Novel pyrido pyridazinone derivative compound and pharmaceutical composition comprising same

Abstract

The present invention relates to a novel pyrido pyridazinone derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, a pharmaceutical composition comprising same, a method for preventing or treating ENPP1-related diseases using same, and uses thereof.

Description

[0001] Description of the Invention

[0002]

Title of invention

[0003]

Technical Field

[0004]

Background

[0005]

Technical Problem

[0006] 1) The present invention provides a compound represented by any one of the following chemical formulas 1 to 3, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0007] <Chemical Formula 1>

[0008] In the above chemical formula 1,

[0009] L1 and L2 are each independently -L a - U- and the above L ais a 3- to 6-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of a single bond, N, 0 and S in the ring, (C1-C5 alkylene)-(3- to 6-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring), 6- to 14-membered arylene, (C1-C5 alkylene)-(6- to 14-membered arylene), NH, NH(C1-C5 alkylene)-(3- to 6-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring), NH-(6- to 14-membered arylene), NH(C1-C5 alkylene)-(6- to 14-membered arylene), NH (C1-C5 alkylene)-(5- to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and ) in the ring, O-(C1-C5 alkylene)-(3- to 5-membered heterocycloalkylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and ) in the ring, or a divalent functional group of a fused ring in which two or more rings are bonded while sharing atoms, and the L a At least one of the groups may be independently substituted or unsubstituted with a halogen;

[0010] U is a single bond, Cl- C8 alkylene or Cl- C8 alkenylene, and R1 and R2 are each independently H, B(OH)2, CN, C(=O)NH-OH, N(C1- C5 alkyl)(C1- C5 alkyl), NH(C1- C5 alkyl), NH2, NH-C(=0)-NH2, NH-P(=0)(OH)2, NH- P(=S)(OH)2, NH-S(=0)2-NH 2IO (C1- C5 alkyl), 0- (C3-C6 cycloalkyl), OH, 0- P (=O) (OH)2, OP (=S) (OH)2, P (=O) (OH)2, P (=S) (OH)2, SP (=O) (OH)2 or s- P (=S) (OH)2, and in the above chemical formula 1, each independently satisfies the valence A combined single bond or double bond,

[0011] A1 is 0, NR 3a R 3b or 0R 3c and R 3a , R 3b and R 3c are each independently H, C1-

[0012] C5 alkyl or C3-C6 cycloalkyl, and A2 is N or N(- L4- R4),

[0013] L4 is a single bond, C1-C5 alkylene, C(=0), C(=o)- (C1-C5 alkylene), C(=O)O(C1- C5 alkylene), C(=S), S(=0)2, (C1-C5 alkylene) - C(=0), (C1-C5 alkylene) - C(=O)NH or (C1-C5 alkylene) - C(=0)0,

[0014] R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), 6-14 membered aryl, 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring, 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring,

[0015] R4's C1-C5 alkyl, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring, or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein at least one of these groups may be independently substituted or unsubstituted with C1-C5 alkyl, C1-C5 alkoxy, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), N02 or halogen,

[0016] At least one of the carbons forming the ring of a 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S of R4 may be C(=0) A3 is CH, CH2 or N, and A4 is CR5a or CHR 5b and R 5a and R 5b are each independently H or C1-C5 alkyl, A5 is CR6 or N, R6 is H or C1-C5 alkyl, and in the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in the above chemical formula 1, and A6 in the above chemical formula 2 is 0R 3c and R 3c is the same as defined in Chemical Formula 1, and in Chemical Formula 3, L1, R1, A2, A3, A4 and A5 are the same as defined in Chemical Formula 1.

[0017] 2) According to one embodiment of the present invention, in the chemical formula 1 of 1),

[0018] L1 and L2 are each independently -L a - L b - and the above L ais a single bond, a 3- to 6-membered heterocycloalkylene containing 1 to 3 C1-C5 alkylene in the ring, (C1-C5 alkylene) - (a 3- to 6-membered heterocycloalkylene containing 1 to 3 Ns in the ring), phenylene, (C1-C5 alkylene) - phenylene, NH, NH (C1-C5 alkylene) - (a 3- to 6-membered heterocycloalkylene containing 1 to 3 Ns in the ring), NH-phenylene, NH (C1-C5 alkylene) - phenylene, NH (C1-C5 alkylene) - (a 5- to 12-membered heteroarylene containing 1 to 3 Ns in the ring), O- (C1-C5 alkylene) - (a 3- to 6-membered heterocycloalkylene containing 1 to 3 Ns in the ring), or a tetrahydroisoquinoline divalent functional group, and the L a At least one of which may be independently substituted or unsubstituted with a halogen,

[0019] L b is a single bond, C1-C5 alkylene or C1-C5 alkenylene, R1 and R2 are each independently H, B(OH)2, CN, C(=O)NH-OH, N(C1- C3 alkyl)(Cl- C3 alkyl), NH(C1- C3 alkyl), NH2, NH-C(=0)-NH2, NH-P(=0)(OH)2, NH- P(=S)(OH)2, NH- S(=0)2- NH2, O(C1- C3 alkyl), 0-(C3-C6 cycloalkyl), OH, 0- P(=O)(OH)2, OP(=S)(OH)2, P(=O)(OH)2, P(=S)(OH)2, SP(=O)(OH)2 or S- P(=S)(OH)2, and “=3=” in the above chemical formula 1 is each independently selected to satisfy the valence. A combined single bond or double bond,

[0020] A1 is 0, NR 3a R 3b OR 3c and R 3a , R 3b and R 3c are each independently H, C1-C5alkyl or C3-C6cycloalkyl,

[0021] A2 is N or N(- L4- R4),

[0022] L4 is a single bond, C1-C5 alkylene, C(=0), C(=0)-(C1-C5 alkylene), C(=O)O(C1- C5 alkylene), C(=S), S(=0)2, (C1-C5 alkylene) - C(=0), (C1-C5 alkylene) - C(=O)NH or (C1-C5 alkylene) - C(=0)0,

[0023] R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), 6-14 membered aryl, 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring, 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring,

[0024] R4's C1-C5 alkyl, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring, or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein at least one of these groups may be independently substituted or unsubstituted with C1-C5 alkyl, C1-C5 alkoxy, CN, OH, NH2, MC1-C5 alkyl)(C1-C5 alkyl), N02 or halogen,

[0025] At least one of the carbons forming the ring of a 3- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S of R4 may be C (=0), A3 is CH, CH2 or N, and A4 is CR 5aor CHR 5b and R 5a and R 5b are each independently H or C1-C5 alkyl, A5 is CR6 or N, R6 is H or C1-C5 alkyl, and in the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in the above chemical formula 1, and A6 in the above chemical formula 2 is 0R 3c and R 3c is the same as defined in Chemical Formula 1, and in Chemical Formula 3, L1, R1, A2, A3, A4 and A5 may be the same as defined in Chemical Formula 1.

[0026] 3) According to one embodiment of the present invention, in the chemical formula 1 of 1) or 2),

[0027] L1 and L2 are each independently -L a - L b - and the above L a is a single bond, piperidinylene, piperazinylene, (C1-C5 alkylene)- piperidinylene, (C1-C5 alkylene)-piperazinylene, phenylene, (C1-C5 alkylene)-phenylene, NH, NH (C1- C5 alkylene)-piperidinylene, NH-phenylene, NH (C1- C5 alkylene)-phenylene, NH (C1- C5 alkylene)-pyridinylene, O- (C1-C5 alkylene)-piperidinylene or Above L a At least one or more of which may be independently substituted with a halogen,

[0028] L bis a single bond, C1-C5 alkylene or C1-C5 alkenylene, R1 and R2 are each independently H, B(OH)2, CN, C(=0)NH-OH, C(=0)OH, N(C1- C3 alkyl)(Cl- C3 alkyl), NH(C1- C3 alkyl), NH2, NH-C(=0)-NH2, NH-P(=0)(OH)2, NH- P(=S)(OH)2, NH- S(=0)2- NH2, O(C1- C3 alkyl), 0-(C3-C6 cycloalkyl), OH, 0- P(=O)(OH)2, OP(=S)(OH)2, P(=O)(OH)2, P(=S)(OH)2, SP(=O)(OH)2 or s- P(=S)(OH)2, and in the above chemical formula 1, are each independently To satisfy the valence A combined single bond or double bond,

[0029] A1 is 0, NR 3a , R 3b OR 3c and R 3a , R 3b and R 3c are each independently H, C1-C5 alkyl or C3-C6 cycloalkyl,

[0030] A2 is N or N(- L4- R4),

[0031] L4 is a single bond, C1-C5 alkylene, C(=0), C(=0)-(C1-C5 alkylene), C(=O)O(C1- C5 alkylene), C(=S), S(=0)2, (C1-C5 alkylene) - C(=0), (C1-C5 alkylene) - C(=O)NH or (C1-C5 alkylene) - C(=0)0,

[0032] R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl,

[0033] At least one or more of H of the above C1-C5 alkyl, phenyl, naphryl, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl of R4 may be independently substituted or unsubstituted with C1-C5 alkyl, C1-C5 alkoxy, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), N02 or halogen,

[0034] At least one of the carbons forming the ring of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl of R4 may be C(=0), A3 is CH, CH2 or Si, and A4 is CR 5a or CHR 5b And,

[0035] R 5a and R 5b are each independently H or C1-C5 alkyl, A5 is CR6 or Si, R6 is H or C1-C5 alkyl, and in the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in the above chemical formula 1, and A6 in the above chemical formula 2 is OR 3c and R 3c is the same as defined in Chemical Formula 1, and in Chemical Formula 3, L1, R1, A2, A3, A4 and A5 may be the same as defined in Chemical Formula 1.

[0036] 4) According to one embodiment of the present invention, in the chemical formula 1 of any one of 1) to 3),

[0037] L1 and L2 are each independently -L a - L b - and the above L ais a 3- to 6-membered heterocycloalkylene containing 1 to 3 heteroatoms independently selected from the group consisting of a single bond, N, 0 and S in the ring, a 6- to 14-membered arylene or (C1-C5 alkylene) - (6- to 14-membered arylene),

[0038] L b is a single bond or C1-C8 alkylene, and R1 and R2 are each independently H, NH (C1- C5 alkyl), NH2, NH- S (=0) 『 NH2, O (C1- C5 alkyl) or P (=0) (OH)2; “=3=” in the above chemical formula 1 is each independently a single bond or double bond bonded to satisfy the valence,

[0039] A1 is 0,

[0040] A2 is N(- L4- R4),

[0041] L4 is a single bond, C1-C5 alkylene, C(=0), (C1-C5 alkylene) - C(=0) or (C1- C5 alkylene) -C(=0)0,

[0042] R4 is a 3-6 membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of H, C1-C5 alkyl, C3-C6 cycloalkyl, N, 0 and S, CN, NH2 or N(C1-C5 alkyl)(C1-C5 alkyl),

[0043] At least one of the H of the above C1-C5 alkyl of R4 may be independently substituted with C1-C5 alkoxy or halogen, and A3 is Si; A4 is CR 5a , R 5a is visible; A5 is CR6, R6 is visible; In the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in chemical formula 1, and A6 of the above chemical formula 2 is 0R 3c and R 3cIn the chemical formula 3, L1, R1, A2, A3, A4 and A5 may be the same as those defined in chemical formula 1.

[0044] 5) According to one embodiment of the present invention, in the chemical formula 1 of any one of 1) to 4),

[0045] L1 and L2 are each independently -L a - L b - and the above L a is a single bond, piperidinylene, phenylene, (C1-C5 alkylene)-phenylene,

[0046] L b is a single bond or C1-C8 alkylene;

[0047] R1 and R2 are each independently H, NH(C1- C5 alkyl), NH2, NH-S(=0)2-NH2, O(C1- C5 alkyl) or P(=0)(OH)2; “=3=” in the above chemical formula 1 is each independently a single bond or double bond bonded to satisfy the valence;

[0048] A1 is 0; 2 is N(- R4),

[0049] L4 is a single bond, C1-C5 alkylene, C(=0), (C1-C5 alkylene) - C(=0) or (C1- C5 alkylene) -C(=0)0,

[0050] R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CN, NH2 or N(C1- C5 alkyl)(C1- C5 alkyl),

[0051] At least one of the H of the C1-C5 alkyl of R4 may be independently substituted with C1-C5 alkoxy or halogen; A3 is Si; A4 is CR 5a , R 5a is visible; A5 is CR6, R6 is visible; In the above chemical formula 2, L2, R2, A 2I A3, A4 and A5 are the same as defined in Chemical Formula 1, and A6 in Chemical Formula 2 is 0R 3cand R 3c In the chemical formula 3, L1, R1, A2, A3, A4 and A5 may be the same as those defined in chemical formula 1.

[0052] 6) In the present invention, each functional group of 1) to 5) can be defined as follows. In the present invention, the term "Cm-Cn" (wherein m and n are each independently an integer of 1 or more) means the number of carbons, for example, 'C1-C5 alkyl' means alkyl having 1 to 5 carbons. In the present invention, "substitution" or "substituted with ~" is defined to include the implicit condition that such substitution depends on the allowable valency of the substituted atom and the substituent, and that the substitution induces a stable compound, for example, a compound that is not naturally transformed by rearrangement, cyclization, elimination, etc. In the present invention, "single bond" means a case where adjacent atoms or atomic groups are directly bonded to each other. In the chemical formula of this specification, among those represented as “- L-” as a divalent functional group and defined for L, when L is a single bond, it means that atoms on both sides are directly connected by L, and when L is a single bond as a divalent functional group, it is substantially the same as when L does not exist. In the present invention, unless otherwise stated, “alkyl” means a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group. Examples of alkyl include, but are not limited to, one or more selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl, etc. In the present invention, unless otherwise stated, “alkylene” means a divalent functional group derived from alkyl defined as above. In the present invention, “alkenylene” may be a divalent functional group containing one or more double bonds in the definition of alkylene. Alkenylene may include - CH=CH-, -CH=C(CH3)-, - CH=CH- CH2-, - CH2- CH=CH- CH2-, - CH2- CH=CH- CH2- CH=CH-, etc.In the present invention, "alkoxy" means a monovalent functional group of the form -0-R, wherein R means alkyl. In this case, alkyl is the same as defined above. In the present invention, unless otherwise stated, "cycloalkyl" means a monovalent functional group of a monocyclic or polycyclic saturated hydrocarbon ring having 3 or more carbon atoms, and may include, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydropentarenyl, decahydronaphthalenyl, etc. In the present invention, unless otherwise stated, "cycloalkylene" means a divalent functional group derived from cycloalkyl as defined above. In the present invention, unless otherwise stated, "heterocycloalkyl" means a monocyclic or polycyclic ring in which at least one carbon atom forming the cycloalkyl ring defined above is substituted with a heteroatom selected from the group consisting of N, 0, and S. Examples of heterocycloalkyl include, but are not limited to, one or more selected from oxiranyl, dioxolanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. In the present invention, examples of a functional group in which at least one of the carbon atoms forming the heterocycloalkyl ring is C(=0) include. In the present invention, unless otherwise stated, "heterocycloalkylene" means a divalent functional group derived from heterocycloalkyl as defined above. In the present invention, unless otherwise stated, "aryl" means a monocyclic or polycyclic aromatic cyclic group having one or more aromatic rings, which are fused or non-fused. Examples of aryl include, but are not limited to, one or more selected from phenyl, naphthalenyl, indenyl, and anthracenyl. In the present invention, unless otherwise stated, "arylene" means a divalent functional group derived from aryl as defined above. In the present invention, unless otherwise stated, "heteroaryl" means a monocyclic or polycyclic aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of N, 0, and S in the ring and having one or more aromatic rings, which are fused or non-fused. Examples of heteroaryl include pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazole, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, One or more selected from triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazole, etc. may be mentioned, but is not limited thereto. In the present invention, unless otherwise stated, "heteroarylene" means a divalent functional group derived from heteroaryl defined as above.In the present invention, "fused ring" means a polycyclic ring in which two or more different rings are bonded while sharing atoms. The fused ring includes, for example, a structure in which a saturated hydrocarbon ring and an aromatic hydrocarbon ring are fused, a structure in which a cycloalkene ring and a saturated hydrocarbon ring are fused, a structure in which an aromatic hydrocarbon ring and a cycloalkene ring are fused, and a structure in which at least one of the carbon atoms of such a fused structure is substituted with a heteroatom. When the fused ring includes two or more heteroatoms, the heteroatoms may be the same as or different from each other. Examples of divalent functional groups of the fused ring include, In the present invention, when === in the chemical formula is a single bond, it means " (single solid line), and when === is a double bond, it means " = " (double solid line). That is, === shown in the chemical formula in the present invention can be a single bond or a double bond so as to satisfy the valence depending on the definition of the atoms connected thereby. In the present invention, "halogen" can be F, Cl, Br or I unless otherwise specified. In addition, terms and abbreviations used in this specification have their original meanings unless otherwise defined.

[0053] 6) According to one embodiment of the present invention, in any one of 1) to 5), the present invention provides a compound described in Table 1 below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0054] [Table 1] ¬

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] A composition comprising a compound represented by any one of formulae 1 to 3, a method of using a compound represented by any one of formulae 1 to 3, and a use of a compound represented by any one of formulae 1 to 3 The present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound represented by any one of formulae 1 to 3, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. In the present invention, "stereoisomer" includes diastereomers and optical isomers, and optical isomers include not only enantiomeric isomers but also mixtures of enantiomeric isomers and racemates. In the present invention, "pharmaceutically acceptable" may mean physiologically acceptable and not causing an allergic reaction such as gastrointestinal disorder or dizziness or a similar reaction when administered to a subject. The pharmaceutically acceptable salt of the present invention can be prepared by a conventional method known to those skilled in the art. For example, it may be an organic acid salt prepared with acetic acid, citric acid, etc. The "hydrate" of the present invention is a compound represented by any one of the above chemical formulas 1 to 3, a compound of the above Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and water are bound by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may contain water in a ratio of about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc.The "solvate" of the present invention is a compound represented by any one of the above chemical formulas 1 to 3, a compound of the above Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a solvent other than water, which are bound by non-covalent intermolecular forces, and may include a stoichiometric or non-stoichiometric amount of the solvent. Specifically, the solvate may include solvent molecules in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may include about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc. A compound represented by any one of the above chemical formulas 1 to 3, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutical composition comprising the same as an active ingredient exhibit ENPP1 inhibitory activity and can be used for the prevention, treatment, or improvement of ENPP1-related diseases. In the present invention, "ENPP1-related disease" means a disease that can be treated by inhibiting ENPP1, and may be, for example, at least one selected from the group consisting of cancer, hypophosphatemia, chondrocalcinosis, osteoarthritis, aortic valve calcification, viral or bacterial infection, cystic fibrosis, type 2 diabetes, and Alzheimer's disease, but is not limited thereto. The cancer may be a solid cancer. The pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by any one of the above chemical formulas 1 to 3, the compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.At this time, the pharmaceutically acceptable carrier is one commonly used in the art at the time of formulation, and may be at least one selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. In addition, the pharmaceutical composition of the present invention may additionally include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, or a preservative in addition to the above components. The present invention provides a method for preventing or treating an ENPP1-related disease, comprising administering to a subject a compound represented by any one of the above chemical formulae 1 to 3, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same. The method for preventing or treating an ENPP1-related disease of the present invention may comprise administering a therapeutically effective amount of a compound represented by any one of the above chemical formulae 1 to 3, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same. In the present invention, "prevention" means any act of inhibiting or delaying the onset of an ENPP1-related disease by administering a compound represented by any one of the above chemical formulae 1 to 3, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.In the present invention, "treatment" means any act in which the symptoms of an ENPP1-related disease are improved or beneficially changed by administering a compound represented by any one of the above chemical formulae 1 to 3 of the present invention, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention provides a use of a compound represented by any one of the above chemical formulae 1 to 3, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same, for the prevention or treatment of an ENPP1-related disease. The present invention provides a use of a compound represented by any one of the above chemical formulae 1 to 3, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention or treatment of an ENPP1-related disease.

[0095]

Effect of the invention

[0096]

Mode for carrying out the invention

[0097] <Chemical Reaction Formula 1>

[0098] (a) PPh3, I2, imidazole, CH2Cl2; (b) P(0)H(0Bn)2, DBU, ACN, 40 °C; (c)

[0099] TFA, CH2Cl2; “Bn” means benzyl, and in the chemical reaction formulas below, “Bn” also represents benzyl.

[0100] [Step a] Tart-butyl 4-(2-iodoethyl)piperidine-1-carboxylate

[0101] Synthesis of (tert-butyl 4-(2-iodoethyl)piperidine-l-carboxylate)

[0102] PPhs (1.5 eq) and imidazole (1.5 eq) were dissolved in CH2Cl2, iodine (1.5 eq) was added, and the mixture was stirred for about 10 minutes. tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1.0 eq) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for about 2 hours. The completion of the reaction was confirmed, and the mixture was quenched with a 5% sodium thiosulphate solution and filtered through cel i te. The filtrate was extracted with brine and CH2Cl2 as the organic layer. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0103] [Step b] Synthesis of tert-butyl 4-(2-(bis(benzyloxy)phosphoryl)ethyl)piperidine-1-carboxylate tert-Butyl 4-(2-iodoethyl)piperidine-1-carboxylate was dissolved in acetonitrile, and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (5.0 eq) was added. The mixture was stirred at 40 °C for about 10 minutes. Dibenzyl phosphite (1.0 eq) was added dropwise to the reaction mixture, and the mixture was stirred at 40 °C for about 2 hours. After confirming the completion of the reaction, distilled water was added, and then the organic layer was extracted using brine and EtOAc. The water remaining in the organic phase was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0104] [Step Synthesis of dibenzyl (2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid (1:1) tert-Butyl 4-(2-(bis(benzyloxy)phosphoryl)ethyl)piperidine-1-carboxylate (*八-butyl 4-(2-(bis(benzyloxy)phosphoryl)ethyl)piperidine-

[0105] It should be noted that there seems to be an unclear or incorrect expression " *八-butyl" in the original text which remains as it is in the translation due to the requirement of preserving the original text exactly.1—carboxylate) was dissolved in TFA / DCM and stirred at room temperature for 1 hour. After confirming the completion of the reaction, the desired product was obtained by concentration under reduced pressure. Synthesis Example 2

[0106] <Chemical Reaction Formula 2>

[0107] (a) zrBuLi, DIPA, DMF, THF, -78 °C: (b) hydrazine sul fate, NaOAc, H2O, ref lux; (c) NaOMe, MeOH

[0108] [Step a] Synthesis of 4,6-dichloro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one (4,6-di chi or ol-hydr oxyf ur o [3,4-c]pyridin-3(1H)-one n-BuLi (1.6 M) (46.7 ml) was added to THF (100 ml) at -78°C,

[0109] DIPA (diisopropyl amine) (16.65 ml) was added over approximately 15 minutes. The reaction mixture was stirred at -78°C for approximately 1 hour, and 2,6-Dichloronicotinic acid (7.12 g) was added over approximately 10 minutes. The mixture was continued to stir at -78°C for approximately 2 hours, and DMF (23.26 ml) was added while maintaining T<-70°C. The reaction mixture was stirred at -78°C for 1 hour, warmed to -50°C for 30 minutes, and then allowed to slowly warm to room temperature. The reaction was quenched by adding IN HC1 until the reaction mixture reached an acidic pH. The organic layer was extracted with EtOAc and washed thoroughly with brine. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was used without further purification.

[0110] [Step b] Synthesis of 5,7-dichloropyrido[3,4-bipyridazin-4(3H)-one (5,7- di chi or opyr i do [3,4- d]pyridazin-4(3H)-one)

[0111] 4,6-Dichloro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one (4,6-dichloro-l- hydr oxy furo[3,4-c]pyridin-3(1H)-one) (9.37 g) was added to water (100 ml) and stirred, and hydrazine sulfate (10.58 ml) and NaOAc (13.56 g) were added to the reaction mixture. The reaction mixture was stirred under reflux for about 2 hours. The reaction mixture was cooled to room temperature and distilled water was added. The organic layer was extracted using EtOAc and washed with a saturated aqueous solution of Na2CO3. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the desired product without further purification.

[0112] [Step c] Synthesis of 7-chloro-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one (7-chloro-5-methoxypyr ido[3, 4-d ]pyridazin-4(3H)-one)

[0113] 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one (5,7-dichloropyr ido[3,4-d]pyr idazin-4(3H)-one) was dissolved in MeOH, NaOMe (1.2 eq) was added, and the mixture was stirred at room temperature for about 12 hours. After confirming the completion of the reaction, the mixture was washed with CH2Cl2 and filtered. The solid filtrate was dried to obtain the desired product. Example 1: Preparation of compound 334

[0114] <Chemical Reaction Formula 3>

[0115] (a) DIPEA, DMF, reflux; (b) 4N HC1, Dioxane; (c) TEA, THF, reflux; (d) 4N HC1, Dioxane

[0116] [Step a] Synthesis of tert-butyl ((1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-bipyridazin-7-yl)piperidin-4-yl)methyl)carbamate Synthesis of 7-chloro-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one (7-chl oro-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one) obtained in Synthesis Example 2

[0117] Dissolve in DMF (Dimethyl formamide) and add tert-butyl (piperidin-4-ylmethyl)carbamate (1.2 eq) and DI PEA (N,N-Diisopropyl ethyl amine, 2.0 eq) and reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using EtOAc (ethyl acetate) and washed several times using brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0118] [Step b] Synthesis of 7-(4-(aminomethyl)piperidin-1-yl)-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one hydrochloride (1:1) tert-Butyl ((1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)carbamate was dissolved in dioxane. 4N HCl (0.5 M) dissolved in dioxane was added to the reaction mixture and stirred at room temperature. The completion of the reaction was confirmed and filtered. The solid filtrate was dried to obtain the desired product.

[0119] [Step c] Synthesis of tert-butyl (N-((1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate 7-(4-(aminomethyl)piperidin-1-yl)-5-methoxypyrido[3,4-d]pyridazine

[0120] 4(3H)—one HC1 (7-(4-( ami nomethyl )piper idin-l-yl )-5-methyl thoxypyri do [3 , 4- d]pyridazin- 4(3H)-one hydrochloride) was dissolved in THF (tetrahydrofuran). To the reaction mixture, (tert-butoxycarbonyl ) ((4-(dimethylamino)pyridin-1-ium-1-yl)sulfonyl)amide (1.2 eq) and TEA (triethylamine, 2.0 eq) were added, and the mixture was stirred under reflux for 24 h. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using brine and EtOAc. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0121] [Step d] Synthesis of N-((1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)aminosulfonamide (N-((1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)aminosulfonamide) tert-butyl (N-((1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate tert-butyl (N-((l- ( 5-methyl-4-oxo-3,4-dihydr opyr i do [ 3,4-d ]pyri diz i n-7-y 1 )pi per idi n-4 - yl )methyl )sulfamoyl )carbamate) was dissolved in Dioxane. 4N HC1 (0.5 M) dissolved in Dioxane was added to the reaction mixture and stirred at room temperature. After confirming the completion of the reaction, the crude product was purified by reverse phase column chromatography and concentrated in vacuo to obtain the desired product. 1 H NMR (400 MHz, DMSO) 5 11.94 (s, 1H) , 7.89 (s, 1H) , 6.61 (t, J =

[0122] 6.0 Hz, IH), 6.53 (s, IH), 6.49 (s, 2H), 4.41 (d, J = 12.4 Hz, 2H), 3.91 (s, 3H), 2.95 (t, J = 12.1 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H) , 1.82 (d, J = 11.2 Hz, 3H), 1.21 - 1.05 (m, 2H) .

[0123] LC / MS (ESI) m / z: 369.23 [M+H]+ Example 2: Preparation of compound 335

[0124] <Chemical Reaction Formula 4>

[0125] (a) NaH, lodomethane, DMF, 0°C; (b) DIPEA, DMF, reflux; (c) 4N HC1,

[0126] Dioxane; (d) TEA, THF, reflux; (e) 4N HC1, Dioxane

[0127] [Step a] Synthesis of 7-chloro-5-methoxy-3-methylpyrido[3,4-bipyridazin-4(3H)-one (7-chi or o-5-methoxy-3-meth t hy 1 pyr ido[3, 4-d ]pyridazin-4(3H)-one) 7-chloro-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one (7-chloro-5-methoxypyr ido[3, 4- d]pyridazin-4(3H)-one) obtained in Synthesis Example 2 was dissolved in DMF. NaH (60%, 2.5 eq) was slowly added to the reaction mixture at 0°C and stirred. After about 10 minutes, lodomethane (4.0 eq) was added. The mixture was stirred at 0°C for about 20 minutes, and distilled water was added to terminate the reaction. The organic layer was extracted with EtOAc and washed thoroughly with brine. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0128] [Step b] Synthesis of tert-butyl ((1-(5-methoxy- 3-methyl- 4-oxo- 3 ,4-dihydropyrido[3, 4-bipyridazin- 7 -yl)piperidin- 4-yl)methyl)carbamate)

[0129] 7-Chloro-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF, and 1.2 eq of 7-chloro-butyl (piperidin-4-ylmethyl)carbamate and 2.0 eq of DI PEA were added, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using EtOAc and washed several times with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0130] [Step c] 7-(4-(aminomethyl)piperidin-1-yl)-5-methoxy-3-methylpyrido [3, 4-bipyridazin-4(3H)-one HC1 (1:1) (7-(4-(aminomethyl )piper idin-l-yl )-5-methoxy-

[0131] Synthesis of tert-butyl ((1-(5-methoxy-3-methoxy-3-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)carbamate) was dissolved in dioxane. 4N dissolved in Dioxane in the reaction mixture

[0132] HC1 (0.5 M) was added and stirred at room temperature. The reaction was completed and filtered. The solid filtrate was dried to obtain the desired product.

[0133] [Step d]Hert-butyl (N-((1-(5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-bipyridazin-7-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate

[0134] Synthesis of ( tert -butyl ( N- ( ( 1- ( 5-me t hoxy-3-me t hy 1 —4— oxo — 3 , 4-di hydr opyr ido[3,4 - d] pyr i daz in- 7- yl ) pipe idin-4-yl ) methyl ) sul famoyl ) carbamate)

[0135] 7-(4-(aminomethyl)piperidin-1-yl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one HC1 (7-(4-( ami nomethyl )piper idin-l-yl )-5-methoxy-3' methyl pyr i do [3,4-d] pyr idazin-4(3H) -one hydrochloride) was dissolved in THF. To the reaction mixture, (tert-butoxycarbonyl)((4-(dimethylamino)pyridin-1-ium-1-yl)sulfonyl)amide (1.2 eq) and TEA (2.0 eq) were added, and the mixture was stirred under reflux for 24 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using brine and EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0136] [Step e] Synthesis of N-((1-(5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)aminosulfonamide tert-Butyl (N-((1-(5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate was dissolved in Dioxane. 4N HCl (0.5 M) dissolved in Dioxane was added to the reaction mixture and stirred at room temperature. After confirming the completion of the reaction, the crude product was purified by reverse-phase column chromatography and concentrated in vacuo to obtain the desired product.

[0137] 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 6.60 (t, J = 6.0 Hz, 1H), 6.53 (s, 1H), 6.48 (s, 2H), 4.40 (d, J = 12.5 Hz, 2H), 3.91 (s, 3H), 3.53 (s, 3H), 2.95 (t, J = 12.1 Hz, 2H), 2.79 (t, J = 5.8 Hz, 2H), 1.82 (d, J = 11.8 Hz, 3H), 1.21 - 1.06 (m, 2H).

[0138] LC / MS (ESI) m / z: 383.25 [M+H]+ Example 3: Preparation of Compound 336

[0139]

[0140] <Chemical Reaction Formula 5>

[0141] (a) NH3, MeOH, microwave, 130 °C; (b) DIPEA, DMF, reflux; (c) 4N HC1,

[0142] Dioxane; (d) TEA, THF, reflux; (e) 4N HC1, Dioxane

[0143] [Step a] Synthesis of 5-amino-7-chloropyrido[3,4-d]pyridazin-4(3H)-one (5-amino-7-chl or opyr ido[3, 4-d ]pyr i daz i n-4(3H)-one)

[0144] 5,7-Dichloropyrido[3,4-d]pyridazin-4(3H)-one was added to NH3 dissolved in MeOH. The mixture was stirred for 30 minutes under microwave conditions at 130 °C. After confirming the completion of the reaction, distilled water (0.2 M) was added, and the precipitated solid was washed with distilled water and filtered. The solid filtrate was dried to obtain the desired product.

[0145] [Step b] Synthesis of tert-butyl ((1- (5-amino- 4-oxo- 3, 4-dihydropyrido[3,4- d]pyridazin- 7-yl)piperidin- 4-yl)methyl)carbamate)

[0146] 5-Amino-7-chloropyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF, and tert-butyl (piperidin-4-ylmethyl)carbamate (1.2 eq) and DIPEA (2.0 eq) were added. The mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using EtOAc and washed several times with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0147] [Step c] Synthesis of 5-amino-7-(4-(aminomethyl)piperidin-1-yl)pyrido[3,4-bipyridazin-4(3H)-one HC1 (1:1) (5-amino-7-(4-(aminomethyl)piperidin-1-yl)pyrido[3,4-d]pyridazin-4(3H)-one hydrochloride (1:1)) tert-butyl ((1-(5-amino-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)carbamate ( tert- butyl ((1-(5-amino-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)carbamate ( tert- 4-d ] pyr i daz in— 7— y Dpiper idi n— 4— y 1 )methyl ) carbamate e ) was dissolved in Dioxane. 4N HC1 (0.5 M) dissolved in Dioxane was added to the reaction mixture and stirred at room temperature. The completion of the reaction was confirmed and filtered. The solid filtrate was dried to obtain the desired product.

[0148] [Step d] Synthesis of tert-butyl (N- ((1-(5-amino-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate)

[0149] 5—amino-7-(4-(aminomethyl)piperidin— yl)pyrido[3,4- d]pyridazin- 4(3H)—one HC1 (5—amino— 7— (4— (ami nomethyl )pi peri din— 1— yl)pyri do [3,4— d ]pyridazin-4(3H )-one hydrochloride) was dissolved in THF. To the reaction mixture, (tert-butoxycarbonyl)((4-(dimethylamino)pyridin- 1-ium- 1-yl)sulfonyl)amide {{tert-butoxycarbonyl )((4—(dimethylamino)pyri din— 1—ium—l—yl )sulfonyl)ami de) (1.2 eq) and TEA (2.0 eq) were added, and the mixture was stirred under reflux for 24 h. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using brine and EtOAc. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0150] [Step e] Synthesis of N-((1-(5-amino-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)aminosulfonamide (N-((1-(5-amino-4-oxo-3,4-di hydr opyr ido[3,4-d ]pyridazin— 7— y 1 ) pi pe ridin— 4— yl )methyl )ami nosulfonamide) tert-butyl (N-((1-(5-amino-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)methyl)sulfamoyl)carbamate (tert-butyl (N-((l-(5-ami no— 4— oxo— 3 , 4-dihydropyridin-4-yl)methyl)sulfamoyl)carbamate) was dissolved in dioxane. 4N HC1 (0.5 M) dissolved in dioxane was added to the reaction mixture and stirred at room temperature. After confirming the completion of the reaction, the crude product was purified by reverse phase column chromatography and concentrated in vacuo to obtain the desired product.

[0151] 1 H NMR (400 MHz, DMSO) 5 11.95 (s, 1H) , 8.08 (s, 1H) , 7.81 (s, 1H) , 6.99 (s, IH), 6.58 (t, J = 6.2 Hz, IH) , 6.47 (s, 2H) , 6.13 (s, IH) , 4.39 (d, J = 12.9 Hz, 2H), 2.85 (t, J = 12.1 Hz, 2H) , 2.78 (t, J = 6.1 Hz, 2H) , 1.77 (d, J = 10.7 Hz, 3H), 1.15 - 0.98 (m, 2H) .

[0152] LC / MS (ESI) m / z: 354.25 [M+H]+ Example 4: Preparation of compound 337

[0153] <Chemical Reaction Formula 6>

[0154] (a) DIPEA, DMF, reflux; (b) H2, Pd / C, EtOH / THF

[0155] [Step a] Synthesis of dibenzyl (2- (1- (5-methoxy- 4-oxo- 3, 4-dihydropyrido [3,4-bipyridazin- 7 -yl)piperidin- 4 -yl)ethyl)phosphonate) 7-chloro- 5-methoxypyrido [3,4- d]pyridazin- 4(3H)-one obtained in Synthesis Example 2 was dissolved in DMF. Dibenzyl (2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid) (1.2 eq) and DI PEA (2.0 eq) obtained according to the chemical reaction scheme 1 were added to the reaction mixture, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using EtOAc and washed thoroughly using brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0156] [Step b] Synthesis of (2-(1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)ethyl)phosphonic acid ((2-(1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)ethyl)phosphonic acid) dibenzyl (2-(1-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)ethyl)phosphonic acid) 3,4-dihydropyrrolidone [ 3 , 4-d ]pyrrolidone (Dpiper idi n 4 y 1 )ethyl )phosphonate) was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated in vacuo to obtain the desired product.

[0157] 1 H NMR (400 MHz, DMSO) 5 11.93 (s, 1H) , 7.89 (s, 1H) , 6.52 (s, 1H) , 4.41 (d, J = 12.9 Hz, 2H), 3.90 (s, 3H) , 2.92 (t, J = 11.9 Hz, 2H) , 1.79 (d, J = 12.4 Hz, 2H), 1.66 - 1.38 (m, 5H) , 1.16 — 1.02 (m, 2H) .

[0158] LC / MS (ESI) m / z: 369.24 [M+H]+ Example 5: Preparation of compound 338

[0159] <Chemical Reaction Formula 7>

[0160] (a) NaH, lodomethane, DMF, 0°C; (b) DIPEA, DMF, reflux; (c) H2, Pd / C, EtOH / THF

[0161] [Step a] Synthesis of 7-chloro-5-methoxy-3-methylpyrido[3,4- d]pyridazin- 4(3H)-one 7-chloro-5-methoxypyrido[3,4- d]pyridazin- 4(3H)-one (7-chloro-5-methoxypyrido[3,4- d]pyridazin- 4(3H)-one) obtained in Synthesis Example 2 was dissolved in DMF. NaH (60%, 2.5 eq) was slowly added to the reaction mixture at 0°C and stirred. After about 10 minutes, lodomethane (4.0 eq) was added. The mixture was stirred at 0°C for about 20 minutes, and distilled water was added to terminate the reaction. The organic layer was extracted using EtOAc and washed thoroughly with brine. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0162] [Step b] Synthesis of dibenzyl (2- (1- (5-methoxy- 3-methyl- 4-oxo- 3,4-dihydropyrido[3,4-bipyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonate ( di benzyl ( 2— ( 1— ( 5-methoxy-3-methoxy- 1 —4— oxo— 3 , 4~di hydr opyr ido[3 ,4— d]pyridazin-7-yl )piperidin-4-yl )ethyl ) phosphonate)

[0163] 7-Chloro-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF. Dibenzyl (2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid) (1.2 eq) and DIPEA (2.0 eq) were added to the reaction mixture, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed thoroughly with brine. After the remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0164] [Step c] Synthesis of (2-(1-(5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)ethyl)phosphonic acid ((2-(1-(5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)ethyl)phosphonic acid)dibenzyl (2-(1-(5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)ethyl)phosphonate (dibenzyl (2- (1-(5-methoxy-3-methyl-1-4-oxo-3,4-dihydr opyr i do [3,4-d]pyri di daz in— 7— y Dpiperidi n— 4-yl)ethyl )phosphonate) was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitr i le) and concentrated in vacuo to obtain the desired product.

[0165] 1 H NMR (400 MHz, DMS0) 5 7.93 (s, 1H) , 6.51 (s, 1H) , 4.41 (d, J = 12.2 Hz, 2H), 3.91 (s, 3H) , 3.52 (s, 3H) , 2.92 (t, J = 12.2 Hz, 2H) , 1.79 (d, J = 12.0 Hz, 2H), 1.64 - 1.37 (m, 5H) , 1.17 - 1.02 (m, 2H) .

[0166] LC / MS (ESI) m / z: 383.24 [M+H]+ Example 6: Preparation of compound 339

[0167]

[0168] <Chemical Reaction Formula 8>

[0169] (a) NH3, MeOH, microwave, 130 °C; (b) DIPEA, DMF, reflux; (c) H2, Pd / C,

[0170] EtOH / THF

[0171] [Step a] Synthesis of 5-amino-7-chloropyrido[3,4-d]pyridazin-4(3H)-one (5-amino-7-chl or opyr ido[3, 4-d ]pyridazin-4(3H)-one)

[0172] 5,7-dichloropyrido[3,4- d]pyridazin- 4(3H)-one was added to NH3 dissolved in MeOH. The mixture was stirred for 30 minutes under microwave conditions at 130 °C. After confirming the completion of the reaction, distilled water (0.2 M) was added, and the precipitated solid was washed with distilled water and filtered. The solid filtrate was dried to obtain the desired product.

[0173] [Step b] Synthesis of dibenzyl (2- (1- (5-amino- 4-oxo- 3, 4-dihydropyrido [3,4-bipyridazin- 7 -yl)piperidin- 4- yl)ethyl)phosphonate)

[0174] 5-Amino-7-chloropyrido[3,4- d]pyridazin- 4(3H)-one was dissolved in DMF. Dibenzyl (2-(piperidin- 4-yl)ethyl)phosphonate trifluoroacetic acid) (1.2 eq) and DI PEA (2.0 eq) were added to the reaction mixture, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed sufficiently with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0175] [Step c] Synthesis of (2-(1-(5-amino-4-oxo-3,4-dihydropyrido[3,4-bipyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid ((2-(1-(5-amino- 4-oxo- 3,4-dihydropyrido[3,4-d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid) dibenzyl (2-(1-(5-amino- 4-oxo- 3,4-dihydropyrido[3,4-d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid) dibenzyl (2-(1-(5-amino- 4-oxo- 3,4-dihydropyrido[3,4-d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonate [3,4-d]pyridin-4-yl phosphonate (1,4-dimethyl- ...

[0176] 1 H NMR (400 MHz, DMSO) 5 11.94 (s, 1H) , 8.08 (s, 1H) , 7.81 (s, 1H) ,

[0177] 6.98 (s, IH), 6.11 (s, IH), 4.40 (d, J = 12.2 Hz, 2H), 2.81 (t, J = 12.3 Hz,

[0178] 2H), 1.74 (d, J = 11.7 Hz, 2H) , 1.58 - 1.38 (m, 5H), 1.09 - 0.96 (m, 2H) .

[0179] LC / MS (ESI) m / z: 354.25 [M+H]+ Example 7: Preparation of compound 340

[0180] <Chemical Reaction Formula 9>

[0181] (a) methylamine, DIPEA, DMSO; (b) DIPEA, DMF, reflux; (c) H2, Pd / C, EtOH / THF

[0182] [Step a] Synthesis of 7-chloro-5-(methylamino)pyrido[3,4-d]pyridazin-4(3H)-one (7-chloro-5-(methyl amino)pyrido[3,4-d]pyridazin-4(3H)-one)

[0183] 5,7-Dichloropyrido[3,4-d]pyridazin-4(3H)-one (5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one) was dissolved in DMS0(dimethyl sulfoxide). Methylamine (1.5 eq) and DI PEA (2.0 eq) were added to the reaction mixture, and the mixture was stirred for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the precipitated solid was washed with distilled water and filtered. The solid filtrate was dried to obtain the desired product. [Step b] Dibenzyl (2-(1-(5-(methylamino)-4-oxo-3,4-dihydropyrido[3,4-bipyridazin-7-yl)piperidin-4-yl)ethyl)phosphonate

[0184] Synthesis of (di benzyl (2— (1— (5— (methylamino)— 4— oxo— 3,4— di hydr opyr ido[3,4-d] pyr idazin-7- yl )piper idin-4-yl ) ethyl )phosphonate)

[0185] 7-Chloro-5-(methylamino)pyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF. Dibenzyl (2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid) (1.2 eq) and DIPEA (2.0 eq) were added to the reaction mixture, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed thoroughly with brine. After the remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0186] [Step c] Synthesis of (2-(1-(5-(methylamino)-4-oxo-3,4-dihydropyrido[3,4-bipyridazin-7-yl)piperidin-4-yl)ethyl)phosphonic acid ((2-(1-(5-(methylamino)-4-oxo-3,4-dihydropyrido[3,4-bipyridazin-7-yl)piperidin-4-yl)ethyl)phosphonic acid) dibenzyl (2-(1-(5-(methylamino)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidin-4-yl)ethyl)phosphonate (dibenzyl (2-(l-(5-

[0187] ( me t hy 1 am i no ) — 4— oxo— 3 , 4— di hydr opyr i do [ 3 , 4— d ] pyr i daz in— 7— y 1 ) pi per idin— 4— yl ) ethyl ) phosphonate) was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the product was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated in vacuo to obtain the desired product.

[0188] 1 H NMR (400 MHz, DMS0) 5 11.98 (s, 1H) , 8.64 (d, J = 4.4 Hz, 1H) , 7.81 (s, IH), 6.05 (s, IH), 4.42 (d, J = 12.9 Hz, 2H) , 2.92 (d, J = 4.7 Hz, 3H), 2.84 (t, J = 11.9 Hz, 2H), 1.75 (d, J = 12.0 Hz, 2H), 1.58 - 1.26 (m, 5H), 1.09 - 0.97 (m, 2H).

[0189] LC / MS (ESI) m / z: 368.28 [M+H]+ Synthesis Example 10

[0190]

[0191] <Chemical Reaction Formula 10>

[0192] (a) RX, Cs2CO3, DMF; (b) DIPEA, DMF, reflux; (c) H2, Pd / C, EtOH / THF In the above chemical reaction formula 10, R is - L4- R4,

[0193] L4 is a single bond, C1-C5 alkylene, C(=0), C(=0)- (C1-C5 alkylene), C(=O)O(C1- C5 alkylene), C(=S), S(=0)2, (C1-C5 alkylene) - C(=0), (C1-C5 alkylene) - C(=0)NH or (C1-C5 alkylene) - C(=0)0,

[0194] R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), 6-14 membered aryl, 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring, 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring,

[0195] R4's C1-C5 alkyl, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring, or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein at least one of these groups may be independently substituted or unsubstituted with C1-C5 alkyl, C1-C5 alkoxy, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), N02 or halogen,

[0196] At least one of the carbons forming the ring of a 3- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S of R4 may be C(=0).

[0197] [Step a] Synthesis of 10A 7-chloro- 5-methoxypyrido[3,4- d]pyridazin- 4(3H)-one obtained in Synthesis Example 2 was dissolved in DMF. RX (1.2 eq) and Cs2CO3 (2.0 eq) were added to the reaction mixture, and the mixture was stirred at room temperature. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed thoroughly with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0198] [Step b] Synthesis of 10B The above-obtained 10A was dissolved in DMF. Dibenzyl (2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid) (1.2 eq) and DI PEA (2.0 eq) were added to the reaction mixture, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using EtOAc and washed thoroughly with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0199] [Step c] Synthesis of 10C The obtained 10B was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered with Cell i te. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated in vacuo to obtain the desired product. Example 8: Preparation of compound 341 The compound was finally obtained using 2-bromoacetamide as R-X through the same process as the synthetic method (a-c) of the above chemical reaction scheme 10.

[0200] 1 H NMR (400 MHz, DMSO) 5 7.93 (s, 1H) , 7.44 (s, 1H) , 7.10 (s, 1H) , 6.53 (s, IH), 4.49 (s, 2H) , 4.41 (d, J = 12.8 Hz, 2H) , 3.90 (s, 3H) , 2.92 (t, J = 12.2 Hz, 2H), 1.79 (d, J = 11.9 Hz, 2H), 1.58 — 1.41 (m, 5H) , 1.15 - 1.02 (m, 2H).

[0201] LC / MS (ESI) m / z: 426.22 [M+H]+ Example 9: Preparation of compound 342 The compound was finally obtained using 3-bromopropanenitr i le as R- X through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above.

[0202]

[0203] 1 H NMR (400 MHz, DMSO) 5 8.01 (s, 1H) , 6.56 (s, 1H) , 4.42 (d, J =

[0204] 11.7 Hz, 2H), 4.19 (t, J = 6.3 Hz, 2H), 3.91 (s, 3H), 2.96 - 2.90 (m, 4H), 1.79 (d, J = 11.8 Hz, 2H), 1.61 - 1.40 (m, 5H), 1.15 - 1.02 (m, 2H) .

[0205] LC / MS (ESI) m / z: 422.23 [M+H]+ Example 10: Preparation of compound 343 The compound was finally obtained using dimethylcarbamic chloride as R-X through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above. 1 H NMR (400 MHz, DMSO) 5 8.05 (s, 1H) , 6.63 (s, 1H) , 4.43 (d, J = 11.2 Hz, 2H), 3.92 (s, 3H) , 3.02 (s, 3H) , 2.97 (t, J = 12.1 Hz, 2H) , 2.81 (s, 3H), 1.80 (d, J = 12.1 Hz, 2H) , 1.66 - 1.35 (m, 5H) , 1.16 — 1.03 (m, 2H) .

[0206] LC / MS (ESI) m / z: 440.24 [M+H]+ Example 11: Preparation of compound 344 The compound was finally obtained using methyl 2-bromoacetate as R-X through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above.

[0207] 1H NMR (400 MHz, DMSO) 5 7.96 (s, IH) , 6.55 (s, IH) , 4.71 (s, 2H) , 4.41 (d, J = 11.9 Hz, 2H), 3.89 (s, 3H) , 3.67 (s, 3H) , 2.93 (t, J = 12.1 Hz, 2H), 1.79 (d, J = 11.6 Hz, 2H) , 1.58 - 1.38(m, 5H) , 1.14 - 1.02 (m, 2H) .

[0208] LC / MS (ESI) m / z: 441.21 [M+H] + Example 12: Preparation of compound 345

[0209]

[0210] <Chemical Reaction Formula 11>

[0211] (a) NaOH, H2O / MeOH; (b) H2, Pd / C, EtOH / THF

[0212] [Chemical Reaction Formula 10(ab)] Methyl 2- (7- (4- (2-

[0213] (Bis(benzyloxy)phosphoryl)ethyl)piperidin-1-yl)-5-methoxy-4-oxopyrido[3,4-d]pyridazin-3(4H)-yl)acetate (methyl 2-(7-(4-(2-

[0214] Synthesis of (bis(benzyl oxy )phosphor 1 )ethyl )piper idin-l-yl ) — 5— me t hoxy— 4— oxopy r ido[3 ,4 - bi pyr idazin- 3(4H)- yl )acetate) The compound was obtained through the same process as the synthetic method (a-b) of the above chemical reaction scheme 10.

[0215] [Step a] 2-(7-(4-(2-(bis(benzyloxy)phosphoryl)ethyl)piperidin-L-yl)-5-methoxy-4-oxopyrido[3,4-d]pyridazin-3(4H)-yl)acetic acid (2-(7-(4-(2-

[0216] (bis(benzyloxy)phosphoryl 1)ethyl )piperidin-l-yl ) — 5— me t hoxy— 4— oxopy r ido[3 ,4- bipyridazin- 3(4H)- yl )acetic acid) Synthesis of methyl 2-(7-(4-(2-(bis(benzyloxy)phosphoryl)ethyl)piperidin- 1-yl)- 5-methoxy-4-oxopyrido[3 , 4- d]pyridazin- 3(4H)-yl)acetate (methyl 2-(7-(4-(2- (bis(benzy 1 oxy)phosphoryl 1 )ethyl )piperidin-l-yl ) — 5— me t hoxy— 4— oxopy ri do [ 3 , 4 - d]pyridazin- 3(4H)- yl )acetate) was dissolved in EbO / MeOH. NaOH (5.0 eq) was added to the reaction mixture and stirred at 50 °C for about 24 hours. After confirming the completion of the reaction, impurities were extracted and removed from the organic layer using EtOAc. The pH of the remaining aqueous layer was adjusted to 2 or lower using IN HC1, and the organic layer was extracted using brine and EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the desired product.

[0217] [Step b] Synthesis of 2-(5-methoxy-4-oxo-7-(4-(2-phosphonoethyl)piperidin-1-yl)pyrido[3,4-d]pyridazin-3(4H)-yl)acetic acid (2-(5-methoxy-4-oxo-7-(4-(2-phosphonoethyl)piper idin-l-yl)pyr i do[3,4—d]pyridazin-3(4H)-y1)acetic acid)

[0218] 2-(7-(4-(2-(bis(benzyloxy)phosphoryl)ethyl)piperidin-1-yl)-5-methoxy-4-oxopyrido[3,4-d]pyridazin-3(4H)-yl)acetic acid (2-(7-(4-(2-

[0219] (bis(benzy 1 oxy)phosphor 1 )ethyl )piper idin-l-yl ) —5— me t hoxy— 4— oxopy r ido[3 , 4— d]pyr i daz in-3 (4H)-yl ) acetic acid) was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Cell i te. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitr i le) and concentrated in vacuo to obtain the desired product.

[0220] 1 H NMR (400 MHz, DMS0) 5 7.96 (s, 1H) , 6.55 (s, 1H) , 4.61 (s, 2H) , 4.42 (d, J = 12.1 Hz, 2H), 3.91 (s, 3H) , 2.94 (t, J = 12.2 Hz, 2H) , 1.79 (d, J = 12.0 Hz, 2H), 1.67 - 1.34 (m, 5H) , 1.17 — 1.02 (m, 2H) .

[0221] LC / MS (ESI) m / z: 427.20 [M+H]+ Example 13: Preparation of compound 346

[0222] <Chemical Reaction Formula 12>

[0223] (a) K2CO3, Pd(dppf)Cl2, 1,4-Di oxane, H2O, 90 °C; (b) 4N HC1, Dioxane, r. t; (c) 『er'—BuOH, anhydrous CH2Cl2, 0°C; (d) 4N HC1, Dioxane, r .t

[0224] [Step a] Synthesis of tert-butyl (4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-bipyridazin-7-yl)benzyl)carbamate Synthesis Example 2 7-chloro-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one (7— chloro— 5— methoxypyrido[3,4— d]pyridazin— 4(3H)— one) was dissolved in 1,4-Dioxane : EbO (3:1). Tert-butyl (4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate was added to the reaction mixture. butyl (4-(4, 4,5, 5-tetramethyl-

[0225] 1,3, 2-dioxabor o 1 an-2-y 1 ) benzy 1 ) carbamate ) (1.2 eq), K2CO3 (2.2 eq) and Pd(dppf)Cl2 (20 mol%) were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, filter through Celite. After adding distilled water, the organic layer was extracted using EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0226] [Step b] Synthesis of 7-(4-(aminomethyl)phenyl)-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one HC1 (1:1) (7-(4-(aminomethyl)phenyl)-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one hydrochloride (1:1)) tert-butyl (4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)benzyl)carbamate) Dissolved in dioxane. 4N HC1 (0.5 M) dissolved in dioxane was added to the reaction mixture and stirred at room temperature. The reaction was completed and filtered. The solid filtrate was dried to obtain the desired product.

[0227] [Step c] Synthesis of tert-butyl (N- (4- (5-methoxy- 4-oxo- 3, 4-dihydropyrido[3, 4-bipyridazin- 7-yl)benzyl)sulfamoyl)carbamate ( tert- butyl (N- (4- (5-methoxy- 4-oxo- 3, 4-dihydropyrido[3, 4-bipyridazin- 7-yl)benzyl)sulfamoyl)carbamate )

[0228] Chlorosulfonyl isocyanate (1.2 eq) and tert-Butanol (1.2 eq) were dissolved in anhydrous DCM at 0°C and stirred for about 30 min. The mixture was slowly added to a mixture of 7-(4-(aminomethyl)phenyl)—5-methoxypyrido[3,4-d]pyridazin-4(3H)-one HC1 (1:1) (7-(4-(aminomethyl)pheny 1)—5—methoxypyrido[3,4-d]pyridazin-4(3H)-one hydrochloride (1:1)) (1.0 eq) and TEA (3.0 eq) in anhydrous DCM at 0°C and stirred for about 2 h. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using EtOAc. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was used without further purification.

[0229] [Step d] Synthesis of N-(4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)benzyl)aminosulfonamide (N-(4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)benzyl)aminosulfonamide) tert-butyl (N-(4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)benzyl)sulfamoyl)carbamate <tert- butyl (N- (4- (5- methoxy- 4- oxo- 3 , 4- d i hydr opyr i do [ 3 , 4-d ] pyr i daz i n— 7— y 1 ) benzy Dsul f amoy 1 ) carbamat e )를 Di oxane에 녹였다. 반응 혼합물에 Dioxane에 용해된 4N HC1 (0.5 M)을 첨가하고 상온에서 교반 하였다. 반응 종결을 확인하고 , 반응 혼합물을 포화 NaHCO3수용액으로 중화한 후 , DCM을 사용하여 유기층을 추출하였다. 유기층에 남아 있는 수분을 anhydrous magnesium sulfate로 완전히 제거한 후 여과하였다. 여과액을 감압 농축하여 얻은 미정제물을 컬럼 크로마토그래피로 정제하고 진공 농축하여 원하는 생성물을수득하였다.

[0230] 1 H NMR (400 MHz, MeOD) 5 8.26 (s, 1H) , 8.19 (d, J = 8.1 Hz, 2H) , 7.78 (s, IH), 7.55 (d, J = 8.1 Hz, 2H) , 4.31 (s, 2H) , 4.21 (s, 3H) .

[0231] LC / MS (ESI) m / z: 362.20 [M+H]+ Example 14: Preparation of compound 348

[0232] <Chemical Reaction Formula 13>

[0233] (a) BnOH, NaH, DMF, 0°C; (b) DIPEA, DMF, reflux; (c) H2, Pd / C, EtOH / THF

[0234] [Step a] Synthesis of 5-(benzyloxy)-7-chloropyrido[3, 4-bipyridazin-4(3H)-one (5-(benzyloxy)-7-ch 1 oropyr ido[3, 4~d]pyridazin-4(3H)-one) 5,7-dichloropyrido[3, 4- d]pyridazin-4(3H)-one (5,7-di chloropyr ido[3, 4- d]pyridazin- 4(3H)-one) was dissolved in DMF. NaH (60%, 2.5 eq) was slowly added to the reaction mixture at 0°C. After about 10 min, Benzyl alcohol (1.2 eq) was added and stirred at 0°C for about 1 h. After confirming the completion of the reaction, distilled water was added, and the precipitated solid was washed with distilled water and filtered. The solid filtrate was dried to obtain the desired product.

[0235] [Step b] Dibenzyl (2- (1- (5- (benzyloxy)-4-oxo-3, 4-dihydropyrido [3,4-bipyridazin-7-yl)piperidin-4-yl)ethyl)phosphonate (Dibenzyl (2- (1- (5-

[0236] Synthesis of (benzyl oxy ) —4— oxo— 3,4-di hydr opyr ido[3,4-d] pyr i daz in— 7— y 1 ) pi per idin— 4— yl )ethyl )phosphonate)

[0237] 5-(Benzyloxy)-7-chloropyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF. Dibenzyl(2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid (1.2 eq) and DI PEA (2.0 eq) obtained according to the chemical reaction scheme 1 were added to the reaction mixture, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed sufficiently with brine. After the remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0238] [Step c] Synthesis of (2- (1-(4, 5-dioxo- 3, 4, 5, 6-tetrahydropyrido[3,4- d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid ( (2- (1-(4, 5-dioxo- 3, 4, 5, 6-tetrahydropyrido[3, 4- d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid) dibenzyl (2- (1-(5- (benzyloxy)- 4 -oxo- 3, 4-dihydropyrido[3,4- d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonate (Dibenzyl (2- (1-(5-

[0239] (benzyl oxy ) — 4— oxo — 3 , 4— di hydr opyr i do [ 3 , 4— d ] pyr i daz in — 7— y 1 ) pi per idin— 4— yl ) ethyl ) phosphonate) was dissolved in EtOH / THF. Pd / C (Pal ladium on carbon, 10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitr i le) and concentrated in vacuo to obtain the desired product.

[0240] 1 H NMR (400 MHz, DMSO) 5 12.62 (s, 1H) , 12.53 (s, 1H) , 8.08 (s, 1H) , 6.53 (s, IH), 4.38 (s, 2H) , 2.91 (t, J = 11.9 Hz, 2H) , 1.77 (dd, J = 8.4, 4.7 Hz, 2H), 1.61 - 1.37 (m, 5H), 1.05 (dd, J = 20.8, 11.8 Hz, 2H).

[0241] LC / MS (ESI) m / z: 355.24 [M+H]+ Example 15: Preparation of compound 349 <Chemical Reaction Formula 14>

[0242] (a) K2CO3, Pd(dppf)Cl2, 1,4-Di oxane, H2O, 90 °C; (b) TMSBr, Chloroform [Step a] Synthesis of diethyl (4-(5-methoxy-4-oxo-3,4- dihydropyrido[3,4-bipyridazin-7-yl)phenethyl)phosphonate Synthesis of 7-chloro-5-methoxypyrido[3,4- d]pyridazin-4(3H)-one (7— chloro— 5— methoxypyrido[3,4— d]pyridazin— 4(3H)— one) was dissolved in 1,4-Dioxane : EbO (3:1). Diethyl (4-(4, 4, 5, 5 -tetramethyl- 1,3, 2-dioxaborolan- 2 -yl)phenethyl)phosphonate (diethyl (4-(4,4,5,5-tetramethyl- 1,3, 2-di oxabor 01 an-2-y 1 ) phene t hy 1 )phosphonat e ) (1.2 eq), K2CO3 (2.2 eq), Pd(dppf)Cl2 (20 mol%) were added to the reaction mixture, and the mixture was stirred at 90°C for about 1 hour. After confirming the completion of the reaction, the mixture was filtered with Celite. After adding distilled water, the organic layer was extracted using EtOAc. After completely removing the moisture remaining in the organic layer with anhydrous magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0243] [Step b] Synthesis of (4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonic acid (4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonic acid Synthesis of diethyl (4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonic acid (diethyl (4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonate (diethyl (4-(5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7- (( ...

[0244] 1 H NMR (400 MHz, DMS0) 5 12.68 (s, 1H) , 8.25 (s, 1H) , 8.13 (d, J =

[0245] 8.0 Hz, 2H), 7.92 (s, 1H), 7.42 (d, J = 8.1 Hz, 2H), 4.11 (s, 3H), 2.87 (dd,

[0246] J = 16.8, 8.5 Hz, 2H), 1.92 - 1.79 (m, 2H).

[0247] LC / MS (ESI) m / z: 362.21 [M+H]+ Example 16: Preparation of compound 350

[0248] <Chemical Reaction Formula 15>

[0249] (a) NaH, lodomethane, DMF, 0°C; (b) DIPEA, DMF, reflux; (c) H2, Pd / C,

[0250] EtOH / THF [Step a] Synthesis of 5-(benzyloxy)-7-chloro-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (5-(benzyloxy)-7-ch 1 oro-3-methyl pyr ido[3, 4-d]pyridazin-4(3H)-one)

[0251] 5-(Benzyloxy)-7-chloropyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF. (60%, 2.0 eq) was slowly added to the reaction mixture at 0°C and stirred. After about 10 minutes, lodome thane (1.5 eq) was added. The mixture was stirred for about 30 minutes at 0°C. After confirming the completion of the reaction, distilled water was added, and the precipitated solid was washed with distilled water and filtered. The solid filtrate was dried to obtain the desired product.

[0252] [Step b] Dibenzyl (2- (1- (5- (benzyloxy ) - 3 -methyl - 4 -oxo - 3,4- dihydropyrido [3,4 - bipyridazin - 7 -yl) piperidin - 4 -yl) ethyl) phosphonate

[0253] Synthesis of (D i benzyl ( 2- ( 1- ( 5- ( benzy 1 oxy ) - 3- me t hy 1 -4- oxo- 3 , 4~d ihydr opyr ido [3,4- d ] pyr idazi n-7-yl ) pipe idin-4-yl ) ethyl ) phosphonate)

[0254] 5-(Benzyloxy)-7-chloro-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (5-(benzyloxy)-7-ch 1 or o-3-methylpyrido[3,4-d]pyridazin-4(3H)-one) was dissolved in DMF. Dibenzyl(2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid (1.2 eq) and DI PEA (2.0 eq) obtained according to the chemical reaction scheme 1 were added to the reaction mixture, and the mixture was stirred under reflux for about 24 h. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed thoroughly using brine. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain the desired product. [Step c] (2-(1-(3-methyl-4,5-dioxo- 3,4,5,6-tetrahydropyrido [3,4- d]pyridazin- 7 -yl)piperidin- 4 -yl )ethyl)phosphonic acid ((2-(l-(3-methyl-4,5-dioxo-

[0255] Synthesis of dibenzyl (2- (1- (5- (benzyloxy)-3 -methyl- 4 -oxo- 3, 4 -dihydropyrido [3,4- d]pyridazin- 7 -yl)piperidin- 4 -yl)ethyl)phosphonate (Dibenzyl (2- (1- (5- (benzyloxy)-3 -methyl- 4 -oxo- 3, 4 -dihydropyrido [3,4- d]pyridazin- 7 -yl)piperidin- 4 -yl)ethyl)phosphonate

[0256] (benzyl oxy ) — 4— oxo — 3 , 4— di hydr opyr i do [ 3 , 4— d ] pyr i daz in — 7— y 1 ) pi per idin— 4— yl ) ethyl ) phosphonate) was dissolved in EtOH / THF. Pd / C (Pal ladium on carbon, 10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitr i le) and concentrated in vacuo to obtain the desired product.

[0257] 1 H NMR (400 MHz, DMS0) 5 12.56 (s, 1H) , 8.11 (s, 1H) , 6.51 (s, 1H) , 4.38 (d, J = 12.0 Hz, 2H) , 3.61 (s, 3H) , 2.91 (t, J = 11.9 Hz, 2H) , 1.77 (d, J = 11.2 Hz, 2H), 1.62 - 1.39 (m, 5H) , 1.05 (qd, J = 12.5, 3.6 Hz, 2H) .

[0258] LC / MS (ESI) m / z: 369.22 [M+H]+ Synthesis Example 16 <Chemical Reaction Formula 16>

[0259] (a) PPh3, I2, imidazole, CH2Cl2; (b) P(0)H(0Bn)2, Cs2CO3, DMF, rt

[0260] [Step a] Synthesis of 2-(4-(2-iodoethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[0261] PPhs (1.5 eq) and imidazole (1.5 eq) were dissolved in CH2Cl2, iodine (1.5 eq) was added, and the mixture was stirred for about 10 minutes. 2-(4-(4, 4, 5, 5 -tetramethyl- 1,3,2 -dioxaborolan- 2 -yl)phenyl)ethan-1-ol (1.0 eq) dissolved in DCM was added dropwise to the reaction mixture at 0°C, and the mixture was stirred at room temperature for about 2 hours. The completion of the reaction was confirmed, and the mixture was quenched with a 5% sodium thiosulfate aqueous solution and filtered through cel ite. The organic layer was extracted using DCM and washed thoroughly with brine. After the remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0262] [Step b] Synthesis of Dibenzyl (4-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenethyl)phosphonate

[0263] 2-(4-(2-iodoethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2-(4-(2-iodoethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) was dissolved in DMF. P(0)H(0Bn)2 (2.0 eq) and Cs2CO3 (3.0 eq) were added to the reaction mixture. The mixture was stirred at room temperature for about 24 h. After adding distilled water, the organic layer was extracted using EtOAc and washed several times with brine. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product. Example 17: Preparation of compound 351

[0264] <Chemical Reaction Formula 17>

[0265] (a) K2CO3, Pd(dppf)Cl2, 1,4-Di oxane, H2O, 90°C; (b) H2, Pd / C, EtOH / THF

[0266] [Step a] Dibenzyl (4-(5-(benzyloxy)-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonate (Dibenzyl (4-(5-

[0267] Synthesis of (benzyl oxy ) — 3— me t hy 1 — 4— oxo— 3 , 4— di hydr opyr i do [ 3 , 4— d ] pyr idazin-7- yl )phenethyl ) phosphonate)

[0268] 5-(Benzyloxy)-7-chloro-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (5-(benzy 1 oxy ) —7— ch 1 or 0— 3— me t hy 1 pyr i do [ 3 , 4— d ] pyr i daz in— 4 (3H) -one ) to 1,4-

[0269] Dioxane: Dissolved in H2O (3:1). Dibenzyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)phosphonate) (1.2 eq), K2CO3 (2.2 eq), Pd(dppf)Cl2 (20 mol%) obtained in Synthesis Example 16 were added to the reaction mixture, and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, filtered with Celite. After adding distilled water, the organic layer was extracted using EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0270] [Step b] Synthesis of (4-(3-methyl- 4,5-dioxo- 3,4,5,6-tetrahydropyrido[3,4-bipyridazin- 7-yl)phenethyl)phosphonic acid) Dibenzyl (4-(5-(benzyloxy)-3-methyl- 4-oxo- 3,4-dihydropyrido[3,4-d]pyridazin- 7-yl)phenethyl)phosphonic acid) Dibenzyl (4-(5-(benzyloxy)-3-methyl- 4-oxo- 3,4-dihydropyrido[3,4-d]pyridazin- 7-yl)phenethyl)phosphonate hydr opyr i do [ 3 , 4-d ] pyr i daz in— 7— y 1 ) phene thy 1 ) phosphonat e ) was dissolved in EtOH / THF. Pd / C (Pal ladium on carbon, 10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated under vacuum to obtain the desired product.

[0271] 1 H NMR (400 MHz, DMS0) 5 11.91 (s, 1H) , 8.22 (s, 1H) , 7.84 (s, 2H) , 7.41 (d, J = 8.2 Hz, 2H), 7.08 (s, IH) , 3.67 (s, 3H) , 2.85 (dd, J = 17.2, 8.9 Hz, 2H), 1.94 - 1.80 (m, 2H).

[0272] LC / MS (ESI) m / z: 362.19 [M+H]+ Example 18: Preparation of compound 352

[0273]

[0274] <Chemical Reaction Formula 18>

[0275] (a) B2pi n2, KOAc, Pd(dppf)Cl21, 2-Di methoxyethane, 95 °C; b) K2CO3,

[0276] Pd ( dpp f ) C 12 , Dioxane , H2O , 90 °C; (c) TFA, CH2CI2, rt; (d) DIPEA, THF, rt;

[0277] (e) 4N HC1 , Dioxane, r . t

[0278] [Step a] Synthesis of (5-methoxy- 3-methyl- 4-oxo- 3,4-dihydropyrido[3,4-d]pyridazin- 7-yl)boronic acid

[0279] 7-Chloro-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one was dissolved in 1,2-dimethoxyethane. To the reaction mixture were added B2Pin2(Bis(pinacolato)diboron) (1.2 eq), KOAc (3.0 eq), and Pd(dppf)Cl2 (10 mol%). The mixture was stirred at 95°C for about 1 h. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain a crude product that was used without further purification. [Step b] Synthesis of tert-butyl (4-((5-methoxy-3-methyl- 4-oxo- 3 , 4-dihydropyrido[3,4- d]pyridazin- 7 -yl)methyl)phenyl)carbamate)

[0280] (5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)boronic acid ((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)boronic acid) was dissolved in 1,4-Dioxane:H2O (3:1). Tert-butyl (4-(bromomethyl)phenyl)carbamate (1.2 eq), K2CO3 (2.2 eq), and Pd(dppf)Cl2 (10 mol%) were added to the reaction mixture, and the mixture was stirred at 90°C for about 1 h. The mixture was stirred for a while. After confirming the completion of the reaction, it was filtered with Cell i te. After adding distilled water, the organic layer was extracted using EtOAc. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0281] [Step c] Synthesis of 7-(4-aminobenzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one trifluoroacetic acid (1:1) (7-(4-aminobenzyl)-5-methoxy-3-methyl pyr i do[3,4-d]pyridazin-4(3H)-one tri f luoroacet ic acid (1:1)) tert-butyl (4-((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)carbamate <tert- butyl (4- ( (5- methoxy- 3- methyl- 4- oxo-3 , 4-d i hydr opyr i do [ 3 , 4-d ] pyr i daz i n— 7— y 1 )methyl )pheny 1 ) carbamat e )를 TFA / DCM 에 녹이고 상온에서 1 시간 동안 교반 하였다. 반응 종결을 확인하고 , 감압 농축하여 원하는 생성물을 수득하였다. [단계 d] 타트-부틸 (N- (4- ( (5 -메톡시 -3 -메틸- 4 -옥소- 3 , 4- 디히들 피리도 [3, 4 -비피리다진- 7 -일)메틸)페닐)설파모일)카바메이트 (、tert- butyl ( N— ( 4— ( ( 5— me t hoxy— 3— me t hy 1 — 4— oxo— 3 , 4— d i hydr opyr ido[3,4-d] pyr idazin-7- yl )methyl ) phenyl )sulfamoyl )carbamate)의 합성

[0282] 7-(4-aminobenzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one trifluoroacetic acid (7-(4-aminobenzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one trifluoroacetic acid) was dissolved in THF. To the reaction mixture, (tert-butoxycarbonyl)((4-(dimethylamino)pyridin-1-ium-1-yl)sulfonyl)amide (1.2 eq) and TEA (3.0 eq) were added, and the mixture was stirred at room temperature. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using EtOAc. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0283] [Step e] N-(4-((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)aminosulfonamide

[0284] Synthesis of ( N— ( 4— ( ( 5-methoxy-3-methoxy-1 —4— oxo— 3 , 4— di hydr opyr i do [ 3 , 4— d ] pyr idazin- 7-yl )methyl )phenyl )aminosulfonamide) tert-butyl (N- (4-( (5 -methoxy-3 -methyl- 4 -oxo- 3 , 4 -dihydylpyrido [3 , 4- d]pyridazin- 7 -yl)methyl)phenyl)sulfamoyl)carbamate tert-butyl (N- (4-( (5-methoxy-3-methoxy-1 —4— oxo— 3 , 4— di hydr opyr i do [ 3 , 4— d ] pyr idazin- 7 - yl )methyl )phenyl )sulfamoyl )carbamate) was dissolved in Dioxane. 4N HC1 (0.5 M) dissolved in Dioxane was added to the reaction mixture and stirred at room temperature. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure to obtain the desired product.

[0285] NMR (400 MHz, DMSO) 59.43 (s, 1H), 8.23 ​​(s, 1H), 7.26 (d, J= 8.5

[0286] Hz, 2H), 7.12 (d, J= 6.9 Hz, 3H), 7.04 (s, 2H), 4.06 (s, 2H), 4.00 (s, 3H), 3.64

[0287] (s, 3H).

[0288] LC / MS (ESI) m / z: 376.19 [M+H? Example 19: Preparation of compound 353

[0289] <Chemical Reaction Formula 19>

[0290] (a) Imidazole, TBSC1, CH2Cl2; (b) K2CO3, Pd(dppf)Cl2, Dioxane, H2O,

[0291] 90 °C; (c) TBAF, THF, rt; (d) PPh3, I2, imidazole, CH2C12; (e) P(0)H(0Bn)2,

[0292] CS2CO3, DMF;(f) H2, Pd / C, EtOH / THF [Step a] ((4-(bromomethyl)benzyl)oxy) (tert-butyl)dimethylsilane (((4-

[0293] Synthesis of (bromomethyl )benzyl )oxy)(tert-butyl)dimethylsi lane)

[0294] (4-(bromomethyl)phenyl)methanol ( (4- (bromomethyl ) phenyl )methanol )

[0295] Dissolved in DCM. Imidazole (1.5 eq) and TBSC1 (2.5 eq) were added at 0°C and stirred at room temperature. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using DCM, and the remaining moisture was completely removed with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0296] [Step b] Synthesis of 7-(4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (7-(4-(((tert-butyldimethylsi lyl)oxy)methyl)benzyl)—5—methoxy—3—methylpyr ido[3,4-d]pyridazin-4(3H)-one)

[0297] ((7-borono-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-5-yl)oxy)methylium (((7-borono-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin—5—yl)oxy)methylium) was dissolved in 1,4-Dioxane:H2O (3:1). To the reaction mixture, ((4-(bromomethyl)benzyl)oxy)(tert-butyl)dimethylsilane (((4-

[0298] (bromomethyl)benzyl)oxy)(『erf— butyl )dimethylsi lane) (1.2 eq), K2CO3 (2.2 eq) and Pd(dppf)Cl2 (10 mol%) were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, the mixture was filtered through Celite. After adding distilled water, the organic layer was extracted using EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0299] [Step c] Synthesis of 7-(4-(hydroxymethyl)benzyl)-5-methoxy-3-methylpyrido[3,4-bipyridazin-4(3H)-one (7-(4-(hydroxymethyl)benzyl)-5-methoxy-3-methylpyrido[3,4-bipyridazin-4(3H)-one)

[0300] 7-(4-((( tert-butyldimethylsilyl)oxy)methyl)benzyl)-5-methoxy-3-methylpyrido[3 , 4- d]pyridazin-4(3H)-one (7-(4-(( ( tert-butyldimethylsilyl)oxy)methyl)benzyl)— 5—methoxy— 3— methylpyrido[3 , 4— d]pyridazin- 4(3H)-one) was dissolved in THF. 1.0 M TBAF (1.2 eq) was added to the reaction mixture and stirred for about 30 minutes. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and the remaining moisture was completely removed using anhydrous magnesium sulfate S and filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0301] [Step d] Synthesis of 7-(4-(iodomethyl)benzyl)-5-methoxy-3-methylpyrido[3,4-bipyridazin-4(3H)-one (7—(4—(Iodomethyl)benzyl)—5—methoxy-3-methylpyrido[3,4-bipyridazin-4(3H)-one)

[0302] PPhs (1.5 eq) and imidazole (1.5 eq) were dissolved in CH2Cl2, iodine (1.5 eq) was added, and the mixture was stirred for about 20 minutes. 7-(4-(hydroxymethyl)benzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (7-(4-(hydroxymethyl)benzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one) dissolved in DCM was added dropwise to the reaction mixture at 0°C, and the mixture was stirred at room temperature for about 2 hours. The completion of the reaction was confirmed, quenched with 5% sodium thiosulfate aqueous solution, and filtered through celite. The organic layer was extracted using DCM and washed thoroughly with brine. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0303] [Step e] Synthesis of Dibenzyl (4- ((5-methoxy- 3-methyl- 4-oxo- 3, 4-dihydropyrido [3,4-bipyridazin- 7-yl)methyl)benzyl)phosphonate

[0304] 7-(4-(Iodomethyl)benzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (7-(4-(i odomethyl)benzyl)-5-methoxy-3-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one) was dissolved in DMF. Dibenzyl phosphite (1.5 eq) and Cs2CO3 (2.0 eq) were added to the reaction mixture and stirred for about 1 hour. After confirming the completion of the reaction and adding distilled water, the organic layer was extracted using EtOAc and washed several times with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0305] [Step f] Synthesis of (4-((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4- d]pyridazin-7-yl)methyl)benzyl)phosphonic acid ((4-((5-methoxy-3-methoxy-3-methoxy-1-4-oxo-3,4-dihydropyrido[3,4- d]pyridazin-7-yl)methyl)benzyl)phosphonic acid) Dibenzyl (4-((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4- d]pyridazin-7-yl)methyl)benzyl)phosphonate (Dibenzyl (4-((5-methoxy-3-methoxy-3-methoxy-1-4-oxo-3, 4-dihydropyrrolidone [ 3 , 4— d ]pyrrolidone (1 ) methyl 1 ) benzy 1 ) phosphonate was dissolved in EtOH / THF. Pd / C (Pal ladium on carbon, 10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered with Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated under vacuum to obtain the desired product.

[0306] 1 H NMR (400 MHz, DMSO) 5 8.19 (s, 1H) , 7.23 (d, J = 7.9 Hz, 2H) , 7.16 (dd, J = 8.0, 1.8 Hz, 2H) , 7.13 (s, IH) , 4.05 (s, 2H) , 4.00 (s, 3H) , 3.63 (s, 3H), 2.83 (d, J = 21.2 Hz, 2H) .

[0307] LC / MS (ESI) m / z: 376.19 [M+H]+ Example 20: Preparation of compound 354

[0308]

[0309] <Chemical Reaction Formula 20>

[0310] (a) Na2CO3, Pd(dppf)Cl2, Dioxane, H2O, 90 °C; (b) P(0)H(0Bn)2, Pd(PPh3)4, TEA, anhydrous Toluene, reflux; (c) H2, Pd / C, EtOH / THF

[0311] [Step a] Synthesis of 7-(4-bromobenzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (7-(4-br omobenzyl)-5-methoxy-3-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one)

[0312] ((7-borono-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-5-yl)oxy)methylium) was dissolved in 1,4-Dioxane:H2O (3:1). 1-Bromo-4-(bromomethyl)benzene (1.2 eq), Na2CO3 (2.2 eq), and Pd(dppf)Cl2 (10 mol%) were added to the reaction mixture, and the mixture was stirred at 90°C for about 1 h. After confirming the completion of the reaction, the mixture was filtered with Cell i te. After adding distilled water, the organic layer was extracted using EtOAc. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0313] [Step b] Synthesis of Dibenzyl (4-( (5-methoxy-3-methyl-4-oxo-3, 4-dihydropyrido[3,4-bipyridazin-7-yl)methyl)phenyl)phosphonate)

[0314] 7-(4-Bromobenzyl)-5-methoxy-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (7-(4-bromobenzy 1)—5— methoxy-3-methylpyrido[3,4—d]pyridazin—4(3H)-one), dibenzyl phosphite (1.2 eq), Pd(PPhs)4 (10 mol%) and TEA (1.2 eq) were added to anhydrous toluene and stirred under reflux. The reaction was confirmed to be complete and filtered with Cell i te. After adding distilled water, the organic layer was extracted using EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0315] [Step c] Synthesis of (4-((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)phosphonic acid) Dibenzyl (4-((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)phosphonic acid) Dibenzyl (4-((5-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)phosphonate [3,4—d]pyridazin-7-yl)methyl)pheny 1)phosphonat e) was dissolved in EtOH / THF. Pd / C (Pal ladium on carbon, 10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated under vacuum to obtain the desired product.

[0316] 1 H NMR (400 MHz, DMSO) 5 8.22 (s, 1H) , 7.62 (dd, J = 12.4, 7.9 Hz, 2H), 7.37 (d, J = 5.2 Hz, 2H) , 7.14 (s, IH) , 4.14 (s, 2H) , 3.99 (s, 3H) , 3.63 (s, 3H).

[0317] LC / MS (ESI) m / z: 362.20 [M+H]+ Example 21: Preparation of compound 355

[0318] <Chemical equation 21> (a) B2P i n2, KOAc, Pd(dppf)Cl21, 2-D i me thoxye thane, 95 °C: (b) NaiaCCh, Pd(dppf)Cl2, Dioxane, H2O, 90 °C; (c) P(0)H(0Bn)2, Pd(PPh3)4, TEA, anhydrous Toluene, reflux; (d) H2, Pd / C, EtOH / THF

[0319] [Step a] Synthesis of (5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)boronic acid Synthesis of 7-chloro-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one (7— chloro— 5— methoxypyrido[3,4— d]pyridazin— 4(3H)— one) obtained in Synthesis Example 2 was synthesized using 1,2-

[0320] Dimethyl thoxye thane was dissolved. B2Pin2(Bi s (p inacol at o)di boron) (1.2 eq), KOAc (3.0 eq), and Pd(dppf)Cl2 (10 mol%) were added to the reaction mixture. The mixture was stirred at 95°C for approximately 1 h. After confirming the completion of the reaction, it was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain a crude product that was used without further purification.

[0321] [Step b] Synthesis of 7-(4-bromobenzyl)-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one (7-(4~br omobenzyl)-5-methoxypyr i do[3,4-d]pyridazin-4(3H)-one)

[0322] (5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)boronic acid)

[0323] 1,4-Dioxane: Dissolved in H2O (3:1). 1-Bromo-4-(bromomethyl)benzene (1.2 eq), Na2CO3 (2.2 eq), and Pd(dppf)Cl2 (10 mol%) were added to the reaction mixture, and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, the mixture was filtered through Celite. After adding distilled water, the organic layer was separated using EtOAc. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0324] [Step c] Synthesis of dibenzyl (4-((5-methoxy-4-oxo-3,4-dihydropyrido[3,4- d ]pyridazin-7-yl)methyl)phenyl)phosphonate (Dibenzy 1 (4-((5-methoxy-4-oxo-3,4-dihydropyrido[3,4- d ]pyridazin-7-yl)methyl)phenyl)phosphonate)

[0325] 7-(4-bromobenzyl)-5-methoxypyrido[3,4-d]pyridazin-4(3H)-one (7-(4-bromobenzy 1) — 5— methoxypyrido[3,4-d]pyridazin- 4(3H)-one), dibenzyl phosphite (1.2 eq), Pd(PPhs)4 (10 mol%) and TEA (1.2 eq) were added to anhydrous toluene and stirred under reflux. After confirming the completion of the reaction, the mixture was filtered through Celite. After adding distilled water, the organic layer was extracted using EtOAc. After the remaining moisture was completely removed with anhydrous magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0326] [Step d] Synthesis of (4-((5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)phosphonic acid) Dibenzyl (4-((5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)phosphonic acid) Dibenzyl (4-((5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)methyl)phenyl)phosphonate (Di benzyl (4-((5-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7- ((methyl)phenyl)phosphonate) was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated in vacuo to obtain the desired product.

[0327] 1 H NMR (400 MHz, DMS0) 5 12.65 (s, 1H) , 8.19 (s, 1H) , 7.56 (dd, J = 11.1, 7.9 Hz, 2H), 7.24 (d, J = 6.2 Hz, 2H) , 7.10 (s, IH) , 4.09 (s, 2H) , 3.99 (s, 3H).

[0328] LC / MS (ESI) m / z: 348.20 [M+H]+ Example 22: Preparation of compound 356

[0329] <Chemical Reaction Formula 22>

[0330] (a) DIPEA, DMF, reflux; (b) H2, Pd / C, EtOH / THF

[0331] [Step a] Synthesis of dibenzyl (2- (1- (4-oxo-3,4-dihydropyrido [3,4- d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphate

[0332] 7-Bromopyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF. Dibenzyl(2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid) (1.2 eq) and DIPEA (2.0 eq) obtained according to the chemical reaction scheme 1 were added to the reaction mixture, and the mixture was stirred under reflux for about 15 hours. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed sufficiently with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0333] [Step b] Synthesis of (2- (1- (4-oxo- 3, 4-dihydropyrido [3,4- d]pyridazin- 7-yl)piperidin-4-yl)ethyl)phosphonic acid) Dibenzyl (2- (1- (4-oxo- 3, 4-dihydropyrido [3, 4- d]pyridazin- 7-yl)piperidin-4-yl)ethyl)phosphonic acid) Dibenzyl (2- (1- (4-oxo- 3, 4-dihydropyrido [3, 4- d]pyridazin- 7-yl)piperidin-4-yl)ethyl)phosphate Dipiper idi n— 4— y 1 )ethyl )phosphonat e ) was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated in vacuo to obtain the desired product.

[0334] 1 H NMR (400 MHz, DMSO) 5 12.28 (s, 1H) , 8.94 (s, 1H) , 8.07 (s, 1H) , 7.00 (s, IH), 4.48 (d, J= 13.1 Hz, 2H) , 2.94 (t, J= 11.8 Hz, 2H) , 1.79 (d, J = 12.8 Hz, 2H), 1.66 - 1.37 (m, 5H), 1.16 - 0.97 (m, 2H).

[0335] LC / MS (ESI) m / z: 339.1 [M+H] + Example 23: Preparation of compound 357

[0336]

[0337] <Chemical Reaction Formula 23>

[0338] (a) NaH, lodomethane, DMF, 0°C; (b) DIPEA, DMF, reflux; (c) H2, Pd / C, EtOH / THF

[0339] [Step a] Synthesis of 7-bromo-3-methylpyrido[3,4-d]pyr idazi n~4 (3H)-one

[0340] 7-Bromopyrido[3,4-d]pyridazin-4(3H)-one was dissolved in DMF. NaH (60%, 2.5 eq) was slowly added to the reaction mixture at 0°C and stirred. After about 10 minutes, lodome thane (4.0 eq) was added. The mixture was stirred at 0°C for about 20 minutes, and distilled water was added to terminate the reaction. The organic layer was extracted using EtOAc and washed thoroughly with brine. The remaining moisture in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0341] [Step b] Synthesis of dibenzyl (2- (1- (3-methyl- 4-oxo- 3, 4-dihydropyrido[3,4-bipyridazin- 7 -yl)piperidin- 4 -yl)ethyl)phosphonate 7-bromo-3-methylpyrido[3,4- d]pyridazin- 4(3H)-one was dissolved in DMF. Dibenzyl (2-(piperidin-4-yl)ethyl)phosphonate trifluoroacetic acid) (1.2 eq) and DI PEA (2.0 eq) were added to the reaction mixture and stirred under reflux for about 24 hours. After confirming the completion of the reaction, distilled water was added, the organic layer was extracted using EtOAc, and washed thoroughly with brine. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0342] [Step c] Synthesis of (2- (1- (3-methyl- 4-oxo- 3, 4-dihydropyrido [3, 4-bipyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid) dibenzyl (2- (1- (3-methyl- 4-oxo- 3, 4-dihydropyrido [3, 4-d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid) dibenzyl (2- (1- (3-methyl- 4-oxo- 3, 4-dihydropyrido [3, 4-d]pyridazin- 7-yl)piperidin- 4-yl)ethyl)phosphonic acid) 3,4-dihydropyrrolidone [ 3 , 4-d ]pyrrolidone (Dpiper idi n 4 y 1 )ethyl )phosphonate) was dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated in vacuo to obtain the desired product.

[0343] 1 H NMR (400 MHz, DMS0) 5 8.98 (s, 1H) , 8.12 (s, 1H) , 7.00 (s, 1H) ,

[0344] 4.47 (d, J = 13.1 Hz, 2H), 3.62 (s, 3H), 2.94 (t, J = 11.9 Hz, 2H), 1.79 (d, J = 12.0 Hz, 2H), 1.67 - 1.37 (m, 5H), 1.18 - 0.99 (m, 2H) .

[0345] LC / MS (ESI) m / z: 353.1 [M+H] +Example 24: Preparation of compound 358

[0346] <Chemical Reaction Formula 24>

[0347] (a) K2CO3, Pd(dppf)Cl2, 1,4-Di oxane, H2O, 90°C; (b) H2, Pd / C, EtOH / THF

[0348] [Step a] Synthesis of dibenzyl (4-(4-oxo-3,4-dihydropyrido[3,4- d]pyridazin-7-yl)phenethyl)phosphonate

[0349] 7-bromopyrido[3,4-d]pyridazin-4(3H)-one (7-bromopyr ido[3,4-d]pyr idazin- 4(3H)- one) was dissolved in 1,4-Dioxane: H2O (3:1). To the reaction mixture, dibenzyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)phosphonate (1.2 eq), K2CO3 (2.2 eq), and Pd(dppf)Cl2 (20 mol%) obtained in Synthesis Example 16 were added, and the mixture was stirred at 90°C for about 1 hour. After confirming the completion of the reaction, the mixture was filtered with Celite. After adding distilled water, the organic layer was extracted using EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain the desired product.

[0350] [Step b] Synthesis of (4-(4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonic acid) Dibenzyl (4-(4-oxo-3,4-dihydropyrido[3,4~d]pyridazin-7-yl)phenethyl)phosphonic acid) # Dissolved in EtOH / THF. Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile) and concentrated in vacuo to obtain the desired product.

[0351] 1 H NMR (400 MHz, DMS0) 5 12.95 (s, 1H) , 9.47 (s, 1H) , 8.41 (d, J = 10.0 Hz, 2H), 8.15 (d, J = 8.2 Hz, 2H) , 7.44 (d, J = 8.2 Hz, 2H) , 2.92 - 2.81 (m, 2H), 1.94 - 1.77 (m, 2H) .

[0352] LC / MS (ESI) m / z: 332.1 [M+H] + Example 25: Preparation of compound 359

[0353]

[0354] <Chemical Reaction Formula 25>

[0355] (a) K2CO3, Pd(dppf)Cl2, 1,4-Di oxane, H2O, 90°C; (b) H2, Pd / C, EtOH / THF

[0356] [Step a] Synthesis of dibenzyl (4-(3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphate

[0357] 7-Bromo-3-methylpyrido[3,4-d]pyridazin-4(3H)-one was dissolved in 1,4-Dioxane:H2O (3:1). To the reaction mixture, dibenzyl (4-(4, 4, 5, 5 -tetramethyl- 1,3, 2-dioxaborolan- 2 -yl)phenethyl)phosphonate (1.2 eq), K2CO3 (2.2 eq), and Pd(dppf)Cl2 (20 mol%) obtained in Synthesis Example 16 were added, and the mixture was stirred at 90°C for about 1 hour. After confirming the completion of the reaction, the mixture was filtered with Celite. After adding distilled water, the organic layer was extracted using EtOAc. The moisture remaining in the organic layer was completely removed with anhydrous magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the desired product. [Step b] Synthesis of (4-(3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonic acid) and dibenzyl (4-(3-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)phenethyl)phosphonic acid. phene t hy 1 ) phosphonat e ) # Dissolved in EtOH / THF.Palladium on carbon (10 wt%) was added and stirred under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Cell i te. The filtrate was concentrated under reduced pressure, and the crude product was purified using Prep-HPLC (mobile phase A: 0.1% formic acid in water, mobile phase B: Acetonitrile) and concentrated in vacuo to obtain the desired product.

[0358] 1 H NMR (400 MHz, DMS0) 5 9.49 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 3.75 (s) , 3H) , 2.91 - 2.82 (m, 2H) , 1.93 - 1.79 (m, 2H) .

[0359] LC / MS (ESI) m / z:346.1 [M+H] + Example 26: Preparation of compound 360 The compound was finally obtained using 1-iodopropane as R-X through the same process as the synthesis method (a-c) of the above chemical reaction scheme 10.

[0360]

[0361] 1 H NMR (400 MHz, DMSO) 5 7.95 (s, 1H) , 6.52 (s, 1H) , 4.41 (d, J = 13.0 Hz, 2H), 3.94 - 3.87 (m, 5H) , 2.92 (t, J = 11.9 Hz, 2H) , 1.78 (d, J = 12.4 Hz, 2H), 1.67 (dd, J = 14.5, 7.3 Hz, 2H) , 1.62 - 1.37 (m, 5H) , 1.07 (dd, = 11.9, 8.1 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H) .

[0362] LC / MS (ESI) m / z: 411.2 [M+H] + Example 27: Preparation of compound 361 The compound was finally obtained using iodoethane as RX through the same process as the synthesis method (a-c) of the chemical reaction scheme 10 above. 1 H NMR (400 MHz, DMSO) 5 7.96 (s, 1H) , 6.52 (s, 1H) , 4.41 (d, J = 12.8 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H) , 3.90 (s, 3H) , 2.92 (t, J = 11.9 Hz, 2H), 1.78 (d, J = 11.5 Hz, 2H) , 1.61 - 1.39 (m, 5H) , 1.21 (t, J = 7.1 Hz, 3H), 1.09 (dd, J = 16.4, 7.6 Hz, 2H) .

[0363] LC / MS (ESI) m / z: 397.2 [M+H] + Example 28: Preparation of compound 362 The compound was finally obtained using (chloromethyl)cyclopropane as RX through the same process as the synthesis method (a-c) of the chemical reaction scheme 10 above.

[0364] 1 H NMR (400 MHz, DMSO) 5 7.95 (s, IH) , 6.52 (s, IH) , 4.40 (s, 2H) , 3.91 (s, 3H), 3.82 (d, J = 7.1 Hz, 2H), 2.92 (t, J = 12.2 Hz, 2H) , 1.79 (d, J = 11.7 Hz, 2H), 1.67 - 1.37 (m, 5H), 1.26 - 1.02 (m, 3H), 0.45 (d, J = 7.9 Hz, 2H), 0.33 (d, J = 5.3 Hz, 2H).

[0365] LC / MS (ESI) m / z: 423.2 [M+H] +Example 29: Preparation of compound 363 The compound was finally obtained using 1-bromo-2-f luoroethane as R-X through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above.

[0366] 1 H NMR (400 MHz, DMSO) 5 7.98 (s, 1H) , 6.54 (s, 1H) , 4.77 (t, J =

[0367] 4.9 Hz, IH), 4.65 (t, J = 4.9 Hz, IH), 4.41 (d, J = 12.4 Hz, 2H), 4.29 (t,

[0368] J = 4.9 Hz, IH), 4.22 (t, J = 5.0 Hz, IH), 3.91 (s, 3H), 2.92 (t, J = 12.1

[0369] Hz, 2H), 1.79 (d, J = 11.5 Hz, 2H) , 1.63 - 1.37 (m, 5H), 1.09 (dd, J = 12.4,

[0370] 5.4 Hz, 2H).

[0371] LC / MS (ESI) m / z: 415.2 [M+H] + Example 30: Preparation of compound 364 The compound was finally obtained using 1-bromo-2-methoxyethane as R-X through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above.

[0372] 1 H NMR (400 MHz, DMS0) 5 7.96 (s, IH), 6.52 (s, IH) , 4.41 (d, J =

[0373] 12.3 Hz, 2H), 4.12 (t, J = 5.8 Hz, 2H), 3.91 (s, 3H), 3.62 (t, J = 5.8 Hz,

[0374] 2H), 3.23 (s, 3H), 2.92 (t, J = 11.8 Hz, 2H), 1.79 (d, J = 12.0 Hz, 2H),

[0375] 1.64 - 1.39 (m, 5H), 1.16 - 1.02 (m, 2H) .

[0376] LC / MS (ESI) m / z: 427.2 [M+H]+ Example 31: Preparation of compound 365 As RX by the same process as the synthetic method (a-c) of the above chemical reaction scheme 10

[0377] The compound was finally obtained using (chloromethyl)cyclobutane. 1 H NMR (400 MHz, DMSO) 5 7.93 (s, 1H) , 6.50 (s, 1H) , 4.40 (d, J = 12.4 Hz, 2H), 3.99 (d, J = 7.3 Hz, 2H) , 3.90 (s, 3H) , 2.91 (t, J = 11.9 Hz, 2H), 2.75 - 2.67 (m, IH), 1.94 (ddd, J = 8.8, 6.6, 3.1 Hz, 2H), 1.88 - 1.71 (m, 6H), 1.64 - 1.36 (m, 5H), 1.08 (dd, J = 21.0, 11.8 Hz, 2H) .

[0378] LC / MS (ESI) m / z: 437.2 [M+H] + Example 32: Preparation of compound 366 The compound was finally obtained using 1,1-di f luoro-2-iodoethane as R-X through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above.

[0379] 1H NMR (400 MHz, DMSO) 5 8.00 (s, IH) , 6.56 (s, IH) , 6.49 - 6.11 (m, IH), 4.50 - 4.26 (m, 4H) , 3.91 (s, 3H) , 2.93 (t, J = 12.2 Hz, 2H) , 1.79 (d, J = 11.7 Hz, 2H), 1.65 - 1.33 (m, 5H), 1.16 - 0.97 (m, 2H).

[0380] LC / MS (ESI) m / z: 433.2 [M+H] + Example 33: Preparation of compound 367 The compound was finally obtained using 1-chloropropan-2-one as R-X through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above.

[0381] 1 H NMR (400 MHz, DMS0) 5 7.96 (s, IH) , 6.56 (s, IH), 4.80 (s, 2H),

[0382] 4.42 (d, J = 12.4 Hz, 2H), 3.90 (s, 3H), 2.94 (t, J = 12.2 Hz, 2H), 2.15 (s,

[0383] 3H), 1.79 (d, J = 11.3 Hz, 2H), 1.64 - 1.37 (m, 5H), 1.09 (dd, J = 21.4,

[0384] 11.9 Hz, 2H).

[0385] LC / MS (ESI) m / z: 425.2 [M+H]+ Example 34: Preparation of compound 368 The compound was finally obtained using chloro(methoxy)methane as RX through the same process as the synthetic method (a-c) of the chemical reaction scheme 10 above. 1H NMR (400 MHz, DMSO) 5 7.97 (s, 1H) , 6.56 (s, 1H) , 5.22 (s, 2H) , 4.43 (d, J = 11.9 Hz, 2H), 3.91 (s, 3H) , 3.28 (s, 3H) , 2.94 (t, J = 12.0 Hz, 2H), 1.79 (d, J = 12.2 Hz, 2H), 1.65 - 1.37 (m, 5H), 1.09 (d, J = 9.4 Hz, 2H).

[0386] LC / MS (ESI) m / z: 413.2 [M+H] + Example 35: Preparation of compound 369 The compound was finally obtained using bromocyclopropane as RX through the same process as the synthesis method (a-c) of the above chemical reaction scheme 10.

[0387] 1 H NMR (400 MHz, DMSO) 5 7.91 (s, IH) , 6.51 (s, IH) , 4.41 (d, J = 12.9 Hz, 2H), 3.93 (s, 3H) , 3.84 - 3.75 (m, IH) , 2.92 (t, J = 11.8 Hz, 2H) , 1.78 (d, J = 12.3 Hz, 2H), 1.62 — 1.39 (m, 5H) , 1.08 (dd, J = 20.9, 11.9 Hz, 2H), 0.92 - 0.81 (m, 4H) .

[0388] LC / MS (ESI) m / z: 409.2 [M+H] + Experimental Example 1

[0389] (1) ENPP1 enzyme activity assay using pNP-TMP as a substrate p-Nitrophenyl thymidine 5'-monophosphate (pNP-TMP) is a synthetic substrate of ENPP1 and is hydrolyzed by ENPP1 into nucleotide 5'-monophosphate and p-nitrophenol (a colored product). The amount of p-nitrophenol product formed was measured using the absorbance at 405 nm, which is expressed in direct proportion to the enzyme activity.

[0390] IC 50 For determination of the values, different concentrations of each inhibitor and substrate pNP-TMP (final concentration 100 μM) were added to opposite sides of the wells and were not mixed. Human ENPP1 enzyme (R&D systems) was diluted in buffer (50 mM Tr i s-HCl, pH 9.0, 1 mM CaCl2, 0.2 mM ZnCh) to a final concentration of 20 ng / well. The prepared enzyme buffer was added to the wells to induce reactions simultaneously and mixed for 10 s using a plate shaker. The reactions were initiated by incubating at 37 °C for 5 min. The amount of product formed was measured directly on a Tecan® spectrophotometer. Maximum activity control samples (without inhibitor, with enzyme, substrate and buffer: MAX) and background control samples (without enzyme, with substrate and buffer: MIN) were evaluated simultaneously to calculate the % inhibition at each compound concentration as follows. Inhibition % = 100- [Compound-MIN] / [MAX-MIN] * IC for % inhibition vs. compound concentration 50 Values ​​were measured by fitting inhibition curves (% inhibition versus inhibitor concentration) using a four-parameter variable slope model in Sof tMax Pro 5.4. 1 software.

[0391] (2) ENPP1 enzyme activity assay using cGAMP as a substrate

[0392] ENPP! hydrolyzes 2' 3' -cGAMP ( cGAMP) > into 5' -AMP and 5' -GMP. The 5' -AMP formed from the reaction was detected using AMP-Glo® Kit (Promega). The Kit contains two reagents, Reagent I terminates the enzymatic reaction, removes ATP (using adenyl cyclase), and converts the generated 5' -AMP to 5' -ADP (using phosphotransferase), and Reagent II converts 5' -ADP to 5' -ATP and generates a luminescent signal depending on the amount of 5' -ATP using the luciferase / luciferin reaction. Different concentrations of ENPP1 inhibitors were pre-incubated with 10 ng of human ENPP1 enzyme (R&D Systems) at 37 °C for 15 minutes. The reaction was initiated by adding 20 μM 2'3'-cGAMP and incubating at 37 °C for 30 minutes. The final mixture contained buffer 50 mM Tris pH 9.5, 250 mM NaCl, 0.5 mM CaCl2, 1 μM ZnCl2, and 1% DMSO. After 30 minutes of incubation, the reaction was stopped by adding 18 μL of the mixture and 12 μL of reagent I to a white-black plate and incubating for 1 hour at room temperature. Subsequently, 25 μL of reagent II was added to the reaction and incubated for 1 hour at room temperature to convert the 5'-ADP formed from reagent I to 5'-ATP and light. The luminescence signal was measured with a Tecan® instrument. The maximum activity control sample (containing enzyme, substrate and buffer in the absence of ENPP1 inhibitor: MAX) and the background control sample (containing enzyme, substrate and buffer in the absence of enzyme: MIN) were evaluated simultaneously to calculate the % inhibition at each compound concentration as follows.Inhibition % = (([MAX-MIN] - [Compound- MIN]) / [MAX-MIN])*100 The IC50 values ​​for inhibition % versus compound concentration were measured by fitting the inhibition curve using a four-parameter variable slope model in GraphPad Prism® software. (3) Experimental results The above (1) and (2) were performed for each of the compounds of the present invention, and the results are shown in Table 2 below.

[0393] [Table 2] Experimental Example 2

[0394] (1) Cellular enzymatic assay of ENPP1 inhibitor using pNP-TMP as a substrate

[0395] ENPP1 is mainly expressed on the surface of the cell membrane and hydrolyzes 2'3'-cGAMP to produce 5'-GMP and 5'-AMP. In addition, ENPP1 also has the ability to hydrolyze the synthetic substrate pNP-TMP into nucleotide-5'-monophosphate and the colored product p-nitrophenol. Considering this, the enzymatic activity of ENPP1 was measured using pNP-TMP as a substrate in cultured MDA-MB-231 cells. The amount of p-nitrophenol product formed in the culture medium was measured using the absorbance at 405 °C, which was directly proportional to the activity of ENPP1. That is, the lower the 0D value at 405 °C, the better the potency of the ENPP1 inhibitor. Specifically, each inhibitor at five different concentrations was diluted 200X in DMEM medium without FBS to prepare the final assay concentration. 100,000 MDA-MB-231 cells per well in 48-well plates were cultured in DMEM containing FBS at 37 °C, 5% CO2 for 24 h. The medium was removed, washed twice with DPBS, and 190 uL of inhibitors were added. The cells were pre-incubated for 60 min at 37 °C, 5% CO2. Subsequently, 10 uL of 4 mM (final concentration 200 uM) pNP-TMP solution was added to each well and mixed with inhibitors for 2 h, and the 0D values ​​were read at 405 °C using a Tecan® spectrophotometer. ICso values ​​in terms of % inhibition versus compound concentration were determined by fitting inhibition curves using a four-parameter variable slope model in GraphPad Pr i sm® software.

[0396] (2) Experimental results: The above (1) was performed for each of the original compounds, and the results are shown in Table 3 below.

[0397] [Table 3]

[0398]

Claims

【Scope of Claims】 【

1. A compound represented by any one of the following chemical formulae 1 to 3, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof: <화학식 1> In the above chemical formula 1, L1 and L2 are each independently -L a - L b - and the above L a is a 3- to 6-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of a single bond, N, 0 and S in the ring, (C1-C5 alkylene)-(3- to 6-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring), 6- to 14-membered arylene, (C1-C5 alkylene)-(6- to 14-membered arylene), NH, NH(C1-C5 alkylene)-(3- to 6-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring), NH-(6- to 14-membered arylene), NH(C1-C5 alkylene)-(6- to 14-membered arylene), NH (C1-C5 alkylene)-(5- to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and ) in the ring, O-(C1-C5 alkylene)-(3- to 5-membered heterocycloalkylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and ) in the ring, or a divalent functional group of a fused ring in which two or more rings are bonded while sharing atoms, and the L a At least one of the groups may be independently substituted or unsubstituted with a halogen; L b is a single bond, C1- C8 alkylene or C1- C8 alkenylene, and R1 and R2 are each independently H, B(OH)2, CN, C(=0)NH-OH, N(C1- C5 alkyl) (C1-C5 alkyl) , NH (C1- C5 alkyl) , NH2 , NH-C (=0)-NH2 , NH-P (=0) (OH) 2 , NH- P (=S) (OH) 2 , NH- S (=0) 2- NH2 , O (C1- C5 alkyl) , O- (C3-C6 cycloalkyl) , OH , O- P (=O) (OH) 2 , OP (=S) (OH) 2 , P (=O) (OH) 2 , P (=S) (OH) 2 , SP (=O) (OH) 2 or s- P(=S)(OH)2, and each of the chemical formula 1 independently satisfies the valence A combined single bond or double bond, A1 is 0, NR 3a R 3b or 0R 3c and R 3a , R 3b and R 3c are each independently H, C1-C5alkyl or C3-C6cycloalkyl, A2 is N or N(- L4- R4), L4 is a single bond, C1-C5 alkylene, C(=0), C(=0)- (C1-C5 alkylene), C(=O)O(C1- C5 alkylene), C(=S), S(=0)2, (C1-C5 alkylene) - C(=0), (C1-C5 alkylene) - C(=O)NH or (C1-C5 alkylene) - C(=0)0, R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), 6-14 membered aryl, 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring, 3-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring, R4's C1-C5 alkyl, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring, or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein at least one of these groups may be independently substituted or unsubstituted with C1-C5 alkyl, C1-C5 alkoxy, CN, OH, NH2, MC1-C5 alkyl) (C1-C5 alkyl), N02 or halogen, At least one of the carbons forming the ring of a 3- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S of R4 may be C (=0), A3 is CH, CH2 or N, and A4 is CR5a or CHR 5b and R 5a and R 5b are each independently H or C1- C5 alkyl, A5 is CR6 or N, R6 is H or C1-C5 alkyl, in the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in the above chemical formula 1, and A6 in the above chemical formula 2 is 0R 3c and R 3c is the same as defined in Chemical Formula 1, and in Chemical Formula 3, L1, R1, A2, A3, A4 and A5 are the same as defined in Chemical Formula 1. 【

2. In claim 1, in the chemical formula 1, L1 and L2 are each independently -L a - L b - and the above L a is a single bond, a 3-membered to 3-membered ring containing 1 to 3 SiO2 atoms. 6-membered heterocycloalkylene, (C1-C5 alkylene) - (3-6 membered heterocycloalkylene containing 1 to 3 N in the ring), phenylene, (C1-C5 alkylene)-phenylene, NH, NH (C1-C5 alkylene) - (3-6 membered heterocycloalkylene containing 1 to 3 C in the ring), NH-phenylene, NH (C1-C5 alkylene)-phenylene, NH (C1-C5 alkylene)- (5- to 12-membered heteroarylene containing 1 to 3 Si in the ring), O-(C1- C5 alkylene) -(3- to 6-membered heterocycloalkylene containing 1 to 3 N in the ring) or tetrahydroisoquinoline difunctional group, and the L a At least one of which may be independently substituted or unsubstituted with a halogen, L b is a single bond, C1-C5 alkylene or C1-C5 alkenylene, and R1 and R2 are each independently H, B(OH)2, CN, C(=0)NH-OH, N(C1- C3 alkyl)(Cl- C3 alkyl), NH(C1- C3 alkyl), NH2, NH-C(=0)-NH2, NH-P(=0)(OH)2, NH- P(=S)(OH)2, NH-S(=0)2-NH 2I O (C1- C3 alkyl), 0- (C3-C6 cycloalkyl), OH, 0- P (=O) (OH)2, OP (=S) (OH)2, P (=O) (OH)2, P (=S) (OH)2, SP (=O) (OH)2 or s- P (=S) (OH)2, and in the above chemical formula 1, each independently satisfies the valence A combined single bond or double bond, A1 is 0, NR 3a R 3b or 0R 3c and R 3a , R 3b and R 3c are each independently H, C1-C5alkyl or C3-C6cycloalkyl, A2 is N or N(- L4- R4), L4 is a single bond, C1-C5 alkylene, C(=0), C(=0)-(C1-C5 alkylene), C(=O)O(C1- C5 alkylene), C(=S), S(=0)2, (C1-C5 alkylene) - C(=0), (C1-C5 alkylene) - C(=O)NH or (C1-C5 alkylene) - C(=0)0, R4 is a 5-membered to 6-membered heteroatom containing 1 to 3 heteroatoms in the ring, independently selected from the group consisting of H, C1-C5 alkyl, C3-C6 cycloalkyl, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), 6- to 14-membered aryl, N, 0 and A 3-6 membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of 12-membered heteroaryl, N, 0 and S in the ring, R4's C1-C5 alkyl, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring, or 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein at least one of these groups may be independently substituted or unsubstituted with C1-C5 alkyl, C1-C5 alkoxy, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), N02 or halogen, At least one of the carbons forming the ring of a 3- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S of R4 may be C (=0), A3 is CH, CH2 or Si, and A4 is CR 5a or CH R 5b and R 5a and R 5b are each independently H or C1-C5 alkyl, A5 is CR6 or Si, R6 is H or C1-C5 alkyl, and in the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in the above chemical formula 1, and A6 in the above chemical formula 2 is 0R 3c and R 3c is the same as defined in Chemical Formula 1, and in Chemical Formula 3, L1, R1, A2, A3, A4 and A5 are defined in Chemical Formula 1. A compound represented by chemical formulae 1 to 3, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, which is identical to that of the compound. 【

3. In claim 1, in the chemical formula 1, L1 and L2 are each independently -L a - L b - and the above L a is a single bond, piperidinylene, piperazinylene, (C1-C5 alkylene)- piperidinylene, (C1-C5 alkylene)-piperazinylene, phenylene, (C1-C5 alkylene)-phenylene, NH, NH (C1- C5 alkylene)-piperidinylene, NH-phenylene, NH (C1- C5 alkylene)-phenylene, NH (C1- C5 alkylene)-pyridinylene, O- (C1-C5 alkylene)-piperidinylene or and the above L a At least one or more of which may be independently substituted with a halogen, L b is a single bond, C1-C5 alkylene or C1-C5 alkenylene, R1 and R2 are each independently H, B(OH)2, CN, C(=0)NH-OH, C(=0)OH, N(C1- C3 alkyl)(Cl- C3 alkyl), NH(C1- C3 alkyl), NH2, NH-C(=0)-NH2, NH-P(=0)(OH)2, NH- P(=S)(OH)2, NH- S(=0)2- NH2, O(C1- C3 alkyl), 0-(C3-C6 cycloalkyl), OH, 0- P(=O)(OH)2, OP(=S)(OH)2, P(=O)(OH)2, P(=S)(OH)2, SP(=O)(OH)2 or s- P(=S)(OH)2, and in the above chemical formula 1, are each independently To satisfy the atomic number A combined single bond or double bond, A1 is 0, NR 3a , R 3b OR 3c and R 3a , R 3b and R 3c are each independently H, C1-C5 alkyl or C3-C6 cycloalkyl, A2 is N or N(- L4- R4), L4 is a single bond, C1-C5 alkylene, C(=0), C(=0)- (C1-C5 alkylene), C(=O)O(C1- C5 alkylene), C(=S), S(=0)2, (C1-C5 alkylene) - C(=0), (C1-C5 alkylene) - C(=O)NH or (C1-C5 alkylene) - C(=0)0, R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CF3, CN, OH, NH2, N(C1-C5 alkyl) (C1-C5 alkyl), phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl, At least one or more of H of the above C1-C5 alkyl, phenyl, naphryl, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl of R4 may be independently substituted or unsubstituted with C1-C5 alkyl, C1-C5 alkoxy, CF3, CN, OH, NH2, N(C1-C5 alkyl)(C1-C5 alkyl), NO2 or halogen, At least one of the carbons forming the ring of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl of R4 may be C(=0), A3 is CH, CH2 or N, and A4 is CR 5a or CHR 5b and R 5a and R 5b are each independently H or C1-C5 alkyl, A5 is CR6 or N, R6 is H or C1-C5 alkyl, in the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in the above chemical formula 1, and A6 in the above chemical formula 2 is OR 3c and R 3c A compound represented by chemical formulae 1 to 3, wherein L1, R1, A2, A3, A4 and A5 in chemical formula 3 are the same as defined in chemical formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. 【

4. In claim 1, in the chemical formula 1, L1 and L2 are each independently -L a - U- and the above L a is a 3- to 6-membered heterocycloalkylene containing 1 to 3 heteroatoms independently selected from the group consisting of a single bond, N, 0 and S in the ring, a 6- to 14-membered arylene or (C1-C5 alkylene) - (6- to 14-membered arylene), L b is a single bond or C1-C8 alkylene, and R1 and R2 are each independently H, NH (C1-C5 alkyl), NH2, NH- S (=0) NH2, O (C1-C5 alkyl) or P (=0) (OH)2; in the above chemical formula 1, each independently satisfies the valence A combined single bond or double bond, A1 is 0, This 2nd is N(- L4- R4), L4 is a single bond, C1-C5 alkylene, C(=0), (C1-C5 alkylene) - C(=0) or (Cl- C5 alkylene) -C(=0)0, R4 is a 3-6 membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of H, C1-C5 alkyl, C3-C6 cycloalkyl, N, 0 and , CN, NH2 or N(C1-C5 alkyl)(C1-C5 alkyl), At least one of the H of the C1-C5 alkyl of R4 may be independently substituted with C1-C5 alkoxy or halogen, and A3 is Si; A4 is CR 5a , R 5a is visible; A5 is CR6, R6 is visible; In the above chemical formula 2, L2, R2, A 2I A3, A4 and A5 are the same as defined in Chemical Formula 1, and A6 in Chemical Formula 2 is 0R 3c and R 3c A compound represented by chemical formulas 1 to 3, wherein in the chemical formula 3, L1, R1, A2, A3, A4 and A5 are the same as defined in chemical formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. 【

5. In claim 4, in the chemical formula 1, L1 and L2 are each independently -L a - L b - and the above L a is a single bond, piperidinylene, phenylene, (C1-C5 alkylene)-phenylene, L b is a single bond or C1-C8 alkylene; R1 and R2 are each independently H, NH(C1- C5 alkyl), NH2, NH- S(=0)『 NH2, O(C1- C5 alkyl) or P(=0)(OH)2; in the above chemical formula 1, each independently satisfies the valence A bonded single bond or double bond; A1 is 0; 2 is N(- L4- R4), L4 is a single bond, C1-C5 alkylene, C(=0), (C1-C5 alkylene) - C(=0) or (C1- C5 alkylene) -C(=0)0, R4 is H, C1-C5 alkyl, C3-C6 cycloalkyl, CN, NH2 or N(C1- C5 alkyl)(C1- C5 alkyl), At least one of the H of the C1-C5 alkyl of R4 may be independently substituted with C1-C5 alkoxy or halogen; A3 is Si; A4 is CR 5a , R 5a is visible; A5 is CR6, R6 is visible; In the above chemical formula 2, L2, R2, A2, A3, A4 and A5 are the same as defined in chemical formula 1, and A6 of the above chemical formula 2 is 0R 3c and R 3c A compound represented by chemical formulas 1 to 3, wherein in the chemical formula 3, L1, R1, A2, A3, A4 and A5 are the same as defined in chemical formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. 【

6. In claim 1, the compound represented by the chemical formulae 1 to 3 is at least one selected from the group consisting of compounds shown in the table below, a compound represented by the chemical formulae 1 to 3, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof: m   611 A pharmaceutical composition for preventing or treating an ENPP1-related disease, comprising as an active ingredient a compound represented by chemical formulas 1 to 3 according to any one of claims 1 to 6, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof. 【

8. A pharmaceutical composition according to claim 7, wherein the pharmaceutical composition exhibits ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) inhibitory activity. 【In claim 7, the ENPP1-related disease is at least one selected from the group consisting of cancer, hypophosphatemia, chondrocalcinosis, osteoarthritis, aortic valve calcification, viral or bacterial infection, cystic fibrosis, type 2 diabetes, and Alzheimer's disease, pharmaceutically Composition. 【

10. A method for preventing or treating an ENPP1-related disease, comprising administering to a subject a therapeutically effective amount of a compound represented by any one of chemical formulae 1 to 3 according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof.

11. Use of a compound represented by any one of chemical formulae 1 to 3 according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof for the prevention or treatment of ENPP1-related diseases.

12. Use of a compound represented by any one of chemical formulae 1 to 3 according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with ENPP1.

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