Hz, 1H), 8.05 (s, 1H), 7.88 - 7.79 (m, 1H), 7.76 - 7.67 (m, 1H), 7.60 - 7.46 (m, 1H), 7.18 - 7.07 (m, 1H), 7.05 - 6.91 (m, 1H), 3.81 (s, 3H), 3.32 (t, J = 3.5 Hz, 2H), 2.85 (q, J = 10.2, 8.4 Hz, 3H).

[0559] LCMS (m / z): 364 (M+H).

[0560]

[0561] Example 27. Preparation of methyl 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate

[0562] A mixture of the compound of Example 2 (50 mg, 0.126 mmol), methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (39 mg, 0.138 mmol), K2CO3 (35 mg, 0.251 mmol), and Pd(PPh3)4 (15 mg, 0.013 mmol) was added to dioxane:water (4:1) (30 mL) and heated in a sealed tube at 100°C for 2 h. The solution was diluted with brine (200 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by column chromatography to give methyl 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate (35 mg, 60%) as a white solid.

[0563] 1 H-NMR (400 MHz, Chloroform-d) δ 8.66 (t, J = 2.2 Hz, 1H), 8.23 ​​(s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.71 (dd, J = 8.6, 2.4 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.34 - 7.29 (m, 2H), 7.12 - 7.05 (m, 1H), 6.64 (s, 1H), 4.43 (s, 2H), 4.04 (s, 3H), 3.69 (s, 3H), 3.64 (s, 2H).

[0564] LCMS (m / z): 468 (M+H).

[0565]

[0566] Example 28. Preparation of 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid

[0567] To a solution of the compound of Example 27 (25 mg, 0.053 mmol) dissolved in THF / water (50 mL, 3:1) was added NaOH (11 mg, 0.267 mmol). The reaction mixture was stirred at ambient temperature for 24 h. THF was removed in vacuo, and the resulting solution was acidified with 1 N hydrochloric acid. Additional water was added (50 mL), and the aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid (15 mg, 62%).

[0568] 1 H-NMR (400 MHz, DMSO-d6)δ12.21(s,1H),10.72-10.45(m,1H),8.84-8.71(m,1H),8.53-8.38(m,1H),7.98-7.60(m,3H),7.50(dd,J = 8.2, 3.8 Hz, 1H), 7.34 - 7.11 (m, 2H), 6.83 (q, J = 3.8 Hz, 1H), 6.60 (s, 1H), 4.26 (s, 2H), 3.83 (s, 3H), 3.56 (s, 2H).

[0569] LCMS (m / z): 454 (M+H).

[0570]

[0571] Example 29. Preparation of 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0572] (2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (12 mg, yield: 21%).

[0573] 1 H-NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.32 (dd, J = 7.7, 4.3 Hz, 1H), 8.07 (s, 1H), 7.92 - 7.80 (m, 2H), 7.77 (s, 1H), 7.24 - 7.12 (m, 1H), 7.06 - 6.95 (m, 2H), 6.93 - 6.80 (m, 1H), 4.22 (s, 3H), 3.88 - 3.80 (m, 2H), 3.38-3.20 (m, 2H), 2.91 - 2.81 (m, 2H), 1.75 - 1.62 (m, 2H).

[0574] LCMS (m / z): 468 (M+H).

[0575]

[0576] Example 30. Preparation of 4,4'-dimethoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-3-sulfonamide

[0577] (4-methoxyphenyl)boronic acid was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (9 mg, yield: 17%).

[0578] 1H-NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.39 - 8.27 (m, 1H), 8.06 (s, 1H), 7.94 - 7.83 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.04 - 6.90 (m, 3H), 3.85 (s, 3H), 3.75 (s, 3H), 3.37 - 3.31 (m, 2H), 2.91 - 2.80 (m, 2H).

[0579] LCMS (m / z): 440 (M+H).

[0580]

[0581] Example 31. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(pyridin-4-yl)benzenesulfonamide

[0582] The compound of Example 9 was reacted with 4-pyridineboronic acid according to the manufacturing method of Example 27 to obtain the title compound (16 mg, yield: 32%).

[0583] 1 H-NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.58 (d, J = 5.0 Hz, 2H), 8.39 - 8.28 (m, 1H), 8.13 - 8.04 (m, 2H), 8.05 - 7.98 (m, 1H), 7.89 (d, J = 2.7 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H), 3.35 - 3.31 (m, 2H), 2.85 (t, J = 6.7 Hz, 2H).

[0584] LCMS (m / z): 411 (M+H).

[0585]

[0586] Example 32. Preparation of 1-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid

[0587] Methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain methyl 1-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylate (40 mg, yield: 66%).

[0588] Methyl 1-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylate was reacted according to the manufacturing method of Example 28 to obtain the title compound (21 mg, yield: 53%).

[0589] 1 H-NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.32 (d, J = 3.0 Hz, 1H), 8.04 (s, 1H), 7.95 - 7.78 (m, 3H), 7.48 (t, J = 5.2 Hz, 2H), 7.38 - 7.31 (m, 2H), 7.25 (d, J = 8.7 Hz, 1H), 3.86 (d, J = 2.3 Hz, 3H), 3.13 (dd, J = 5.3, 2.1 Hz, 3H), 2.85 (d, J = 7.4 Hz, 2H), 1.42 (s, 2H), 1.12 (d, J = 4.2 Hz, 2H).

[0590] LCMS (m / z): 494 (M+H).

[0591]

[0592] Example 33. Preparation of 2-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid

[0593] Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain methyl 2-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate (10 mg, yield: 63%).

[0594] Methyl 2-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate was reacted according to the manufacturing method of Example 28 to obtain the title compound (5 mg, yield: 8%).

[0595] 1 H-NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.06 - 7.72 (m, 4H), 7.50 (d, J = 7.7 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 3.82 (s, 3H), 3.54 (s, 3H), 2.83 (s, 3H).

[0596] LCMS (m / z): 468 (M+H).

[0597]

[0598] Example 34. Preparation of 4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-carboxylic acid

[0599] Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain methyl 4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-carboxylate (48 mg, yield: 84%).

[0600] Methyl 4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-carboxylate was reacted according to the manufacturing method of Example 28 to obtain the title compound (10 mg, yield: 21%).

[0601] 1 H-NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.10 - 7.85 (m, 5H), 7.67 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.9 Hz, 1H), 4.08 (s, 3H), 3.86 (s, 2H), 2.84 (t, J = 6.7 Hz, 2H).

[0602] LCMS (m / z): 454 (M+H).

[0603]

[0604] Example 35. Preparation of 2-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid

[0605] 2-Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate was reacted with the compound of Example 56 according to the manufacturing method of Example 27 to obtain methyl 2-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate (9 mg, yield: 15%).

[0606] Methyl 2-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate was reacted according to the manufacturing method of Example 28 to obtain the title compound (2 mg, yield: 4%).

[0607] 1 H-NMR (400 MHz, Methanol-d4) δ 7.99 - 7.91 (m, 1H), 7.58 - 7.50 (m, 3H), 7.33 (d, J = 7.9 Hz, 3H), 7.27 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 3.50 (t, J = 7.1 Hz, 1H), 2.99 (t, J = 6.8 Hz, 2H).

[0608] LCMS (m / z): 456 (M+H).

[0609]

[0610] Example 36. Preparation of 1-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid

[0611] Methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate and 2-bromo-5-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide were reacted according to the manufacturing method of Example 27 to obtain methyl 1-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylate (11 mg, yield: 18%).

[0612] Methyl 1-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylate was reacted according to the manufacturing method of Example 28 to obtain the title compound (2 mg, yield: 3%).

[0613] 1 H-NMR (400 MHz, Methanol-d4) δ 8.01 - 7.77 (m, 2H), 7.42 - 7.17 (m, 6H), 7.12 (d, J = 8.0 Hz, 1H), 3.49 (t, J = 6.5 Hz, 2H), 2.99 (t, J = 6.9) Hz, 2H), 1.52 (q, J = 3.9 Hz, 2H), 1.18 - 1.11 (m, 2H).

[0614] LCMS (m / z): 482 (M+H).

[0615]

[0616] Example 37. Preparation of 1-(3',5'-difluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid

[0617] 2-Bromo-4,6-difluorobenzenesulfonyl chloride and the compound of intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain 2-bromo-4,6-difluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide (510 mg, yield: 66%).

[0618] Methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate and 2-bromo-4,6-difluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide were reacted according to the manufacturing method of Example 27 to obtain methyl 1-(3',5'-difluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylate (16 mg, yield: 32%).

[0619] Methyl 1-(3',5'-difluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylate was reacted according to the manufacturing method of Example 28 to obtain the title compound (2 mg, yield: 3%).

[0620] 1 H-NMR (400 MHz, DMSO-d6) Methanol-d4) δ 7.86 (s, 1H), 7.52 (s, 1H), 7.42 - 7.02 (m, 6H), 3.32 (d, J = 2.4 Hz, 4H), 1.52 (q, J = 3.8 Hz, 2H), 1.12 (p, J = 3.8 Hz, 2H).

[0621] LCMS (m / z): 500 (M+H).

[0622]

[0623] Example 38. Preparation of 1-(4-(7-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-2,3-dihydrobenzofuran-5-yl)phenyl)cyclopropane-1-carboxylic acid

[0624] Methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate was reacted with the compound of Example 5 according to the manufacturing method of Example 27 to obtain methyl 1-(4-(7-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-2,3-dihydrobenzofuran-5-yl)phenyl)cyclopropane-1-carboxylate (31 mg, yield: 47%).

[0625] Methyl 1-(4-(7-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-2,3-dihydrobenzofuran-5-yl)phenyl)cyclopropane-1-carboxylate was reacted according to the manufacturing method of Example 28 to obtain the title compound (2 mg, yield: 3%).

[0626] 1 H-NMR (400 MHz, Methanol-d4) δ 8.39 (d, J = 2.6 Hz, 1H), 8.13 - 8.02 (m, 1H), 7.67 (dd, J = 15.8, 2.2 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.34 - 7.16 (m, 3H), 4.72 (t, J = 8.4 Hz, 2H), 3.59 - 3.40 (m, 2H), 3.32 (d, J = 2.2 Hz, 2H), 3.05 - 2.88 (m, 2H), 1.52 (ddd, J = 6.8, 4.3, 2.3 Hz, 2H), 1.16 - 1.05 (m, 2H).

[0627] LCMS (m / z): 506 (M+H).

[0628]

[0629] Example 39. Preparation of 4'-(aminomethyl)-4-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride

[0630] tert-Butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and 2-bromo-5-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide were reacted according to the manufacturing method of Example 27 to obtain tert-butyl((4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (108 mg, yield: 82%).

[0631] tert-Butyl((4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)methyl)carbamate was dissolved in 1 ml of methanol, 0.5 ml of HCl (in dioxane) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated and washed with diethyl ether to obtain the title compound (63 mg, yield: 71%).

[0632] 1 H-NMR (400 MHz, Methanol-d4) δ 8.17 (d, J = 2.7 Hz, 1H), 7.98 - 7.79 (m, 2H), 7.49 - 7.38 (m, 3H), 7.34 - 7.24 (m, 3H), 4.16 (s, 2H), 3.61 - 3.53 (m, 3H), 3.15 (t, J = 6.7 Hz, 2H).

[0633] LCMS (m / z): 467 (M+H).

[0634]

[0635] Example 40. Preparation of 4'-(aminomethyl)-3,5-difluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride

[0636] tert-Butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and 2-bromo-4,6-difluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide were reacted according to the manufacturing method of Example 27 to obtain tert-butyl((3',5'-difluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)methyl)carbamate (46 mg, yield: 35%).

[0637] tert-Butyl((3',5'-difluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)methyl)carbamate was dissolved in 1 ml of methanol, 0.5 ml of HCl (in dioxane) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated and washed with diethyl ether to obtain the title compound (25 mg, yield: 22%).

[0638] 1 H-NMR (400 MHz, Methanol-d4) δ 8.32 (d, J = 12.5 Hz, 2H), 7.61 - 7.18 (m, 5H), 6.96 (d, J = 7.6 Hz, 1H), 4.17 (s, 2H), 3.62 (d, J = 4.6 Hz, 3H).

[0639] LCMS (m / z): 445 (M+H).

[0640]

[0641] Example 41. Preparation of 5-(4-(aminomethyl)phenyl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide

[0642] tert-Butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate was reacted with the compound of Example 5 according to the manufacturing method of Example 27 to obtain tert-butyl(4-(7-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-2,3-dihydrobenzofuran-5-yl)benzyl)carbamate (28 mg, yield: 43%).

[0643] tert-Butyl(4-(7-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-2,3-dihydrobenzofuran-5-yl)benzyl)carbamate was dissolved in 1 ml of methanol, 0.5 ml of HCl (in dioxane) was added, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated and the pH was adjusted to 9-10 with 1 N NaOH aqueous solution. Water was further added (50 mL), and the aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by column chromatography to obtain the title compound (10 mg, yield: 19%).

[0644] 1 H-NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H), 8.06 (s, 1H), 7.75 (s, 1H), 7.67 - 7.29 (m, 4H), 4.01 (s, 1H), 3.71 - 3.39 (m, 6H), 2.97 (s, 3H).

[0645] LCMS (m / z): 451 (M+H).

[0646]

[0647] Example 42. Preparation of ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)propanoate

[0648] Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazol-1-yl)propanoate was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (21 mg, yield: 17%).

[0649] 1 H-NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.31 - 8.27 (m, 1H), 8.10 (s, 1H), 7.85 - 7.75 (m, 1H), 7.79 - 7.70 (m, 3H), 7.54 - 7.49 (m, 1H), 7.15 - 7.11 (m, 1H), 4.50-4.40 (m, 1H), 4.20-4.10 (m, 2H), 3.80 (s, 3H), 3.40 - 3.29 (m, 2H), 3.25 - 3.18 (m, 2H), 1.45 (s, 3H), 1.25-1.10 (m, 3H).

[0650] LCMS (m / z): 500(M+H).

[0651]

[0652] Example 43. Preparation of 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)propanoic acid

[0653] The compound of Example 42 was reacted according to the manufacturing method of Example 28 to obtain the title compound (11 mg, yield: 65%).

[0654] 1H-NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.30 (d, J = 23.1 Hz, 2H), 8.07 (s, 1H), 7.89 - 7.71 (m, 3H), 7.50 - 7.45 (m, 1H), 7.16 (d, J = 8.7 Hz, 1H), 5.12 - 4.99 (m, 1H), 3.84 (s, 3H), 3.39 - 3.23 (m, 2H), 2.90 - 2.80 (m, 2H), 1.63 (s, 3H).

[0655] LCMS (m / z): 472 (M+H).

[0656]

[0657] Example 44. Preparation of 5-(2-aminopyrimidin-5-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0658] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (14 mg, yield: 45%).

[0659] 1 H-NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.53 - 8.41 (m, 2H), 8.32 (t, J = 2.2 Hz, 1H), 8.08 (s, 1H), 7.88 (t, J = 2.9 Hz, 2H), 7.83 - 7.72 (m, 1H), 7.22 (dd, J = 8.8, 1.8 Hz, 1H), 6.83 (s, 2H), 3.84 (s, 3H), 3.32 (dt, J = 6.9, 3.0 Hz, 3H), 2.86 (t, J = 6.6 Hz, 2H).

[0660] LCMS (m / z): 427 (M+H).

[0661]

[0662] Example 45. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)benzenesulfonamide

[0663] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (6 mg, yield: 18%).

[0664] 1 H-NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 2.7 Hz, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 8.04 - 8.00 (m, 2H), 7.70 (dd, J = 8.7, 2.5 Hz, 2H), 7.20 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.80 (t, J = 6.9 Hz, 1H), 5.94 (s, 1H), 4.09 (s, 3H), 3.61 - 3.53 (m, 2H), 3.08 (t, J = 6.7 Hz, 2H).

[0665] LCMS (m / z): 450 (M+H).

[0666]

[0667] Example 46. Preparation of 3',5'-difluoro-4'-hydroxy-4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-3-sulfonamide

[0668] 2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (16 mg, yield: 47%).

[0669] 1H-NMR (400 MHz, DMSO-d6)δ10.47(s,1H),10.32(s,1H),8.36-8.28(m,1H),8.09(s,1H),7.92-7.84(m,2H),7.87-7.78(m,1H),7.34-7.26(m,2H),7.21(dt,J = 7.5, 3.4 Hz,1H), 3.85 (s, 3H), 3.34 - 3.26 (m, 2H), 2.89 - 2.81 (m, 2H).

[0670] LCMS (m / z): 462 (M+H).

[0671]

[0672] Example 47. Preparation of tert-butyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetate

[0673] The compound of Example 9 was reacted with tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazol-1-yl)acetate according to the manufacturing method of Example 27 to obtain the title compound (19 mg, yield: 15%).

[0674] 1 H-NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.32 (t, J = 2.7 Hz, 1H), 8.16 - 8.10 (m, 1H), 8.06 (s, 1H), 7.90 - 7.79 (m, 3H), 7.79 - 7.71 (m, 1H), 7.20 - 7.13 (m, 1H), 4.89 (s, 2H), 3.83 (s, 3H), 3.34 - 3.26 (m, 2H), 2.86 (t, J = 6.3 Hz, 2H), 1.38 (s, 9H).

[0675] LCMS (m / z): 514 (M+H).

[0676]

[0677] Example 48. Preparation of 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetic acid

[0678] The compound of Example 47 was dissolved in 1 ml of methanol, and 1 ml of hydrochloric acid was added. Confirmed by TLC and the pH was adjusted to 5 with 1N-NaOH aqueous solution. The title compound (9 mg, yield: 63%) was obtained by purification by column chromatography.

[0679] 1 H-NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.33 (t, J = 3.0 Hz, 1H), 8.16 - 8.10 (m, 1H), 8.07 (s, 1H), 7.90 - 7.85 (m, 1H), 7.82 (q, J = 3.3, 2.7 Hz, 2H), 7.78 - 7.71 (m, 1H), 7.20 - 7.13 (m, 1H), 4.90 (s, 2H), 3.82 (s, 3H), 3.35 - 3.28 (m, 2H), 2.86 (t, J = 6.5 Hz, 2H).

[0680] LCMS (m / z): 458 (M+H).

[0681]

[0682] Example 49. Preparation of ethyl 3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanoate

[0683] Ethyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (20 mg, yield: 54%).

[0684] 1H-NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.35 - 8.31 (m, 1H), 8.09 (s, 1H), 7.94 - 7.87 (m, 2H), 7.87 - 7.80 (m, 1H), 7.51 - 7.43 (m, 2H), 7.31 - 7.19 (m, 3H), 4.00 (qt, J = 7.1, 1.6 Hz, 2H), 3.85 (s, 3H), 2.91 - 2.77 (m, 4H), 2.59 (t, J = 7.6 Hz, 2H), 1.10 (t, J = 1.6 Hz, 3H).

[0685] LCMS (m / z): 510 (M+H).

[0686]

[0687] Example 50. Preparation of 3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanoic acid

[0688] The compound of Example 49 was reacted according to the manufacturing method of Example 28 to obtain the title compound (12 mg, yield: 85%).

[0689] 1 H-NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 10.46 (s, 1H), 8.35 - 8.27 (m, 1H), 8.08 (s, 1H), 7.96 - 7.78 (m, 3H), 7.52 - 7.40 (m, 2H), 7.33 - 7.18 (m, 3H), 3.84 (s, 3H), 2.92 - 2.72 (m, 4H), 2.56 - 2.48 (m, 2H)

[0690] LCMS (m / z): 482 (M+H).

[0691]

[0692] Example 51. Preparation of 5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0693] 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (16 mg, yield: 53%).

[0694] 1 H-NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.36 - 8.26 (m, 1H), 8.06 (s, 1H), 7.92 - 7.82 (m, 1H), 7.79 - 7.71 (m, 1H), 7.69 - 7.59 (m, 1H), 7.19 - 7.08 (m, 1H), 6.23 - 6.11 (m, 1H), 4.21 - 4.12 (m, 1H), 3.95 - 3.88 (m, 1H), 3.83 (s, 3H), 3.80 - 3.68 (m, 2H), 3.41 - 3.32 (m, 2H), 2.94 - 2.77 (m, 2H), 2.42 - 2.24 (m, 2H).

[0695] LCMS (m / z): 416 (M+H).

[0696]

[0697] Example 52. Preparation of tert-butyl 4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0698] The compound of Example 9 was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to the manufacturing method of Example 27 to obtain the title compound (34 mg, yield: 55%).

[0699] 1H-NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.35 - 8.22 (m, 1H), 8.07 (s, 1H), 7.89 - 7.80 (m, 1H), 7.77 - 7.67 (m, 1H), 7.62 (dd, J = 9.2, 2.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.06 (s, 1H), 3.93 (s, 2H), 3.81 (s, 3H), 3.47 (d, J = 5.7 Hz, 2H), 3.32 (dd, J = 6.9, 2.8 Hz, 2H), 2.86 (t, J = 6.6 Hz, 2H), 2.39-2.31 (m, 2H), 1.38 (s, 9H).

[0700] LCMS (m / z): 515 (M+H).

[0701]

[0702] Example 53. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzenesulfonamide hydrochloride

[0703] The compound of Example 52 was dissolved in 1 ml of methanol, 0.5 ml of HCl (in dioxane) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated and washed with diethyl ether to obtain the title compound (35 mg, yield: 83%).

[0704] 1H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.19 (s, 2H), 8.32 (t, J = 3.0 Hz, 1H), 8.11 (s, 1H), 7.89 (d, J = 3.9 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.72 - 7.57 (m, 1H), 7.17 (dd, J = 9.5, 3.4 Hz, 1H), 6.17 - 6.01 (m, 1H), 3.83 (s, 3H), 3.72 - 3.58 (m, 2H), 3.39 - 3.13 (m, 4H), 2.94 - 2.79 (m, 2H), 2.64 - 2.52 (m, 2H).

[0705] LCMS (m / z): 415 (M+H).

[0706]

[0707] Example 54. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzenesulfonamide

[0708] 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (32 mg, yield: 55%).

[0709] 1 H-NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.40 - 8.27 (m, 2H), 8.03 (s, 1H), 7.94 - 7.68 (m, 5H), 7.16 (t, J = 7.3 Hz, 1H), 5.34 (d, J = 10.5 Hz, 1H), 3.96 - 3.86 (m, 1H), 3.83 (s, 3H), 3.70 - 3.52 (m, 1H), 2.94 - 2.80 (m, 2H), 2.18 - 1.82 (m, 4H), 1.74 - 1.43 (m, 4H).

[0710] LCMS (m / z): 484 (M+H).

[0711]

[0712] Example 55. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1H-pyrazol-4-yl)benzenesulfonamide

[0713] The compound of Example 54 was dissolved in 1 ml of methanol, and 0.5 ml of HCl (in dioxane) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 9-10 with 1N-NaOH. Additional water was added (50 mL), and the aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by column chromatography to obtain the title compound (15 mg, yield: 31%).

[0714] 1 H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.19 (s, 2H), 8.32 (t, J = 3.0 Hz, 1H), 8.11 (s, 1H), 7.89 (d, J = 3.9 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.72 - 7.57 (m, 1H), 7.17 (dd, J = 9.5, 3.4 Hz, 1H), 6.17 - 6.01 (m, 1H), 3.83 (s, 3H), 3.72 - 3.58 (m, 2H), 3.39 - 3.13 (m, 4H), 2.94 - 2.79 (m, 2H), 2.64 - 2.52 (m, 2H).

[0715] LCMS (m / z): 400 (M+H).

[0716]

[0717] Example 56. Preparation of 2-bromo-5-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0718] The compound of 2-bromo-5-fluorobenzenesulfonyl chloride and intermediate 2 were reacted according to the manufacturing method of Example 1 to obtain the title compound (80 mg, yield: 55%).

[0719] 1 H-NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.46 - 8.31 (m, 1H), 8.10 (t, J = 5.4 Hz, 1H), 7.96 - 7.77 (m, 3H), 7.56 - 7.37 (m, 1H), 3.44 - 3.33 (m, 2H), 2.99 - 2.83 (m, 2H).

[0720] LCMS (m / z): 401 (M+H).

[0721]

[0722] Example 57. Preparation of 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0723] The compound of Example 9 was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (12 mg, yield: 40%).

[0724] 1 H-NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.37 - 8.27 (m, 1H), 8.09 (d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.92 - 7.67 (m, 3H), 7.22 - 7.10 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.39 - 3.30 (m, 2H), 2.92 - 2.79 (m, 2H).

[0725] LCMS (m / z): 414 (M+H).

[0726]

[0727] Example 58. Preparation of 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0728] 2-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanamide was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (8 mg, yield: 23%).

[0729] 1 H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.40 - 8.23 ​​(m, 2H), 8.01 (s, 1H), 7.93 - 7.66 (m, 4H), 7.26 (s, 2H), 7.22 - 7.05 (m, 1H), 3.81 (s, 3H), 3.41 - 3.30 (m, 2H), 2.91 - 2.82 (m, 2H), 1.71 (s, 6H).

[0730] LCMS (m / z): 485 (M+H).

[0731]

[0732] Example 59. Preparation of ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanoate

[0733] Ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (28 mg, yield: 45%).

[0734] 1H-NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.42 - 8.25 (m, 2H), 8.04 (s, 1H), 7.95 - 7.68 (m, 5H), 7.23 - 7.09 (m, 1H), 4.11 - 3.98 (m, 2H), 3.83 (s, 3H), 3.39-3.29 (m, 2H), 2.93 - 2.83 (m, 2H), 1.74 (s, 6H), 1.15 - 1.00 (m, 3H).

[0735] LCMS (m / z): 514 (M+H).

[0736]

[0737] Example 60. Preparation of 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid

[0738] The compound of Example 59 was reacted according to the manufacturing method of Example 28 to obtain the title compound (12 mg, yield: 20%).

[0739] 1 H-NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.32 (s, 1H), 8.43 - 8.25 (m, 2H), 8.04 (s, 1H), 7.96 - 7.69 (m, 4H), 7.24 - 7.07 (m, 1H), 3.83 (s, 3H), 3.42 - 3.32 (m, 2H), 2.94 - 2.81 (m, 2H), 1.73 (s, 6H).

[0740] LCMS (m / z): 486 (M+H).

[0741]

[0742] Example 61. Preparation of 5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0743] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (14 mg, yield: 46%).

[0744] 1 H-NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.33 - 8.20 (m, 1H), 8.05 (s, 1H), 7.86 - 7.78 (m, 1H), 7.76 - 7.63 (m, 1H), 7.60 (dd, J = 9.2, 2.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.04 (s, 1H), 3.91 (s, 2H), 3.80 (s, 3H), 3.48 (d, J = 5.7 Hz, 2H), 3.31 (dd, J = 6.9, 2.8 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.38 (s, 3H), 2.32-2.28 (m, 2H).

[0745] LCMS (m / z): 457 (M+H).

[0746]

[0747] Example 62. Preparation of 5-(5,6-dihydro-2H-pyran-3-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0748] 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (14 mg, yield: 46%).

[0749] 1H-NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.28 (d, J = 7.0 Hz, 1H), 8.07 (s, 1H), 7.90 - 7.79 (m, 1H), 7.69 - 7.59 (m, 1H), 7.59 - 7.41 (m, 1H), 7.20 - 7.04 (m, 1H), 6.24 - 6.11 (m, 1H), 4.36 - 4.25 (m, 2H), 3.80 (s, 3H), 3.70 - 3.58 (m, 2H), 3.40 - 3.29 (m, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.25 - 2.10 (m, 2H).

[0750] LCMS (m / z): 416 (M+H).

[0751]

[0752] Example 63. Preparation of 4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-sulfonamide

[0753] 2-(Cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (15 mg, yield: 30%).

[0754] 1H-NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.35 - 8.21 (m, 1H), 8.06 (s, 1H), 7.92 - 7.77 (m, 1H), 7.69 (dt, J = 7.8, 3.8 Hz, 1H), 7.62 - 7.47 (m, 1H), 7.09 (dd, J = 8.9, 5.0 Hz, 1H), 6.13 - 5.99 (m, 1H), 3.80 (s, 3H), 3.32 (dd, J = 7.1, 3.2 Hz, 2H), 2.85 (q, J = 6.0, 5.5 Hz, 2H), 2.30 - 2.17 (m, 2H), 2.16 - 2.03 (m, 2H), 1.73 - 1.59 (m, 2H), 1.58 - 1.43 (m, 2H).

[0755] LCMS (m / z): 414 (M+H).

[0756]

[0757] Example 64. Preparation of 4',4'-difluoro-4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-sulfonamide

[0758] 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (8 mg, yield: 25%).

[0759] 1H-NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.39 - 8.24 (m, 1H), 8.06 (s, 1H), 7.91 - 7.81 (m, 1H), 7.78 - 7.71 (m, 1H), 7.68 - 7.57 (m, 1H), 7.13 (tt, J = 8.9, 5.0 Hz, 1H), 5.91 (s, 1H), 3.82 (s, 3H), 3.38 - 3.29 (m, 2H), 2.93 - 2.80 (m, 2H), 2.76 - 2.50 (m, 4H), 2.23 - 2.02 (m, 2H).

[0760] LCMS (m / z): 450 (M+H).

[0761]

[0762] Example 65. Preparation of 2-methoxy-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0763] 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazol-1-yl)piperidine was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (12 mg, yield: 33%).

[0764] 1 H-NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.01 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.69 - 7.62 (m, 3H), 7.42 (dd, J = 8.4, 2.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.10-3.98 (m, 1H), 3.65 (s, 3H), 2.82 - 2.68 (m, 4H), 2.15 (s, 3H), 1.98 - 1.91 (m, 4H).

[0765] LCMS (m / z): 497 (M+H).

[0766]

[0767] Example 66. Preparation of N-ethyl-2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetamide

[0768] A mixture of the compound of Example 48 (20 mg, 0.044 mmol), EDCI (13 mg, 0.066 mmol), ethanamine (4 mg, 0.087 mmol), HOBt (6 mg, 0.044 mmol), and DIPEA (9 mg, 0.066 mmol) was stirred in dichloromethane (20 mL) for 24 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (8 mg, yield: 38%).

[0769] 1 H-NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.33 (d, J = 2.9 Hz, 1H), 8.08 (s, 1H), 7.96 - 7.63 (m, 4H), 7.54 - 7.45 (m, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 4.71 (s, 2H), 3.82 (s, 3H), 2.89 - 2.72 (m, 6H), 1.02 - 0.97 (m, 3H).

[0770] LCMS (m / z): 485 (M+H).

[0771]

[0772] Example 67. Preparation of N-ethyl-3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanamide

[0773] The compound of Example 50 was reacted according to the manufacturing method of Example 66 to obtain the title compound (11 mg, yield: 52%).

[0774] 1 H-NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.36 - 8.28 (m, 1H), 8.10 - 8.02 (m, 1H), 7.94 - 7.86 (m, 2H), 7.86 - 7.77 (m, 2H), 7.47 - 7.40 (m, 2H), 7.25 - 7.21 (m, 3H), 3.84 (s, 3H), 2.91 - 2.72 (m, 6H), 2.42-2.38 (m, 2H), 2.34 - 2.29 (m, 2H), 0.96 - 0.90 (m, 3H).

[0775] LCMS (m / z): 509 (M+H).

[0776]

[0777] Example 68. Preparation of ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetate

[0778] Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (11 mg, yield: 31%).

[0779] 1H-NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.39 - 8.26 (m, 1H), 8.21 - 8.08 (m, 1H), 8.03 (s, 1H), 7.93 - 7.67 (m, 4H), 7.24 - 7.09 (m, 1H), 5.07 - 4.95 (m, 2H), 4.20 - 4.03 (m, 2H), 3.82 (s, 3H), 3.40 - 3.29 (m, 2H), 2.94 - 2.77 (m, 2H), 1.21 - 1.15 (m, 3H).

[0780] LCMS (m / z): 486 (M+H).

[0781]

[0782] Example 69. Preparation of 5-(1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0783] A mixture of the compound of Example 55 (50 mg, 0.125 mmol), K2CO3 (35 mg, 0.250 mmol), and 5-(1-chloroethyl)-3-isopropyl-1,2,4-oxadiazole (24 mg, 0.138 mmol) was stirred in DMF (10 mL) for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (22 mg, yield: 39%).

[0784] 1H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.42 (d, J = 7.7 Hz, 1H), 8.36 - 8.25 (m, 1H), 8.03 (s, 1H), 7.92 - 7.84 (m, 4H), 7.25 - 7.09 (m, 1H), 6.09 - 5.93 (m, 1H), 3.84 (s, 3H), 2.89 - 2.83 (m, 4H), 2.72 - 2.68 (m, 1H), 1.87 (s, 3H), 1.20 (s, 6H).

[0785] LCMS (m / z): 538 (M+H).

[0786]

[0787] Example 70. Preparation of 2-methoxy-5-(1-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0788] 5-(1-chloroethyl)-3-methyl-1,2,4-oxadiazole was reacted with the compound of Example 55 according to the manufacturing method of Example 69 to obtain the title compound (6 mg, yield: 43%).

[0789] 1 H-NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.37 - 8.28 (m, 1H), 8.03 (s, 1H), 7.95 - 7.82 (m, 3H), 7.81 - 7.68 (m, 2H), 7.21 - 7.13 (m, 1H), 5.90-5.75 (m, 1H), 3.83 (s, 3H), 2.88 - 2.83 (m, 4H), 2.70 (s, 3H), 1.71 (s, 3H).

[0790] LCMS (m / z): 510 (M+H).

[0791]

[0792] Example 71. Preparation of 5-(1-(1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0793] 5-(1-chloroethyl)-3-(4-fluorophenyl)-1,2,4-oxadiazole was reacted with the compound of Example 55 according to the manufacturing method of Example 69 to obtain the title compound (11 mg, yield: 31%).

[0794] 1 H-NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.54 - 8.40 (m, 1H), 8.32 (s, 1H), 8.12 - 7.67 (m, 5H), 7.56 - 7.34 (m, 2H), 7.21 - 7.14 (m, 1H), 6.18 - 6.10 (m, 1H), 5.89 - 5.74 (m, 1H), 4.47 - 4.30 (m, 1H), 3.84 (s, 3H), 2.94 - 2.80 (m, 2H), 2.77 - 2.59 (m, 2H), 1.94 (s, 3H).

[0795] LCMS (m / z): 590 (M+H).

[0796]

[0797] Example 72. Preparation of 5-(1-isopropyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0798] The compound of Example 9 was reacted with 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (18 mg, yield: 34%).

[0799] 1H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.32 (t, J = 2.9 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.93 - 7.67 (m, 4H), 7.22 - 7.10 (m, 1H), 4.52 - 4.37 (m, 1H), 3.84 (s, 3H), 3.40-3.30 (m, 2H), 2.95 - 2.80 (m, 2H), 1.39 (s, 6H).

[0800] LCMS (m / z): 442 (M+H).

[0801]

[0802] Example 73. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzenesulfonamide

[0803] The compound of Example 9 was reacted with 4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (21 mg, yield: 37%).

[0804] 1 H-NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.46 - 8.28 (m, 2H), 8.12 - 8.00 (m, 2H), 7.97 - 7.81 (m, 2H), 7.30 - 7.17 (m, 1H), 3.86 (s, 3H), 3.39 - 3.30 (m, 2H), 2.92 - 2.80 (m, 2H).

[0805] LCMS (m / z): 468 (M+H).

[0806]

[0807] Example 74. Preparation of 5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0808] The compound of Example 9 was reacted with 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (23 mg, yield: 43%).

[0809] 1 H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.37 - 8.24 (m, 1H), 8.22 - 8.12 (m, 1H), 8.02 (s, 1H), 7.84 (d, J = 6.7 Hz, 2H), 7.73 (t, J = 8.4 Hz, 2H), 7.13 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H), 3.73 - 3.61 (m, 1H), 3.36-3.30 (m, 2H), 2.92 - 2.77 (m, 2H), 1.09 - 0.98 (m, 2H), 0.96 - 0.85 (m, 2H).

[0810] LCMS (m / z): 440 (M+H).

[0811]

[0812] Example 75. Preparation of 2-methoxy-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0813] The compound of Example 9 was reacted with 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (21 mg, yield: 36%).

[0814] 1H-NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.75 (dd, J = 7.8, 4.7 Hz, 1H), 8.45 - 8.28 (m, 2H), 8.10 - 7.99 (m, 2H), 7.99 - 7.82 (m, 2H), 7.28 - 7.15 (m, 1H), 3.86 (s, 3H), 3.52 (s, 3H), 3.38 - 3.29 (m, 2H), 2.92 - 2.78 (m, 2H).

[0815] LCMS (m / z): 478 (M+H).

[0816]

[0817] Example 76. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide

[0818] 1-(Tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (17 mg, yield: 29%).

[0819] 1 H-NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.36 - 8.28 (m, 1H), 8.24 (d, J = 3.9 Hz, 1H), 8.03 (s, 1H), 7.94 - 7.83 (m, 2H), 7.83 - 7.68 (m, 2H), 7.15 (dd, J = 8.5, 4.1 Hz, 1H), 4.42 - 4.27 (m, 1H), 3.99 - 3.86 (m, 2H), 3.83 (s, 3H), 3.50 - 3.36 (m, 2H), 3.36 - 3.29 (m, 2H), 2.93 - 2.78 (m, 2H), 1.99 - 1.87 (m, 4H).

[0820] LCMS (m / z): 484 (M+H).

[0821]

[0822] Example 77. Preparation of 5-(6-fluoropyridin-3-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0823] The compound of Example 9 was reacted with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine according to the manufacturing method of Example 27 to obtain the title compound (22 mg, yield: 42%).

[0824] 1 H-NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.45 (t, J = 4.5 Hz, 1H), 8.38 - 8.29 (m, 1H), 8.19 (t, J = 7.7 Hz, 1H), 8.05 (s, 1H), 8.01 - 7.95 (m, 1H), 7.94 - 7.85 (m, 2H), 7.34 - 7.16 (m, 2H), 3.87 (s, 3H), 3.40-3.35 (m, 2H), 2.91 - 2.80 (m, 2H).

[0825] LCMS (m / z): 429 (M+H).

[0826]

[0827] Example 78. Preparation of 5-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0828] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (18 mg, yield: 30%).

[0829] 1H-NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.37 - 8.21 (m, 2H), 8.06 (s, 1H), 7.84 (tt, J = 8.4, 4.2 Hz, 1H), 7.61 (dd, J = 7.1, 4.6 Hz, 1H), 7.54 - 7.42 (m, 1H), 7.33 (s, 2H), 7.28 - 7.15 (m, 1H), 3.86 (s, 3H), 3.39 - 3.30 (m, 2H), 2.94 - 2.77 (m, 2H).

[0830] LCMS (m / z): 495 (M+H).

[0831]

[0832] Example 79. Preparation of 2-methoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0833] 1-(Oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (16 mg, yield: 29%).

[0834] 1 H-NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.42 - 8.24 (m, 2H), 8.03 (s, 1H), 7.98 - 7.82 (m, 3H), 7.83 - 7.71 (m, 1H), 7.26 - 7.09 (m, 1H), 5.59 - 5.42 (m, 1H), 4.95 - 4.77 (m, 4H), 3.83 (s, 3H), 3.41 - 3.29 (m, 2H), 2.94 - 2.74 (m, 2H).

[0835] LCMS (m / z): 456 (M+H).

[0836]

[0837] Example 80. Preparation of 5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0838] 2-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (25 mg, yield: 47%).

[0839] 1 H-NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.40 - 8.27 (m, 1H), 8.17 - 8.07 (m, 1H), 8.03 (s, 1H), 7.89 - 7.73 (m, 3H), 7.64 - 7.43 (m, 1H), 7.23 - 7.09 (m, 1H), 4.85 (s, 1H), 4.14 - 4.06 (m, 2H), 3.83 (s, 3H), 3.74 - 3.66 (m, 2H), 3.40 - 3.30 (m, 2H), 2.92 - 2.77 (m, 2H).

[0840] LCMS (m / z): 444 (M+H).

[0841]

[0842] Example 81. Preparation of 5-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0843] The compound of Example 9 was reacted with 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (15 mg, yield: 41%).

[0844] 1H-NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.37 - 8.18 (m, 2H), 8.05 (s, 1H), 7.92 - 7.79 (m, 1H), 7.75 (d, J = 5.6 Hz, 1H), 7.62 - 7.51 (m, 1H), 7.29 - 7.17 (m, 1H), 4.64 - 4.47 (m, 1H), 3.85 (s, 3H), 3.40 - 3.30 (m, 2H), 2.95 - 2.80 (m, 2H), 1.55 - 1.26 (m, 6H).

[0845] LCMS (m / z): 510 (M+H).

[0846]

[0847] Example 82. Preparation of 5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0848] The compound of Example 9 was prepared by the method of Example 27 using 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole to obtain the title compound (9 mg, yield: 25%).

[0849] 1 H-NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.33 - 8.24 (m, 1H), 8.18 (d, J = 6.7 Hz, 1H), 8.06 (s, 1H), 7.91 - 7.80 (m, 1H), 7.77 - 7.68 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.31 - 7.09 (m, 1H), 4.29 - 4.03 (m, 2H), 3.83 (s, 3H), 3.40 - 3.31 (m, 2H), 2.96 - 2.82 (m, 2H), 1.47 - 1.31 (m, 3H).

[0850] LCMS (m / z): 496 (M+H).

[0851]

[0852] Example 83. Preparation of 5-(isoxazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0853] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole was reacted with the compound of Example 9 according to the manufacturing method of Example 27 to obtain the title compound (13 mg, yield: 45%).

[0854] 1 H-NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.36 - 8.15 (m, 2H), 8.02 (s, 1H), 7.90 - 7.76 (m, 2H), 7.70 (d, J = 5.6 Hz, 1H), 7.60 - 7.49 (m, 1H), 7.30 - 7.18 (m, 1H), 3.82 (s, 3H), 3.39 - 3.28 (m, 2H), 2.93 - 2.78 (m, 2H).

[0855] LCMS (m / z): 401 (M+H).

[0856]

[0857] Example 84. Preparation of 5-(3,5-dimethylisoxazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0858] The title compound (14 mg, yield: 45%) was obtained by mixing 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole with the compound of Example 9 using the manufacturing method of Example 27.

[0859] 1H-NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.37 - 8.16 (m, 1H), 8.04 (s, 1H), 7.88 - 7.75 (m, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.58 - 7.47 (m, 1H), 7.28 - 7.15 (m, 1H), 3.80 (s, 3H), 3.37 - 3.25 (m, 2H), 2.90 - 2.75 (m, 2H), 2.3 (s, 3H), 2.1 (s, 3H).

[0860] LCMS (m / z): 429 (M+H).

[0861]

[0862] Example 85. Preparation of tert-butyl 4-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0863] The compound of Example 9 was reacted with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate according to the manufacturing method of Example 27 to obtain the title compound (25 mg, yield: 59%).

[0864] 1H-NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.37 - 8.17 (m, 1H), 8.00 (s, 1H), 7.90 - 7.81 (m, 1H), 7.77 (s, 1H), 7.74 - 7.67 (m, 1H), 7.58 - 7.40 (m, 2H), 7.13 (d, J = 8.6 Hz, 1H), 4.51 - 4.38 (m, 1H), 4.35 - 4.17 (m, 2H), 4.04 - 3.96 (m, 2H), 3.81 (s, 3H), 3.35-3.30 (m, 2H), 2.87 - 2.79 (m, 2H), 2.04 - 1.92 (m, 2H), 1.82 - 1.71 (m, 2H), 1.38 (s, 9H).

[0865] LCMS (m / z): 583 (M+H).

[0866]

[0867] Example 86. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide hydrochloride

[0868] The compound of Example 85 was reacted according to the manufacturing method of Example 53 to obtain the title compound (14 mg, yield: 37%).

[0869] 1H-NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.16 (s, 1H), 8.89 (s, 1H), 8.40 - 8.30 (m, 1H), 8.22 (dd, J = 7.6, 4.9 Hz, 1H), 8.11 (s, 1H), 8.01 - 7.82 (m, 3H), 7.75 (dt, J = 8.4, 4.3 Hz, 1H), 7.15 (dd, J = 9.1, 5.8 Hz, 1H), 4.52 - 4.38 (m, 1H), 3.83 (s, 3H), 3.41 - 3.21 (m, 4H), 3.14 - 2.95 (m, 2H), 2.94 - 2.81 (m, 2H), 2.24 - 2.04 (m, 4H).

[0870] LCMS (m / z): 483 (M+H).

[0871]

[0872] Example 87. Preparation of 5-bromo-2-methoxy-N-(6-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[0873] 5-Bromo-2-methoxybenzenesulfonyl chloride and 3-amino-6-methyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one were reacted according to the manufacturing method of Example 1 to obtain the title compound (2 mg, yield: 8%).

[0874] 1 H-NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.30 (d,J = 2.6 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 3.35 (td, J = 6.7, 2.8 Hz, 2H), 3.2 (s, 3H), 2.89 (t, J = 6.7 Hz, 2H).

[0875] LCMS (m / z): 427 (M+H).

[0876]

[0877] Example 88. Preparation of tert-butyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0878] Step 1. Preparation of 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0879] The title compound (840 mg, 94%) was obtained by the method of step 2 of intermediate 4 as tert-butyl 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate.

[0880] Step 2. Preparation of tert-butyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0881] 5-Bromo-2-methoxybenzenesulfonyl chloride and tert-butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate were reacted according to the manufacturing method of Example 1 to obtain the title compound (201 mg, yield: 39%).

[0882] 1 H-NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.87 - 7.67 (m, 2H), 7.25 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.40 (s, 2H), 3.82 (s, 3H), 3.54 (t, J = 5.9 Hz, 2H), 1.36 (s, 9H).

[0883] LCMS (m / z): 499 (M+H).

[0884]

[0885] Example 89. Preparation of tert-butyl 3-((2,5-dimethoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0886] 2,5-Dimethoxybenzenesulfonyl chloride and tert-butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate were reacted according to the manufacturing method of Example 1 to obtain the title compound (125 mg, yield: 69%).

[0887] 1 H-NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 11.4, 2.7 Hz, 2H), 7.17 - 7.06 (m, 2H), 4.39 (s, 2H), 3.77 (s, 3H), 3.68 (s, 3H), 3.53 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 1.36 (s, 9H).

[0888] LCMS (m / z): 450 (M+H).

[0889]

[0890] Example 90. Preparation of 5-fluoro-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride

[0891] The title compound (34 mg, yield: 98%) was obtained by reacting tert-butyl 3-((5-fluoro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate according to the manufacturing method of Example 53.

[0892] 1H-NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.23 (s, 2H), 8.14 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 8.0, 3.2 Hz, 1H), 7.45 (ddd, J = 9.1, 8.0, 3.2 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 9.2, 4.0 Hz, 1H), 4.21 (s, 2H), 3.82 (s, 3H), 3.53 (s, 1H), 3.37 (d, J = 6.4 Hz, 2H), 2.93 (t, J = 6.3 Hz, 2H).

[0893] LCMS (m / z): 338 (M+H).

[0894]

[0895] Example 91. Preparation of 5-fluoro-2-bromo-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride

[0896] The title compound (128 mg, yield: 95%) was obtained by reacting tert-butyl 3-((5-fluoro-2-bromo)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate according to the manufacturing method of Example 53.

[0897] 1 H-NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.27 (s, 2H), 8.20 (d, J = 2.6 Hz, 1H), 7.99 - 7.71 (m, 2H), 7.52 - 7.30 (m, 2H), 4.22 (s, 2H), 3.37 (s, 2H), 2.94 (t, J = 6.3 Hz, 2H).

[0898] LCMS (m / z): 387 (M+H).

[0899]

[0900] Example 92. Preparation of 5-chloro-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride

[0901] The title compound (22 mg, yield: 99%) was obtained by reacting tert-butyl 3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate according to the manufacturing method of Example 53.

[0902] 1 H-NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.37 (s, 2H), 8.15 (d, J = 2.5 Hz, 1H), 7.80 - 7.50 (m, 2H), 7.40 (d, J = 2.5 Hz, 1H), 7.21 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.37 (d, J = 6.8 Hz, 2H), 2.95 (t, J = 6.3 Hz, 2H).

[0903] LCMS (m / z): 354 (M+H).

[0904]

[0905] Example 93. Preparation of 5-bromo-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride

[0906] The title compound (169 mg, yield: 96%) was obtained by reacting tert-butyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate according to the manufacturing method of Example 53.

[0907] 1H-NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.26 (s, 2H), 8.14 (d, J = 2.5 Hz, 1H), 7.83 - 7.68 (m, 2H), 7.39 (d, J = 2.5 Hz, 1H), 7.16 (d, J = 8.9 Hz, 1H), 4.22 (s, 2H), 3.83 (s, 3H), 3.37 (d, J = 6.9 Hz, 2H), 2.94 (t, J = 6.3 Hz, 2H).

[0908] LCMS (m / z): 399 (M+H).

[0909]

[0910] Example 94. Preparation of 2,5-dimethoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride

[0911] The title compound (111 mg, yield: 99%) was obtained by reacting tert-butyl 3-((2,5-dimethoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate according to the manufacturing method of Example 53.

[0912] 1 H-NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.26 (s, 2H), 8.15 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 2.9 Hz, 1H), 7.18 - 7.06 (m, 2H), 4.21 (s, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 3.36 (s, 2H), 2.92 (t, J = 6.3 Hz, 2H).

[0913] LCMS (m / z): 350 (M+H).

[0914]

[0915] Example 95. Preparation of ethyl 3-((5-fluoro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0916]

[0917] Step 1. Preparation of 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0918] 80 mL of methanol was added tert-butyl 4-oxopiperidine-1-carboxylate (8.3 g, 41.656 mmol, 1.0 eq) and 1-methyl-3,5-dinitropyridin-2(1H)-one (9.124 g, 45.822 mmol, 1.1 q) at room temperature, followed by the addition of 20 mL of 2 M ammonia solution (2 M in MeOH). The mixture was stirred at 70 °C for more than 12 hours. The progress of the reaction was monitored using TLC. After the reaction was completed, the temperature was cooled to room temperature. The mixture was concentrated under reduced pressure. The concentrated mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified using silica gel column chromatography under the condition of 10% ethyl acetate / hexane developing solvent to obtain the title compound as a solid (7.732 g, yield: 66%).

[0919] LCMS (m / z): 280.20 (M+H).

[0920] Step 2.3 - Preparation of nitro-5,6,7,8-tetrahydro-1,6-naphthyridine

[0921] To a solution of tert-butyl 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.0 g, 3.58 mmol, 1.0 eq) in 10 mL of methanol was slowly added a dioxane solution containing 4 M HCl (4.47 ml, 17.90 mmol, 5.0 eq) at 0°C while stirring. The mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was concentrated and basified with 2 M ammonia solution (2 M in MeOH). The basified mixture was concentrated under reduced pressure. Water and ethyl acetate were extracted. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated to obtain the title compound (0.61 g, yield: 95%) as a solid.

[0922] LCMS (m / z): 180.1 (M+H).

[0923] Step 3. Preparation of ethyl-3-nitro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0924] To a solution of 3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (313 mg, 1.746 mmol, 1.0 eq) and triethylamine (212 mg, 2.095 mmol, 1.2 eq) in 6 mL of dichloromethane was slowly added ethyl chloroformate (227 mg, 2.095 mmol, 1.2 eq) at 0°C while stirring. The mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored using TLC. The mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified using silica gel column chromatography under the condition of 20% ethyl acetate / hexane developing solvent to obtain the title compound as a solid (7.732 g, yield: 66%).

[0925] LCMS (m / z): 252.2 (M+H).

[0926] Step 4. Preparation of ethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate

[0927] To a solution of ethyl-3-nitro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate (188 mg, 0.748 mmol, 1.0 eq) and tetrahydroxydiboron (201 mg, 2.245 mmol, 3.0 eq) in 2 mL of dimethylformamide was slowly added 4,4'-bipyridine (23 mg, 0.150 mmol, 0.2 eq) at 0 degrees while stirring. After stirring for an additional 30 minutes, the mixture was warmed to room temperature and stirred for more than 1 hour. The progress of the reaction was monitored using TLC. The mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified using silica gel column chromatography under the condition of 5% methanol / dichloromethane as a developing solvent to obtain the title compound as a solid (135 mg, yield: 81%).

[0928] LCMS (m / z): 222.2 (M+H).

[0929] Step 5. Ethyl 3-((5-fluoro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0930] To a solution of 5-fluoro-2-methoxybenzenesulfonyl chloride (30 mg, 0.134 mmol, 1.0 eq) and ethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate (32 mg, 0.147 mmol, 1.1 eq) in 2 mL of dichloromethane was added triethylamine (0.03 mL, 0.249 mmol, 2.0 eq) at 0 degrees. The mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was concentrated. The concentrated mixture was purified by silica gel column chromatography using methanol / dichloromethane as a developing solvent to obtain the title compound (19 mg, yield: 35%) as a solid.

[0931] 1 H-NMR (400 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.49 (dd, J = 7.5, 3.3 Hz, 1H), 7.35 (s, 1H), 7.25 (d, J = 1.4 Hz, 1H), 7.23 (d, J = 7.3 Hz, 2H), 7.03 - 6.93 (m, 2H), 4.58 (d, J = 3.1 Hz, 2H), 4.16 (tq, J = 7.0, 3.3, 2.8 Hz, 2H), 4.07 - 3.99 (m, 3H), 3.73 (s, 2H), 2.89 (s, 2H), 1.27 (tt, J = 7.0, 2.7 Hz, 3H).

[0932] LCMS (m / z): 410.0 (M+H).

[0933]

[0934] Example 96. Preparation of ethyl 3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0935] The title compound (21 mg, yield: 39%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and ethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate according to the manufacturing method of Example 1.

[0936] 1 H-NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.73 (t, J = 2.8 Hz, 1H), 7.45 (dt, J = 8.9, 2.4 Hz, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.01 - 6.89 (m, 2H), 4.63 - 4.55 (m, 2H), 4.20 - 4.12 (m, 2H), 4.04 (d, J = 2.1 Hz, 3H), 3.73 (s, 2H), 2.89 (s, 2H), 1.26 (dt, J = 7.1, 3.8 Hz, 3H).

[0937] LCMS (m / z): 426.0 (M+H).

[0938]

[0939] Example 97. Preparation of ethyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0940] The title compound (27 mg, yield: 54%) was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride and ethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate according to the manufacturing method of Example 1.

[0941] 1H-NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.90 - 7.83 (m, 1H), 7.60 (dd, J = 8.8, 2.6 Hz, 1H), 7.34 (s, 1H), 7.24 (s, 4H), 6.92 (d, J = 9.0 Hz, 2H), 4.59 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.06 - 4.02 (m, 3H), 3.74 (s, 2H), 2.90 (t, J = 5.8 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0942] LCMS (m / z): 470.0 (M+H).

[0943]

[0944] Example 98. Preparation of neopentyl 3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0945] To a solution of 5-chloro-2-methoxybenzenesulfonyl chloride (30 mg, 0.134 mmol, 1.0 eq) and neopentyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate (39 mg, 0.147 mmol, 1.1 eq) in 2 mL of dichloromethane was added triethylamine (0.03 mL, 0.249 mmol, 2.0 eq) at 0 degrees. The mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was concentrated. The concentrated mixture was purified by silica gel column chromatography using methanol / dichloromethane as a developing solvent to obtain the title compound (42 mg, yield: 72%) as a solid.

[0946] 1H-NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 7.61 (dt, J = 8.7, 2.0 Hz, 1H), 7.29 (s, 1H), 7.20 (dt, J = 8.9, 1.7 Hz, 1H), 4.48 (s, 2H), 3.85 - 3.81 (m, 3H), 3.68 (t, J = 1.7 Hz, 2H), 3.62 (s, 2H), 2.74 (s, 2H), 0.89 - 0.83 (m, 9H).

[0947] LCMS (m / z): 468.1 (M+H).

[0948]

[0949] Example 99. Preparation of neopentyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0950] The title compound (26 mg, yield: 58%) was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride and neopentyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate according to the manufacturing method of Example 1.

[0951] 1 H-NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.04 (t, J = 3.7 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.28 (s, 1H), 7.13 (dd, J = 8.9, 5.5 Hz, 1H), 4.47 (s, 2H), 3.84 - 3.79 (m, 3H), 3.70 - 3.66 (m, 2H), 3.62 (s, 2H), 2.73 (d, J = 6.3 Hz, 2H), 0.86 (d, J = 5.2 Hz, 9H).

[0952] LCMS (m / z): 512.0 (M+H).

[0953]

[0954] Example 100. Preparation of neopentyl 3-((5-methoxy-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0955] The title compound (43 mg, yield: 87%) was obtained by reacting 5-methoxy-2-methoxybenzenesulfonyl chloride and neopentyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate according to the manufacturing method of Example 1.

[0956] 1 H-NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.05 (s, 1H), 7.27 (s, 1H), 7.22 (d, J = 2.9 Hz, 1H), 7.10 (d, J = 5.3 Hz, 2H), 4.45 (s, 2H), 3.79 - 3.72 (m, 3H), 3.70 - 3.55 (m, 7H), 2.71 (s, 2H), 0.85 (d, J = 9.2 Hz, 9H).

[0957] LCMS (m / z): 464.1 (M+H).

[0958]

[0959] Example 101. Preparation of 2-fluoroethyl-3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0960] The title compound (37 mg, yield: 67%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and 2-fluoroethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate according to the manufacturing method of Example 1.

[0961] 1H-NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.06 (t, J = 2.8 Hz, 1H), 7.66 (t, J = 2.9 Hz, 1H), 7.61 (dt, J = 9.0, 2.9 Hz, 1H), 7.28 (t, J = 2.8 Hz, 1H), 7.22 - 7.17 (m, 1H), 4.68 - 4.61 (m, 1H), 4.51 (t, J = 4.0 Hz, 3H), 4.30 - 4.25 (m, 1H), 4.22 - 4.17 (m, 1H), 3.83 (d, J = 2.7 Hz, 3H), 3.62 (s, 2H), 2.74 (d, J = 6.3 Hz, 2H).

[0962] LCMS (m / z): 444.0 (M+H).

[0963]

[0964] Example 102. Preparation of 2-fluoroethyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0965] The title compound (36 mg, yield: 71%) was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride and 2-fluoro-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate according to the manufacturing method of Example 1.

[0966] 1H-NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.08 - 8.01 (m, 1H), 7.78 - 7.69 (m, 2H), 7.27 (d, J = 7.7 Hz, 1H), 7.13 (t, J = 8.7 Hz, 1H), 4.62 (d, J = 9.5 Hz, 1H), 4.50 (d, J = 9.3 Hz, 3H), 4.26 (d, J = 9.3 Hz, 1H), 4.19 (q, J = 5.6, 3.8 Hz, 1H), 3.81 (dd, J = 8.9, 3.9 Hz, 3H), 3.61 (s, 2H), 2.73 (s, 2H).

[0967] LCMS (m / z): 487.9 (M+H).

[0968]

[0969] Example 103. Preparation of 2-fluoroethyl-3-((5-methoxy-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0970] The title compound (22 mg, yield: 44%) was obtained by reacting 5-methoxy-2-methoxybenzenesulfonyl chloride and 2-fluoroethyl-3-amino-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate according to the manufacturing method of Example 1.

[0971] 1H-NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.09 - 8.01 (m, 1H), 7.26 (d, J = 6.0 Hz, 1H), 7.23 - 7.18 (m, 1H), 7.14 - 7.05 (m, 2H), 4.62 (d, J = 7.8 Hz, 1H), 4.48 (d, J = 17.6 Hz, 3H), 4.26 (t, J = 7.9 Hz, 1H), 4.19 (dt, J = 7.8, 4.3 Hz, 1H), 3.79 - 3.72 (m, 3H), 3.71 - 3.65 (m, 3H), 3.61 (s, 2H), 2.72 (d, J = 6.5 Hz, 2H).

[0972] LCMS (m / z): 440.0 (M+H).

[0973]

[0974] Example 104. Preparation of 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0975]

[0976] Step 1. N-Isopropyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0977] To a solution of 3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (130 mg, 0.716 mmol, 1.0 eq) and triethylamine (0.20 mL, 1.43 mmol, 2.0 eq) in 2 mL of dichloromethane, 4-nitrophenyl carbonochloridate (216 mg, 1.07 mmol, 1.5 eq) was slowly added at 0°C while stirring. The mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored using TLC to confirm whether the starting material, 3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine, was consumed. Isopropylamine (0.19 mL, 2.15 mmol, 3.0 eq) was slowly added at 0°C. The mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored using TLC. After the reaction was completed, the mixture was extracted with water and ethyl acetate. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography using 70% ethyl acetate / hexane as a developing solvent to obtain the title compound (166 mg, yield: 87%) as a solid.

[0978] LCMS (m / z): 265.1 (M+H).

[0979] Step 2.3-Amino-N-isopropyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0980] N-Isopropyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide was reacted according to the preparation method of step 2 of intermediate 4 to obtain the title compound (89 mg, yield: 61%).

[0981] LCMS (m / z): 235.1 (M+H).

[0982] Step 3.3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0983] The title compound (22 mg, yield: 40%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and 3-amino-N-isopropyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[0984] 1 H-NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.19 (d, J = 8.8 Hz, 2H), 6.25 (d, J = 7.4 Hz, 1H), 4.37 (s, 2H), 3.83 (d, J = 1.5 Hz, 3H), 3.71 (q, J = 6.5 Hz, 1H), 3.54 (d, J = 6.0 Hz, 2H), 3.13 (dd, J = 5.4, 1.9 Hz, 1H), 2.67 (d, J = 5.9 Hz, 2H), 1.01 (dd, J = 6.6, 1.7 Hz, 6H).

[0985] LCMS (m / z): 439.0 (M+H).

[0986]

[0987] Example 105. Preparation of 3-((5-fluoro-2-methoxyphenyl)sulfonamido)-N-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0988] The title compound (38 mg, yield: 66%) was obtained by reacting 5-fluoro-2-methoxybenzenesulfonyl chloride and 3-amino-N-isopropyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[0989] 1H-NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.04 (q, J = 2.6 Hz, 1H), 7.50 (tt, J = 5.1, 3.0 Hz, 1H), 7.44 (tt, J = 8.4, 2.9 Hz, 1H), 7.22 - 7.16 (m, 2H), 6.24 (d, J = 7.4 Hz, 1H), 4.36 (d, J = 3.7 Hz, 2H), 3.84 - 3.78 (m, 3H), 3.70 (dt, J = 12.2, 6.0 Hz, 1H), 3.53 (dd, J = 6.1, 4.1 Hz, 2H), 2.66 (t, J = 5.5 Hz, 2H), 1.04 - 0.97 (m, 6H).

[0990] LCMS (m / z): 423.1 (M+H).

[0991]

[0992] Example 106. Preparation of 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0993] The title compound (27 mg, yield: 47%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and 3-amino-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[0994] 1H-NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.23 - 7.16 (m, 2H), 6.54 (d, J = 5.7 Hz, 1H), 4.37 (s, 2H), 3.82 (s, 3H), 3.53 (t, J = 5.6 Hz, 2H), 2.96 (q, J = 6.5 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 1.35 (q, J = 7.3 Hz, 2H), 1.19 (dt, J = 13.6, 8.5 Hz, 5H), 0.80 (t, J = 7.0 Hz, 3H)

[0995] LCMS (m / z): 467.1 (M+H).

[0996]

[0997] Example 107. Preparation of 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[0998] The title compound (9 mg, yield: 21%) was obtained by reacting 5-fluoro-2-methoxybenzenesulfonyl chloride and 3-amino-N-(2,2-difluoroethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[0999] 1H-NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.05 (s, 1H), 7.65 (dd, J = 2.7, 1.5 Hz, 1H), 7.61 (dt, J = 8.7, 2.0 Hz, 1H), 7.22 - 7.17 (m, 2H), 7.02 (s, 1H), 6.08 - 5.75 (m, 1H), 4.42 (s, 2H), 3.85 - 3.81 (m, 3H), 3.57 (t, J = 5.6 Hz, 2H), 3.42 - 3.31 (m, 3H), 2.69 (t, J = 5.8 Hz, 2H).

[1000] LCMS (m / z): 461.0 (M+H).

[1001]

[1002] Example 108. Preparation of 3-((5-bromo-2-methoxyphenyl)sulfonamido)-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1003] The title compound (30 mg, yield: 68%) was obtained by reacting 5-fluoro-2-methoxybenzenesulfonyl chloride and 3-amino-N-(2,2-difluoroethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[1004] 1H-NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.05 (t, J = 2.9 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.21 (t, J = 2.9 Hz, 1H), 7.14 (dd, J = 8.8, 3.0 Hz, 1H), 7.02 (d, J = 5.1 Hz, 1H), 5.91 (td, J = 56.3, 4.0 Hz, 1H), 4.42 (s, 2H), 3.82 (d, J = 2.9 Hz, 3H), 3.57 (t, J = 6.0 Hz, 2H), 3.43 - 3.30 (m, 3H), 2.69 (t, J = 5.7 Hz, 2H).

[1005] LCMS (m / z): 505.0 (M+H).

[1006]

[1007] Example 109. Preparation of 5-chloro-2-methoxy-N-(6-(morpholine-4-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[1008] The title compound (14 mg, yield: 33%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and (3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(morpholino)methanone according to the manufacturing method of Example 1.

[1009] 1H-NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.04 (t, J = 3.8 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.61 (dd, J = 8.8, 2.9 Hz, 1H), 7.26 (d, J = 2.6) Hz, 1H), 7.20 (t, J = 7.1 Hz, 1H), 4.26 (d, J = 5.1 Hz, 2H), 3.88 - 3.81 (m, 3H), 3.53 (q, J = 4.8 Hz, 4H), 3.39 (t, J = 6.0 Hz, 2H), 3.12 (q, J = 4.9 Hz, 4H), 2.79 - 2.72 (m, 2H).

[1010] LCMS (m / z): 467.0 (M+H).

[1011]

[1012] Example 110. Preparation of 5-bromo-2-methoxy-N-(6-(morpholine-4-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[1013] The title compound (25 mg, yield: 53%) was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride and (3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(morpholino)methanone according to the manufacturing method of Example 1.

[1014] 1H-NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.04 (t, J = 2.8 Hz, 1H), 7.74 (ddt, J = 14.3, 5.6, 3.0 Hz, 2H), 7.26 (d, J = 2.9 Hz, 1H), 7.17 - 7.12 (m, 1H), 4.26 (d, J = 5.6 Hz, 2H), 3.83 (d, J = 2.7 Hz, 3H), 3.53 (q, J = 4.9, 3.8 Hz, 4H), 3.40 (d, J = 6.0 Hz, 2H), 3.14 - 3.10 (m, 4H), 2.76 (d, J = 6.2 Hz, 2H).

[1015] LCMS (m / z): 511.0 (M+H).

[1016]

[1017] Example 111. Preparation of 3-((5-bromo-2-methoxyphenyl)sulfonamido)-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1018] Step 1. Preparation of 3-N-methyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1019] The amine substituent was used as a metaamine, and the reaction was carried out according to the manufacturing method of step 2 of Example 104, and the mixture was used in the next step without purification.

[1020] Step 2.3 Preparation of N-methyl-3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1021] 3-N-methyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide was reacted according to the preparation method of step 2 of intermediate 4 to obtain the title compound (10 mg, yield: 12%).

[1022] Step 3.3 Preparation of ((5-bromo-2-methoxyphenyl)sulfonamido)-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1023] The title compound (3 mg, yield: 13%) was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride and -N-methyl-3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[1024] 1 H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.68 - 7.54 (m, 2H), 7.20 - 7.16 (m, 2H), 4.35 (s, 2H), 3.82 (s, 3H), 3.53 (t, J = 5.6 Hz, 2H), 2.96 (q, J = 6.5 Hz, 2H), 2.67 (s, 3H)

[1025] LCMS (m / z): 456.0 (M+H).

[1026]

[1027] Example 112. Preparation of 5-chloro-N-(6-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide

[1028] Step 1.6 - Preparation of isopropyl-3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine

[1029] 3-Nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (300 mg, 1.0 eq) was dissolved in 10 ml of tetrahydrofuran. Acetone (0.17 ml, 2.0 eq), DIPEA (1.0 ml, (5 eq) and triacetoxysodium borohydride (504 mg, 2.0 eq) were added and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with aqueous sodium bicarbonate solution and ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered and concentrated. The title compound (50 mg, 20%) was obtained through column chromatography.

[1030] Step 2.6 - Preparation of isopropyl-3-amino-5,6,7,8-tetrahydro-1,6-naphthyridine

[1031] 6-Isopropyl-3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine was reacted according to the manufacturing method of step 2 of intermediate 4 to obtain the title compound (40 mg, 92%).

[1032] Step 3.5 Preparation of chloro-N-(6-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide

[1033] The title compound (5 mg, yield: 12%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and 6-isopropyl-3-amino-5,6,7,8-tetrahydro-1,6-naphthyridine according to the manufacturing method of Example 1.

[1034] 1 H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.0 (t, J = 3.8 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.61 (dd, J = 8.8, 2.9 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.20 (t, J = 7.1 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 2H), 3.09 (t, J = 7.2 Hz, 2H), 3.02 - 2.85 (m, 3H), 1.08 (d, J = 6.8 Hz, 6H).

[1035] LCMS (m / z): 396.0 (M+H).

[1036]

[1037] Example 113. Preparation of 5-bromo-N-(6-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide

[1038] The title compound (3 mg, yield: 6%) was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride and 6-isopropyl-3-amino-5,6,7,8-tetrahydro-1,6-naphthyridine according to the manufacturing method of Example 1.

[1039] 1 H-NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.24 (s, 2H), 8.18 (d, J = 2.5 Hz, 1H), 7.80 - 7.64 (m, 2H), 7.29 (d, J = 2.5 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H), 3.91 (s, 3H), 3.65 (s, 2H), 3.15 (t, J = 7.2 Hz, 2H), 3.18 - 2.75 (m, 3H), 1.12 (d, J = 6.2 Hz, 6H).

[1040] LCMS (m / z): 441.0 (M+H).

[1041]

[1042] Example 114. Preparation of 3-5-chloro-2-methoxy-N-(6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[1043] Step 1.3 Preparation of nitro-6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[1044] 3-Nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (200 mg, 1.0 eq), 2-bromopyrimidine (138 mg, 1.1 eq), sodium tert-butoxide (152 mg, 2.0 eq), BINAP (24 mg, 0.05 eq) and Pd2(dba)3 (15 mg, 0.02 eq) were added to 3 ml of toluene. The mixture was replaced with nitrogen and stirred at 100°C for 12 hours. The mixture was confirmed by TLC and filtered through a Celite pad. The obtained solution was concentrated and purified by column chromatography to obtain the title compound (110 mg, 53%).

[1045] Step 2.3 Preparation of amino-6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[1046] 3-Nitro-6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine was reacted according to the preparation method of step 2 of intermediate 4 to obtain the title compound (40 mg, 85%).

[1047] Step 3.3 Preparation of 5-chloro-2-methoxy-N-(6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[1048] The title compound (5 mg, yield: 6%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and 6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-amine according to the manufacturing method of Example 1.

[1049] 1H-NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.35 (dd, J = 7.5, 1.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.50 (t, J = 7.5 Hz, 1H), 4.47 (s, 2H), 3.93 (s, 3H), 3.71 (t, J = 7.1 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H).

[1050] LCMS (m / z): 432.0 (M+H).

[1051]

[1052] Example 115. Preparation of 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-phenyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1053] Step 1.3 Preparation of Nitro-N-phenyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1054] A mixture synthesized by reacting an amine substituent with aniline according to the manufacturing method of Step 1 of Example 104 was extracted with water and ethyl acetate after the reaction was completed. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography under ethyl acetate / hexane as a developing solvent to obtain the title compound (61 mg, yield: 27%) as a solid.

[1055] LCMS (m / z): 299.3 (M+H).

[1056] Step 2.3 Preparation of amino-N-phenyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1057] 3-Nitro-N-phenyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide was reacted according to the preparation method of step 2 of intermediate 4 to obtain the title compound (42 mg, yield: 76%).

[1058] LCMS (m / z): 257.1 (M+H).

[1059] Step 3.3 Preparation of ((5-chloro-2-methoxyphenyl)sulfonamido)-N-phenyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1060] The title compound (36 mg, yield: 60%) was obtained by reacting 5-fluoro-2-methoxybenzenesulfonyl chloride and 3-amino-N-phenyl-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[1061] 1 H-NMR (400 MHz, DMSO-d6) δ 10.31 (d, J = 7.5 Hz, 1H), 8.56 (d, J = 7.5 Hz, 1H), 8.15 - 7.99 (m, 1H), 7.73 - 7.56 (m, 2H), 7.47 - 7.36 (m, 2H), 7.30 - 7.14 (m, 4H), 6.97 - 6.85 (m, 1H), 4.54 (d, J = 6.7 Hz, 2H), 3.92 - 3.80 (m, 3H), 3.69 (d, J = 6.3 Hz, 2H), 2.76 (d, J = 6.1 Hz, 2H).

[1062] LCMS (m / z): 473.0 (M+H).

[1063]

[1064] Example 116. Preparation of 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(cyclopropylmethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1065] Step 1. Preparation of N-(cyclopropylmethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1066] A mixture synthesized by reacting cyclopropylmethanamine hydrochloride as an amine substituent according to the manufacturing method of Step 1 of Example 104 was extracted with water and ethyl acetate after the reaction was completed. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography under ethyl acetate / hexane as a developing solvent to obtain the title compound (72 mg, yield: 23%) as a solid.

[1067] LCMS (m / z): 277.1 (M+H).

[1068] Step 2.3 Preparation of amino-N-(cyclopropylmethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1069] N-(Cyclopropylmethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide was reacted according to the preparation method of step 2 of intermediate 4 to obtain the title compound (39 mg, yield: 61%).

[1070] LCMS (m / z): 247.1 (M+H).

[1071] Step 3.3 Preparation of ((5-chloro-2-methoxyphenyl)sulfonamido)-N-(cyclopropylmethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1072] The title compound (36 mg, yield: 64%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and 3-amino-N-(cyclopropylmethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[1073] 1H-NMR (400 MHz, DMSO-d6) δ 10.33 - 10.26 (m, 1H), 8.05 (dt, J = 5.9, 2.9 Hz, 1H), 7.63 (ddt, J = 14.1, 5.3, 3.2 Hz, 2H), 7.20 (t, J = 7.8) Hz, 2H), 6.65 (d, J = 5.6 Hz, 1H), 4.39 (t, J = 3.4 Hz, 2H), 3.83 (dd, J = 7.2, 3.3 Hz, 3H), 3.54 (dt, J = 8.3, 4.8 Hz, 2H), 2.85 (q, J = 6.8, 5.3 Hz, 2H), 2.67 (q, J = 5.9, 5.3 Hz, 2H), 0.86 (s, 1H), 0.30 (dtt, J = 8.2, 5.8, 3.5 Hz, 2H), 0.08 (qd, J = 6.5, 4.1 Hz, 2H).

[1074] LCMS (m / z): 451.0 (M+H).

[1075]

[1076] Example 117. Preparation of 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(2-fluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1077] Step 1. Preparation of N-(2-fluoroethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1078] A mixture synthesized by reacting 2-fluoroethane-1-amine hydrochloride as the amine substituent according to the manufacturing method of Step 1 of Example 104 was extracted with water and ethyl acetate after the reaction was completed. The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography under ethyl acetate / hexane as a developing solvent to obtain the title compound (55 mg, yield: 18%) as a solid.

[1079] LCMS (m / z): 269.1 (M+H).

[1080] Step 2.3 Preparation of amino-N-(2-fluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1081] N-(2-fluoroethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide was reacted according to the preparation method of step 2 of intermediate 4 to obtain the title compound (46 mg, yield: 94%).

[1082] LCMS (m / z): 239.1 (M+H).

[1083] Step 3.3 Preparation of ((5-chloro-2-methoxyphenyl)sulfonamido)-N-(2-fluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide

[1084] The title compound (23 mg, yield: 35%) was obtained by reacting 5-fluoro-2-methoxybenzenesulfonyl chloride and 3-amino-N-(2-fluoroethyl)-3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide according to the manufacturing method of Example 1.

[1085] 1 H-NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.20 (dd, J = 8.4, 2.3 Hz, 2H), 6.84 (d, J = 6.9) Hz, 1H), 4.44 - 4.37 (m, 3H), 4.32 - 4.27 (m, 1H), 3.85 - 3.81 (m, 3H), 3.56 (t, J = 5.0 Hz, 2H), 3.31 (d, J = 5.4 Hz, 1H), 3.27 - 3.22 (m, 1H), 2.69 (d, J = 7.9 Hz, 2H).

[1086] LCMS (m / z): 443.0 (M+H).

[1087]

[1088] Example 118. Preparation of 5-chloro-N-(6-(3,3-dimethylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide

[1089] Step 1.3 Preparation of 3-dimethyl-1-(3-nitro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)butan-1-one

[1090] 3-Nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (100 mg, 1.0 eq) was dissolved in 2 ml of methylene chloride, and 0.13 ml of triethylamine was added at 0 degrees. 3,3-Dimethylbutanoyl chloride (65 mg, 1.05 eq) was slowly added to the mixed solution at the same temperature. The mixture was warmed to room temperature and stirred for 1 hour. After confirming the completion of the reaction by TLC, the mixture was concentrated and used in the next reaction without further purification (140 mg).

[1091] LCMS (m / z): 278.3 (M+H).

[1092] Step 2.1 Preparation of (3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one

[1093] 3,3-Dimethyl-1-(3-nitro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)butan-1-one was reacted according to the manufacturing method of step 2 of intermediate 4 to obtain the title compound (61 mg, yield: 48%).

[1094] LCMS (m / z): 248.3 (M+H).

[1095] Step 3.5 Preparation of chloro-N-(6-(3,3-dimethylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide

[1096] The title compound (10 mg, yield: 18%) was obtained by reacting 5-chloro-2-methoxybenzenesulfonyl chloride and 1-(3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one according to the manufacturing method of Example 1.

[1097] 1 H-NMR (400 MHz, Methanol-d4) δ 8.07 (d, J = 17.3 Hz, 1H), 7.72 (s, 1H), 7.39 (s, 2H), 7.13 (d, J = 8.5 Hz, 1H), 4.74 - 4.63 (m, 2H), 3.97 - 3.79 (m, 5H), 2.85 (d, J = 33.0 Hz, 3H), 2.38 (s, 2H), 0.99 (dd, J = 43.6, 8.9 Hz, 9H).

[1098] LCMS (m / z): 452.9 (M+H).

[1099]

[1100] Example 119. Preparation of 5-bromo-N-(6-(3,3-dimethylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide

[1101] The title compound (15 mg, yield: 24%) was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride and 1-(3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,3-dimethylbutan-1-one according to the manufacturing method of Example 1.

[1102] 1H-NMR (400 MHz, Methanol-d4) δ 8.14 - 8.03 (m, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.1 Hz, 1H), 7.44 (d, J = 34.8 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 4.68 (d, J = 22.5 Hz, 2H), 4.00 - 3.78 (m, 5H), 2.86 (dd, J = 33.2, 6.1 Hz, 3H), 2.39 (d, J = 5.1 Hz, 2H), 0.99 (dd, J = 42.0, 4.6) Hz, 9H).

[1103] LCMS (m / z): 497.4 (M+H).

[1104]

[1105] Example 120. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide

[1106] The compound of Example 9 was reacted with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine according to the manufacturing method of Example 27 to obtain the title compound (16 mg, yield: 46%).

[1107] 1 H-NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.21 (d, J = 3.8 Hz, 1H), 8.69 - 8.54 (m, 2H), 8.34 (dd, J = 4.0, 2.6 Hz, 1H), 8.30 (d, J = 3.9) Hz, 1H), 8.11 - 8.00 (m, 2H), 7.96 - 7.82 (m, 4H), 7.24 (dd, J = 8.8, 3.9 Hz, 1H), 3.87 (s, 3H), 3.37 - 3.30 (m, 2H), 2.90 - 2.79 (m, 2H).

[1108] LCMS (m / z): 477.5 (M+H).

[1109]

[1110] Example 121. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

[1111] The compound of Example 9 was reacted with 1',3',5'-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1'H-1,4'-bipyrazole according to the manufacturing method of Example 27 to obtain the title compound (18 mg, yield: 52%).

[1112] 1 H-NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.30 (d, J = 2.7 Hz, 1H), 8.07 (s, 1H), 7.87 (d, J = 2.7 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.45 - 7.37 (m, 1H), 7.18 (d, J = 8.5 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H), 3.38 - 3.31 (m, 2H), 2.86 (t, J = 6.5 Hz, 2H), 2.06 (s, 3H), 1.97 (s, 3H).

[1113] LCMS (m / z): 442.5(M+H).

[1114]

[1115] Example 122. Preparation of 5-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[1116] The compound of Example 9 was reacted with 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (12 mg, yield: 36%).

[1117] 1H-NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.31 (s, 1H), 8.28-8.19 (m, 1H), 8.04 (s, 1H), 7.92-7.83 (m, 2H), 7.82-7.71 (m, 2H), 7.13 (d, J = 8.7 Hz, 1H), 3.83 (s, 3H), 3.36-3.30 (m, 2H), 2.93 - 2.78 (m, 2H), 1.50 (s, 9H).

[1118] LCMS (m / z): 456.5(M+H).

[1119]

[1120] Example 123. Preparation of 5-(1-butyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide

[1121] The compound of Example 9 was reacted with 1-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (18 mg, yield: 54%).

[1122] 1 H-NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.30 (s, 1H), 8.14 (d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.90 - 7.79 (m, 2H), 7.79 - 7.66 (m, 2H), 7.14 (dd, J = 8.8, 5.5 Hz, 1H), 4.04 (q, J = 6.6 Hz, 2H), 3.81 (s, 3H), 3.35-3.31 (m, 2H), 2.90 - 2.79 (m, 2H), 1.79 - 1.64 (m, 2H), 1.24 - 1.15 (m, 2H), 0.90 - 0.78 (m, 3H).

[1123] LCMS (m / z): 456.5(M+H).

[1124]

[1125] Example 124. Preparation of 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-phenyl-1H-pyrazol-4-yl)benzenesulfonamide

[1126] The compound of Example 9 was reacted with 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the manufacturing method of Example 27 to obtain the title compound (21 mg, yield: 60%).

[1127] 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.00 (d, J = 4.2 Hz, 1H), 8.39 - 8.30 (m, 1H), 8.15 (d, J = 4.2 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.93 - 7.80 (m, 4H), 7.54 - 7.41 (m, 2H), 7.34 - 7.18 (m, 2H), 3.86 (s, 3H), 3.37 - 3.30 (m, 2H), 2.91 - 2.79 (m, 2H).

[1128] LCMS (m / z): 476.5(M+H).

[1129]

[1130] The structural formulas of the compounds manufactured in Example 1-124 are summarized and shown in Table 1 below.

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143] Experimental Example 1: TNAP Inhibitory Activity

[1144] The TNAP inhibitory activity of the compound according to the present invention was analyzed through a colorimetric assay.

[1145] The experiment was conducted with reference to the protocol of the Alkaline phosphatase assay kit ab83369.

[1146] The enzyme (TNAP, Tissue None specific Alkaline Phosphatase), substrate (pNPP, p-Nitrophenyl phosphate), and compound were all prepared in stock using the ALP assay buffer contained in ab83369.

[1147] - TNAP enzyme: TNAP stock 0.2 μg / μl was diluted to 0.2 ng / μl using ALP assay buffer.

[1148] - Substrate: pNPP was dissolved in ALP assay buffer to make 5 mM and then diluted to 1 mM.

[1149] - Both test compounds and positive control compounds (MLS-0038949, SBI-425, DS-1211) dissolved in DMSO were diluted 10-fold using ALP assay buffer. IC 50For measurement, the concentration of the test substance was divided into 11 sections (0, 1, 5, 10, 25, 50, 100, 250, 500, 1000, 10000 nM) including 0 between 0 and 10 μM.

[1150] 0.2 ng / μl TNAP enzyme was dispensed into 96-well plates (Costar) at 10 μl each, and 15 μl of a 10-fold diluted test substance was added each. The plates were incubated for 10 minutes at room temperature, shielded from light, to allow the enzyme and the compound to interact. After incubation, 125 μl of 1 mM substrate (pNPP) was added, and the plates were incubated for 2 hours at room temperature, shielded from light, to allow the enzyme, substrate, and test compound to interact. The absorbance was measured at 405 nm using a microplate reader (microplate Readers, Tecan spark), and the IC was determined using GraphPad Prism 9. 50 The amount of p-nitrophenol produced was calculated through absorbance, and the degree of inhibition of TNAP activity was evaluated through the degree of inhibition of p-nitrophenol production, and the concentration of the compound that inhibited by 50% was IC 50 The IC of the positive control group was calculated as the value 50 IC of test compounds based on (190 nM) 50 The value has been determined.

[1151] The results are shown in Table 2 below.

[1152] IC 50 The values ​​are “A” indicates 10 nM or less, “B” indicates more than 10 nM and less than or equal to 100 nM, “C” indicates more than 100 nM and less than or equal to 1000 nM (1 μM), and “D” indicates more than 1000 nM (1 μM). IC of the positive control group 50 The values ​​were B for DS-1211 and C for MLS-0038949 and SBD-425.

[1153] Example IC 50 Example IC 50 Example IC50 Example IC 50 1B32B63C94B2B33B64D95C3B34C65D96B4B35A66D97C5C36B67C98C6A37D68B99C7A38D69C100C8B39B70C101B9A40D71 D102B10C41D72B103B11D42A73C104B12D43B74C105B13C44C75C106C14C45C76C107B15C46C77C108B16C47C78D109B1 7D48B79C110B18D49B80C111B19D50B81B112C20D51C82A113C21D52C83B114B22C53C84B115B23D54C85C116B24D55C8 6C117B25D56C87C118B26B57C88C119B27C58D89B120C28B59C90C121C29C60C91D122B30D61C92B123B31C62B93B124C

[1154]

[1155] Experimental Example 2: Evaluation of Calcification Inhibitory Efficacy in Saos-2 Cells

[1156] 1. Preparation of Saos-2 cells

[1157] To confirm the inhibitory effect of TNAP on calcification-induced saos-2 cells, saos-2 cells were cultured in a culture medium at 37°C, 95% humidity, and 5% CO2 in an incubator. RPMI-1640 (Corning) supplemented with 10% FBS (Gibco) and 1% Pen / Strep (Gibco) was used as the growth medium.

[1158] Saos-2 cells were cultured at 1.5x10 4 The dogs were seeded in 48-well plates and used in the experiment when they reached 80-90% confluency after 2 days of stabilization.

[1159] 2. Osteogenic differentiation of Saos2 cells

[1160] After saos-2 cells were cultured in 48-well plates to 80–90% confluency, the proliferation medium was removed and replaced with osteogenic media (OM). OM consisted of DMEM (Gibco), 10% FBS, 1% Pen / Strep, 100 nM dexamethasone (Sigma), 10 mM β-glycerophosphate (Sigma), and 0.05 mM L-ascorbic acid (Sigma). Osteogenic differentiation of saos-2 cells was induced in OM for 7 days, and the OM was replaced every 2–3 days.

[1161] 3. Inhibition of osteogenic differentiation and calcification by test compounds

[1162] When inducing calcification in Saos-2 cells through OM, TNAP inhibitor test compounds were treated at concentrations of 0.5, 1, 5, and 10 μl, excluding the control group (OM), and the test compounds were also treated together according to the OM replacement cycle. At this time, MLS-0038949, SBI-425, and DS-1211 compounds were treated together as positive controls for comparison.

[1163] 4. Confirmation and quantification of calcification using Alizarin Red staining

[1164] Seven days after OM induction, the medium was removed from each well and washed twice with PBS. After fixation with 4% paraformaldehyde for 1 hour, the fixative was removed and washed twice with deionized water (DW). ARS solution was added and stained for 1 hour while shaking. When sufficient red staining occurred, the dye was removed, the wells were carefully washed with DW, dried, and the stained images were photographed. The red-stained area represents OM-induced calcification, and the degree of calcification was determined based on the degree of redness. To quantify this, 10% cetylpyridinium chloride was dispensed into the wells and the dye was dissolved. The dissolved solution was transferred to a 96-well plate, and the absorbance was measured at 540 nm.

[1165] The degree of reduction in the measured absorbance of the test compound based on the absorbance for OM was evaluated as the degree of inhibition of calcification.

[1166] 5. Results

[1167] The calcification inhibition efficacy of the test compound in saos-2 cells is expressed as “A” for 50% or more inhibition at a test compound treatment concentration of 1 μM, “B” for 50% or less inhibition, and “C” for no efficacy. All positive control groups showed calcification inhibition efficacy A in saos-2 cells.

[1168] Example Calcification inhibition Example Calcification inhibition Example Calcification inhibition Example Calcification inhibition 1A32A63C94A2A33A64C95A3A34A65C96A4A35A66C97A5B36A67B98A6A37C68A99C7A38C69C100A8A39A70A101C9A40C71C102A10A41C72A103A11A42A73A104A12C43A74A105A13A44A75A106A14A45A76A107A15A46A77A10 8A16A47A78C109A17C48A79A110A18C49A80A111A19C50A81A112C20C51A82A113C21C52A83A114A22A53B84A115A23C54A85C116 A24C55A86C117A25C56A87C118A26A57A88A119A27A58B89A120C28A59A90B121C29A60A91C122C30B61A92A123A31A62A93A124C

[1169]

[1170] Experimental Example 3: Warfarin-induced calcification mouse animal model experiment

[1171] 1. Animals: C57BL / 6 mice (OrientBio, Seongnam, Korea)

[1172] Gender: Male

[1173] Age on arrival: C57BL / 6 (6 weeks)

[1174] Housing: Animals were housed in filter-capped polycarbonate cages, five per cage, in a sterile cleanroom with controlled temperature (25°C) and humidity (45–55%). The light:dark cycle was 12 h:12 h, and sterilized food and water were provided ad libitum.

[1175] Guidelines: All animals were treated in accordance with the Animal Care and Handling Guidelines of Yeungnam University, Gyeongsan, Republic of Korea.

[1176] 2. General experimental method: In vivo drug administration

[1177] After acclimating the mice for one week, they were divided into groups and tested.

[1178] After acclimation for one week, the mice were randomly divided into groups.

[1179] The subjects were divided into a group that received no treatment (A), a group that induced calcification by treating with warfarin and vitamin K1 (B), a group that received oral administration of 0.5% CMC (carboxymethyl cellulose) (C), and a group that received a test compound. The test compounds selected were compounds of Example 1 (K) and Example 6 (L).

[1180] All groups, except the untreated control group (Normal), were administered both warfarin and vitamin K1 at 8:00 AM and warfarin alone at 8:00 PM for 4 weeks.

[1181] Heart tissue samples were obtained from each group and used for analysis.

[1182] Individual heart samples were cross-sectioned around the origin / root of the ascending aorta. Histological sections were then prepared from all received samples. All cross-sectioned cardio-aortic valve areas were refixed in 10% neutral buffered formalin for 24 hours to prepare histological samples. After paraffin embedding, two serial sections, 3–4 μm thick, were prepared from each paraffin block and stained with hematoxylin and eosin (HE) for routine histopathology or von Kossa (VK) for calcium deposition. To observe more detailed changes, a computer-assisted image analysis program and a histological camera system were used to calculate the mean aortic valve thickness (μm) and the number of inflammatory cells infiltrating the aortic valve area (cells / mm2) in the HE staining, and the mean calcified aortic valve area (% / mm2) in the VK staining in the histopathological analysis. As shown in Table 4, the number of inflammatory cells decreased and the calcification area was significantly reduced compared to the calcification-induced group.

[1183] Meanwhile, Fig. 1 shows the stained results. According to this, in the calcification group (B) by warfarin and vitamin K1, it was confirmed through HE staining that the tissue thickness increased and inflammatory cells gathered due to increased inflammation, and the increased calcification was stained black by von Kossa staining, and in the treatment groups of Example 1 and 6 (K, L), the blackened area was significantly reduced.

[1184] Group average thickness (μm) Inflammatory cell count (cells / mm 2 )Calcification area (% / mm) 2 )Normal group (A)72.06±8.3125.20±13.311.00±0.33Calcified group (B)155.74±14.12385.20±70.345.75±0.95Vehicle treatment group (C)152.30±8.78386.80±77.925.77±0.58Example 1 treatment group (K)112.42±10.81144.40±43.122.45±0.64Example 6 treatment group (L)91.69±15.7080.40±14.901.16±0.30

[1185]

[1186] Experimental Example 4: Vitamin D-induced calcification mouse animal model experiment

[1187] Experimental animals were prepared similarly to Experimental Example 3. Excluding the normal group, four groups were administered high-dose (6.5 x 105 IU / Kg) of vitamin D3 subcutaneously once daily for a total of three days to induce calcification. Treatments in Examples 1 and 6 were administered orally together from the first day of vitamin D3 administration, and then administered for five more days without vitamin D3 administration, for a total of eight days, once daily.

[1188] Samples were obtained and analyzed in the same manner as in Experimental Example 3. As shown in Table 5, the number of inflammatory cells decreased and the calcification area was significantly reduced compared to the calcification-induced group.

[1189] Meanwhile, Fig. 2 shows the stained results. According to this, in the calcification group (B) by high-dose vitamin D3, it was confirmed through HE staining that the tissue thickness increased and inflammatory cells gathered due to increased inflammation, and the increased calcification was stained black by von Kossa staining, and in the treatment groups of Examples 1 and 6 (K, L), the blackened area was significantly reduced.

[1190] Group average thickness (μm) Inflammatory cell count (cells / mm 2 )Calcification area (% / mm) 2 )Normal group (A)43.05±10.3022.80±10.061.30±0.56Calcified group (B)113.80±23.85184.89±19.3712.89±2.18Vehicle treatment group (C)112.55±12.34182.22±23.1413.19±2.54Example 1 treatment group (K)64.26±12.34110.89±21.647.95±1.16Example 6 treatment group (L)51.76±10.3958.89±17.322.44±0.92

[1191]

[1192] As demonstrated in Experimental Examples 1 to 4, the compounds of the present invention not only effectively inhibit TNAP, but are also highly effective in inhibiting and slowing the progression of ectopic calcification. Therefore, they are expected to be very useful in the prevention or treatment of diseases associated with overexpression or overactivation of TNAP or diseases associated with ectopic calcification.

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 is hydrogen, halogen, unsubstituted or substituted phenyl, or C 1-10 It is alkoxy; R 2 is hydrogen; R 3 is hydrogen or halogen; R 4 is hydrogen, halogen, unsubstituted or substituted phenyl, unsubstituted or substituted 5-9 membered heteroaryl, unsubstituted or substituted 6-membered cycloalkenyl substituted with one or more halogens, unsubstituted or substituted 6-membered heterocycloalkenyl, or C 1-10 It is alkoxy; R 5 is hydrogen or halogen; or R 1 Inland R 5 The two adjacent substituents in the group together form -(CH2)mO-, -O-(CH2)mO-, or -O-(CH2)m-CO-NH-, while the remaining three substituents are as described above; The above substituted phenyl is C 1-10 Alkoxy, carboxyl, unsubstituted or substituted C 1-10 Substituted with 1 to 3 substituents selected from 3-6 membered cycloalkyl substituted with alkyl, carboxyl, halogen and hydroxyl, or substituted at two adjacent positions to form -O-(CH2)mO-, wherein the substituted C 1-10 Alkyl is carboxyl, C 1-10 Alkoxycarbonyl, amino or C 1-10 Substituted with alkylaminocarbonyl; The above substituted 5-9 membered heteroaryl is halogen, amino, unsubstituted C 1-10 Alkyl, substituted C 1-10 Alkyl, NH2CO-, unsubstituted or substituted 4-6 membered heterocycloalkyl, C 1-10 Substituted with 1 to 3 substituents selected from alkylsulfonyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl and phenyl, wherein the substituted C 1-10 Alkyl is carboxyl, C 1-10 Alkoxycarbonyl, C 1-10 Alkylaminocarbonyl, C 1-10 A 5-6 membered heteroaryl substituted with alkyl or phenyl substituted with one or more halogens, a 4-6 membered heterocycloalkyl substituted with one or more halogens or hydroxyl, is C 1-10 Alkyl or C 1-10 substituted with alkoxycarbonyl; The above substituted 6-membered heterocycloalkenyl is C 1-10 Alkoxycarbonyl or C 1-10 substituted with alkylcarbonyl; R 6a and R 6b are all hydrogen or together are oxo; R 7 Silver hydrogen, 5-6 membered heteroaryl, -CO x -R 8a , -CONR 8b R 8c , or C 1-10 alkyl, where x is 1 or 2, R 8a and R 8b are each independently unsubstituted or substituted C 1-10 Alkyl, or C 6-10 Aryl, where the substituted C 1-10 Alkyl is substituted with one or more halogens, or 3-6 cycloalkyl, R 8c is hydrogen or R 8b and these together with the substituted nitrogen atom form a 5-6 membered heterocycloalkyl; wherein m is an integer from 1 to 4; The above n is an integer from 1 to 3.

2. In paragraph 1, The above R 1 is hydrogen, halogen, unsubstituted or substituted phenyl, or C 1-5 It is alkoxy, The above substituted phenyl is cyclopropyl substituted with carboxyl, or unsubstituted or substituted C 1-5 Alkyl, where C is substituted 1-5 Alkyl is substituted with carboxyl or amino, A compound or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, The above R 4 is hydrogen, halogen, unsubstituted or substituted phenyl, 9-membered bicyclic heteroaryl, unsubstituted or substituted 5-6-membered heteroaryl, 6-membered cycloalkenyl unsubstituted or substituted with one or more halogens, or 6-membered heterocycloalkenyl containing one heteroatom among unsubstituted or substituted O, N, or C 1-5 It is alkoxy, The above substituted phenyl is C 1-5 Alkoxy, carboxyl, unsubstituted or substituted C 1-5 Substituted with 1 to 3 substituents selected from alkyl, carboxyl-substituted cyclopropyl, halogen and hydroxyl, or substituted at two adjacent positions to form -O-(CH2)mO-, wherein the substituted C 1-5 Alkyl is carboxyl, C 1-5 Alkoxycarbonyl, amino or C 1-5 Substituted with alkylaminocarbonyl; The above substituted 5-6 membered heteroaryl is halogen, amino, unsubstituted C 1-5 Alkyl, substituted C 1-5 Substituted with 1 to 3 substituents selected from alkyl, NH2CO-, unsubstituted or substituted 4-6 membered heterocycloalkyl, methylsulfonyl, cyclopropyl, 6 membered heteroaryl and phenyl, wherein the substituted C 1-5 Alkyl is carboxyl, C 1-5 Alkoxycarbonyl, C 1-5 Alkylaminocarbonyl, C 1-5 A 5-membered heteroaryl substituted with alkyl or phenyl substituted with one or more halogens, a 4-6-membered heterocycloalkyl substituted with one or more halogens or hydroxyl, is C 1-5 Alkyl or C 1-5 substituted with alkoxycarbonyl; The above substituted 6-membered heterocycloalkenyl is C 1-5 Alkoxycarbonyl or C 1-5 substituted with alkylcarbonyl; The above m is an integer from 1 to 3, A compound or a pharmaceutically acceptable salt thereof.

4. In paragraph 3, R 1 Inland R 5 Two adjacent substituents in the group are combined -(CH2)mO-, -O-(CH2)mO-, or -O-(CH 2)m When forming -CO-NH-, the remaining three substituents are each independently hydrogen, halogen, or substituted phenyl, The above substituted phenyl is a 3-6 membered cycloalkyl substituted with carboxyl, or an amino substituted C 1-10 Substituted with alkyl, The above m is an integer from 1 to 3, A compound or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, R 1 Inland R 5 The two adjacent substituents are R 1 and R 2 And, R 1 and R 2 together with -(CH2)mO-, -O-(CH2)mO-, or -O-(CH 2)m When forming -CO-NH-, The remaining three substituents are each independently hydrogen, halogen, or substituted phenyl, The above substituted phenyl is cyclopropyl substituted with carboxyl, or amino substituted C 1-5 substituted with alkyl; or The above R 1 Inland R 5 The two adjacent substituents are R 2 and R 3 And, R 2 and R 3 together form -O-(CH2)mO- or -O-(CH2)m-CO-NH-, and the remaining three substituents are all hydrogen; The above m is an integer from 1 to 2, A compound or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, R 7 Silver hydrogen, 6-membered heteroaryl, -CO x -R 8a , -CONR 8b R 8c or C 1-5 alkyl, where x is 1 or 2, R 8a is unsubstituted or substituted with 1 halogen C 1-6 It is alkyl, R 8b is unsubstituted or substituted C 1-6 alkyl, or phenyl, C substituted here 1-6 Alkyl is substituted with 1 or 2 halogens, or cyclopropyl, R 8c is hydrogen or R 8b and these together with the substituted nitrogen atom form a 6-membered heterocycloalkyl, A compound or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, R 1 Silver C 1-5 alkoxy, halogen, hydrogen, unsubstituted or substituted phenyl; R 2 is hydrogen; R 3 is hydrogen or halogen; R 4 is hydrogen, halogen, unsubstituted or substituted phenyl, pyrazolopyridine, unsubstituted or substituted 5-6 membered heteroaryl, unsubstituted or substituted 6 membered cycloalkenyl substituted with one or more halogens, unsubstituted or substituted heterocycloalkenyl containing one heteroatom among O, N, or C 1-5 It is alkoxy; R 5 is hydrogen or halogen; or R 1 Inland R 5 Two adjacent substituents in the group are together -(CH2)mO-, -O-(CH2)mO-, or -O-(CH 2)m -CO-NH-, while the remaining three are each independently hydrogen, halogen, or substituted phenyl, wherein the substituted phenyl is cyclopropyl substituted with carboxyl, or amino substituted C 1-3 substituted with alkyl; The above substituted phenyl is C 1-5 Alkoxy, carboxyl, unsubstituted or substituted C 1-5 substituted with cyclopropyl substituted with alkyl, carboxyl, or substituted with 1 to 3 substituents selected from halogen and hydroxyl, or substituted at two adjacent positions to form -O-(CH2)mO-, C substituted here 1-5 Alkyl is carboxyl, C 1-5 Alkoxycarbonyl, amino or C 1-5 Substituted with alkylaminocarbonyl; The above substituted 5-6 membered heteroaryl is halogen, amino, unsubstituted C 1-5 Alkyl, substituted C 1-5 Substituted with 1 to 3 substituents selected from alkyl, NH2CO-, unsubstituted or substituted 4-6 membered heterocycloalkyl, methylsulfonyl, cyclopropyl, 6 membered heteroaryl and phenyl, C substituted here 1-5 Alkyl is carboxyl, C 1-5 Alkoxycarbonyl, C 1-5 Alkylaminocarbonyl, C 1-5 5-membered heteroaryl substituted with alkyl or 1 halogen substituted phenyl, substituted with 1 or more halogens, or hydroxyl, Substituted 4-6 membered heterocycloalkyl is C 1-5 Alkyl or C 1-5 substituted with alkoxycarbonyl; The above substituted 6-membered heterocycloalkenyl is C 1-5 Alkoxycarbonyl or C 1-5 substituted with alkylcarbonyl; R 6a and R 6b are all hydrogen or together are oxo; R 7 Silver hydrogen, pyrimidinyl, -CO x -R 8a , -CONR 8b R 8c , or C 1-5 alkyl, where x is 1 or 2, R 8a is unsubstituted or substituted with one halogen C 1-6 It is alkyl, R 8b is unsubstituted or substituted C 1-6 alkyl, or phenyl, C substituted here 1-6 Alkyl is substituted with 1 or 2 halogens, or cyclopropyl, R 8c is hydrogen or R 8b and these together with the substituted nitrogen atom form morpholinyl; wherein m is an integer of 1 or 2; The above n is an integer from 1 to 3, A compound or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, R 1 Silver hydrogen, halogen, or methoxy; R 2 is hydrogen; R 3 is hydrogen or halogen; R 4 is hydrogen, halogen, or methoxy; R 5 is hydrogen or halogen; or R 1 Inland R 5 Two adjacent substituents in the middle are together , , or The remaining three substituents are each independently hydrogen, halogen, or substituted phenyl, wherein the substituted phenyl is cyclopropyl substituted with carboxyl, or amino substituted C 1-3 substituted with alkyl; R 6a and R 6b are all hydrogen or together are oxo; R 7 Silver hydrogen, or C 1-3 It is alkyl; The above n is an integer from 1 to 3, A compound or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, The compound or a pharmaceutically acceptable salt thereof is any one selected from the following: <1> 5-Chloro-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide; <2> 5-Bromo-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide; <3> 2,5-Dimethoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide; <4> 5-Fluoro-2-methoxy-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide; <5> 5-Bromo-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <6> 5-chloro-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <7> 2,5-Dimethoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <8> 5-Fluoro-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <9> 5-Bromo-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <10> 5-Bromo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <11> 2-Bromo-5-fluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide; <12> 2-Bromo-4,6-difluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzenesulfonamide; <13> 5-Chloro-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide; <14> 5-Bromo-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide; <15> 5-Fluoro-2-methoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide; <16> 2,5-Dimethoxy-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)benzenesulfonamide; <17> 5-Bromo-N-(5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <18> N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <19> N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <20> 5-Chloro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <21> 5-Fluoro-N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <22> 5-Chloro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <23> 5-Fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <24> N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide; <25> 3-Oxo-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide; <26> 2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <27> Methyl 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetate; <28> 2-(4'-methoxy-3'-(N-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid; <29> 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <30> 4,4'-Dimethoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-3-sulfonamide; <31> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(pyridin-4-yl)benzenesulfonamide; <32> 1-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid; <33> 2-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid; <34> 4'-Methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-carboxylic acid; <35> 2-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)acetic acid; <36> 1-(4'-fluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid; <37> 1-(3',5'-difluoro-2'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid; <38> 1-(4-(7-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-2,3-dihydrobenzofuran-5-yl)phenyl)cyclopropane-1-carboxylic acid; <39> 4'-(Aminomethyl)-4-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride; <40> 4'-(Aminomethyl)-3,5-difluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-2-sulfonamide hydrochloride; <41> 5-(4-(aminomethyl)phenyl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2,3-dihydrobenzofuran-7-sulfonamide; <42> Ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)propanoate; <43> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)propanoic acid; <44> 5-(2-aminopyrimidin-5-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <45> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)benzenesulfonamide; <46> 3',5'-Difluoro-4'-hydroxy-4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-[1,1'-biphenyl]-3-sulfonamide; <47> tert-Butyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetate; <48> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetic acid; <49> Ethyl 3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanoate; <50> 3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanoic acid; <51> 5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <52> tert-Butyl 4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate; <53> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzenesulfonamide hydrochloride; <54> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzenesulfonamide; <55> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1H-pyrazol-4-yl)benzenesulfonamide; <56> 2-Bromo-5-fluoro-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <57> 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <58> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanamide; <59> Ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanoate; <60> 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanoic acid; <61> 5-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <62> 5-(5,6-dihydro-2H-pyran-3-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <63> 4-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-sulfonamide; <64> 4',4'-Difluoro-4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-sulfonamide; <65> 2-Methoxy-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <66> N-Ethyl-2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetamide; <67> N-Ethyl-3-(4'-methoxy-3'-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)-[1,1'-biphenyl]-4-yl)propanamide; <68> Ethyl 2-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)acetate; <69> 5-(1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <70> 2-Methoxy-5-(1-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <71> 5-(1-(1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <72> 5-(1-Isopropyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <73> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzenesulfonamide; <74> 5-(1-Cyclopropyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <75> 2-Methoxy-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <76> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide; <77> 5-(6-Fluoropyridin-3-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <78> 5-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <79> 2-Methoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <80> 5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <81> 5-(1-Isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <82> 5-(1-Ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <83> 5-(Isoxazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <84> 5-(3,5-dimethylisoxazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <85> tert-Butyl 4-(4-(4-methoxy-3-(N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)sulfamoyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; <86> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide hydrochloride; <87> 5-Bromo-2-methoxy-N-(6-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <88> tert-Butyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <89> tert-Butyl 3-((2,5-dimethoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <90> 5-Fluoro-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride; <91> 5-Fluoro-2-bromo-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride; <92> 5-chloro-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride; <93> 5-Bromo-2-methoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride; <94> 2,5-Dimethoxy-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide hydrochloride; <95> Ethyl 3-((5-fluoro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <96> Ethyl 3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <97> Ethyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <98> Neopentyl 3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <99> Neopentyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <100> Neopentyl 3-((5-methoxy-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <101> 2-Fluoroethyl-3-((5-chloro-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <102> 2-Fluoroethyl 3-((5-bromo-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <103> 2-Fluoroethyl-3-((5-methoxy-2-methoxyphenyl)sulfonamido)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate; <104> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <105> 3-((5-Fluoro-2-methoxyphenyl)sulfonamido)-N-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <106> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-pentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <107> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <108> 3-((5-Bromo-2-methoxyphenyl)sulfonamido)-N-(2,2-difluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <109> 5-chloro-2-methoxy-N-(6-(morpholine-4-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <110> 5-Bromo-2-methoxy-N-(6-(morpholine-4-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <111> 3-((5-Bromo-2-methoxyphenyl)sulfonamido)-N-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <112> 5-chloro-N-(6-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide; <113> 5-Bromo-N-(6-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide; <114> 3-5-chloro-2-methoxy-N-(6-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <115> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-phenyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <116> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(cyclopropylmethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <117> 3-((5-chloro-2-methoxyphenyl)sulfonamido)-N-(2-fluoroethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxamide; <118> 5-Chloro-N-(6-(3,3-dimethylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide; <119> 5-Bromo-N-(6-(3,3-dimethylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-methoxybenzenesulfonamide; <120> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzenesulfonamide; <121> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide; <122> 5-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <123> 5-(1-Butyl-1H-pyrazol-4-yl)-2-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)benzenesulfonamide; <124> 2-Methoxy-N-(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-(1-phenyl-1H-pyrazol-4-yl)benzenesulfonamide.

10. In any one of paragraphs 1 to 9, The compound is characterized by inhibiting tissue-nonspecific alkaline phosphatase (TNAP). A compound or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for the prevention or treatment of a disease related to overexpression or overactivation of tissue-nonspecific alkaline phosphatase (TNAP), comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient: The diseases include pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), craniometaphyseal dysplasia (CMD), ossification of the yellow ligament (OYL), arterial calcification, calcification of joints, arthrosis deformans, osteoarthritis, ankylosis of the joint, idiopathic infantile arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC), progressive osseous heteroplasia (POH), Keutel syndrome, and vascular disease associated with chronic renal failure. Calcification (vascular calcification associated with chronic renal failure) (chronic renal failure includes glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic calcification, calciphylaxis, calcific tendinitis of the longus colli muscle, fibrodysplasia ossificans progressive;FOP), calcific aortic stenosis, pericarditis calculosa, atherosclerotic vascular calcification, calcific uremic arteriopathy (CUA), Kawasaki disease, calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget's disease, idiopathic basal ganglia calcification (IBGC), heterotopic ossification (HO), calcific aortic valve disease (CAVD), aortic valve stenosis (AVS), Selected from the group consisting of calcific tendinitis, ossification of the posterior longitudinal ligament (OPLL), ossification of the anterior longitudinal ligament (OALL), diffuse idiopathic skeletal hyperostosis (DISH), meniscal calcification, and peritoneal calcification.; 12. A pharmaceutical composition according to claim 11, characterized in that the compound inhibits tissue-nonspecific alkaline phosphatase (TNAP).

13. A method for treating a disease associated with overexpression or overactivation of tissue-nonspecific alkaline phosphatase (TNAP), comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

14. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a disease associated with overexpression or overactivation of tissue-nonspecific alkaline phosphatase (TNAP).

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