NR2f6 inhibitor and uses thereof

Abstract

The present invention relates to a compound represented by chemical formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof, a pharmaceutical composition comprising same, a method for preventing or treating NR2F6-related diseases using same, and uses thereof. The compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or solvate or hydrate thereof, and the pharmaceutical composition comprising same according to the present invention may be useful for preventing or treating NR2F6-related diseases.

Description

[0001] Description of the Invention

[0002]

Title of invention

[0003] NR2F6 inhibitors and uses thereof

[0004]

Technical Field

[0005]

Background Technology

[0006] Nuclear Receptor Subfamily 2 Group F Member 6 (NR2F6), also known as V-erbA-related protein 2 (EAR-2), is an orphan member of the nuclear receptor superfamily of ligand-activated receptors. Recently, NR2F6 has attracted attention as a potential novel immune checkpoint target in cancer immunotherapy. NR2F6 acts as a transcription factor in various cell subsets, such as Th1, Th17, CD4 T cells, and CD8 T cells, and directly binds to multiple regions within the promoter loci of key cytokines, such as IL-2, IFNx, and TNFα, thereby antagonizing the DNA accessibility of the NFAT and AP-1 transcription factors. NR2F6 plays a critical role in overall cellular homeostasis and various diseases, including cancer. Specifically, substantial preclinical evidence suggests that NR2F6 expression is associated with increased tumor progression and poor overall patient survival, and that NR2F6 overexpression generates effector T cells that fail to mount a robust immune response against malignant tumors. Therefore, there is a pressing need to develop therapeutics that inhibit NR2F6, which induces immune cell activation and immune cell suppression in autoimmune diseases.

[0007]

Contents of the invention

[0008]

Technical Problem

[0009]

Technical Solution

[0010] (1) The present invention provides a compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof.

[0011] [Chemical Formula I] In the above chemical formula I,

[0012] Ai is a 3-8 membered heterocycloalkyl having one or more heteroatoms selected from C1-C8 cycloalkyl, N, 0 and , a 6-14 membered aryl or a 5-12 membered heteroaryl having one or more heteroatoms selected from N, 0 and , wherein one or more groups of Ai are each independently C1-C6 alkyl, C1-C5 alkoxy, a 6-14 membered aryl, a 5-12 membered heteroaryl having one or more heteroatoms selected from N, 0 and , - NR1R2, - C(=O)Ri, - C(=O)ORi, -S(=0)2RI, -C(=N)OHRI, -NHC(=O)RI, -C(=O)NHRI, -C1-C4 alkylene- OH, -CN, -OH, - CF2H, -CFS or may be substituted or unsubstituted with halogen,

[0013] Ri and R2 are each independently H, 0, -0H, or C1-C6 alkyl,

[0014] Li is C1-C6 alkylene, - C(=O)NH- , -C1-C6 alkylene - C(=O)NH- , - C(=O)NH- Cl- C6 alkylene-, -NHC(=O)-, -NH-NHC=O, - NH(C=O)- NH- , - NHC(=O)- Cl- C6 alkylene-, -C1-C6 alkylene- NHC(=O)_, -S(=0)2NH-, -NHS(=0)2-, -NH-, -S(=0)2-, -NHC(=O)O-, -C(=0)0-, -C(=0)-, or - 0-, wherein one or more of the groups of Li are each independently C1-C6 alkyl, C3-C6 cycloalkyl, - Cl- C4 alkylene- OH, -CN, -0H or halogen. may be substituted or unsubstituted,

[0015] A2 is C1-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and , 6-14 membered aryl, 5-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and

[0016] 12-membered heteroaryl (At this time, the above m is 0, 1, 2,

[0017] 3, 4 or 5, and Xi and X2 are each independently C, N, CH or NH), wherein one or more of the above A2 may be independently substituted or unsubstituted with Ra or - L2- Ra,

[0018] L2 is C1-C6 alkylene, - C(=O)NH- , -C1-C6 alkylene - C(=O)NH- , - C(=O)NH- Cl- C6 alkylene- , -NHC(=O)- , -NH-NHC=O, - NH(C=O)- NH- , - NHC(=O)- Cl- C6 alkylene- , -C1-C6 alkylene- NHC(=O)- , -C1-C6 alkylene- NH- , -NH-C1-C6 alkylene- , -S(=0)2NH- , - NHS(=0)2- , -NH- , -S(=0)2- , -NHC(=O)O- , -C(=0)0- , -C(=0)- , or -0-,

[0019] Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and , 3-8 membered heterocycloalkenyl containing one or more heteroatoms selected from N, 0 and , 6-14 membered aryl or 5-12 membered heteroaryl containing one or more heteroatoms selected from N, 0 and , wherein one or more of Ra is each independently - ORb, -C(=O)Rb, - C(=O)ORb, -SRb, S(=0)2Rb, -NRbRc, - C(=O)NRbRc, - NRbC(=O)Rc, -S(=0)2NRbRc, - NRbS(=0)2Rc, -C1-C4 alkylene- NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and , 6-14 membered aryl, 5-12 membered heteroaryl containing one or more heteroatoms selected from N, 0 and , - C1-C4 alkylene- OH, -C1-C4 alkylene- CF3,_- CN, -OH, -CF2H, -CF3 or may be substituted or unsubstituted with halogen,

[0020] Rb and each independently is H, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, N, O and one or more heteroatoms selected from a 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and, -C1-C4 alkylene-OH, -CN, -OH, -CF2H, -CF3 or halogen, wherein one or more of the above Rb and are each independently C1-C6 alkyl, C1-C8 cycloalkyl, 6- to 14-membered aryl, -NRdRe, -CF3 or halogen may be substituted or unsubstituted,

[0021] Rd and Re are each independently H or C1-C6 alkyl, and halogen is F, Cl, Br or I. However, "2,5-dimethyl-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)furan-3-carboxamide" in the compound represented by the above Chemical Formula I may be excluded.

[0022] (2) In the above (1), in the above Chemical Formula I

[0023] Ai is 6- to 14-membered aryl or 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and, wherein one or more of the above Ai are each independently C1-C6 alkyl, C1-C5 alkoxy, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and, -NR1R2, -C1-C4 alkylene-OH,

[0024] -CN, -OH, -CF2H, -CFS or halogen may be substituted or unsubstituted, and R1 and R2 are each independently H or 0,

[0025] Li is - C(=O)NH-, -C1-C6 alkylene - C(=O)NH-, - C(=O)NH- Cl- C6 alkylene-, - NHC(=O)-, -NHC(=O)-C1-C6 alkylene-, -C1-C6 alkylene- NHC(=O)-, -S(=0)2NH-, - NHS(=0)2 -or - NHC(=O)O-, wherein one or more of the above Li groups may be independently substituted or unsubstituted with C1-C6 alkyl, C3-C6 cycloalkyl, - Cl- C4 alkylene- OH, -CN, -0H or halogen,

[0026] A2 is a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, 0 and (At this time, m is 0, 1, 2, 3, 4 or 5, and Xi and

[0027] X2 is independently C, N, CH or NH), wherein one or more of the above A2 may be independently substituted or unsubstituted with Ra or - L2- Ra,

[0028] L2 is -C1-C6 alkylene- NH-, -NH-C1-C6 alkylene-, -S(=0)2NH-, -NHS(=0)2-, - NH- or - 0-,

[0029] Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and , 3-8 membered heterocycloalkenyl containing one or more heteroatoms selected from N, 0 and , 6-14 membered aryl or 5-12 membered heteroaryl containing one or more heteroatoms selected from N, 0 and , wherein one or more of Ra is each independently - ORb, -C(=O)Rb, - C(=O)ORb, -SRb, S(=0)2Rb, -NRbRc, - C(=O)NRbRc, - NRbC(=O)Rc, -S(=0)2NRbRc, - NRbS(=0)2Rc, -C1-C4 alkylene- NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and , 6-14 membered aryl, 5-12 membered heteroaryl containing one or more heteroatoms selected from N, 0 and , - C1-C4 alkylene- OH, -C1-C4 alkylene- CF3, -CN, -OH, -CF2H, -CF3 or may be substituted or unsubstituted with halogen,

[0030] Rb and Therefore are each independently H, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, N, O and one or more heteroatoms selected from a 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and, -C1-C4 alkylene-OH, -CN, -OH, -CF2H, -CF3 or halogen, wherein one or more of the Rb and Therefore are each independently C1-C6 alkyl, C1-C8 cycloalkyl, 6- to 14-membered aryl, -NRdRe, -CF3 or halogen and may be substituted or unsubstituted,

[0031] Rd and Re are each independently H or C1-C6 alkyl, and the halogen may be F, Cl, Br or I. (3) In the above (1) or (2), in Formula I,

[0032] Ai is 6- to 14-membered aryl or 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and, wherein one or more of the Ai are each independently C1-C6 alkyl, C1-C5 alkoxy, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and, -NR1R2, -C1-C4 alkylene-OH, -CN, -OH, -CF2H, -CF3 or halogen and may be substituted or unsubstituted,

[0033] R1 and R2 are each independently H or O,

[0034] Li is -NHC(=O)-, -NHC(=O)-C1-C6 alkylene-, -C1-C6 alkylene-NHC(=O)-, -NHS(=O)2- or -NHC(=O)O-,

[0035] A2 is a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, 0 and (At this time, the above m is 3, 4 or 5, and Xi and X2 are each independently C, N, CH or NH), wherein one or more of the above A2 may be independently substituted or unsubstituted with Ra or - L2- Ra,

[0036] L2 is -C1-C6 alkylene- NH-, -NHS(=0)2-, -NH- or - o-, Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, N, 0 and a 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from , N, 0 and a 3-8 membered heterocycloalkenyl containing one or more heteroatoms selected from , 6-14 membered aryl or 5-12 membered heteroaryl containing one or more heteroatoms selected from N, 0 and , wherein one or more of Ra are each independently - ORb, -C(=O)Rb, - C(=O)ORb, -SRb, -NRbRc, - C(=O)NRbRc, - NRbC(=O)Rc, -S(=0)2NRbRc, -NRbS(=0)2Rc, -C1-C4 alkylene- NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, N, 0 and 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from, 6-14 membered aryl, -C1-C4 alkylene- CF3, -CN, -OH, -CF2H, -CF3 or halogen, which may be substituted or unsubstituted,

[0037] Rb and each independently is H, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, N, O and a 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from, 6- to 14-membered aryl, -CF3 or halogen, wherein one or more of the Rb and each independently is C1-C6 alkyl, C1-C8 cycloalkyl, 6- to 14-membered aryl, -NRdRe, -CF3 or halogen and may be substituted or unsubstituted,

[0038] Rd and Re are each independently H or C1-C6 alkyl, and the halogen may be F, Cl, Br or I. (4) In any one of the above (1) to (3), the formula I may be represented by formula la, formula lb or formula Ic.

[0039] [Formula la] In the formula la, Xi, X2, X3, X4 and X5 are each independently C, N, CH, or, where the H of CH and or is each independently Ra or -L『Ra and may be substituted or unsubstituted, and in formula lb, X1, X2 and X3 are each independently C, N, CH, or, where the H of CH and or is each independently Ra or Ra may be substituted or unsubstituted, and in the above chemical formula Ic, Xi and X2 are each independently C, N, CH, or Pa, wherein the CH and or Pa groups may each be independently substituted or unsubstituted with Ra or - L2- Ra, and m is 0, 1, 2, 3, 4, or 5, and in each of the above chemical formulas la, lb, and Ic, Ai, Li, L2, and Ra are each the same as defined for the above chemical formula I in (1). However, in the compound represented by the above chemical formula Ic, “2, 5 -dimethyl- N- (7, 8, 9, 10-tetrahydro- 6H-benzo [4, 5] imidazo [1, 2- a] azepin- 3 -yl) furan- 3-carboxamide” may be excluded.

[0040] (5) In the above (4), in the chemical formula la,

[0041] X1, X2, X3, X4 and X5 are each independently C, N, CH, or P, wherein CH and or P may each be independently substituted or unsubstituted with Ra or - L2- Ra,

[0042] Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , wherein one or more of Ai is independently C1-C6 alkyl, C1-C5 alkoxy, a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , - NR1R2, -C1-C4 alkylene- 0H, -CN, -OH, -CF2H, -CFS or halogen, which may be substituted or unsubstituted,

[0043] Ri and R2 are each independently H or 0,

[0044] Li is -NHC(=O)-, -NHC(=O)-C1-C6 alkylene-, -C1-C6 alkylene-NHC(=O)-, -NHS(=0)2 - or -NHC(=O)O-,

[0045] L2 is -C1-C6 alkylene-NH-, -NHS(=O)『, -NH- or -0-,

[0046] Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, a 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and, a 3- to 8-member heterocycloalkenyl containing one or more heteroatoms selected from N, O and, a 6- to 14-member aryl or a 5- to 12-member heteroaryl containing one or more heteroatoms selected from N, O and, wherein one or more substituents of the Ra are each independently -ORb, -C(=O)Rb, -C(=O)ORb, -SRb, -NRbRc, -C(=O)NRbRc, -NRbC(=O)Rc, -S(=0)2NRbRc, -NRbS(=0)2Rc, -C1-C4 alkylene-NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, a 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and, a 6- to 14-member aryl, -C1-C4 alkylene-CF3, -CN, -OH, -CF2H, -CF3 or halogen, and Rb and Rc are each independently H, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, a 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and, a 6- to 14-member aryl, -CFs or halogen, wherein one or more substituents of the Rb and Rc are each independently C1-C6 alkyl, C1-C8 cycloalkyl, a 6- to 14-member aryl, -NRdRe, -CF3 or halogen, and may be substituted or unsubstituted,

[0047] Rd and Re are each independently H or C1-C6 alkyl, and the halogen can be F, Cl, Br or I.

[0048] (6) In the above (4), in the chemical formula lb,

[0049] X1, X2 and X3 are each independently N, CH, or P, wherein CH and or P may each independently be substituted or unsubstituted with Ra,

[0050] Ai is a 5- to 12-membered heteroaryl group containing one or more heteroatoms selected from N, 0, and wherein one or more of Ai may be independently substituted or unsubstituted with C1-C6 alkyl,

[0051] Li is - NHC(=O)-,

[0052] Ra can be H, C1-C8 cycloalkyl or 6- to 14-membered aryl. (7) In the above (4), in the chemical formula Ic, m is 4,

[0053] X1 and X2 are each independently C or N,

[0054] Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, 0, and wherein one or more of Ai may be independently substituted or unsubstituted with C1-C6 alkyl, C1-C5 alkoxy, or - 0H,

[0055] Li may be -NHC(=O)-. In one embodiment, in the chemical formula I This means that the number of atoms in the ring varies depending on, for example, m In this case of 4 people It can represent the structure. In one embodiment, it means that the number of atoms in the ring varies depending on m in the chemical formula Ic, for example, when m is 4, the chemical formula Ic is

[0056] In the present invention, the term “Cm-Cn” (wherein m and n are each independently an integer greater than or equal to 1) 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 leads to a stable compound, for example, a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc. In the present invention, “single bond” means a case where adjacent atoms or groups of atoms are directly bonded. In the present invention, “alkyl” means a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group, unless otherwise specified. 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. In the present invention, unless otherwise stated, “alkylene” means a divalent functional group derived from alkyl defined as above. In the present invention, unless otherwise stated, “alkynylene” means a divalent functional group derived from alkyl containing at least one carbon-carbon triple bond in the alkyl. Examples of alkynylene include: However, the present invention is not limited thereto. In the present invention, unless otherwise stated, “alkenyl” means an unsaturated hydrocarbon group containing at least one carbon-carbon double bond in the alkyl. In the present invention, unless otherwise stated, “alkoxy” means a monovalent group derived from a straight-chain or branched saturated hydrocarbon moiety represented by 0CnH2n+l. Examples of alkoxy include, but are not limited to, one or more selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy, etc. Unless otherwise stated, “cycloalkyl” in the present invention means a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures. It also includes all double ring structures such as bridged ring or spiro structure. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, spiro [4.4]nonanyl, spiro [3.3]heptanyl, bicyclo [3.1.0]hexanyl, bicyclo [3.1.1]heptanyl, and bicyclo [2.2.1]heptanyl, adamantyl. However, the present invention is not limited thereto. In the present invention, unless otherwise stated, “cycloalkenyl” means a cyclic group including at least one carbon-carbon double bond in the cycloalkyl, and the cycloalkenyl is not an aromatic ring. Examples of the cycloalkenyl may include at least one selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl, but is not limited thereto. In the present invention, unless otherwise stated, “heterocycloalkyl” means a cyclic group in which at least one carbon atom forming a ring in the cycloalkyl is independently substituted with a heteroatom or functional group selected from the group consisting of N, 0, S, SO, and S02. Examples of heterocycloalkyl include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, oxepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl, aziridinyl, , but is not limited thereto. In the present invention, unless otherwise stated, “heterocycloalkenyl” means a cyclic group in which at least one carbon atom forming the ring in the cycloalkenyl is independently substituted with a heteroatom or functional group selected from the group consisting of N, 0, S, SO and S02, and the heterocycloalkenyl is not an aromatic ring. Examples of heterocycloalkenyl include, Hereinafter, the term "heterocycloalkenylene" will be understood to mean a divalent functional group derived from a heterocycloalkenyl group as defined above, unless otherwise stated. In the present invention, unless otherwise stated, "aryl" will be understood to mean a monocyclic or polycyclic aromatic ring 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, biphenyl, naphthalenyl, tetrahydronaphthyl, indenyl, and anthracenyl. In the present invention, unless otherwise stated, "arylene" will be understood to mean a divalent functional group derived from an aryl group as defined above, unless otherwise stated. In the present invention, unless otherwise stated, “heteroaryl” means a monocyclic or polycyclic aromatic heterocycle containing at least one heteroatom selected from the group consisting of N, 0 and S within the ring and having one or more fused or non-fused aromatic rings. Examples of heteroaryl include, but are not limited to, one or more selected from thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isooxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, benzoxadiazolyl, thienothiophenyl, quinolinyl, isoquinolinyl, and purinyl. In the present invention, “heteroarylene” means a divalent functional group derived from heteroaryl as defined above, unless otherwise stated. In the present invention, “halogen” may be F, Cl, Br, or I, unless otherwise stated. In addition, terms and abbreviations used in this specification have their original meanings unless otherwise defined.In the present invention, the symbol “三 =三 “ represents a single bond or a double bond. Whether “三=三” is a single bond or a double bond can be determined according to the allowable valence of the atoms connected to each other through “三 =三”.

[0057] (8) The present invention provides a compound selected from the compounds described in Table 1 below, its stereoisomers, its pharmaceutically acceptable salts, its solvates or hydrates. [Table 1]

[0058]

[0059]

[0060] In the present invention, "stereoisomer" includes diastereomer and optical isomer, and optical isomer includes not only enantiomer but also mixture of enantiomer and racemate. In the present invention, "pharmaceutically acceptable" may mean physiologically acceptable and does not typically cause allergic reactions such as gastrointestinal disorders or dizziness or similar reactions when administered to a subject. In the present invention, "pharmaceutically acceptable salt" means a salt commonly used in the pharmaceutical industry, for example, an inorganic ionic salt manufactured with calcium, potassium, sodium or magnesium, etc.; an inorganic acid salt manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; Organic acid salts made with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, spartic acid, ascorbic acid, carbonic acid or vanillic acid; sulfonic acid salts made with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid; amino acid salts made with glycine, arginine or lysine; and amine salts made with trimethylamine, triethylamine, ammonia, pyridine or picoline; but the types of salts meant in the present invention are not limited by these listed salts. The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods known to those skilled in the art. The "hydrate" of the present invention is a compound represented by the formula I 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 contains about 0.05% water per mole of the active ingredient.It can be included in a ratio of about 25 mol to about 10 mol, and more specifically, it can 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. The "solvate" of the present invention is a compound represented by Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a solvent other than water are bound by non-covalent intermolecular forces, and can include the solvent in a stoichiometric or non-stoichiometric amount. Specifically, the solvate can 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, it can 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. The present invention provides a pharmaceutical composition comprising (as an active ingredient) a compound represented by the above chemical formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive. The pharmaceutically acceptable additive is an additive commonly used in the pharmaceutical field and can be appropriately selected by a person skilled in the art. For example, the pharmaceutically acceptable additives include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the additives may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like.The compound represented by the above chemical formula I of the present invention, the compound of the above Table 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate, and the pharmaceutical composition containing them (as an active ingredient) may exhibit NR2F6 (Nuclear Receptor Subfamily 2 Group F Member 6) inhibitory activity. The compound represented by the above chemical formula I of the present invention, the compound of the above Table 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate, and the pharmaceutical composition containing them (as an active ingredient) may be an NR2F6 inhibitor, an NR2F6 antagonist, and may be for the prevention or treatment of NR2F6-related diseases. The NR2F6-related diseases may include cancer. The compound represented by the above chemical formula I of the present invention, the compound of the above table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing them (as an active ingredient) may be used for the prevention or treatment of cancer. The cancer may be a solid cancer, and may be, for example, ovarian cancer, colon cancer, melanoma, and related solid cancers, but is not necessarily limited thereto. The present invention relates to uses and methods for the prevention or treatment.

[0061] (1) A method for preventing or treating a disease or cancer related to NR2F6, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound represented by the above chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing them (as an active ingredient);

[0062] (2) Use of a compound represented by the above chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing them (as an active ingredient) for the prevention or treatment of NR2F6-related diseases or cancer;

[0063] (3) Use of the compound represented by the above chemical formula I, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate, and a pharmaceutical composition containing them (as an active ingredient) in the manufacture of a medicament for the prevention or treatment of NR2F6-related diseases or cancer; and

[0064] (4) Provided are compounds represented by the above formula I, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, and pharmaceutical compositions comprising them (as active ingredients) for use in the prevention or treatment of NR2F6-related diseases or cancers. In the preventive or therapeutic method and use of the present invention, the compounds represented by the formula I, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, and pharmaceutical compositions comprising them are substantially the same as those described in the compounds represented by the formula I of the present invention and pharmaceutical compositions comprising them. In addition, the present invention

[0065] (1) A method for preventing or treating a disease or cancer related to NR2F6, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound selected from the compounds described in Table 2 below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing the same (as an active ingredient);

[0066] (2) Use of a compound selected from the compounds described in Table 2 below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing them (as an active ingredient) for the prevention or treatment of NR2F6-related diseases or cancer;

[0067] (3) Use of a compound selected from the compounds described in Table 2 below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing them (as an active ingredient) in the manufacture of a medicament for preventing or treating NR2F6-related diseases or cancer; and

[0068] (4) A compound selected from the compounds listed in Table 2 below for use in the prevention or treatment of NR2F6-related diseases or cancer, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition comprising them (as an active ingredient) are provided.

[0069] [Table 2]

[0070]

[0071]

[0072]

[0073]

[0074] In the present invention, "prevention" means all acts of delaying the onset of an NR2F6-related disease by administering a compound represented by the above-mentioned chemical formula I according to the present invention, a compound of Tables 1 and 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing them (as an active ingredient). In the present invention, "treatment" means all acts of improving or beneficially changing the symptoms of an NR2F6-related disease by administering a compound represented by the above-mentioned chemical formula I according to the present invention, a compound of Tables 1 and 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutical composition containing them (as an active ingredient). In the present invention, an NR2F6-related disease may include cancer. In the present invention, cancer may be a solid tumor, for example, ovarian cancer, colon cancer, melanoma, and related solid tumors, but is not necessarily limited thereto.

[0075]

Effect of the invention

[0076]

Mode for Carrying Out the Invention

[0077] Preparation of N-(1H-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxamide

[0078] [Step 1]

[0079] 1H-benzo[d]imidazol-5-amine, 2,5-dimethylfuran-3-carboxylic acid, 1-

[0080] [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1-[Bi s(dimethylami no)methylene]-1H-1,2,3-tri azolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HATU) was dissolved in dimethyl formamide (DMF), N,N-diisopropylethylamine (DIPEA) was added, and the mixture was stirred at 110°C for 4 hours. After the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (EA). The mixed organic layer of the extract was washed with water, dried over magnesium sulfate (MgSCU), and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(1H-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxamide. Example 2

[0081] Preparation of 2,5-dimethyl-N-(l-phenyl-1H-benzo[(1]imidazol-5-yl)furan-3-carboxamide L-precipitated water DMF DMSO

[0082] [Step 1]

[0083] 5-Nitro-1H-benzo[d]imidazole, iodobenzene, and potassium carbonate (K2CO3) were dissolved in dimethyl sulfoxide (DMSO), then cuprous iodide (Cui) and L-proline were added and stirred at 140 °C for 16 hours. After the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with ethanol. The combined organic layers of the extracts were washed with water, dried over MgSO, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound 5-nitro-1-phenyl-1H-benzo[d]imidazole (5-nitr ol-pheny 1 -IH-benzo[d]imidazole 1 e).

[0084] [Step 2]

[0085] 5-Nitro-1-phenyl-1H-benzo[d]imidazole and sodium dithionite (Dong⑵으⑵⑴) were dissolved in ethanol (EtOH):distilled water (4:1) and stirred at 100 °C for 16 hours. After the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound 1-phenyl-1H-benzo[d]imidazol-5-amine.

[0086] [Step 3]

[0087] Compound 2,5-dimethyl-N-(1-phenyl-1H-benzo[d]imidazol-5-yl)furan-3-carboxamide (2,5-dimethyl — N— (1-pheny1 -1H-benzo [d] imidazo1 — 5— y1) furan-3-carboxamide) was obtained in the same manner as in Step 1 of Example 1, except that 1-phenyl-1H-benzo [d] imidazol-5-amine was used. Example 3

[0088] 4-Hydroxy-3-methoxy-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)benzamide (4-117(11'0乂7-3-11161±0乂7-시-

[0089] (7,8,9,10-Tetrahydro—6H— benzo [4,5] imidazo [1,2-a] azepin— 3— yl) benzamide) Preparation DMF

[0090] [Step 1]

[0091] Compound 4-hydroxy-3-methoxy-N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-amine) was prepared in the same manner as in Step 1 of Example 1, except that 4-hydroxy-3-methoxybenzoic acid was used. benzo[4, 5] imidazo[l,2— a]azepin— 3— yl)benzamide) was obtained. Example 4

[0092] Preparation of N-(l-cyclohexyl-lH-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxamide

[0093]

[0094] [Step 1] Dissolve benzenesulfonyl chloride in DMF, stir at room temperature for 20 minutes, then add 2-fluoro-5-nitroaniline and stir at room temperature for 30 minutes. Filter the resulting solid, wash it with diethyl ether. Transfer the solid to a flask, neutralize it with 4M aqueous sodium hydroxide (NaOH), and extract with toluene. Wash the mixed organic layer of the extract with water, dry it with MgSO4, and concentrate it under reduced pressure to obtain N'-(2-fluoro-5-nitrophenyl)-N,N-dimethylformimidamide.

[0095] [Step 2]

[0096] Dissolve N'-(2-fluoro-5-nitrophenyl)-N,N-dimethylformimidamide and cyclohexanamine in DMSO, and stir at 140 °C for 16 hours. After the reaction is completed, cool the mixture to room temperature, dilute it with water, and extract with toluene. Wash the mixed organic layer of the extract with water, dry it with MgSO4, and concentrate it under reduced pressure. Purify the concentrated material by column chromatography to obtain 1-cyclohexyl-5-nitro-1H-benzo[d]imidazole.

[0097] [Step 3]

[0098] 1-Cyclohexyl-5-nitro-1H-benzo[d]imidazole was dissolved in tetrahydrofuran (THF), palladium on carbon (Pd / C) was added, and the mixture was stirred under hydrogen gas for 6 hours. The completed reaction mixture was filtered to remove palladium, and the solvent was concentrated under reduced pressure to obtain compound 1-cyclohexyl-1H-benzo[d]imidazol-5-amine without any purification process.

[0099] [Step 4]

[0100] Compound N-(l-cyclohexyl-lH-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxamide was obtained in the same manner as in step 1 of Example 1, except that 1-cyclohexyl-lH-benzo[d]imidazol-5-amine was used. Example 5 Preparation of 2,5-dimethyl-N-(2-phenyl-1H-benzo[d]imidazol-5-yl)furan-3-carboxamide water DMF

[0101] [Step 1]

[0102] 4-nitrobenzene-1,2-diamine, benzaldehyde (benzald lyde), and benzyl alcohol were dissolved in a DMSO:distilled water (1:1) solvent and stirred at 120°C for 16 hours. The resulting solid was filtered through a filter and washed with water and ethanol. The washed solid was dried to obtain compound 2-phenyl-1H-benzo[d]imidazol— 5—amine.

[0103] [Step 2]

[0104] Compound 2,5-dimethyl-N-(2-phenyl-1H-benzo[d]imidazol-5-amine) was obtained in the same manner as in step 1 of Example 1, except that 2-phenyl-1H-benzo[d]imidazol-5-amine was used. Preparation of 2,5-dimethyl- N- (3-(pyridin-2-ylamino)phenyl)furan-3-carboxamide (2,5-dimethyl— N— (3— (pyridin— 2— ylamino)phenyl )furan— 3— carboxamide)

[0105] [Step 1]

[0106] (3-Nitrophenyl)boronic acid, pyridin-2-amine, and copper(II) acetate (Cu(OAc)₂) were dissolved in 1,2-dichloroethane (1,2-DCE) and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with toluene. The mixed organic layer of the extract was washed with water and dried over MgSO₄, and then concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N1-(pyridin-2-yl)benzene-1,3-diamine (N1-(pyridin-2-yl)benzene-1,3-diamine).

[0107] [Step 2]

[0108] Compound 2,5-dimethyl-N-(3-(pyridin-2-ylamino)phenyl)furan-3-carboxamide (2,5-dimethyl-N-(3-(pyridin-2-ylamino)phenyl)furan-3-carboxamide) was obtained in the same manner as in Step 1 of Example 1, except that N1-(pyridin-2-yl)benzene-1,3-diamine (N1-(pyridin-2-yl)benzene-1,3-diamine) was used. Example 7

[0109] Preparation of N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)-1H-pyrrole-3-carboxamide (N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)-1H-pyrrole-3-carboxamide) DIPEA DMF

[0110] [Step 1]

[0111] Compound N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-amine) was prepared in the same manner as in Step 1 of Example 1, except that 1H-pyrrole-3-carboxylic acid was used, thereby obtaining the compound N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)-1H-pyrrole-3-carboxamide (ci-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-amine) a]azepin— 3— yl )— 1H— pyrrole— 3— carboxamide)# obtained. 8 in practice

[0112] Preparation of N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)oxazole-4-carboxamide

[0113] [Step 1]

[0114] Compound N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-amine) (7,8,9,10—tetrahydro— 6H— benzo[4,5]imidazotl,2-a]azepi n-3-amine) was prepared in the same manner as in step 1 of example 1, except that oxazole-4-carboxylic acid was used. )oxazole— 4— carboxamide) was obtained. Example 9

[0115] Preparation of N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)isoxazole—3-carboxamide

[0116] [Step 1] The compound N-(7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-3-amine) (7,8,9,10—tetrahydro— 6H— benzo[4,5]imidazotl,2-a]azepi n-3-amine) and isoxazole-3-carboxylic acid were used in the same manner as in Step 1 of Example 1, except that isoxazole-3-carboxylic acid was used to prepare the compound N-(7,8,9,10-tetrahydro- 6H-benzo[4,5]imidazo[1,2-a]azepin-3-yl)isoxazole-3-carboxamide (N-(7,8,9, 10-tetrahydro- 6H- benzo[4,5]imidazo[l,2- a]azepin- 3- yl) isoxazole- 3- carboxamide) was obtained. 10

[0117] N-(3-(cyclohexylamino)phenyl)-2,5-dimethylfuran-3-carboxamide (N-(3-

[0118] Preparation of ( eye lohexy 1 ami no)phenyl )—2,5— dimethyl fur an— 3— carboxamide)

[0119] [Step 1] Under nitrogen gas, Cui, 1,1'-bi-2-naphthol (BINOL), tripotassium phosphate (K3PO4) were mixed, 1-iodo-3-nitrobenzene and cyclohexanamine were added, and the mixture was stirred at 120°C for 3 hours. After the reaction, the mixture was filtered through a celite filter, and the solvent was concentrated under reduced pressure to obtain the compound N-cyclohexyl-3-nitroaniline without any purification process.

[0120] [Step 2]

[0121] Compound N1-cyclohexylbenzene-1,3-diamine (Si1-0701Sa16Ya61126116-1,3-(daj111yuan16)) was obtained in the same manner as in Step 3 of Example 4, except that N-cyclohexyl-3-nitroaniline (N-cyclohexyl-3-nitroani1ine) was used.

[0122] [Step 3]

[0123] Compound N-(3-(cyclohexylamino)phenyl)-2,5-dimethylfuran-3-carboxamide (Si-(3-(cyclohexylaniino)phenyl)-2,5-dimethyl furan-3-carboxamide) was obtained in the same manner as in Step 1 of Example 1, except that N1-cyclohexylbenzene-1,3-diamine (Si1-0701Sa16Ya61126116-1,3-(daj111dou116)) was used. In the implementation of 11

[0124] Preparation of N-(2-cyclohexyl-1H-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxamide (N-(2-cyclohexyl-1H-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxami de)

[0125]

[0126] [Step 1] Dodecylbenzenesulfonic acid (DBSA) was dissolved in distilled water, and 4-nitrobenzene-1,2-diamine and iodine were added. Cyclohexanecarbaldehyde was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solid was filtered and dried. The dried material was purified by column chromatography to obtain compound 2-cyclohexyl-5-nitro-1H-benzo[d]imidazole.

[0127] [Step 2]

[0128] 2-Cyclohexyl-5-nitro-1H-benzo[d]imidazole, iron (Fe), and acetic acid (AcOH) were dissolved in EtOH and stirred at 80°C for 3 hours. After the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with Toyo. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound 2-cyclohexyl-1H-benzo[d]imidazol— 5— amine.

[0129] [Step 3]

[0130] 2-Cyclohexyl-1H-benzo[d]imidazol-5-amine and 2,5-dimethylfuran-3-carboxylic acid, HATU were dissolved in DMF, DIPEA was added, and the mixture was stirred at 40°C for 4 hours. The mixture was diluted with water and extracted with Toyo. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(2-cyclohexyl-1H-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxamide (N-(2-cyclohexyl-1H-benzo[d]imidazol-5-yl)-2,5-dimethylfuran-3-carboxamide). Example 12

[0131] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)furan-3-carboxamide water

[0132] [Step 1] Under nitrogen gas, (4-methoxyphenyl)boronic acid, 6-chloropyridazin-3-amine, tetrakis(triphenylphosphine)palladium(O), Pd(PPh3)4, and potassium carbonate (K2CO3) were dissolved in a 1,4-dioxane (1,4-Dioxane) : distilled water (4:1) solvent and stirred at 100°C for 16 hours. After the reaction, the mixture was diluted with water and extracted with distilled water. The mixed organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-methoxypheny 1 ) pyr i daz in— 3— am i ne ).

[0133] [Step 2]

[0134] 6-(4-methoxyphenyl)pyridazin-3-amine and furan-3-carboxylic acid, HATIJ were dissolved in DMF, DIPEA was added, and the mixture was stirred at 110°C for 4 hours. After cooling the reaction mixture to room temperature, water was added to the reaction solution to precipitate it, and the solid was filtered to obtain it. The obtained solid was purified by column chromatography to obtain compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)furan-3-carboxamide. Example 13

[0135] N-(6-(6-Aminopyridin-3-yl)pyridazin-3-yl)furan-3-carboxamide (N-(6-

[0136] (6—Aminopyridin—3—yl)pyridazin—3—yl)furan—3—carboxamide) Preparation Dine in F 1,4-Dioxane water

[0137] [Step 1]

[0138] Compound N-(6-Chloropyridazin-3-yl)furan-3-carboxamide (N-(6-Chloropyridazin-3-yl)furan-3-carboxamide) was obtained in the same manner as in Step 1 of Example 1, except that 6-chloropyridazin-3-amine and furan-3-carboxylic acid were used.

[0139] [Step 2]

[0140] Compound N-(6-(6-Aminopyridin-3-yl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(6-Aminopyridin-3-yl)pyridazin-3-yl)furan-3-carboxamide) was obtained in the same manner as in Step 1 of Example 12, except that N-(6-Chloropyridazin-3-yl)furan-3-carboxamide and (6-Aminopyridin-3-yl)boronic acid were used. Example 14

[0141] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide) , water

[0142] [Step 1] (4-(trifluoromethyl)phenyl)boronic acid ( (4-

[0143] (trifluoromethyl)phenyl)boronic acid), 6-chloropyridazin-3-amine, Pd(PPhs)4, K2CO3 were dissolved in a 1,4-Dioxane:distilled water (4:1) solvent and stirred at 100°C for 16 hours. The mixture after reaction was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated substance was purified by column chromatography to obtain compound 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine.

[0144] [Step 2]

[0145] 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0146] (trifluoromethyl)phenyl)pyridazin-3-amine), furan-3-carboxylic acid, and HATU were dissolved in DMF, DIPEA was added, and the mixture was stirred at 110°C for 4 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction solution to precipitate the compound, and the solid was filtered to obtain it. The obtained solid was purified by column chromatography to obtain the compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide. Example 15

[0147] N-(6-(3-morpholinophenyl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(3-morpho 1 i nopheny 1 ) pyr i daz in— 3— y 1 )fur an— 3— car boxam i de )

[0148] [Step 1]

[0149] Compound (6-(3-morpholinophenyl)pyridazin-3-amine) was obtained in the same manner as in step 1 of Example 12, except that (3-morpholinophenyl)boronic acid was used.

[0150] [Step 2]

[0151] Compound N-(6-(3-morpholinophenyl)pyridazin-3-yl)furan- was prepared in the same manner as in step 2 of Example 12, except that (6-(3-morpholinophenyl)pyridazin-3-amine) was used.

[0152] 3-Carboxamide (N- (6- (3-morphol i nophenyl )pyridazin- 3- yl )furan- 3-carboxamide)# obtained. Example 16

[0153] Preparation of 2,5-dimethyl-N-(6-phenylpyridazin-3-yl)furan-3-carboxamide o HO

[0154] Pd(dppf)CI2CH2CI2HATU

[0155] Na2CO3DIPEA

[0156] 1,4-Dioxane DMF water

[0157] [Step 1] Phenylboronic acid, 6-chloropyridazin-3-amine, bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex under nitrogen gas

[0158] (Bi s (diphenylphosphino) ferrocene] di chloro opal ladium( II ) complex with dichloromethane , Pd(dppf )C12CH2(〕12) , sodium carbonate (Sodium Carbonate , Na2CC)3) was dissolved in a 1 , 4-Dioxane:distilled water (5:1) solvent and stirred at 90°C for 16 hours. The mixture after reaction was diluted with water and extracted with ethanol. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound 6-phenylpyridazin-3-amine. [Step 2]

[0159] 6-Phenylpyridazin-3-amine and 2,5-dimethylfuran-3-carboxylic acid, HATU were dissolved in DMF, DIPEA was added, and the mixture was stirred at 40°C for 4 hours. The mixture was diluted with water and extracted with distilled water. The combined organic layers of the extracts were washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound 2,5-dimethyl-N-(6-phenylpyridazin-3-yl)furan-3-carboxamide. Example 17

[0160] Preparation of N-(6-phenylpyridazin-3-yl)nicotinamide , - oxane water

[0161] [Step 1] Compound 6-phenylpyridazin-3-amine was obtained in the same manner as Step 1 of Example 16.

[0162] [Step 2] Step 16 of Example 16, except that nicotinic acid was used.

[0163] Compound N-(6-phenylpyridazin-3-yl)nicotinamide (ci-(6-phenylpyridazin— 3— yl )ni cot inamide) was obtained by the same method as in Example 2. Example 18

[0164] Preparation of N-(6-phenylpyridazin-3-yl)picolinamide

[0165] Pd(dppf)Cl2CH2Cl2 DIPEA N82CO3 DMF 1,4-Dioxane water

[0166] [Step 1] Compound 6-phenylpyridazin-3-amine was obtained in the same manner as Step 1 of Example 16.

[0167] [Step 2] Compound N-(6-phenylpyridazin-3-yl)picolinamide (ci-(6-phenylpyridazin— 3— yl)pi col inamide) was obtained in the same manner as in Step 2 of Example 16, except that picolinic acid was used. Example 19

[0168] Preparation of N-(6-phenylpyridazin-3-yl)isonicotinamide NS2CO3 DIPEA 1,4-Dioxane DMF water

[0169] [Step 1] Compound 6-phenylpyridazin-3-amine was obtained in the same manner as Step 1 of Example 16.

[0170] [Step 2] The compound N-(6-phenylpyridazin-3-yl)isonicotinamide (N-(6-pheny 1 pyr i daz in— 3— y 1 ) isonicot i nam ide)# was obtained in the same manner as in Step 2 of Example 16, except that isonicotinic acid was used. Example 20

[0171] Preparation of N-(6-(2-methylbenzo[d]oxazol-6-yl)pyridazin-3-yl)furan-3-carboxamide water

[0172] [Step 1]

[0173] Compound 6-(2-methylbenzo [d]oxazol-6-yl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (2-methylbenzo [d]oxazol-6-yl)boronic acid was used.

[0174] [Step 2]

[0175] Compound N-(6-(2-methylbenzo [d]oxazol-6-yl)pyridazin-3-yl)furan-3-carboxamide was obtained by the same method as in step 2 of Example 12, except that 6-(2-methylbenzo [d]oxazol-6-yl)pyridazin-3-amine was used. In Example 21

[0176] Preparation of N-(6-(3-methoxyphenyl)pyridazin-3-yl)furan-3-carboxamide

[0177] [Step 1]

[0178] Compound 6-(3-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-methoxyphenyl)boronic acid was used.

[0179] [Step 2]

[0180] Compound N-(6-(3-methoxyphenyl)pyridazin-3-yl)furan-3-carboxamide was obtained by the same method as in step 2 of Example 12, except that 6-(3-methoxyphenyl)pyridazin-3-amine was used. Example 22

[0181] N-(6-([1,1'-biphenyl]-4-yl)pyridazin-3-yl)furan-3-carboxamide(ci-(6-

[0182] ( [ 1 , 1 ' — bi pheny 1 ] — 4— y 1 ) pyr i daz in— 3— yl )fur an— 3— car boxam i de )'s low]jo [Step 1]

[0183] Compound 6-([1,1'-biphenyl]-4-yl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that [1,1'-biphenyl]-4-yl boron ic acid was used.

[0184] [Step 2]

[0185] Compound N-(6-([1,1'-biphenyl]-4-yl)pyridazin-3-yl)furan-3-carboxamide was obtained by the same method as in step 2 of Example 12, except that 6-([l,r-biphenyl]-4-yl)pyridazin-3-amine was used. Example 23

[0186] Preparation of N-(6-(2-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide water [Step 1] (2-(trifluoromethyl)phenyl)boronic acid ( (2-

[0187] (trifluoromethyl)phenyl)boronic acid), 6-chloropyridazin-3-amine, Pd(PPhs)4, K2CO3 were dissolved in a 1,4-Dioxane:distilled water (4:1) solvent and stirred at 100°C for 16 hours. The mixture after reaction was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated substance was purified by column chromatography to obtain compound 6-(2-(trifluoromethyl)phenyl)pyridazin-3-amine.

[0188] [Step 2]

[0189] 6-(2-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(2-

[0190] (trifluoromethyl)phenyl)pyridazin-3-amine), furan-3-carboxylic acid, and HATU were dissolved in DMF, DIPEA was added, and the mixture was stirred at 110°C for 4 hours. After cooling the reaction mixture to room temperature, water was added to the reaction solution to precipitate it, and the solid was filtered to obtain it. The obtained solid was purified by column chromatography to obtain N-(6-(2-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide. Example 24 Preparation of N-(6-(4-phenoxyphenyl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(4-phenoxypheny 1 )pyridazin— 3— y 1 )fur an— 3— car box am i de ) water

[0191] [Step 1]

[0192] 6-(4-phenoxyphenyl)pyridazin-3-amine (6-(4-phenoxypheny 1 )pyridazin-3-amine) was obtained in the same manner as in step 1 of Example 12, except that (4-phenoxyphenyl)boronic acid was used.

[0193] [Step 2]

[0194] Compound N-(6-(4-phenoxyphenyl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(4-phenoxypheny 1 )pyridazin-3-yl)furan-3-carboxamide)# was obtained by the same method as in step 2 of Example 12, except that 6-(4-phenoxyphenyl)pyridazin-3-amine was used. Example 25

[0195] N-(6-(3-acetamidophenyl)pyridazin-3-yl)furan-3-carboxamide (N-(6-

[0196] (3-acet am i dopheny 1)pyr idazin— 3— yl )furan— 3— carboxamide) water

[0197] [Step 1]

[0198] N-(3-(6-aminopyridazin-3-yl)phenyl)acetamide was obtained in the same manner as in step 1 of Example 12, except that (3-acetamidophenyl)boronic acid was used.

[0199] [Step 2]

[0200] N-(6-(3-acetamidophenyl)pyridazin-3-yl)furan-3-carboxamide was obtained by the same method as in step 2 of Example 12, except that N-(3-(6-aminopyridazin-3-yl)phenyl)acetamide was used. Example 26

[0201] Preparation of 2-methoxy-N-(6-(4-methoxyphenyl)pyridazin-3-yl)isonicotinamide

[0202] Pd(dppf)CI2CH2CI2HATU Na2COg DIPEA 1,4-Dioxane DMF water

[0203] [Step 1] Under nitrogen gas, (4-methoxyphenyl)boronic acid and 6-chloropyridazin-3-amine, Pd(dppf)C12CH2(〕12,

[0204] Na2C03 was dissolved in a 1,4-Dioxane:distilled water (5:1) solvent and stirred at 90°C for 16 hours. The reaction mixture was diluted with water and extracted with ethanol. The combined organic layers of the extracts were washed with water, dried over MgSO, and concentrated under reduced pressure. The concentrated substance was purified by column chromatography to obtain compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-methoxypheny 1 ) pyr i daz in— 3— am i ne ).

[0205] [Step 2]

[0206] 6-(4-methoxyphenyl)pyridazin-3-amine and 2-methoxyisonicotinic acid were dissolved in HATU# DMF, DIPEA was added, and the mixture was stirred at 40°C for 15 hours. The reaction mixture was diluted with water and extracted with ethanol. The combined organic layers of the extracts were washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound 2-methoxy-N-(6-(4-methoxyphenyl)pyridazin-3-yl)isonicotinamide. Example 27

[0207] N-(6-(4-methoxyphenyl)pyridazin-3-yl)isoxazole-3-carboxamide(ci-(6-

[0208] Preparation of (4-met hoxypheny 1)pyr idazin-3-yl) isoxazole—3—carboxamide) water

[0209] [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-methoxypheny 1)pyridazin-3-amine) was obtained in the same manner as Step 1 of Example 12.

[0210] [Step 2] The compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)isoxazole-3-carboxamide (N-(6-(4-methoxypheny 1 ) pyr i daz in— 3— y 1 ) isoxazol e— 3— car boxam ide)# was obtained in the same manner as in Step 2 of Example 12, except that isoxazole-3-carboxylic acid was used. Example 28

[0211] Preparation of 3 , 5 -difluoro-4- (hydroxymethyl)- N- (6- (3 -methoxyphenyl)pyridazin-3-yl)benzamide (3 , 5-di f 1 uor o-4- ( hydr oxyme t hy 1 )- N- (6- (3 - methoxypheny 1 ) pyr i daz in— 3— y 1 ) benz am i de )

[0212] [Step 1]

[0213] Compound 6-(3-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-methoxyphenyl)boronic acid was used.

[0214] [Step 2]

[0215] 6-(3-methoxyphenyl)pyridazin-3-amine, 3,5-difluoro-4-(hydroxymethyl)benzoic acid, 3,5-difluoro-4-

[0216] Compound 3,5-difluoro-4-(hydroxymethyl)-N-(6-(3-methoxyphenyl)pyridazin—3—yl)benzamide was obtained in the same manner as in Example 12, step 2, except that ( hydroxymethyl)-N-(6-(3-methoxyphenyl)pyridazin—3—yl)benzamide was used. In Example 29

[0217] Preparation of N-(6-(3-methoxyphenyl)pyridazin-3-yl)-2-(3-methylisoxazol-5-yl)acetamide water

[0218] [Step 1]

[0219] Compound 6-(3-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-methoxyphenyl)boronic acid was used.

[0220] [Step 2]

[0221] Compound N-(6-(3-methoxyphenyl)pyridazin-3-yl)-2-(3-methylisoxazol-5-yl)acetamide⑴-(6-(3-methoxyphenyl)pyridazin-3-amine) and 2-(3-methylisoxazol-5-yl)acet ic acid were used in the same manner as in step 2 of Example 12, except that 6-(3-methoxyphenyl)pyridazin-3-amine and 2-(3-methylisoxazol-5-yl)acet ic acid were used. Example 30

[0222] Preparation of N-(6-(3-methoxyphenyl)pyridazin-3-yl)benzo[c][1,2,5]oxadiazole-5-carboxamide 1,4-Dioxane water

[0223] [Step 1]

[0224] Compound 6-(3-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-methoxyphenyl)boronic acid was used.

[0225] [Step 2]

[0226] Compound N-(6-(3-methoxyphenyl)pyridazin-3-yl)benzo[c][1,2,5]oxadiazole-5-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(3-methoxyphenyl)pyridazin-3-amine and benzo[c][1,2,5]oxadiazole-5-carboxylic acid were used. Example 31

[0227] N-(6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-yl)furan-3-carboxamide

[0228] Preparation of ( N- (6- (4-met hoxypheny 1 )— 4,5— dimethylpyr idazin— 3— yl) fur an— 3— carboxamide) water

[0229] [Step 1]

[0230] Compound 6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that 6-chloro-4,5-dimethylpyridazin-3-amine was used.

[0231] [Step 2]

[0232] The compound N-(6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-yl)furan-3-carboxamide was obtained in the same manner as in step 2 of Example 12 except that 6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-amine was used. Example 32

[0233] Preparation of N-(6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-yl)isoxazole-3-carboxamide (N-(6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-yl)isoxazole-3-carboxamide) water

[0234] [Step 1]

[0235] Compound 6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that 6-chloro-4,5-dimethylpyridazin-3-amine was used.

[0236] [Step 2]

[0237] Compound N-(6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-amine, °]isoxazole— 3—carboxylic acid was used in the same manner as in step 2 of Example 12, except that N-(6-(4-methoxyphenyl)-4,5-dimethylpyridazin-3-yl)isoxazole-3-carboxamide was obtained. Example 33

[0238] Preparation of 6-cyano- N- (6-phenylpyridazin-3-yl)picolinamide (6-cyano- N- (6-pheny 1 pyr i daz in— 3— y 1 )picol i nam i de )

[0239] [Step 1] Compound 6-phenylpyridazine-3-amine in the same manner as Step 1 of Example 16

[0240] ( 6-pheny 1 pyr i daz in— 3— am i ne ) was obtained.

[0241] [Step 2]

[0242] Compound 6-cyano-N-(6-phenylpyridazin-3-yl)picolinamide (6-cyano-N-(6-phenylpyridazin-3-yl)picolinamide) was obtained by the same method as in step 2 of Example 16, except that 6-cyanop i col inic acid was used. In Example 34

[0243] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)picolinamide (N-(6-(4-methoxypheny 1 ) pyr i daz in— 3— y 1 )picol i nam i de ) [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-methoxyphenyl)pyr idaz in-3-amine) was obtained in the same manner as Step 1 of Example 26.

[0244] [Step 2] Step 2 of Example 26, except that picolinic acid was used.

[0245] In the same manner as in 2, the compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)picolinamide (N-

[0246] (6-( 4-met hoxypheny 1 ) pyr i daz in— 3— y 1 )picol i nam ide)# obtained. 35 in practice

[0247] N-(6-(3,4-dimethoxyphenyl)pyridazin-3-yl)isoxazole-3-carboxamide (N-

[0248] Preparation of (6-(3, 4-dimethyl-1-oxypheny)pyridazin— 3— yl) isoxazole— 3— carboxamide)

[0249] [Step 1]

[0250] Compound 6-(3,4-dimethoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3,4-dimethoxyphenyl)boronic acid was used. [Step 2]

[0251] Compound N-(6-(3,4-dimethoxyphenyl)pyridazin-3-yl)isoxazole-3-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(3,4-dimethoxyphenyl)pyridazin-3-amine (°]isoxazole-3-carboxylic acid) was used. Example 36

[0252] Preparation of N-(6-(4-ethoxy-3-fluorophenyl)pyridazin-3-yl)isoxazole-3-carboxamide water

[0253] [Step 1]

[0254] Compound was prepared in the same manner as in step 1 of Example 12, except that (4-ethoxy-3-f luorophenyl)boronic acid was used.

[0255] 6-(4-ethoxy-3-fluorophenyl)pyridazin-3-amine was obtained. [Step 2]

[0256] Compound N-(6-(4-ethoxy-3-fluorophenyl)pyridazin-3-yl)isoxazole-3-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(4-ethoxy-3-f luorophenyl)pyridazin-3-amine and isoxazole-3-carboxylic acid were used. Example 37

[0257] 6-cyano- N- (6- (4-methoxyphenyl) pyridazin- 3 -yl) picolinamide (6-07i10-si- (6-

[0258] Preparation of (4-me t hoxypheny 1)pyr idazin— 3— yl )pi col inamide) water

[0259] [Step 1] Compound 6-(4-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as Step 1 of Example 26.

[0260] [Step 2] Compound 6-cyano-N-(6-(4-methoxyphenyl)pyridazin-3-yl)picolinamide was obtained by the same method as in Step 2 of Example 26, except that 6-cyanop i col inic acid was used. In Example 38

[0261] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide water

[0262] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0263] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0264] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0265] [Step 2] Compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide (ci-(6-(4-(trif luoromethyl )phenyl)pyridazin— 3— yl)isoxazole— 3— carboxamide) was obtained in the same manner as in Step 2 of Example 14, except that isoxazole-3-carboxylic acid was used. Example 39

[0266] Preparation of N-(6-(3-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide water

[0267] [Step 1]

[0268] (3-methoxy-4-(trifluoromethyl)phenyl)boronic acid ((3-methoxy-4-

[0269] Compound 6-(3-methoxy-4-, except using ((trifluoromethyl)phenyl)boronic acid, was prepared in the same manner as in Step 1 of Example 12.

[0270] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-06仕0乂7-4-

[0271] (Trifluoromethyl)phenyl)pyridazin-3-amine was obtained.

[0272] [Step 2]

[0273] 6-(3-Methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-methoxy-4-

[0274] (Trifluoromethyl)phenyl)pyridazin-3-amine), °]소옥人}졸—3—카르복실산 (isoxazole-3-carboxylic acid) was used, and compound N-(6-(3-methoxy-4-

[0275] (Trifluoromethyl)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide (시-(6-(3-methoxy—4—(trifluoromethyl)phenyl)pyridazin-3-yl)isoxazole—3—carboxamide) was obtained. In the experiment, 40 <00​​​​​​​(4-Ethoxy-3-(trifluoromethyl)phenyl)boronic acid ( (4- ethoxy- 3-

[0279] (trifluoromethyl)phenyl)boronic acid) was used, and Compound 6-(4-Ethoxy-3-

[0280] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-6Ethoxy-3-

[0281] (trifluoromethyl)phenyl)pyridazin—3—amine) was obtained in the same manner as in Step 1 of Example 12, except that

[0282] [Step 2] 6-(4-Ethoxy-3-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-ethoxy-3-(trifluoromethyl)phenyl)pyridazin—3—amine), °]isoxazole-3-carboxylic acid (isoxazole-3-carboxylic acid) was used, and Compound N-(6-(4-Ethoxy-3-

[0283] (trifluoromethyl)phenyl)pyridazin-3-yl) isoxazole-3-carboxamide (6-(6-(4-ethoxy—3—(trifluoromethyl)phenyl)pyridazin—3—yl) isoxazole—3—carboxamide) was obtained. In Example 41

[0284] 5-Phenyl-N-(6-phenylpyridazin-3-yl) isoxazole-3-carboxamide (5-Phenyl-N-(6-phenylpyridazin-3-yl) isoxazole-3-carboxamide)

[0285] Preparation of N—(6—phenylpyridazin—3—yl) isoxazole—3—carboxamide , water

[0286] [Step 1] Compound 6-phenylpyridazin-3-amine was obtained in the same manner as in Step 1 of Example 16.

[0287] [Step 2]

[0288] Compound 5-phenyl-N-(6-phenylpyridazin-3-yl)isoxazole-3-carboxamide was obtained in the same manner as in Step 2 of Example 16, except that 5-phenylisoxazole-3-carboxylic acid was used.

[0289] Example 42

[0290] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)-5-(pyridin-3-yl)isoxazole-3-carboxamide 1,4-Dioxane water

[0291] [Step 1] Compound 6-(4-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in Step 1 of Example 26.

[0292] [Step 2]

[0293] Compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)-5-(pyridin-3-yl)isoxazole-3-carboxamide was obtained in the same manner as in step 2 of Example 26, except that 5-(pyridin-3-yl)isoxazole-3-carboxylic acid was used. Example 43

[0294] Preparation of N-(6-(4-(trifluoromethoxy)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide

[0295] [Step 1]

[0296] (4-(trifluoromethoxy)phenyl)boronic acid ((4-

[0297] Compound 6-(4-(trifluoromethoxy)phenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (trifluoromethoxy)phenyl)boronic acid) was used.

[0298] [Step 2]

[0299] 6-(4-(trifluoromethoxy)phenyl)pyridazin-3-amine (6-(4-

[0300] Example except that (trif 1 uo r ome t hoxy ) pheny 1 )pyr idazin— 3— amine) and isoxazole- 3-carboxylic acid were used

[0301] In the same manner as in step 2 of 12, compound N-(6-(4-(trifluoromethoxy)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide (N-(6-(4-

[0302] (tr if 1 uo r ome t hoxy ) pheny 1 ) pyr idazin— 3— yl ) isoxazole— 3— carboxamide) was obtained. Example 44

[0303] N- (6- (4-methoxyphenyl)pyridazin-3-yl)thieno[3,2-b]thiophene-2-carboxamide ( N- (6- (4-methoxypheny 1 )py ri daz i n-3 - y 1 ) thi eno[3,2-b]thi ophene-

[0304] Preparation of 2-carboxamide 1,4-Dioxane water

[0305] [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-me thoxyphenyl)pyridazin-3-amine) was obtained in the same manner as Step 1 of Example 26.

[0306] [Step 2] The compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)thieno[3,2-b]thiophene-2-carboxamide was obtained by the same method as in Step 2 of Example 26, except that thieno[3,2-b]thiophene-2-carboxylic acid was used. Example 45

[0307] N-(6-(4-methoxyphenyl)pyridazin-3-yl)-2-(pyrimidin-2-yl)acetamide⑴-

[0308] Preparation of (6-( 4-me t hoxypheny 1 )pyr idazin— 3— yl )— 2— (pyr imidin— 2— yl )acetamide)

[0309] [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-methoxypheny 1)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 26.

[0310] [Step 2]

[0311] Compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)-2-(pyrimidin-2-yl)acetamide was obtained by the same method as in step 2 of Example 26, except that 2-(pyrimidin-2-yl)acetic acid was used. Example 46

[0312] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)-1,2,5-thiadiazole-3-carboxamide , water

[0313] [Step 1] Compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-methoxyphenyl)pyridazin-3-amine) was obtained in the same manner as Step 1 of Example 26.

[0314] [Step 2]

[0315] Compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)-1,2,5-thiadiazole-3-carboxamide was obtained in the same manner as in step 2 of Example 26, except that 1,2,5-thiadiazole-3-carboxylic acid was used. Example 47

[0316] N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)isothiazole-3-carboxamide (N- (6- (4- ( tri f luoromethyl ) phenyl )pyr idazin-3- yl ) isothiazole-

[0317] 3- Manufacture of carboxami de)

[0318] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0319] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0320] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0321] [Step 2] The compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)isothiazole-3-carboxamide was obtained in the same manner as in Step 2 of Example 14, except that isothiazole-3-carboxylic acid was used. Example 48

[0322] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)thiophene-3-carboxamide

[0323] Pd(dppf)Cl2, CH2Cl2, HATU, N,N-diisopropylethylamine, 1,4-dioxane, DMF, water

[0324] [Step 1] Compound 6-(4-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in Step 1 of Example 26.

[0325] [Step 2] Compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)thiophene-3-carboxamide was obtained in the same manner as in Step 2 of Example 26, except that thiophene-3-carboxylic acid was used. Example 49

[0326] Preparation of 5-hydroxy-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide 1,4-dioxane, water

[0327] [Step 1] Compound 6-(4-

[0328] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0329] (tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[0330] [Step 2]

[0331] Compound 5-hydroxy-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)pi col inamide was obtained by the same method as in step 2 of Example 14 except that 5-hydroxypicolinic acid was used. Example 50

[0332] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide 1,4-Dioxane DMF water

[0333] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0334] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0335] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0336] [Step 2] Step 14 of Example 14, except that picolinic acid was used.

[0337] In the same manner as in Example 2, compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (N-(6-(4-( tr if luoromethyl )phenyl )pyridazin-3-yl )picol inamide) was obtained. Example 51

[0338] N-(6-(4-methoxyphenyl)pyridazin-3-yl)-2-(thiophene-3-yl)acetamide(cy-(6-

[0339] Preparation of (4-met hoxypheny 1)pyr idazin-3-yl)— 2— (thiophen— 3— yl )acetamide)

[0340] Pd(dppf)CI2CH2CI2HATU Na2CO3 DIPEA 1,4-Dioxane DMF water

[0341] [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-methoxyphenyl)pyr idaz in-3-amine) was obtained in the same manner as Step 1 of Example 26.

[0342] [Step 2]

[0343] Compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)-2-(thiophen-3-yl)acetamide was obtained by the same method as in step 2 of Example 26 except that 2-(thiophen-3-yl)acet ic acid was used. Example 52

[0344] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)thiazole-5-carboxamide 1,4-Dioxane water [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-me thoxyphenyl)pyridazin-3-amine) was obtained in the same manner as Step 1 of Example 26.

[0345] [Step 2] The compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)thiazole-5-carboxamide (N-(6-(4-methoxypheny 1 )pyridazin— 3— y 1 )thiazol e— 5— car boxam ide)# was obtained in the same manner as in Step 2 of Example 26, except that thiazole-5-carboxylic acid was used. Example 53

[0346] N-(6-(2-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl) 0 ]oxazole-3-carboxamide (N-(6-(2-acetamido-4-

[0347] (tri f luoromethyl ) phenyl ) pyr idazin— 3— yl ) isoxazole— 3— carboxamide)

[0348] [Step 1]

[0349] N-(2-(4, 4,5, 5 -tetramethyl- 1 , 3 , 2 -dioxaborolane- 2 -yl)- 5-

[0350] The compound N-(2-(6-aminopyridazin-3-yl)-5-(trifluoromethyl)phenyl)acetamide (ci-(2-(6-aminopyridazin-3-yl)-5-(trifluoromethyl)phenyl)acetamide) was obtained in the same manner as in step 1 of Example 12, except that N-(2-(4, 4, 5, 5-tetramethyl-1,3, 2- dioxabor o 1 an-2-y 1)—5—(tri fluoromethyl )phenyl )acetamide) was used.

[0351] [Step 2]

[0352] N_(2_(6-aminopyridazine-3-yl)-5-

[0353] (trifluoromethyl)phenyl)acetamide (N- (2- (6-aminopyridazin- 3- yl )-5-

[0354] Compound N-(6-(2-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide (N-(6-(2-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)isoxazole-3-carboxamide) was prepared in the same manner as in step 2 of Example 12, except that isoxazole-3-carboxylic acid was used.

[0355] (trifluoromethyl)phenyl)pyridazin— 3— yl)isoxazole— 3— carboxamide) was obtained. Example 54

[0356] N-(6-(5-(trifluoromethyl)thiophene-2-yl)pyridazin-3-yl)picolinamide⑴-

[0357] Preparation of (6— (5— (trif luoromethyl )thiophen— 2— yl)pyr idaz in— 3— yl)pi col inamide) [Step 1]

[0358] Compound 6-(5-(trifluoromethyl)thiophen- 2-yl)pyridazin- 3-amine was obtained in the same manner as in Step 1 of Example 12, except that 4, 4, 5, 5-tetramethyl- 2- (5-(tri fluoromethyl)thiophen- 2- yl)- 1,3,2-dioxaborolane was used.

[0359] [Step 2]

[0360] 6-(5-(trifluoromethyl)thiophene-2-yl)pyridazin-3-amine(6-(5-

[0361] Compound N-(6-(5-(trifluoromethyl)thiophen-2-yl)pyridazin-3-yl)picolinamide (ci-(6-(5-(trif luoromethyl)thiophen-2-yl)pyridazin-3-yl)pi col inamide) was synthesized by the same method as step 2 of Example 12, except that (trifluoromethyl)thiophen-2-yl)pyridazin-3-yl)pi col inamide) was used. Example 55

[0362] Preparation of N-(6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)picolinamide , water

[0363] [Step 1] (1-Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid under nitrogen gas

[0364] ( (1— methyl— 3—( tr if luoromethyl )— 1H— pyrazol— 4— yl )boronic acid) and 6-chloropyridazin- 3-amine (6- chloropyr idazin- 3-amine), Pd(dppf KhCEbCh , Na2C(〕3

[0365] 1, 4- Dioxane: After dissolving in distilled water (5:1) solvent, it was stirred at 90°C for 16 hours. After the reaction, the mixture was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated substance was purified by column chromatography to obtain compound 6-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-

[0366] 4-yl)pyridazin-3-amine (6-(1-methyl-3-( tr if luoromethyl )-lH- pyrazol-4- yl )pyridazin-3-amine) was obtained.

[0367] [Step 2]

[0368] 6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridazin-3-amine (6-(1-methyl— 3—( tr if luoromethyl )— 1H— pyrazol— 4— yl )pyridazin— 3— amine), picolinic acid, and HATU were dissolved in DMF, then DIPEA was added and the mixture was stirred at 40°C.

[0369] The mixture was stirred for 4 hours. After the reaction, the mixture was diluted with water and extracted with a solvent. The combined organic layers of the extracts were washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)picolinamide (ci-(6-(1-methyl— 3—( trifluoromethyl )— 1H— pyrazol— 4— yl )pyridazin— 3— yl )pi col inamide). Example 56

[0370] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)pyridazine-3-carboxamide (cy-(6-(4-methoxyphenyl)pyridazin—3—yl)pyridazine—3—carboxamide) , water

[0371] [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-me thoxyphenyl)pyridazin-3-amine) was obtained in the same manner as Step 1 of Example 26.

[0372] [Step 2] The compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)pyridazine-3-carboxamide (N-(6-(4-methoxypheny 1 ) pyr i daz in— 3— y 1 ) pyr i daz i ne— 3— car boxam ide)# was obtained in the same manner as in Step 2 of Example 26, except that pyridazine-3-carboxylic acid was used. Example 57

[0373] N-(6-(4-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(4-methoxypheny 1 )pyr i daz in— 3— y 1 )thiazol e— 4— carboxami de ) water

[0374] [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-me thoxyphenyl)pyridazin-3-amine) was obtained in the same manner as Step 1 of Example 26.

[0375] [Step 2] The compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in Step 2 of Example 26, except that thiazole-4-carboxylic acid was used. Example 58

[0376] N-(6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)isoxazole-3-carboxamide (N-(6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)isoxazole— 3—carboxamide) , - oxane water

[0377] [Step 1] Compound 6- (1-methyl-3-) was prepared in the same manner as in Step 1 of Example 55.

[0378] (Trifluoromethyl)-1H-pyrazol-4-yl)pyridazin-3-amine(6-(1-tau-3-

[0379] (tr ifl uoromethyl ) -IH-pyr azol — 4— y 1 ) pyr idazin— 3— amine) was obtained.

[0380] [Step 2] Compound N-(6-(1-methyl-3-) was prepared in the same manner as in Step 2 of Example 55, except that isoxazole-3-carboxylic acid was used.

[0381] (Trifluoromethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)isoxazole-3-carboxamide (N-(6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4- y1)pyr i daz in— 3— y1) i soxazo 1 e— 3— car boxami de ) was obtained. In the embodiment 59 tert-butyl (2-methoxy-4- (6-(thiazole-4-carboxamido)pyridazin-3-yl)phenyl)carbamate (tert-butyl (2-methoxy-4- (6- (thiazole-4-carboxamido)pyridazin-3-yl)phenyl)carbamate) was obtained.

[0382] [Step 1]

[0383] The compound tert-butyl (4-(6-aminopyridazin-3-yl)-2-methoxyphenyl)carbamate was obtained by the same method as in step 1 of Example 12, except that (4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)boronic acid was used.

[0384] [Step 2] The compound tert-butyl (4-(6-aminopyridazin-3-yl)-2-methoxyphenyl)carbamate was prepared in the same manner as in Step 2 of Example 12, except that thiazole-4-carboxylic acid was used. e) was obtained. Example 60

[0385] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)-1,2,5-thiadiazole-3-carboxamide (N-(6-(4-( tr if luoromethyl )phenyl )pyr idaz in-3- y 1 )-1,2,5- thi adi azo le-3- carboxami de)

[0386] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0387] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0388] (trif luoromethyl)phenyl)pyridazin— 3— amine) was obtained.

[0389] [Step 2]

[0390] Compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)-1,2,5-thiadiazole-3-carboxamide)# was obtained by the same method as in step 2 of Example 14, except that 1,2,5-thiadiazole-3-carboxylic acid was used. 61

[0391] 2-(hydroxymethyl)- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole- 4-carboxamide (2- (hydroxymethyl )- N- (6- (4-

[0392] (trif luoromethyl )phenyl )pyr idazin-3-yl )thiazole-4-carboxamide)^| manufacturing water

[0393] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0394] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0395] (trif luoromethyl)phenyl)pyridazin— 3— amine) was obtained.

[0396] [Step 2]

[0397] Compound 2-(hydroxymethyl)-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was prepared in the same manner as in step 2 of Example 14, except that 2-(hydroxymethyl)thiazole-4-carboxylic acid was used.

[0398] (trifluoromethyl)phenyl)pyridazin— 3— yl) thiazole— 4— carboxamide) was obtained. 62

[0399] Preparation of N-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)furan-3-carboxamide

[0400] [Step 1]

[0401] Compound (6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanamine was obtained in the same manner as in step 1 of Example 14, except that (6-chloropyr idazin-3-yl)methanamine was used.

[0402] [Step 2]

[0403] (6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanamine ((6-(4-

[0404] Compound N-((6-(4- (trifluoromethyl)phenyl)pyridazin-3-yl)methyl)furan-3-carboxamide (ci-((6-(4- (trif luoromethy l)phenyl)pyr idazin-3-yl)methanamine) was obtained by the same method as in step 2 of Example 14, except that (trifluoromethyl)phenyl)pyridazin-3-yl)methyl)furan-3-carboxamide) was used. Example 64

[0405] Preparation of 3-fluoro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin- 3-yl)picolinamide water

[0406] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[0407] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0408] (tri f luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0409] [Step 2]

[0410] Compound 3-fluoro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide was obtained by the same method as in step 2 of Example 14, except that 3-fluoropicolinic acid was used. Example 65

[0411] Preparation of 5-fluoro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (5-f luoro-N-(6-(4-( tr if luoromethyl )phenyl )pyridazin-3- yl )picol inamide)

[0412] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[0413] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0414] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0415] [Step 2]

[0416] Compound 5-fluoro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide was obtained by the same method as in step 2 of Example 14, except that 5-fluoropicolinic acid was used. Example 66

[0417] 4-hydroxyphenyl (6- (4-methoxyphenyl)pyridazin- 3 -yl)carbamate (4- hydr oxypheny 1 (6— (4-methoxypheny 1 ) pyr i daz in— 3— y 1 ) carbamat e ) low ]jo c:W o:

[0418] [Step 1] Under nitrogen gas, compound (4-methoxyphenyl)boronic acid and compound 6-chloropyridazin-3-amine,

[0419] Pd(dppf)C12CH2C12, Na'" was dissolved in a 1,4-Dioxane:distilled water (5:1) solvent and stirred at 90°C for 16 hours. The reaction mixture was diluted with water and extracted with a distilled water bath. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated substance was purified by column chromatography to obtain compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-me thoxyphenyl)pyridazin-3-amine).

[0420] [Step 2] The compound 6-(4-methoxyphenyl)pyridazin-3-amine was dissolved in 1,2-DCE, triethylamine (TEA) was added, and the mixture was stirred at 0°C for 10 minutes. The compound bis(trichloromethyl) carbonate was dissolved in 1,2-DCE, and slowly added dropwise to the reaction mixture, followed by stirring at 85°C for 24 hours. The mixture after the reaction was purified by column chromatography to obtain the compound 3-isocyanato-6-(4-methoxyphenyl)pyridazine.

[0421] [Step 3] Compound 3-isocyanato-6-(4-methoxyphenyl)pyridazine, compound hydroquinone, and TEA were dissolved in 1,4-dioxane and stirred at room temperature for 14 hours. The reaction mixture was purified by column chromatography to obtain compound 4-hydroxyphenyl (6-(4-methoxyphenyl)pyridazin-3-yl)carbamate. Example 67

[0422] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[0423] [Step 1] Compound 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0424] (trif luoromethyl)phenyl)pyridazin— 3— amine) was obtained.

[0425] [Step 2] Compound N-(6-(4-) was prepared in the same manner as in Step 2 of Example 14, except that thiazole-4-carboxylic acid was used.

[0426] (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(4-

[0427] (trifluoromethyl)phenyl)pyridazin— 3— yl) thiazole— 4— carboxamide) was obtained. Example 68

[0428] N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-sulfonamide (N-(6-

[0429] (4-(trif 1 uoromethy 1 ) pheny 1 ) pyr i daz in— 3— y 1 )fur an— 3— su 1 f onam i de )'s low ]jo water

[0430] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0431] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0432] (trif luoromethyl )phenyl)pyridazin— 3— amine) was obtained.

[0433] [Step 2] 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0434] (trifluoromethyl)phenyl)pyridazin-3-amine) and furan-3-sulfonyl chloride were dissolved in dichloromethane (DCM), and pyridine was added. After stirring at 60°C for 16 hours, the reaction mixture was diluted with water and extracted with ethanol. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated substance was purified by column chromatography to obtain the compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-sulfonamide (N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-

[0435] 3-sulfonamide) was obtained. Example 69

[0436] N-(6-(4-amino-3-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide⑴-

[0437] Preparation of (6— (4— amino— 3— methoxyphenyl )pyr idazin— 3— yl )thi azole— 4— carboxamide)

[0438] [Step 1] The compound tert-butyl (4-(6-aminopyridazin-3-yl)-2-methoxyphenyl)carbamate was obtained in the same manner as in Step 1 of Example 12, except that (4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)boronic acid was used.

[0439] [Step 2] The compound tert-butyl (4-(6-aminopyridazin-3-yl)-2-methoxyphenyl) carbamate was prepared in the same manner as in Step 2 of Example 12, except that thiazole-4-carboxylic acid was used. 1 (Prayer) Pyridazine— 3 —yl) phenyl) gar White] ■ Mate (tert-butyl ( 2-methyl-4- ( 6-

[0440] (thiazole-4-carboxamido)pyr idazin-3-yl )phenyl )carbamate)# was obtained.

[0441] [Step 3] tert-butyl (2-methoxy-4-(6-(thiazole-4-carboxamido)pyridazin-3-yl)phenyl)carbamate (tert-butyl (2-methoxy-4-(6-(thiazole-4-carboxamido)pyridazin-3-yl)phenyl)carbamate) was dissolved in distilled water and stirred at room temperature for 1 hour. After the reaction was completed, aqueous NaOH solution was added to the mixture, and the precipitated solid was filtered. The filtered solid was dried and purified by column chromatography to obtain the compound N-(6-(4-amino-3-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide. Example 70

[0442] Preparation of N-(6-(4-methoxyphenyl)pyridazin-3-yl)oxazole-4-carboxamide water

[0443] [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine (6-(4-me thoxyphenyl)pyridazin-3-amine) was obtained in the same manner as Step 1 of Example 12.

[0444] [Step 2] The compound N-(6-(4-methoxyphenyl)pyridazin-3-yl)oxazole-4-carboxamide was obtained by the same method as in Step 2 of Example 12 except that oxazole-4-carboxylic acid was used. Example 71

[0445] N-(6-(3-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-methoxypheny 1 )pyr i daz in— 3— y 1 )thiazol e— 4— carboxami de )

[0446]

[0447] [Step 1]

[0448] Compound 6-(3-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-methoxyphenyl)boronic acid was used.

[0449] [Step 2]

[0450] Compound N-(6-(3-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(3-methoxyphenyl)pyridazin-3-amine and thiazole-4-carboxylic acid were used. Example 72

[0451] N-(6-(4-methylpiperazin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide⑴-

[0452] Preparation of (6— (4— methyip i per azin— 1—yl )pyr idaz in— 3— yl )thi azole— 4— carboxamide)

[0453] [Step 1]

[0454] Compound N-(6-(4-methylpiperazin-1-yl)pyridazin-3-amine) was obtained in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. Example 73

[0455] Preparation of N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)isothiazole-3-carboxamide

[0456] [Step 1]

[0457] Compound 6-(2-fluoro-4-(trifluoromethyl)phenyl)boronic acid was prepared in the same manner as in step 1 of Example 12, except that (2-f luoro-4-(trifluoromethyl)phenyl)boronic acid was used.

[0458] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(2-f luoro-4-

[0459] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0460] [Step 2]

[0461] Compound N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was prepared in the same manner as in step 2 of Example 12, except that isothiazole-3-carboxylic acid was used.

[0462] (Trifluoromethyl)phenyl)pyridazin-3-yl)isothiazole-3-carboxamide (N-(6-(2-f luoro— 4— (trifluoromethyl)phenyl)pyridazin— 3— yl)isothiazole-3-carboxamide) was obtained. Example 74

[0463] Preparation of N-(6-(4-ethoxyphenyl)pyridazin-3-yl)isoxazole-3-carboxamide water [Step 1]

[0464] Compound 6-(4-ethoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (4-ethoxyphenyl)boronic acid was used.

[0465] [Step 2]

[0466] Compound N-(6-(4-ethoxyphenyl)pyridazin-3-yl)isoxazole-3-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(4-ethoxyphenyl)pyridazin-3-amine and isoxazole-3-carboxylic acid were used. Example 75

[0467] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)furan-3-carboxamide (ci-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)furan-3-carboxamide) water

[0468] [Step 1]

[0469] Compound 6- (4-) was prepared in the same manner as in step 1 of Example 14, except that 6-chloropyridin- 3-amine was used.

[0470] (Trifluoromethyl)phenyl)pyridin-3-amine (6-(4-(tr if luoromethyl )I)henyl )pyr idin-3-amine) was obtained.

[0471] [Step 2]

[0472] 6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (6-(4-

[0473] Compound N-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)furan-3-carboxamide was obtained by the same method as in step 2 of Example 14, except that (trifluoromethyl)phenyl)pyridin-3-yl)furan-3-carboxamide was used. Example 76

[0474] Preparation of N-(6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[0475] [Step 1] Under nitrogen gas, (3-(trifluoromethyl)phenyl)boronic acid, 6-chloropyridazin-3-amine, Pd(PPhs)4, K2CO3 were dissolved in a 1,4-Dioxane:distilled water (4:1) solvent and stirred at 90 °C for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to give compound 6-(3-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-

[0476] (tr if luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[0477] [Step 2]

[0478] 6-(3-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-

[0479] (trifluoromethyl)phenyl)pyridazin-3-amine), thiazole-4-carboxylic acid, and HATU were dissolved in DMF, DIPEA was added, and the mixture was stirred at 40°C for 4 hours. After the reaction, the mixture was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound N-(6-(3-

[0480] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-(trifluoromethyl)phenyl)pyridazin—3—yl)thiazole—4—carboxamide) was obtained. Example 77

[0481] Preparation of N-(6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)oxazole-4-carboxamide water

[0482] [Step 1] Compound 6-(3-(trifluoromethyl)phenyl)pyridazin-3-amine(6-(3-

[0483] (trif luoromethyl)phenyl)pyridazin— 3— amine) was obtained.

[0484] [Step 2] Compound N-(6-(3-) was prepared in the same manner as in Step 2 of Example 76, except that oxazole-4-carboxylic acid was used.

[0485] (Trifluoromethyl)phenyl)pyridazin-3-yl)oxazole-4-carboxamide (ci-(6-(3-(trif luoromethyl )phenyl)pyridazin—3— yl)oxazole—4— carboxamide) was obtained. 78

[0486] 3-fluoro- N- (6- (4-methoxyphenyl) pyridazin- 3 -yl) picolinamide (3-fluoro- N-

[0487] Preparation of (6-( 4-met hoxypheny 1 ) pyr i daz in— 3— y 1 )picol i nam i de ) [Step 1] The compound 6-(4-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in Step 1 of Example 26.

[0488] [Step 2]

[0489] Compound 3-fluoro-N-(6-(4-methoxyphenyl)pyridazin-3-yl)picolinamide (3-f luoro-N-(6-(4-methoxypheny 1 )pyridazin— 3— y 1 )picol i nam ide)# was obtained in the same manner as in step 2 of Example 26, except that 3-fluoropicolinic acid was used. Example 79

[0490] Preparation of 3-hydroxy- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide water

[0491] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[0492] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-(tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[0493] [Step 2]

[0494] Compound 3-hydroxy-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide was obtained by the same method as in step 2 of Example 14, except that 3-hydroxypicol inic acid was used. Example 80

[0495] Preparation of 3-fluoro-N-(6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide (3-fluoro-N-(6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide) water

[0496] [Step 1] In the same manner as in Step 1 of Example 76, compound 6-(3 -

[0497] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-

[0498] (trifluoromethyl)phenyl)pyridazin-3-amine) was obtained.

[0499] [Step 2] In the same manner as in Step 2 of Example 76, except using 3-fluoropicolinic acid (3-fluoropicolinic acid), compound 3-fluoro-N-(6-(3-

[0500] (trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide hex - day "ai - shi - ⑯ - he -

[0501] (trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide) was obtained. In Example 81

[0502] Preparation of N-(6-(4-ethoxyphenyl)pyridazin-3-yl)-3-fluoropicolylamide (N-(6-(4-ethoxyphenyl)pyridazin-3-yl)-3-fluoropicolylamide) water

[0503] [Step 1]

[0504] Compound 6-(4-ethoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (4-ethoxyphenyl)boronic acid was used.

[0505] [Step 2]

[0506] 6—(4—ethoxyphenyl)pyridazin—3—amine (6—(4—ethoxyphenyl)pyr idaz in—3—amine). Except that 3-fluoropicolinic acid (3-f luoropicol inic acid) was used, the compound N-(6-(4-ethoxyphenyl)pyridazin-3-yl)-3-fluoropicolinamide (N-(6-(4-ethoxyphenyl)pyridazin-3-yl)-3-f luoropicol inamide) was obtained in the same manner as in step 2 of Example 12. Example 82

[0507] 3-Fluoro- N- ((6- (4- (trifluoromethyl)phenyl)pyridazin- 3-yl)methyl)picolinamide (3- f luoro- N- ((6- (4- (trif luoromethyl)phenyl)pyridazin-

[0508] Preparation of 3-yl )methyl )picol inamide

[0509] [Step 1]

[0510] Compound (6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanamine was obtained in the same manner as in step 1 of Example 14, except that (6-chloropyr idazin-3-yl)methanamine was used.

[0511] [Step 2]

[0512] (6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanamine((6-(4-

[0513] Compound 3-fluoro-N-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)picolinamide was obtained by the same method as in step 2 of Example 14, except that 3-fluoropicolinic acid (3-f luoro-N-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)picol inamide) was used. Example 83

[0514] 3-Fluoro- N- (6- (3-methoxyphenyl)pyridazin- 3 -yl)picolinamide (3- f luoro-

[0515] Preparation of N-(6-( 3 -met hoxypheny 1 ) pyr i daz in— 3— y Dpicol i nam i de ) 1,4-Dioxane DMF water

[0516] [Step 1]

[0517] Compound 6-(3-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-methoxyphenyl)boronic acid was used.

[0518] [Step 2]

[0519] Compound 3-fluoro-N-(6-(3-methoxyphenyl)pyridazin-3-amine and 3-fluoropicolinic acid were used in the same manner as in step 2 of Example 12, except that 3-fluoropicolinic acid was used. Example 84

[0520] Preparation of N-(6-(3-methoxyphenyl)pyridazin-3-yl)picolinamide (N-(6-(3-methoxypheny 1 ) pyr i daz in— 3— y 1 )picol i nam i de )

[0521] [Step 1]

[0522] Compound 6-(3-methoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-methoxyphenyl)boronic acid was used.

[0523] [Step 2]

[0524] Compound N-(6-(3-methoxyphenyl)pyridazin-3-yl)picolinamide (N-(6-(3-methoxyphenyl)pyridazin-3-yl)picolinamide) was obtained by the same method as in step 2 of Example 12, except that 6-(3-methoxyphenyl)pyridazin-3-amine and picolinic acid were used. In Example 85

[0525] N-(6-(3-(phenylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide⑴-

[0526] Preparation of (6-(3-(phenyl carbamoyl)phenyl)pyr idaz in— 3— yl )thi azole— 4— carboxamide) water

[0527] [Step 1]

[0528] Compound 3-(6-aminopyridazin-3-yl)-N-phenylbenzamide was obtained by the same method as in step 1 of Example 12 except that (3-(phenylcarbamoyl)phenyl)boronic acid was used.

[0529] [Step 2]

[0530] Compound N-(6-(3-(phenylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (Ci-(6-(3-(phenylcarbanioyl)phenyl)pyridazin—3—yl)thiazole—4—carboxamide) was obtained in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. In Example 86

[0531] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxazole-4-carboxamide 水

[0532] [Step 1] Compound 6-(4-

[0533] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0534] (trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 14.

[0535] [Step 2] Compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxazole-4-carboxamide (N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxazole-4-carboxamide) was obtained in the same manner as in Step 2 of Example 14, except that oxazole-4-carboxylic acid was used. Example 87

[0536] Preparation of N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0537] [Step 1]

[0538] (2-Fluoro-4-(trifluoromethyl)phenyl)boronic acid ((2-fluoro-4-

[0539] (trifluoromethyl)phenyl)boronic acid) was used, and compound 6-(2-fluoro-4-

[0540] (trifluoromethyl)phenyl)pyridin-3-amine (6-(2-fluoro-4-

[0541] (trif luoromethyl )phenyl)pyridin— 3— amine) was obtained.

[0542] [Step 2]

[0543] 6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-amine (6-(2-fluoro-4-

[0544] Compound N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(2-f luoro-4-

[0545] (trifluoromethyl)phenyl)pyridazin— 3— yl) thiazole— 4— carboxamide) was obtained. In the embodiment 88 3-fluoro- N- (6- (2-fluoro- 4- (trifluoromethyl)phenyl)pyridazin- 3- yl)picolinamide (3- f luoro- N- (6- (2- f luoro-4-

[0546] Preparation of (tri f luoromethyl ) phenyl ) pyr idazin— 3— yl ) pi col inamide) 1,4-Dioxane DMF water

[0547] [Step 1]

[0548] (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid ((2- f luoro- 4-

[0549] Compound 6-(2-fluoro-4-) was prepared in the same manner as in step 1 of Example 12, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[0550] (Trifluoromethyl)phenyl)pyridin-3-amine was obtained.

[0551] [Step 2]

[0552] Compound 3-fluoro-N-(6-(2-fluoro-4-

[0553] (Trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide was obtained. Example 89

[0554] Preparation of N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide water

[0555] [Step 1]

[0556] (2-Fluoro-4-(trifluoromethyl)phenyl)boronic acid

[0557] Compound 6-(2-fluoro-4-

[0558] (trifluoromethyl)phenyl)pyridin-3-amine (6-(2-f luoro-4-

[0559] (tri f luoromethyl ) phenyl ) pyr idin— 3— amine) was obtained.

[0560] [Step 2]

[0561] 6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-amine (6-(2-f luoro-4-

[0562] Compound N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide was obtained by the same method as in step 2 of Example 12, except that picolinic acid was used. Example 90

[0563] Preparation of 3-fluoro-N-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)picolinamide (3-f luoro-N-(2-(4-(trif luoroniethyl)phenyl)pyrimidin-5-yl)pi col inamide)

[0564] [Step 1]

[0565] Compound 2-(4-)was prepared in the same manner as in step 1 of Example 14, except that 2-chloropyrimidin-5-amine was used.

[0566] (trifluoromethyl)phenyl)pyrimidin-5-amine(2-(4-

[0567] (trif luoromethyl)phenyl)pyr imidin— 5— amine) was obtained.

[0568] [Step 2]

[0569] 2-(4-(trifluoromethyl)phenyl)pyrimidin-5-amine(2-(4-

[0570] Compound 3-fluoro-N-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)picolinamide was obtained by the same method as in step 2 of Example 14, except that 3-fluoropicolinic acid (3-f luoropicol inic acid) was used. Example 91

[0571] N-(6-(3-acetamidophenyl)pyridazin-3-yl)-3-fluoropicolinamide⑴-

[0572] Preparation of (6— (3— acet amidophenyl )pyr idaz in— 3— y 1 )—3— f luoropi col inamide)

[0573] [Step 1]

[0574] Compound N-(3-(6-aminopyridazin-3-yl)phenyl)acetamide was obtained in the same manner as in step 1 of Example 12, except that (3-acetamidophenyl)boronic acid was used.

[0575] [Step 2]

[0576] The compound N-(6-(3-acetamidophenyl)pyridazin-3-yl)-3-fluoropicolinamide(ci-(6-(3-acetamidophenyl)pyridazin-3-yl)-3-fluoropicolinamide)# was obtained in the same manner as in step 2 of Example 12, except that N-(3-(6-aminopyridazin-3-yl)phenyl)acetamide, 3-fluoropicolinic acid (3-f luoropicol inic acid) was used. Example 92

[0577] N-(6-(3-acetamidophenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-

[0578] Preparation of ( 3-ace t am i dopheny 1 )pyr idazin— 3— yl )thiazole— 4— carboxamide)

[0579] [Step 1]

[0580] Compound N-(3-(6-aminopyridazin-3-yl)phenyl)acetamide was obtained in the same manner as in step 1 of Example 12, except that (3-acetamidophenyl)boronic acid was used.

[0581] [Step 2]

[0582] Compound N-(6-(3-acetamidophenyl)pyridazin-3-yl)thiazole-4-carboxamide)# was obtained in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. Example 93

[0583] Preparation of 3-fluoro-N-(6-(2-fluoro-4-methoxyphenyl)pyridazin-3-yl)picolinamide (3-fl uoro-N-(6-(2-f 1 uor o-4-methoxypheny 1 )pyridazin-3-yl)pi col inamide) water

[0584] [Step 1]

[0585] Compound 6-(2-fluoro-4-methoxyphenyl)pyridin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (2-f 1 uor o-4-methoxypheny l )boronic acid was used.

[0586] [Step 2]

[0587] Compound 3-fluoro-N-(6-(2-fluoro-4-methoxyphenyl)pyridin-3-amine (6-(2-f luoro-4-methoxypheny 1 )pyr idin— 3— amine) and 3-fluoropicolinic acid (3— f luoropicol inic acid) were used in the same manner as in step 2 of Example 12, except that compound 3-fluoro-N-(6-(2-fluoro-4-methoxyphenyl)pyridazin-3-yl)picolinamide (3-f 1 uoro-N- (6-(2-f 1 uor o-4-methoxypheny 1 )pyridazin-3-yl)picolinamide)# was obtained. Example 94

[0588] Preparation of N-(6-(2-fluoro-4-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide 1,4-Dioxane DMF water

[0589] [Step 1]

[0590] Compound was prepared in the same manner as in step 1 of Example 12, except that (2-fluoro-4-methoxyphenyl)boronic acid was used.

[0591] 6-(2-fluoro-4-methoxyphenyl)pyridin-3-amine (6-(2-f luoro-4- methoxypheny 1 ) pyr idin— 3— am i ne ) was obtained.

[0592] [Step 2]

[0593] Compound N-(6-(2-fluoro-4-methoxyphenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(2-f luoro-4-methoxyphenyl)pyridin-3-amine and thiazole-4-carboxylic acid were used. Example 95

[0594] Preparation of 3-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (3-ch 1 oro-N-(6-(4-(trif 1 uoromethyl )phenyl )pyridazin-3-yl )picol inamide) Compound 6- (4 -) in the same manner as step 1 of Example 14

[0595] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0596] (tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[0597] [Step 2]

[0598] Compound 3-chloro-N-(6-(4-)-chloropicolinic acid was prepared in the same manner as in step 2 of Example 14, except that 3-chloropicol inic acid was used.

[0599] (trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (3-chloro-N- (6-(4-

[0600] (tri f luoromethyl ) phenyl )pyridazin- 3- yl )pi col inamide) was obtained. Example 96 Preparation of 3-fluoro- N- (6- (3- (trifluoromethoxy ) phenyl) pyridazin- 3- yl) picolinamide (3- f luoro- N- (6- (3- (tri f luoroniethoxy) phenyl ) pyridazin- 3- yl )pi col inamide) , water

[0601] [Step 1]

[0602] (3-(trifluoromethoxy)phenyl)boronic acid ((3-

[0603] Compound 6-(3-(trifluoromethoxy)phenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 26, except that (tri f luoromethoxy)phenyl )boronic acid) was used.

[0604] [Step 2]

[0605] 6-(3-(trifluoromethoxy)phenyl)pyridazin-3-amine(6-(3-

[0606] Compound 3-fluoro-N-(6-(3-(trifluoromethoxy)phenyl)pyridazin-3-yl)picol inamide was obtained by the same method as in step 2 of Example 26, except that 3-fluoropicolinic acid (3-f luoromethoxy)phenyl)pyridazin-3-yl)picol inamide was used. In Example 97

[0607] Preparation of 3-fluoro-N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)picolylamide water

[0608] [Step 1]

[0609] Compound 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine was obtained in the same manner as in Step 1 of Example 26, except that (4-(trifluoromethyl)phenyl)boronic acid and 4-bromoaniline were used.

[0610] [Step 2]

[0611] 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine

[0612] Compound 3-fluoro-N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)picolylamide was obtained in the same manner as in Step 2 of Example 26, except that 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine and 3-fluoropicolinic acid were used. Example 98

[0613] Preparation of 3 -fluoro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-2-carboxamide

[0614] [Step 1] Compound 6-(4 -

[0615] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0616] (trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 14.

[0617] [Step 2]

[0618] Compound 3 -fluoro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-2-carboxamide (3-fluoro- N- (6-(4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-2-carboxamide) was obtained in the same manner as in Step 2 of Example 14, except that 3 -fluorothiophene-2-carboxylic acid was used. Example 99 Preparation of 3 -fluoro- N- (4- (N- (6 -methoxypyridazin-3-yl)sulfamoyl)phenyl)picolylamide (3-fluoro- N- (4-(N- (6 -methoxypyridazin-3-yl)sulfamoyl)phenyl)picolylamide)<​​​​​Compound 3-fluoro-N-(4-(N-(6-methoxypyridazin-3-yl)sulfamoyl)phenyl)picolinamide was obtained in the same manner as in Step 2 of Example 12, except that 4-amino-N-(6-methoxypyridazin-3-yl)benzenesulfonamide and 3-fluoropicolinic acid were used. In the experiment, 100

[0621] Preparation of 3-fluoro-N-(6-((4-methoxybenzyl)amino)pyridazin-3-yl)picolinamide

[0622] [Step 1] Under nitrogen gas, (4-methoxyphenyl)methanamine, 6-iodopyridazin-3-amine, and K3PO4 were dissolved in DMSO, then CuI and L-hydroxyproline were added, and the mixture was stirred at 50 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with toluene. The mixed organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N3-(4-methoxybenzyl)pyridazine-3,6-diamine.

[0623] [Step 2]

[0624] Compound 3-fluoro- N- (6- ((4-methoxybenzyl)amino)pyridazin-3 -yl)picolinamide was obtained by the same method as in step 2 of Example 12, except that N3- (4-methoxybenzyl)pyridazine-3,6-diamine and 3-fluoropicolinic acid were used. Example 101 3-(trifluoromethyl)-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (3-(trifluoromethyl)-N-(6-(4-

[0625] (tr if luoromethyl ) phenyl ) pyr idazin— 3— yl ) pi col inamide)

[0626] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[0627] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0628] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0629] [Step 2]

[0630] Compound 3-(trifluoromethyl)-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (3-(trifluoromethyl)-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide) was prepared in the same manner as in step 2 of Example 1 4, except that 3-(trifluoromethyl)picolinic acid (3-(trifluoromethyl)picolinic acid) was used.

[0631] (tr if luoromethyl ) phenyl ) pyr idazin— 3— yl ) pi col inamide) was obtained. Example 102

[0632] Preparation of 3-fluoro-N-(6-(3-isopropoxyphenyl)pyridazin-3-yl)picolinamide (3-f 1 uor oN-(6-(3- i sopropoxypheny 1 )pyridazin— 3— yl )pi col inamide) 1,4-Dioxane water

[0633] [Step 1]

[0634] Compound 6-(3-isopropoxyphenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 26, except that (3-isopropoxyphenyl)boronic acid was used.

[0635] [Step 2]

[0636] Compounds were prepared in the same manner as in step 2 of Example 26, except that 6-(3-isopropoxyphenyl)pyridazin-3-amine, 3-fluoropicolinic acid were used.

[0637] 3-fluoro- N- (6- (3-isopropoxyphenyl)pyridazin-3-yl)picolinamide (3- f luoro- N-

[0638] (6— (3— i sopropoxypheny l )pyr idazin— 3— yl )pi col inamide) was obtained. 103

[0639] Preparation of 3-fluoro-N-(6-(3-(methylcarbamoyl)phenyl)pyridazin-3-yl)picolylamide (3-fluoro-N-(6-(3-(methylcarbamoyOphenyOpyridazin-3-yl)picolylamide)) water

[0640] [Step 1]

[0641] (3-(methylcarbamoyl)phenyl)boronic acid ((3-(methylcarbamoyOphenyOboronic acid) was used to obtain compound 3-(and except for 6-aminopyridazin-3-yl)-N-methylbenzamide (3-(6-aminopyridazin-3-yl)-N-methylbenzamide) in the same manner as in Step 1 of Example 26.

[0642] [Step 2]

[0643] 3-(6-aminopyridazin-3-yl)-N-methylbenzamide(3-(6-hex111sweated10hex7heart(1hex2sweated1-3-yl)-N-methylbenzamide), 3-fluoropicolinic acid (3-fluoropicolinic acid) was used to obtain compound 3-fluoro-N-(6-(3-(methylcarbamoyl)phenyl)pyridazin-3-yl)picolylamide except for the same method as in Step 2 of Example 26. Example 104

[0644] Preparation of N-(4'-(trifluoromethyl)-[1,r-biphenyl]-4-yl)thiazole-4-carboxamide (N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)thiazole-4-carboxamide) water

[0645] [Step 1]

[0646] Compound 4'-(trifluoromethyl)-[1,1'-biphenyl]-4-amine was obtained in the same manner as in step 1 of Example 26, except that (4-(tri f luoromethyl)phenyl)boronic acid and 4-bromoaniline were used.

[0647] [Step 2]

[0648] 4'- (trifluoromethyl)- [1,1'-biphenyl] -4 -amine (4'- (trifluoromethyl)-

[0649] Compound N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)thiazole-4-carboxamide (N-(4'-

[0650] (trif luoromethyl )-[!,!' - biphenyl ]- 4- yl )thi azole- 4- carboxamide) was obtained. Example 105

[0651] Preparation of N-(4-methyl-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-4-carboxamide

[0652] [Step 1]

[0653] Compound 4-methyl- was prepared in the same manner as in step 1 of Example 14, except that 5-bromo-4-methylpyridin-2-amine was used.

[0654] 5-(4-(trifluoromethyl)phenyl)pyridin-2-amine(4-methyl-5-(4-

[0655] (tr if luoromethyl )phenyl )pyr idin— 2— amine) was obtained.

[0656] [Step 2]

[0657] 4-methyl- 5- (4- (trifluoromethyl) phenyl) pyridin- 2 -amine (4- methyl- 5- (4-

[0658] Compound N-(4-methyl-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 14, except that thiazole-4-carboxylic acid was used. In Example 106

[0659] N-(6-(3-acetamidophenyl)pyridazin-3-yl)picolinamide (N-(6-(3-acet ami dopheny 1 ) pyr i daz in— 3— y 1 ) pi co 1 i nam i de ) low] , water

[0660] [Step 1]

[0661] Compound N-(3-(6-aminopyridazin-3-yl)phenyl)acetamide (cis-(3-(6-aminopyridazin-3-yl)phenyl)acetamide) was obtained in the same manner as in Step 1 of Example 12, except that ((3-acetamidophenyl)boronic acid) was used.

[0662] [Step 2]

[0663] Compound N-(6-(3-acetamidophenyl)pyridazin-3-yl)picolylamide (N-(6-(3-acetamidophenyl)pyridazin-3-yl)picolylamide) was obtained in the same manner as in Step 2 of Example 12, except that N-(3-(6-aminopyridazin-3-yl)phenyl)acetamide (cis-(3-(6-aminopyridazin-3-yl)phenyl)acetamide) and picolinic acid were used. Example 107

[0664] Preparation of N-(5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)thiazole-4-carboxamide (N-(5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)thiazole-4-carboxamide) water <0​​​​

[0667] [Step 2]

[0668] 5-(4-(trifluoromethyl)phenyl)pyrazin-2-amine (5-(4-

[0669] The compound N-(5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 26, except that thiazole-4-carboxylic acid was used. In Example 108, N-(6-(3-(cyclopropylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained.

[0670] 4- Manufacture of carboxami de) water

[0671] [Step 1]

[0672] (3-(cyclopropylcarbamoyl)phenyl)boronic acid ((3-

[0673] Example 1 except that (cyclopropylcarbamoyl )phenyl )boronic acid) was used

[0674] Compound 3-(6-aminopyridazin-3-yl)-N-cyclopropylbenzamide was obtained by the same method as step 1 of 26.

[0675] [Step 2]

[0676] 3-(6-Aminopyridazin-3-yl)-N-cyclopropylbenzamide, except using thiazole-4-carboxylic acid

[0677] Compound N-(6-(3-(cyclopropylcarbamoyl)phenyl)pyridazin-3-yl)thiazole- was obtained in the same manner as in Step 2 of Example 26

[0678] 4-carboxamide. In Experiment 109

[0679] Preparation of N-(6-fluoro-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-4-carboxamide water

[0680] [Step 1]

[0681] Compound 6-fluoro-5-(4-(trifluoromethyl)phenyl)pyridin-2-amine was obtained in the same manner as in Step 1 of Example 14, except using 5-bromo-6-fluoropyridin-2-amine

[0682] (trifluoromethyl)phenyl)pyridin—2—amine).

[0683] [Step 2]

[0684] 6-Fluoro- 5-(4-(trifluoromethyl)phenyl)pyridin- 2-amine (6-f luoro- 5-(4-

[0685] Compound N-(6-fluoro-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 14, except that (tri f luoromethyl )phenyl )pyridin-2-yl)thiazole-4-carboxamide was used. Example 110

[0686] 3-fluoro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)pyrazine-2-carboxamide (3-fluoro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)pyrazine-2-carboxamide) water

[0687] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0688] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0689] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0690] [Step 2]

[0691] Compound 3 - fluoro - N - (6 - (4 - (trifluoromethyl)phenyl)pyridazin - 3 - yl)pyrazine - 2 - carboxamide was obtained in the same manner as in Step 2 of Example 14, except that 3 - fluoropyrazine - 2 - carboxylic acid was used. Example 111 Preparation of N - (6 - methoxy - 5 - (4 - (trifluoromethyl)phenyl)pyridin - 2 - yl)thiazole - 4 - carboxamide

[0692] [Step 1]

[0693] Compound 6 - methoxy - 5 - (4 - (trifluoromethyl)phenyl)pyridin - 2 - amine was obtained in the same manner as in Step 1 of Example 14, except that 5 - bromo - 6 - methoxypyridin - 2 - amine was used.

[0694] (trifluoromethyl)phenyl)pyridin—2—amine)

[0695] [Step 2]

[0696] 6 - methoxy - 5 - (4 - (trifluoromethyl)phenyl)pyridin - 2 - amine (6 - methoxy - 5 - (4 -

[0697] ((trifluoromethyl)phenyl)pyridin-2-amine), except for using thiazole-4-carboxylic acid (thiazole-4-carboxylic acid), in the same manner as in Step 2 of Example 14, compound N-(6-methoxy-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-4-carboxamide (N-(6-methoxy-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-4-carboxamide) was obtained. In Example 112, N-(6-(2-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[0698] Preparation of 4-carboxamide (N-(6-(2-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide)

[0699] [Step 1]

[0700] N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-

[0701] (trifluoromethyl)phenyl)acetamide (except for using (2-(4,4,5,5-hexamethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)acetamide), in the same manner as in Step 1 of Example 12, compound N-(2-(6-aminopyridazin-3-yl)-5-(trifluoromethyl)phenyl)acetamide (N-(2-(6-aminopyridazin-3-yl)-5-(trifluoromethyl)phenyl)acetamide) was obtained.

[0702] [Step 2]

[0703] N_(2_(6-aminopyridazine-3-yl)-5-

[0704] (trifluoromethyl)phenyl)acetamide (N- (2- (6-aminopyridazin- 3- yl )-5-

[0705] Compound N-(6-(2-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. Example 113

[0706] N-(6-(3-propionamidophenyl)pyridazin-3-yl)thiazole-4-carboxamide⑴-

[0707] Preparation of (6- (3-pr op i onam i dopheny 1 )pyr idaz in— 3— yl )thi azole— 4— carboxamide) water

[0708] [Step 1]

[0709] Compound N-(3-(6-aminopyridazin-3-yl)phenyl)propionamide⑴-(3-(6-aminopyridazin-3-yl)phenyl)propionamide)# was obtained in the same manner as in step 1 of Example 26, except that N-(3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan- 2-yl)phenyl)propionamide) was used.

[0710] [Step 2]

[0711] Compound N-(6-(3-propionamidophenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained by the same method as in step 2 of Example 26, except that thiazole-4-carboxylic acid was used. Example 114

[0712] Preparation of N-(6-(3-isobutyramidophenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0713] [Step 1]

[0714] Compound N-(3-(6-aminopyridazin-3-yl)phenyl)isobutyramide was obtained in the same manner as in step 1 of Example 26, except that (3-isobutyramidophenyl)boronic acid was used.

[0715] [Step 2]

[0716] The compound N-(6-(3-isobutyramidophenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 26, except that N-(3-(6-aminopyridazin-3-yl)phenyl)isobutyramide, thiazole-4-carboxylic acid, was used. Example 115

[0717] Preparation of N-(6-(3-(methylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide , water

[0718] [Step 1]

[0719] Compound 3-(6-aminopyridazin-3-yl)-N-methylbenzamide was obtained in the same manner as in step 1 of Example 26, except that (3-(methylcarbamoyl)phenyl)boronic acid was used.

[0720] [Step 2]

[0721] Compound N-(6-(3-methylbenzamide) was prepared in the same manner as in step 2 of Example 26, except that 3-(6-aminopyridazin-3-yl)-N-methylbenzamide, thiazole-4-carboxylic acid, was used.

[0722] (methylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(ci-(6-(3-

[0723] (methyl carbamoyl ) phenyl ) pyr idazin— 3— yl ) thi azole— 4— carboxami de) was obtained. Example 116

[0724] Preparation of N- (6- (3- (trifluoromethoxy)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N- (6- (3- ( tr if 1 uo r ome t hoxy ) pheny 1 )pyr idazin-3- yl )thiazole-4-carboxami de) , water

[0725] [Step 1]

[0726] (3-(trifluoromethoxy)phenyl)boronic acid ( (3-

[0727] Compound 6-(3-(trifluoromethoxy)phenyl)pyridazin-3-amine (6-(3-( tr if 1 uo r ome thoxy)phenyl )pyridazin-3-amine) was obtained in the same manner as in step 1 of Example 26, except that (tr if 1 uo r ome thoxy)phenyl )boronic acid) was used.

[0728] [Step 2]

[0729] 6-(3-(trifluoromethoxy)phenyl)pyridazin-3-amine (6-(3-

[0730] The compound N-(6-(3-(trifluoromethoxy)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained by the same method as in step 2 of Example 26 except that thiazole-4-carboxylic acid was used. In Example 117

[0731] Preparation of N-(6-(3-(dimethylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0732] [Step 1]

[0733] (3-(dimethylcarbamoyl)phenyl)boronic acid ( (3-

[0734] Compound 3-(6-aminopyridazin-3-yl)-N,N-dimethylbenzamide was obtained in the same manner as in step 1 of Example 26, except that (dimethyl carbamoyl )phenyl )boronic acid) was used.

[0735] [Step 2] The compound N-(6-(3-(dimethylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 26, except that thiazole-4-carboxylic acid was used. Example 118

[0736] N-(6-(3-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[0737] Preparation of 4-carboxamide (N- (6- (3-acetamido- 4-( tr if luoromethyl ) phenyl )pyr idazin-3- yl )thiazole- 4-carboxamide)

[0738] [Step 1]

[0739] 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl)-2-

[0740] (Trifluoromethyl)aniline (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline) was dissolved in DCM solvent, then acetic anhydride (Acetic anhydride, AC2O) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with an aqueous solution of sodium bicarbonate (Sodium bicarbonate, NaHCO3) and extracted with toluene. The mixed organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-

[0741] (Trifluoromethyl)phenyl)acetamide (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)acetamide) was obtained.

[0742] [Step 2]

[0743] N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-

[0744] (Trifluoromethyl)phenyl)acetamide (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)acetamide) was used, and the compound N-(5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)phenyl)acetamide (N-(5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)phenyl)acetamide) was obtained in the same manner as in Step 1 of Example 26.

[0745] [Step 3]

[0746] N- (5- (6-aminopyridazin-3-yl)- 2-

[0747] (trifluoromethyl)phenyl)acetamide (N-(5-(6-ami nopyr idazin-3-yl)-2-

[0748] Compound N-(6-(3-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-acetamido-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) was prepared in the same manner as in step 2 of Example 26, except that thiazole-4-carboxylic acid was used.

[0749] (trif luoromethyl ) phenyl ) pyr idazin— 3— yl ) thi azole— 4— carboxamide) was obtained. 119

[0750] Preparation of N-(6-(2-(benzyloxy)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[0751] [Step 1]

[0752] (2-(benzyloxy)-4-(trifluoromethyl)phenyl)boronic acid ( (2- (benzyloxy)-4-

[0753] Compound 6-(2-(benzyloxy)-4-(trifluoromethyl)phenyl)boronic acid) was prepared in the same manner as in step 1 of Example 12, except that (trifluoromethyl)phenyl)boronic acid was used.

[0754] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(2-(ethex2710乂7)-4-

[0755] (trifluoromethyl)phenyl)pyridazin-3-amine was obtained.

[0756] [Step 2]

[0757] 6-(2-(Benzyloxy)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(2-

[0758] (benzyloxy)-4-(trifluoromethyl)phenyl)pyridazin—3—amine), thiazole-4-carboxylic acid (thiazole-4-carboxylic acid) was used, and the compound N-(6-(2-(benzyloxy)-4-

[0759] (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (Shi-(6-(2-

[0760] (benzyloxy)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide)# was obtained. Example 120

[0761] Preparation of N-(6-(3-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) 1,4-Dioxane DMF water

[0762] [Step 1]

[0763] (3-chloro-4-(trifluoromethyl)phenyl)boronic acid ((3-chloro-4-

[0764] Compound 6-(3-chloro-4-) was prepared in the same manner as in step 1 of Example 12, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[0765] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-chloro-4-

[0766] (tr if luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[0767] [Step 2]

[0768] 6-(3-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-chloro-4-

[0769] (trifluoromethyl)phenyl)pyridazin-3-amine), thiazole-4-carboxylic acid was used, and the compound N-(6-(3-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(ci-(6-(3-sa1101'0-4-

[0770] (tri f luoromethyl )phenyl )pyridazin— 3— yl )thiazole— 4— carboxamide) was obtained. Example 121

[0771] N-(6-(2-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[0772] Preparation of 4-carboxamide (N- (6- (2- (methylamino)- 4- (trif luoromethyl )phenyl )pyridaz in- 3- yl )thiazole- 4- carboxamide)

[0773] [Step 1]

[0774] 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-

[0775] (Trifluoromethyl)aniline (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline), iodomethane, and K2CO3 were dissolved in DMF and stirred at 55 °C for 6 hours. The reaction mixture was diluted with water and extracted with toluene. The combined organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (N-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline).

[0776] [Step 2]

[0777] Compound 6-(2-(methylamino)-4-

[0778] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(2-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 12, except that N-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (N-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline) was used.

[0779] [Step 3]

[0780] Compound N-(6-(2-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was prepared in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used.

[0781] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(ci-(6-(2-(methylamino)—4—(tri f luoromethyl )phenyl )pyridazin—3— yl )thiazole—4— carboxamide)# obtained. Example 122

[0782] Preparation of N-(6-(4-methoxyphenoxy)pyridazin-3-yl)thiazole-4-carboxamide (ci-(6-(4-methoxyphenoxy)pyridazin—3—yl)thiazole—4—carboxamide)

[0783] [Step 1]

[0784] Compound N-(6-(4-methoxyphenoxy)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(4-methoxyphenoxy)pyridazin-3-amine and thiazole-4-carboxylic acid were used. Example 123

[0785] Preparation of N-(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0786] [Step 1]

[0787] Compound 5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (5-chloro-5-methylpyr idazin-3-amine) was prepared in the same manner as in step 1 of Example 14, except that 6-chloro-5-methylpyr idazin-3-amine was used.

[0788] (tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[0789] [Step 2]

[0790] 5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (5-methyl-6-(4-

[0791] Compound N-(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 14, except that (tri f luoromethyl )phenyl )pyridazin-3-amine) and thiazole-4-carboxylic acid were used. Example 124

[0792] Preparation of N-(6-(2-Fluoro-6-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)thiazole-4-carboxamide 1,4-Dioxane DMF water

[0793] [Step 1] Except for using (2-Fluoro-6-(trifluoromethyl)pyridin-3-yl)boronic acid, the compound 6-(2-Fluoro-6-

[0794] (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine was obtained in the same manner as in Step 1 of Example 12.

[0795] (trifluoromethyl)pyridin-3-yl)pyridazin-3-amine)

[0796] [Step 2]

[0797] Except for using 6-(2-Fluoro-6-(trifluoromethyl)pyridin-3-yl)pyridazin-3-amine and thiazole-4-carboxylic acid, the compound N-(6-(2-Fluoro-6-

[0798] (Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(2-f luoro— 6—( tr if luoromethyl )pyr idin-3-yl )pyr idazin— 3— yl ) thiazole— 4— carboxamide)# obtained. 125 in the experiment

[0799] Preparation of N-(6-(3-cyano-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[0800] [Step 1]

[0801] 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl)-2-

[0802] Compound 5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)benzonitrile was prepared in the same manner as in step 1 of Example 12, except that (trifluoromethyl)benzonitrile (5-(4, 4, 5, 5-tetramethyl- 1,3,2- dioxaboro lan- 2-yl)-2-(trifluoromethyl)benzonitrile) was used.

[0803] (Trifluoromethyl)benzonitrile (5-(6-aminopyr idazin-3-yl)-2-

[0804] (trif luoromethyDbenzoni tri le) was obtained.

[0805] [Step 2]

[0806] 5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)benzonitrile(5-(6-am i nopyr i daz i n-3-y 1 ) -2- ( trif 1 uor ome t hy 1 ) benzon itri le), t 0 Compound N-(6-(3-cyano-4-) was prepared in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used.

[0807] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-cyano-4-(trif luoromethyl )phenyl )pyridazin— 3— yl )thi azole— 4— carboxamide) was obtained. Example 126

[0808] Preparation of N-(6-(3-carbamoyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0809] [Step 1]

[0810] N-(6-(3-cyano-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide and K2CO3 were dissolved in DMSO, and 30% aqueous hydrogen peroxide (H2O2) solution was added and stirred at 60°C for 1 hour. The mixture was diluted with distilled water and extracted with distilled water. The combined organic layers of the extracts were washed with distilled water, dried over MgSO, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(6-(3-carbamoyl-4-

[0811] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(ci-(6-(3-carbamoyl— 4—( tr if fluoromethyl )phenyl )pyr idaz in— 3— yl )thiazole— 4— carboxamide)# obtained. Example 127 Methyl 5-(6-(thiazole-4-carboxamido)pyridazin-3-yl)- 2-

[0812] Preparation of (trifluoromethyl)benzoate (methyl 5— (6— (thiazole— 4— carboxamido)pyr idazin— 3-yl )-2-(tri f luoromethyl )benzoate) water

[0813] [Step 1] Methyl 5-(4, 4, 5, 5 -tetramethyl- 1 , 3 , 2 -dioxaborolane- 2 -yl)- 2-

[0814] The compound methyl 5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)benzoate was prepared in the same manner as in step 1 of Example 12, except that methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzoate was used.

[0815] (tri f luoromethyl )benzoate) was obtained.

[0816] [Step 2] The compound methyl 5-(6-(thiazole-4-carboxamido)pyridazin-3-yl)-2-(trifluoromethyl)benzoate was obtained in the same manner as in Step 2 of Example 12, except that thiazole-4-carboxylic acid was used. Example 128

[0817] Preparation of N-(thiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyridazine-3-carboxamide water

[0818] [Step 1]

[0819] Compound 6-(4-(trifluoromethyl)phenyl)pyridazine-3-carboxylic acid was obtained in the same manner as in step 1 of Example 26, except that (4-(trifluoromethyl)phenyl)boronic acid and 6-chloropyridazine-3-carboxylic acid were used.

[0820] [Step 2]

[0821] 6-(4-(trifluoromethyl)phenyl)pyridazine-3-carboxylic acid (6-(4-

[0822] Compound N-(thiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrazole-3-carboxylic acid) was prepared in the same manner as in step 2 of Example 26, except that thiazol-4-amine hydrochloride was used.

[0823] (Trifluoromethyl)phenyl)pyridazine-3-carboxamide (N-(thiazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyridazine—3—carboxamide) was obtained. Example 129

[0824] Preparation of N-(6-(4-fluoro-3-(methylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0825] (4-fluoro-3-(methylcarbamoyl)phenyl)boronic acid((4-£ 11101'0-3-

[0826] Compound 5-(6-aminopyridazin-3-yl)-2-fluoro-N-methylbenzamide was obtained by the same method as in step 1 of Example 26, except that (methyl carbamoyl )phenyl )boronic acid) was used.

[0827] [Step 2]

[0828] Compound N-(6-(4-fluoro-3-yl)-2-methylbenzamide (5-(6-aminopyridazin-3-yl)-2-fluoro-N-methylbenzamide) was prepared in the same manner as in step 2 of Example 26, except that thiazole-4-carboxylic acid was used.

[0829] (Methylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(4-f luoro-3-(methyl carbamoyl ) phenyl )pyridazin— 3— yl )thiazole— 4— carboxamide) was obtained. Example 130

[0830] N-(6-(3-((2-(dimethylamino)ethyl)carbamoyl)phenyl)pyridazin-3-yl)thiazole-

[0831] 4-Carboxamide(Ci-(6-(3-( (2-

[0832] Preparation of (dimethyl ami no)ethyl ) carbamoyl ) phenyl )pyr idazin— 3— yl ) thiazole— 4— carboxamide)

[0833] [Step 1]

[0834] Compound 3-(6-aminopyridazin-3-yl)-N-(2-(dimethylamino)ethyl)benzamide was obtained in the same manner as in step 1 of Example 26, except that (3-((2-(dimethylamino)ethyl)carbamoyl)phenyl)boronic acid) was used.

[0835] [Step 2] Compound N-(6-(3-(2-(dimethylamino)ethyl)benzamide was prepared in the same manner as in Step 2 of Example 26, except that 3-(6-aminopyridazin— 3— yl )—N— (2— (dimethyl ami no)ethyl ) benz am ide) and thiazole-4-carboxylic acid were used.

[0836] (Dimethylamino)ethyl)carbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide⑴- (6-(3-((2-(dimethyl ami no)ethy 1)carbamoyl)phenyl)pyridazin— 3— yl)thiazole— 4— carboxamide)# obtained. 131 in the embodiment

[0837] Preparation of N-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0838] [Step 1]

[0839] (2-chloro-4-(trifluoromethyl)phenyl)boronic acid ( (2-chloro-4-

[0840] Compound 6-(2-chloro-4-) was prepared in the same manner as in step 1 of Example 12, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[0841] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(2-chloro-4-(tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[0842] [Step 2]

[0843] 6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-amine(6-(2-chloro-4-

[0844] Compound N-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-amine) , thiazole-4-carboxylic acid was used in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used.

[0845] (tri f luoromethyl ) phenyl ) pyr idazin— 3— yl ) thi azole— 4— carboxamide) was obtained. Example 132

[0846] 4-bromo-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide (4-bromo-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide) water

[0847] [Step 1] Compound 6-(4 -) in the same manner as step 1 of Example 14

[0848] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(4- (trifluoromethyl)phenyl)pyridazin— 3— amine) was obtained.

[0849] [Step 2]

[0850] Compound 4-bromo-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide was obtained by the same method as in step 2 of Example 14, except that 4-bromothiophene-3-carboxylic acid was used. Example 133

[0851] Preparation of N-(6-(3-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[0852] [Step 1]

[0853] (3-methoxy-4-(trifluoromethyl)phenyl)boronic acid ( (3-methoxy-4-

[0854] Compound 6-(3-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-methoxy-4-(trifluoromethyl)phenyl)boronic acid) was prepared in the same manner as in step 1 of Example 12, except that (trifluoromethyl)phenyl)boronic acid was used.

[0855] (Trifluoromethyl)phenyl)pyridazin—3—amine was obtained.

[0856] [Step 2]

[0857] Compound N-(6-(3-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) was obtained in the same manner as in Step 2 of Example 12, except that 6-(3-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine and thiazole-4-carboxylic acid were used. Example 134

[0858] N-(6-(3-(Z-(Z,Z,Z-trifluoroacetamido)ethyl)-4-[[ID=1⑩]]

[0859] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-(2-

[0860] (2,2,2-trifluoroacetamido)ethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) Preparation water

[0861] [Step 1] 2,2,2-Trifluoro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)acetamide (2,2,2-trifluoro-N-(5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)acetamide)

[0862] Compound N-(5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)phenethyl)acetamide) was prepared in the same manner as in step 1 of Example 12, except that (trifluoromethyl)phenethyl)acetamide) was used.

[0863] (Trifluoromethyl)phenethyl)-2,2,2-trifluoroacetamide (N-(5-(6-aminopyridazin—3—yl)—2—(trifluoromethyl)phenethyl)—2,2,2— trifluoroacetamide) was obtained.

[0864] [Step 2]

[0865] Compound N-(6-(3-(2-(2,2,2-trifluoroacetamido)ethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4 was prepared in the same manner as in step 2 of Example 12, except that N-(5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)phenethy 1)-2,2,2-trifluoroacetamide, thiazole-4-carboxylic acid was used. -Carboxamide (Si-(6-(3-(2-(2,2,2-kJi-11101'0*6kJi111du(10)61±71)-4- (trif luoromethyl )phenyl)pyridazin— 3— yl) thiazole— 4— carboxamide) was obtained. Example 135

[0866] Preparation of N-(6-(3-amino-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide , water

[0867] [Step 1]

[0868] 6-Chloropyridazin-3-amine and thiazole-4-carboxylic acid were dissolved in DMF with HATU, then DIPEA was added and the mixture was stirred at 40 °C for 17 hours. After the reaction was completed, the mixture was diluted with water and extracted with toluene. The combined organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(6-chloropyridazin-3-yl)thiazole-4-carboxamide.

[0869] [Step 2] Under nitrogen gas, (3-amino-4-(trifluoromethyl)phenyl)boronic acid and N-(6-chloropyridazin-3-yl)thiazole-4-carboxamide, Pd(dppf)Cl2·CH2Cl2, Na2CO3, 1,4-dioxane:distilled water (5:1) were dissolved in a solvent and reacted at 120 °C for 2 hours under microwave conditions. After the reaction was completed, the mixture was diluted with water and extracted with toluene. The combined organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(6-(3-amino-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0870] ((trifluoromethyl)phenyl)pyridazin—3—yl)thiazole—4—carboxamide) was obtained. In the experiment, 136

[0871] Preparation of N-(6-(3-(2,2,2-trifluoroacetamido)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-(2,2,2-trifluoroacetamido)phenyl)pyridazin-3-yl)thiazole-4-carboxamide)

[0872] [Step 1]

[0873] Compound N-(3-(6-amino-pyridazin-3-yl)phenyl)-2,2,2-trifluoroacetamide (N-(3-(6-amino-pyridazin-3-yl)phenyl)-2,2,2-trifluoroacetamide) was obtained in the same manner as in Step 1 of Example 26, except that ((3-(2,2,2-trifluoroacetamido)phenyl)boronic acid) was used.

[0874] [Step 2] N-(3-(6-aminopyridazin-3-yl)phenyl)-2,2,2-trifluoroacetamide⑴-(3—(6—aminopyridazin—3—yl)pheny 1)—2,2,2—trifluoroacetamide), thiazole—4-carboxylic acid was used, and the compound N-(6-(3-(2,2,2-trifluoroacetamido)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(thiazole-(6-(3—(2,2,2—tri fluoroacetamido)phenyl)pyr idaz in—3—yl)thiazole—4—carboxamide)# was obtained in the same manner as in Step 2 of Example 26. 137

[0875] N-(6-(3-(N-methylsulfamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide⑴-

[0876] Preparation of (6— (3— (N— methyl sulfamoyl ) phenyl )pyr idaz in— 3— yl )thi azole— 4— carboxamide) water

[0877] [Step 1]

[0878] Compound 3-(6-aminopyridazin-3-yl)-N-methylbenzenesulfonamide was obtained by the same method as in step 1 of Example 26, except that (3-(N-methylsulfamoyOphenyOboronic acid) was used. [Step 2]

[0879] Compound N-(6-(3-(N-methylsulfamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 26, except that 3-(6-aminopyridazin-3-yl)-N-methylbenzenesulfonamide (3-(6-aminopyridazin-3-yl)-N~me t hy 1 benz enesu 1 f onam i de ) and thiazole-4-carboxylic acid were used. Example 138

[0880] Preparation of N-(6-(3-(methylsulfonamido)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0881] [Step 1]

[0882] Compound was prepared in the same manner as in step 1 of Example 26, except that (3- (methylsulphonamido)i)henyl )boronic acid was used.

[0883] N-(3-(6-aminopyridazin-3-yl)phenyl)methanesulfonamide was obtained.

[0884] [Step 2]

[0885] Compound N-(6-(3-(methylsulfonamido)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in Step 2 of Example 26, except that N-(3-(6-aminopyridazin-3-yl)phenyl)methanesulfonamide (cis-(3-(6-aminopyridazin-3-yl)phenyl)methanesulfonamide) and thiazole-4-carboxylic acid were used. Example 139

[0886] Preparation of N-(6-(3-(methylthio)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide 1,4-Dioxane DMF water

[0887] [Step 1]

[0888] Compound 6-(3-(methylthio)-4-

[0889] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-(methylthio)-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 12, except that 4,4,5,5-tetramethyl-2-(3-(methylthio)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane was used.

[0890] [Step 2]

[0891] Compound N-(6-(3-(methylthio)-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was prepared in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used.

[0892] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(ci-(6-(3-(methyl thio)-4-(trifluoromethyl)phenyl)pyridazin— 3— yl)thiazole— 4— carboxamide)# obtained. Example 140

[0893] 5-(6-(thiazole-4-carboxamido)pyridazin-3-yl)-2-

[0894] (Trifluoromethyl)benzoic acid (5- (6- (thiazole- 4- carboxamido) pyr idazin- 3- yl )-2-

[0895] Preparation of (tr if luoromethyl )benzoic acid) water

[0896] [Step 1] Methyl 5-(6-(thiazole-4-carboxamido)pyridazin-3-yl)-2-

[0897] (Trifluoromethyl)benzoate (methyl 5- ( 6- ( thi azo 1 e-4-car boxam i do ) pyr i daz i n- 3- yl )-2- (trifluoromethyl )benzoate) was dissolved in THF: methanol (MeOH) (2: 1) solvent, and 2 N lithium hydroxide (LiOH) aqueous solution was added and reacted at 50°C for 4 hours. After the reaction, the mixture was diluted with water, and 2 N HC1 aqueous solution was slowly added dropwise until the pH reached 4 to 5. The resulting solid was filtered and dried to obtain compound 5-(6-(thiazole-4-carboxamido)pyridazin-3-yl)-2-(trifluoromethyl)benzoic acid. Example 141

[0898] Preparation of N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide

[0899] [Step 1] 4-(trifluoromethyl)piperidine(4-

[0900] (Trifluoromethyl)piperidine, 6-iodopyridazin-3-amine, and K3PO4 were dissolved in DMSO, then CuI and L-proline were added, and the mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and extracted with toluene. The combined organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound 6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-amine.

[0901] [Step 2]

[0902] 6-(4-(Trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4- <​​​Preparation of N-(6-(2-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[0905] [Step 1]

[0906] (2-methyl-4-(trifluoromethyl)phenyl)boronic acid ( (2-methyl-4-

[0907] Compound 6-(2-methyl-4-) was prepared in the same manner as in step 1 of Example 12, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[0908] (Trifluoromethyl)phenyl)pyridazin-3-amine(6-(2-tau-4-

[0909] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[0910] [Step 2]

[0911] Compound N-(6-(2-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(2-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-amine and thiazole-4-carboxylic acid were used. Example 143

[0912] N-(6-(3-(ethylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[0913] Preparation of 4-carboxamide (N- (6- (3- (ethylamino)- 4- ( tri fluoromethyl )phenyl)pyridaz in- 3- yl )thiazole- 4- carboxamide)

[0914] [Step 1]

[0915] 5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl)-2-

[0916] (Trifluoromethyl)aniline (5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan- 2- y1)-2- (trifluoromethyl)aniline) and iodoethane were dissolved in DMF, K2CO3 was added, and the mixture was stirred at 120 °C for 16 hours. The mixture after reaction was diluted with water and extracted with a distilled water. The combined organic layers of the extracts were washed with water, dried over MgS04, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-ethyl- 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan- 2-yl)-2-

[0917] (Trifluoromethyl)aniline (N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaboro lan-2-yl)-2-(trifluoromethyl)aniline) was obtained.

[0918] [Step 2]

[0919] N-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline (except for using cis-61±71-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline) was used, and Compound 6-(3-(ethylamino)-4-

[0920] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-(ethylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 12.

[0921] [Step 3]

[0922] 6-(3-(ethylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-(ethylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine), except for using thiazole-4-carboxylic acid (thiazole-4-carboxylic acid), was used, and Compound N-(6-(3-(ethylamino)-4-

[0923] (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (cis-(6-(3-(ethylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) was obtained. In Experiment 144

[0924] N-(6-(3-((cyclopropylmethyl)amino)-4-

[0925] Preparation of (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (cis-(6-(3-((cyclopropylmethyl)amino)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide)

[0926] [Step 1]

[0927] Compound N was prepared in the same manner as in Step 1 of Example 143, except that ((bromomethyl)cyclopropane) was used.

[0928] (Cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline (cis-(070101)1'0hex7111161±71)-5-(4,4,5,5-c61:du11161±71-1,3,2—dioxaborolan—2—y1)-2-(trifluoromethyl)aniline) was obtained.

[0929] [Step 2]

[0930] Compound 6-(3-((cyclopropylmethyl)amino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-

[0931] ((cyclopropylmethyl)amino)—4—(trifluoromethyl)phenyl)pyridazin—3—amine) was obtained in the same manner as in Step 1 of Example 12, except that N-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline (cis-(070101)1'0hex7111161±71)-5-(4,4,5,5-c61:du11161±71-1,3,2-dioxaborolan-2-y1)-2-(trifluoromethyl)aniline) was used.

[0932] [Step 3]

[0933] Compound N-(6-(3-((cyclopropylmethyl)amino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6— (3— ( (cyclopropylmethyl )amino)— 4— (trifluoromethyl )phenyl )pyridazin— 3 — amine) was prepared in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used.

[0934] ((cyclopropylmethyl)amino)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[0935] 4—Garboxa 1 de (N— (6— (3— ((cyclopropylmethyl )amino)— 4—

[0936] (tr if luoromethyl )phenyl )pyr idaz in— 3— yl ) thiazole— 4— carboxamide) was obtained. Example 145

[0937] Preparation of 5-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole- 4-carboxamide Compound 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[0938] (trif luoromethyl)phenyl)pyridazin— 3— amine) was obtained.

[0939] [Step 2]

[0940] Compound 5-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained by the same method as in step 2 of Example 14, except that 5-chlorothiazole-4-carboxylic acid was used. Example 146

[0941] N- (6- (3- (2, 2, 2-trifluoroethoxy)phenyl)pyridazin- 3 -yl)thiazole- 4-carboxamide (N- (6- (3- (2,2,2- trif luoroethoxy)phenyl)pyridazin- 3- yl)thiazole-

[0942] 4- Manufacture of carboxami de) water

[0943] [Step 1]

[0944] Compound 6-(3-(2,2,2-trifluoroethoxy)phenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-(2,2,2-trif 1 uo r oe t hoxy ) pheny 1 )boronic acid was used.

[0945] [Step 2]

[0946] Compound N-(6-(3-(2,2,2-trifluoroethoxy)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 6-(3-(2,2,2-trifluoroethoxy)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was used. Example 147

[0947] Preparation of 2-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide (2-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide)

[0948] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0949] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0950] (tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[0951] [Step 2]

[0952] Compound 2-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide was obtained by the same method as in step 2 of Example 14, except that 2-chlorothiophene-3-carboxylic acid was used. Example 148

[0953] Preparation of N-(6-(3-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0954] [Step 1]

[0955] 6-(3-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 26, except that (3-f luoro-4-(trifluoromethyl)phenyl)boronic acid was used.

[0956] [Step 2]

[0957] N-(6-(3-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 26, except that thiazole-4-carboxylic acid was used. Example 149

[0958] N-(6-(2-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(2-(cyclopropylmethoxy)-4-

[0959] Preparation of (tr if luoromethyl ) phenyl )pyr idazin— 3— yl )thi azole— 4— carboxamide) water

[0960] [Step 1] Compound 6-(2-) was prepared in the same manner as in Step 1 of Example 12, except that (2-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)boronic acid was used.

[0961] (Cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(2- (cyclopropylmethoxy)— 4—( tr if luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[0962] [Step 2]

[0963] The compound N-(6-(2-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6—(2—(cyclopropylmethoxy)—4—(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) was obtained in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. 150 in Example 12

[0964] N-(6-(3-(4-methylpiperazine-1-carbonyl)phenyl)pyridazin-3-yl)thiazole-4-garbin} 1 Preparation of Gide (N—(6—(3—(4—methylpiperazine—1—carbonyl)phenyl)pyr idazin-3-yl)thiazole-4-carboxamide)

[0965]

[0966] [Step 1]

[0967] (3-(6-Aminopyridazin-3-yl)phenyl)(4-methylpiperazin-1-yl)methanone was obtained in the same manner as in Step 1 of Example 12, except that (4-methylpiperazin-1-yl)(3-(4,4,5,5-tetramethyl-oxaborolan-2-yl)phenyl)methanone was used instead of ((4-methylpiperazin-1-yl)(3-(4, ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone).

[0968] [Step 2]

[0969] Compound N-(6-(3-(4-methylpiperazine-1-carbonyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in Step 2 of Example 12, except that (3-(pyridazin-3-yl)phenyl)(4-methylpiperazin-1-yl)methanone and thiazole-carboxylic acid were used instead of ((3-(6-aminopyridazin-3-yl)phenyl)(4-methylpiperazin-1-yl)methanone and thiazole-4-carboxylic acid).

[0970] N-(6-(3-(cyclopropanecarboxamido)-4-

[0971] (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in Step 2 of Example 12, except that (3-(6-aminopyridazin-3-yl)phenyl)(4-methylpiperazin-1-yl)methanone and thiazole-4-carboxylic acid were used instead of ((3-(6-aminopyridazin-3-yl)phenyl)(4-methylpiperazin-1-yl)methanone and thiazole-4-carboxylic acid).

[0972] ((Eye 1 opr opanecar boxami do) -4 - (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) Preparation

[0973] [Step 1]

[0974] 5-(4, 4, 5, 5 -tetramethyl-1, 3, 2 -dioxaborolan-2 -yl)-2-

[0975] (Trifluoromethyl)aniline (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline) was dissolved in pyridine solvent, then cyclopropanecarbonyl chloride was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with toluene. The mixed organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain the compound N-(5-(4, 4, 5, 5 -tetramethyl-1, 3, 2 -dioxaborolan-2 -yl)-2-

[0976] (Trifluoromethyl)phenyl)cyclopropanecarboxamide (Si-(5-(4,4,5,5-hexyl=wo11 knife-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)cyclopropanecarboxamide) was obtained. [Step 2]

[0977] N-(5-(4, 4, 5, 5 -tetramethyl-1, 3, 2 -dioxaborolan-2 -yl)-2-

[0978] (Trifluoromethyl)phenyl)cyclopropanecarboxamide (N- (5- (4, 4, 5, 5-tetramethyl- 1, 3, 2-di oxaboro 1 an— 2— y 1 ) -2 -

[0979] The compound N-(5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)phenyl)cyclopropanecarboxamide (N-(5-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)phenyl)cyclopropanecarboxamide) was obtained in the same manner as in step 1 of Example 26, except that (trifluoromethyl)phenyl )cyclopropanecarboxamide) was used.

[0980] [Step 3]

[0981] N- (5- (6-aminopyridazin-3-yl)- 2-

[0982] Compound N-(6-(3-(cyclopropanecarboxamido)-4-(trifluoromethyl)phenyl)cyclopropanecarboxamide, thiazole-4-carboxylic acid was prepared in the same manner as in step 2 of Example 26, except that (trifluoromethyl)phenyl)cyclopropanecarboxamide, thiazole-4-carboxylic acid (ci-(5-(6—aminopyr idazin— 3— yl )— 2—(trifluoromethyl )phenyl )cyclopropanecarboxamide, thiazole-4-carboxylic acid) was used.

[0983] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (ci-(6-(3-(eye 1 opr opanecar boxami do)-4-(trif luoromethyl)phenyl)pyridazin-3- yl)thiazole-4-carboxamide) was obtained. Example 152

[0984] Preparation of N-(6-(3-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide , water

[0985] [Step 1] The compound N-(6-chloropyridazin-3-yl)thiazole-4-carboxamide (N-(6-chl oropyr i daz i n-3- y 1) thi azo 1 e-4 - carboxamide) was obtained in the same manner as in Step 1 of Example 135.

[0986] [Step 2]

[0987] (3-hydroxy-4-(trifluoromethyl)phenyl)boronic acid ( (3-hydroxy- 4-

[0988] Compound N-(6-(3-hydroxy-4-) was prepared in the same manner as in step 2 of Example 135, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[0989] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (ci-(6-(3-hydroxy— 4—( tr if fluoromethyl )phenyl )pyridazin— 3— yl )thiazole— 4— carboxamide) was obtained. Example 153

[0990] Preparation of 4-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide (4-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide)

[0991] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[0992] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[0993] (trif luoromethyl )phenyl)pyridazin— 3— amine) was obtained.

[0994] [Step 2]

[0995] Compound 4-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide was obtained by the same method as in step 2 of Example 14, except that 4-chlorothiophene-3-carboxylic acid was used. Example 154

[0996] Preparation of N-(6-(4-(2,2,2-trifluoroethoxy)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[0997] [Step 1]

[0998] Compound 6-(4-(2,2,2-trifluoroethoxy)phenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (4-(2,2,2-trif 1 uo r oe t hoxy ) pheny 1 )boronic acid was used.

[0999] [Step 2]

[1000] Compound N-(6-(4-(2,2,2-trifluoroethoxy)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained by the same method as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. Example 155 Preparation of N-(6-(3-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-methyl-4-( tr if luoromethyl )phenyl )pyr idaz in-3-yl )thiazole-4-carboxamide) , water

[1001] [Step 1]

[1002] (3-methyl-4-(trifluoromethyl)phenyl)boronic acid ( (3-methyl-4-

[1003] Compound 6-(3-methyl-4-) was prepared in the same manner as in step 1 of Example 26, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[1004] (Trifluoromethyl)phenyl)pyridazin-3-amine(6-(3-tau-4-

[1005] (tr if luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[1006] [Step 2]

[1007] Compound N-(6-(3-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in Step 2 of Example 26, except that 6-(3-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-amine and thiazole-4-carboxylic acid were used. In Experiment 156

[1008] Preparation of N-(6-(3-ethoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[1009] [Step 1]

[1010] (3-ethoxy-4-(trifluoromethyl)phenyl)boronic acid

[1011] Compound 6-(3-ethoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine was obtained in the same manner as in Step 1 of Example 26, except that (3-ethoxy-4-(trifluoromethyl)phenyl)boronic acid was used.

[1012] (trifluoromethyl)phenyl)pyridazin—3—amine

[1013]

[1014] [Step 2]​

[1015] 6-(3-Ethoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine, except for using thiazole-4-carboxylic acid, was used in the same manner as in Step 2 of Example 26 to obtain the compound N-(6-(3-ethoxy-4-

[1016] (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide. Example 157

[1017] N-(6-(3-Isopropoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[1018] 4-carboxamide (N-(6-(3-isopropoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) Preparation water

[1019] [Step 1]

[1020] (3-Isopropoxy-4-(trifluoromethyl)phenyl)boronic acid, except for using

[1021] in the same manner as in Step 1 of Example 26 to obtain the compound 6-(3-isopropoxy-4-

[1022] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-180]31'0]30乂7-4-

[1023] (tr if luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[1024] [Step 2]

[1025] Compound N-(6-(3-isopropoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was prepared in the same manner as in step 2 of Example 26, except that 6-(3-isopropoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-isopropoxy-4-(trifluoromethyl)phenyl)pyridazin-3-amine), thiazole-4-carboxylic acid was used.

[1026] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3- i sopr opoxy-4-( trif luoromethyl )phenyl )pyr idazin— 3— yl )thiazole— 4— carboxamide)# obtained. Example 158

[1027] N-(6-(3-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[1028] Preparation of 4-carboxamide (N- (6- (3- (methylamino)- 4- ( tri fluoromethyl )phenyl)pyridaz in- 3- yl )thiazole- 4- carboxamide)

[1029] [Step 1] Step of Example 143, except that iodomethane was used.

[1030] In the same manner as in 1, compound N-methyl- 5- (4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolane-

[1031] 2 - (Trifluoromethyl)aniline (cis-06shi71-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline) was obtained.

[1032] [Step 2] Compound 6-(3-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 12, except that N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline (cis-11161shi71-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)aniline) was used.

[1033] [Step 3]

[1034] Compound N-(6-(3-(methylamino)-4-

[1035] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (cis-(6-(3-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) was obtained in the same manner as in Step 2 of Example 12, except that 6-(3-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-(methylamino)-4-(trifluoromethyl)phenyl)pyridazin-3-amine) and thiazole-4-carboxylic acid (thiazole-4-carboxylic acid) were used.# In Experiment 159

[1036] Preparation of N- (6- (4- ((2, 2, 2-trifluoroethyl)carbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[1037] [Step 1]

[1038] Compound 4-(6-aminopyridazin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide was obtained in the same manner as in step 1 of Example 12, except that (4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)boronic acid was used.

[1039] [Step 2]

[1040] The compound N-(6-(4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was prepared in the same manner as in step 2 of Example 12, except that 4-(6-aminopyridazin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide (4-(6-aminopyridazin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide) and thiazole-4-carboxylic acid were used. carboxamide) was obtained. 160 in practice

[1041] Preparation of 5-chloro- N- (6- (3- (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole- 4-carboxamide

[1042] [Step 1]

[1043] Compound 6-(3-(trifluoromethyl)phenyl)pyridazin-3-amine was obtained in the same manner as in step 1 of Example 12, except that (3-(tri f luoromethyl)phenyl)boronic acid was used.

[1044] [Step 2]

[1045] 6-(3-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-

[1046] Compound 5-chloro-N-(6-(3-(trifluoromethyl)phenyl)pyridazin-3-amine) was prepared in the same manner as in step 2 of Example 12, except that 5-chlorothiazole-4-carboxylic acid was used.

[1047] (Trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (5-sa1101'0-si-(6-(3— (tri f luoromethyl )phenyl )pyridazin—3— yl )thiazole—4— carboxamide) was obtained. Example 161 Preparation of 5-chloro-N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide (5-chloro-N-(6-(4-(tri f luoromethyl )piper idin-1-yl )pyridazin-3- yl )thiazole-4-carboxamide)

[1048] [Step 1] Compound 6- (4 -) in the same manner as step 1 of Example 141

[1049] (trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4-

[1050] (tr if luoromethyl )piper idin-l-yl )pyr idazin— 3— amine) was synthesized.

[1051] [Step 2]

[1052] Compound 5-chloro-N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 141, except that 5-chlorothiazole-4-carboxylic acid was used. Example 162

[1053] Preparation of N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide)

[1054] [Step 1]

[1055] Compound 6-(4-(2, 2, 2-trifluoroethyl)piperazin-1-yl)pyridazin-3—amine (6— (4— (2,2,2— tr i fluoroethyl )pi per az in— 1—yl )pyr idaz in— 3— amine) was obtained in the same manner as in step 1 of Example 141, except that 1-(2, 2,2- trif luoroethyl)piperazine was used.

[1056] [Step 2]

[1057] The compound N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridazin-3-amine was obtained in the same manner as in step 2 of Example 141, except that 6-(4-(2,2,2— tri fluor oethyl)pi per azin— l—yl)pyr idaz in— 3— amine was used. 163 5-chloro- N- (6- (4- (2, 2, 2-trifluoroethyl)piperazin-1-yl)pyridazin-3-yl)thiazole- 4-carboxamide (5-chloro- N- (6- (4- (2,2,2- tri fluoroethyl )piper az in-

[1058] Preparation of 1-yl )pyr idaz in— 3— yl )thi azole— 4— carboxamide)

[1059] [Step 1]

[1060] Compound 6-(4-(2, 2, 2-trifluoroethyl)piperazin-1-yl)pyridazin-3—amine (6—(4—(2,2,2— tri fluoroethyl )piperazin— 1—yl )pyr idazin— 3— amine) was obtained in the same manner as in step 1 of Example 141, except that 1-(2, 2,2- trif luoroethyl)piperazine was used.

[1061] [Step 2]

[1062] Compound 5 -chloro- N- (6- (4- (2,2,2-trifluoroethyl)piperazin-1-yl)pyridazin-3 -amine (6- (4- (2,2,2— tri fluoroethyl)piperazin—l—yl)pyr idaz in— 3— amine), 5 -chlorothiazole- 4~ carboxylic acid (5-chlorothiazole- 4-carboxylic acid) was prepared in the same manner as in step 2 of Example 141, except that 5 -chloro- N- (6- (4- (2,2,2-trifluoroethyl)piperazin-1-yl)pyridazin-3 -yl)thiazole- 4 -carboxamide (5-chloro— N— (6— (4— (2,2,2— tri fluoroethyl)piperazin— 1—yl )pyr idaz in— 3— yl )thiazole- 4-carboxamide) was obtained. Example 164

[1063] Preparation of 2-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiazole- 4-carboxamide water

[1064] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[1065] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1066] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[1067] [Step 2]

[1068] Compound 2-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 14, except that 2-chlorothiazole-4-carboxylic acid was used. Example 165

[1069] Preparation of N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide (N-(6-(4-( tr if luoromethyl ) phenyl )pyr idaz in-3- yl ) thiophene-3-carboxami de) water

[1070] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[1071] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1072] (tr if luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[1073] [Step 2] Compound N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide (N-(6-(4-

[1074] (tr if luoromethyl ) phenyl ) pyr i daz i n-3-y 1 ) thi ophene-3-car boxam ide)# obtained. Example 166

[1075] N- (6- (3- (cyclopentylcarbamoyl)phenyl)pyridazin- 3 -yl)thiazole- 4 -carboxamide (N- (6- (3- (cyclopentyl carbamoyl ) phenyl )pyr idaz in- 3- yl ) thiazole-

[1076] 4- Manufacture of carboxami de) water

[1077] [Step 1]

[1078] (3-(cyclopentylcarbamoyl)phenyl)boronic acid ( (3-

[1079] Compound 3-(6-aminopyridazin-3-yl)-N-cyclopentylbenzamide (3-(6-aminopyridazin-3-yl)-N-cyclopentylbenzamide) was obtained in the same manner as in step 1 of Example 12, except that (eye 1 opent y 1 carbamate 1) pheny 1) bor on ic acid) was used.

[1080] [Step 2]

[1081] The compound N-(6-(3-(cyclopentylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 3-(6-aminopyridazin-3-yl)-N-cyclopentylbenzamide, thiazole-4-carboxylic acid, was used. Example 167 N-(6-(3-(cyclopropanesulfonamido)phenyl)pyridazin-3-yl)thiazole-4-garbin} 1Preparation of Gide (N— (6— (3— (cyclopropanesul fonamido)phenyl )pyridazin-3- yl )thiazole- 4-carboxamide)

[1082] [Step 1]

[1083] (3-(cyclopropanesulfonamido)phenyl)boronic acid((3-

[1084] The compound N-(3-(6-aminopyridazin-3-yl)phenyl)cyclopropanesulfonamide (N-(3-(6-aminopyridazin-3- y 1)pheny 1)eye 1 opropanesu 1 f onam ide)# was obtained in the same manner as in step 1 of Example 12, except that (eye 1 opr opanesu 1 f onami do )pheny 1 )boronic acid) was used.

[1085] [Step 2]

[1086] Compound N-(6-(3-(6-aminopyridazin-3-yl)phenyl)cyclopropanesulfonamide (N-(3-(6-aminopyridazin-3-yl)phenyl)cyclopropanesulfonamide) was prepared in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used.

[1087] (Cyclopropanesulfonamido)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-

[1088] (cyclopropanesul fonamido)i)henyl )pyr idazin— 3— yl ) thiazole— 4— carboxamide) was obtained. Example 168

[1089] N- (6- (3- (cyclopropylcarbamoyl)- 4- (trifluoromethyl) phenyl) pyridazine-

[1090] 3-yl)thiazole-4-carboxamide (N-(6-(3-(cyclopropylcarbamoyl)-4-

[1091] Preparation of (trif luoromethyl )phenyl )pyr idaz in— 3— yl )thi azole— 4— carboxamide)

[1092] [Step 1]

[1093] 5-Chloro-N-cyclopropyl-2-(trifluoromethyl)benzamide(5-Sa1101'0-ci-cyclopropyl-2-(trifluoromethyl)benzamide), 4,4,4',4',5,5,5',5'-octamethyl-

[1094] 2,2'-Bis(1,3,2-dioxaborolane) (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)) was dissolved in 1,4-dioxane, and then palladium(II) acetate (Pd(0Ac)2), potassium acetate (KOAc), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) were added. After stirring at 90 °C for 16 hours, the reacted mixture was diluted with water and extracted with toluene. The mixed organic layer of the extract was washed with water, dried over MgSO4, and concentrated under reduced pressure. The concentrated material was purified by column chromatography to obtain compound N-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide (cis-07010凶0己刀-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide).

[1095] [Step 2]

[1096] Compound 5-(6-aminopyridazin-3-yl)-N-cyclopropyl-2-(trifluoromethyl)benzamide (5-(6-aminopyridazin-3-yl)-N-cyclopropyl-2-(trifluoromethyl)benzamide) was obtained in the same manner as in Step 1 of Example 12, except that N-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide (N-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide) was used.

[1097] [Step 3]

[1098] 5-(6-aminopyridazin-3-yl)-N-cyclopropyl-2-

[1099] (trifluoromethyl)benzamide (5-(6-aminopyridazin-3-yl)-N-cyclopropyl-2-(trifluoromethyl)benzamide), compound N-(6-(3-(cyclopropylcarbamoyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-(cyclopropylcarbamoyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) was obtained in the same manner as in Step 2 of Example 12, except that thiazole-4-carboxylic acid (thiazole-4-carboxylic acid) was used. Example 169

[1100] Preparation of 5-hydroxy- N- (6- (4- (trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide

[1101] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 141.

[1102] (trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4-

[1103] (trif luoromethyl )pi peridi n—l—yl)pyr idaz in— 3— amine) was obtained.

[1104] [Step 2]

[1105] Compound 5-hydroxy-N-(6-) was prepared in the same manner as in step 2 of Example 141, except that 5-hydroxypicolinic acid was used.

[1106] (4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide (5-nalydroxy-

[1107] N-(6-(4-(trif luoromethy Dpi peridi nl-yl)pyridazi n-3-y Dpi col inamide)# obtained. Example 170

[1108] 3-hydroxy-N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide (3-hydroxy-N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide)

[1109] [Step 1] Compound 6-(4-) in the same manner as step 1 of Example 141

[1110] (trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4-

[1111] (tr if luoromethyl )piper idin— 1— yl )pyr idazin— 3— amine) was obtained.

[1112] [Step 2]

[1113] Compound 3-hydroxy-N-(6-) was prepared in the same manner as in step 2 of Example 141, except that 3-hydroxypicolinic acid was used.

[1114] (4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide (3-hydroxy-

[1115] N— (6— (4—( tr if luoromethyl )pi per idin— 1—yl )pyr idazin— 3— yl )pi col inamide) was obtained. Example 171

[1116] Low-sodium sulfate of N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)oxazole-4-carboxamide

[1117] [Step 1] Compound 6- (4 -) in the same manner as step 1 of Example 141

[1118] (Trifluoromethyl)piperidin-1-yl)pyridazin-3-amine (6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-amine) was obtained.

[1119] [Step 2] The compound N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)oxazole-4-carboxamide was obtained in the same manner as in Step 2 of Example 141, except that oxazole-4-carboxylic acid was used. Example 172 N-(6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide

[1120] Preparation of (tr if luoromethyl ) phenyl )pyr idazin— 3— yl )pi col inamide) 1,4-Dioxane DMF water

[1121] [Step 1] Compound 6-(3-) in the same manner as step 1 of Example 76

[1122] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(3-

[1123] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[1124] [Step 2] Step 76 of Example 76, except that picolinic acid was used.

[1125] In the same manner as in Example 2, compound N-(6-(3-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide was obtained. Example 173

[1126] Preparation of N-(6-(3-(methylcarbamoyl)phenyl)pyridazin-3-yl)picolinamide (ci-(6-(3-(methylcarbamoyl)phenyl)pyridazin—3—yl)pi col inamide) water

[1127] [Step 1] Compound 3-(6-aminopyridazin-3-yl)-N-methylbenzamide was obtained in the same manner as Step 1 of Example 103.

[1128] [Step 2] Step of Example 103, except that picolinic acid was used.

[1129] Compound N-(6-(3-(methylcarbamoyl)phenyl)pyridazin-3-yl)picolinamide (N-(6-(3-(methylcarbamoyOphenyOpyridazin-3-yl)picolinamide) was obtained in the same manner as in Example 2. Example 174

[1130] 206 Preparation of 4-nitro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide

[1131] Preparation of 4-amino- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide

[1132] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[1133] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[1134] (trifluoromethyl)phenyl)pyridazin-3-amine was obtained.

[1135] [Step 2] Preparation of the compound of Example 174

[1136] Compound 4-nitro-N-(6-(4-

[1137] (Trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide (4-nitro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide) was obtained in the same manner as in Step 2 of Example 14, except that 4-nitropicol inic acid was used.

[1138] (trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide (Compound of Example 174) was obtained.

[1139] [Step 3] Preparation of the compound of Example 206 Compound 4-nitro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide (4-nitro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide) and tetrahydroxydiboron (Tetrahydroxydiboron, B2(OH)4) were dissolved in DMF, and 4,4'-bipyridyl (4,4'-bipyridyl) was dissolved in DMF and slowly added dropwise to the reaction mixture. After stirring at room temperature for 5 minutes, distilled water was added to the reaction mixture. The precipitated solid was filtered, washed with MeOH and dried to obtain compound 4-amino-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide (4-amino-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide) (Compound of Example 206). Example 175

[1140] Preparation of 5-nitro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide involved 178

[1141] Preparation of 5-amino-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide

[1142]

[1143] [Step 1] Compound 6-(4 -

[1144] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-

[1145] (trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 14.

[1146] [Step 2] Preparation of the compound of Example 175

[1147] The compound 5-nitro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide (the compound of Example 175) was obtained in the same manner as in Step 2 of Example 14, except that 5-nitropicolinic acid was used.

[1148] (trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide(5-ni -to -N-(6-(4-

[1149] (trifluoromethyl)phenyl)pyridazin-3-yl)picolylamide)

[1150] [Step 3] Preparation of the compound of Example 178

[1151] Compound 5-amino-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (5-amino-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide) was obtained in the same manner as in step 3 of Example 174, except that 5-nitro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picol inamide) was used. Example 176

[1152] 3-(Difluoromethyl)-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (3-(di f luoromethyl )-N-(6-(4-

[1153] Preparation of (tr if luoromethyl ) phenyl )pyr idazin— 3— yl )pi col inamide) water

[1154] [Step 1] Compound 6-(4-) in the same manner as step 1 of Example 14

[1155] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1156] (tr if luoromethyl)phenyl)pyr idazin— 3— amine)was obtained.

[1157] [Step 2]

[1158] Compound 3-(difluoromethyl)-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (3-(difluoromethyl)-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide) was prepared in the same manner as in step 2 of Example 14, except that 3-(difluoromethyl)picolinic acid was used.

[1159] (tri f luoromethyl ) phenyl ) pyr idazin— 3— yl ) pi col inamide) was obtained. Example 177

[1160] Preparation of 5-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide (5-chloro- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide) water

[1161] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[1162] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1163] (tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[1164] [Step 2]

[1165] Compound 5-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiophene-3-carboxamide was obtained by the same method as in step 2 of Example 14, except that 5-chlorothiophene-3-carboxylic acid was used. Example 179

[1166] Preparation of N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide DMSO

[1167] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 141.

[1168] (Trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4-

[1169] (trif luoromethyl)piperidin— 1— yl)pyridazin— 3— amine) was obtained.

[1170] [Step 2] The steps of Example 141, except that picolinic acid was used.

[1171] In the same manner as in Example 2, compound N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide (N-(6-(4-(tri fluoromethyl)piperidin-1-yl)pyridazin-3-yl)pi col inamide) was obtained. Example 180

[1172] Preparation of N-(6-(4-fluoro-3-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide , water

[1173] [Step 1]

[1174] (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid ( (4- f luoro-3-

[1175] Compound 6-(4-fluoro-3-) was prepared in the same manner as in step 1 of Example 12, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[1176] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(4-f luoro-3-

[1177] (tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[1178] [Step 2]

[1179] 6-(4-fluoro-3-(trifluoromethyl)phenyl)pyridazin-3-amine (6-(4- f luoro-

[1180] 3-(tri f luoromethyl ) phenyl )pyr idazin- 3-amine) , thiazole- 4 -carboxylic acid (thiazole-

[1181] Compound N-(6-(4-fluoro-3-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(4-f luoro-3-

[1182] (tri f luoromethyl ) phenyl ) pyr idazin— 3— yl ) thi azole— 4— carboxamide) was obtained. Example 181

[1183] Preparation of N-(6-(2-amino-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide , water

[1184] [Step 1] The compound N-(6-chloropyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in Step 1 of Example 135.

[1185] [Step 2]

[1186] 2-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolane-2-yl)-5-

[1187] Compound N-(6-(2-amino-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(2-amino-4-(trif luoromethyl )phenyl)pyridazin-3-yl )thi azo le-4-carboxami de) was obtained by the same method as in step 2 of Example 135, except that (trifluoromethyl)aniline (2-(4,4,5,5-tetramethyl- 1,3,2- dioxaboro lan- 2- y 1)-5- (trif luoromethyl)aniline) was used. Example 182

[1188] 4,5-Dimethoxy-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide

[1189] Preparation of 3-yl)picolinamide water

[1190] [Step 1] In the same manner as in Step 1 of Example 14, compound 6-(4 -

[1191] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(4 -

[1192] (Trifluoromethyl)phenyl)pyridazin-3-amine) was obtained.

[1193] [Step 2]

[1194] In the same manner as in Step 2 of Example 14, except that 4,5-dimethylpicolinic acid (4,5-dimethoxypicolinic acid) was used, compound 4,5-dimethoxy-N-(6-

[1195] (4-(Trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (4,5-(1-bromo-6-(6-

[1196] ((Trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide) was obtained. Example 183 Preparation of 6-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (6-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide)

[1197] [Step 1] In the same manner as in Step 1 of Example 14, compound 6-(4 -

[1198] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1199] (tri f luoromethyl )phenyl )pyridazin— 3— amine) was obtained.

[1200] [Step 2]

[1201] Compound 6-chloro-N-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide(6-sa1101'0-si-(6-(4-(tri f luoromethyl )phenyl )pyridazin-3-yl )pi col inamide)# was obtained in the same manner as in step 2 of Example 14, except that 6-chloropicolinic acid was used. Example 184

[1202] Preparation of N-(6-(3-(N-cyclopropylsulfamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide water

[1203] [Step 1]

[1204] Example 1 except that (3-(N-cyclopropylsulfamoyl)phenyl)boronic acid was used.

[1205] In the same manner as in step 1 of 12, compound 3-(6-aminopyridazin-3-yl)-N-cyclopropylbenzenesulfonamide (3-(6-aminopyr idazin-3-yl)-N-eye 1 opr opy 1 benzenesu 1 f onam ide)# was obtained.

[1206] [Step 2]

[1207] The compound N-(6-(3-(N-cyclopropylsulfamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. 185 N-(6-(4-acetamido-3-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-

[1208] Preparation of 4-carboxamide (N- (6- (4-acetamido- 3- ( tri f luoromethyl ) phenyl )pyridazin-3- yl )thiazole- 4-carboxamide) water

[1209] [Step 1]

[1210] N-(4-(4, 4,5, 5 -tetramethyl- 1 , 3 , 2 -dioxaborolane- 2 -yl)- 2-

[1211] Compound N-(4-(6-aminopyridazin-3-yl)-2-(trifluoromethyl)phenyl)acetamide was obtained in the same manner as in Step 1 of Example 12, except that (trifluoromethyl)phenyl)acetamide (cis-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)acetamide) was used.

[1212] [Step 2]

[1213] N-(4-(6-aminopyridazin-3-yl)-2-

[1214] (trifluoromethyl)phenyl)acetamide (N-(4-(6-aminopyridazin-3-yl)-2-

[1215] (trifluoromethyl)phenyl)acetamide), except that thiazole-4-carboxylic acid was used, compound N-(6-(4-acetamido-3-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in Step 2 of Example 12. Example 186

[1216] Preparation of N-(6-(l-(2, 2, 2-trifluoroethyl)-1, 2, 3, 6-tetrahydropyridin-4-yl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(1-(2, 2,2-trif luoroethyl)- 1,2,3,6-tetrahydropyr idin— 4— y 1 )pyr i daz in— 3— y 1 )thiazol e— 4— car boxami de ) water

[1217] [Step 1]

[1218] Compound 6-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid was obtained in the same manner as in step 1 of Example 12, except that 1-((2,2,2- tr if luoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid was used.

[1219] [Step 2]

[1220] Compound N-(6-(l-(2, 2, 2 -trifluoroethyl)-1,2, 3, 6 -tetrahydropyridin-4-yl)pyridazin-3-amine) was prepared in the same manner as in step 2 of Example 12, except that thiazole-4-carboxylic acid was used. trifluoroethyl)- 1,2,3,6-tetrahydropyr idin— 4— yl)pyr idazin— 3— yl) thiazole— 4— carboxamide) was obtained. 187

[1221] Preparation of 3-methoxy- N- (6- (4- (trifluoromethyl)phenyl)pyridazin- 3-yl)picolinamide

[1222] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[1223] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1224] (trif luoromethyl)phenyl)pyridazin— 3— amine) was obtained.

[1225] [Step 2] Compound 3-methoxy-N-(6-(4-)-(3-methoxypicol inic acid) was prepared in the same manner as in Step 2 of Example 14, except that 3-methoxypicol inic acid was used.

[1226] (Trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (3-06 Shi 0乂7-Shi-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide) was obtained. In the experiment, 188

[1227] N-(6-(3-(Trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide (1)-

[1228] (6—(3—(Trifluoromethyl)phenyl)pyridazin—3—yl)furan—3—carboxamide) Preparation water

[1229] [Step 1] In the same way as in Step 1 of Example 76, compound 6-(3 -

[1230] (Trifluoromethyl)phenyl)pyridazin-3-amine (6-(3-

[1231] (Trifluoromethyl)phenyl)pyridazin—3—amine) was obtained.

[1232] [Step 2] Except for using furan-3-carboxylic acid (furan-3-carboxylic acid), in the same way as in Step 2 of Example 76, compound N-(6-(3 -

[1233] (Trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(3-(trifluoromethyl)phenyl)pyridazin—3—y1)furan—3—carboxamide) was obtained. Example 189

[1234] 5-Chloro-N-(6-(3-(methylthio)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (5-chloro-N-(6-(3-(methylthio)-4-

[1235] Preparation of (tri f luoromethyl ) phenyl )pyr idaz in— 3— yl )thi azole— 4— carboxamide) water

[1236] [Step 1]

[1237] (3-(methylthio)-4-(trifluoromethyl)phenyl)boronic acid ((3-(methylthio)-4-

[1238] Compound 6-(3-(methylthio)-4-(trifluoromethyl)phenyl)boronic acid) was prepared in the same manner as in step 1 of Example 12, except that (trifluoromethyl)phenyl)boronic acid was used.

[1239] (Trifluoromethyl)phenyl)pyridazin-3-amine(6-(3-(taz7soo0)-4-

[1240] (tri f luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[1241] [Step 2]

[1242] 6-(3-(methylthio)-4-(trifluoromethyl)phenyl)pyridazin-3-amine(6-(3-

[1243] (methylthio)— 4— (tr if luoromethyl ) phenyl )pyr idaz in— 3— amine) , 5 —chlorothiazole—

[1244] Compound 5-chloro-N-(6-(3-(methylthio)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (5-(±101'0-Si-(6-(3-(methylthio)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide) was obtained in the same manner as in Step 2 of Example 12, except that 4-carboxylic acid (5-chlorothiazole-4-carboxylic acid) was used. Example 190

[1245] N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-

[1246] 3-carboxamide) Preparation water

[1247] [Step 1]

[1248] (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid ((2-fluoro-4-

[1249] (trifluoromethyl)phenyl)boronic acid) was used. Compound 6-(2-fluoro-4-

[1250] (trifluoromethyl)phenyl)pyridazin-3-amine (6-(2-fluoro-4-

[1251] (trifluoromethyl)phenyl)pyridazin-3-amine) was obtained in the same manner as in Step 1 of Example 12.

[1252] [Step 2] 6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-amine ⑯-Hex-ri-ai-

[1253] N-(6-(2-Fluoro-4-((trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide) was obtained in the same manner as in step 2 of Example 12, except that 4-(trifluoromethyl)phenyl)pyridazin-3-amine was used.

[1254] (Trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide (1)-(16)-hex-1-yl)-6-(trifluoromethyl)phenyl)pyridazin-3-yl)furan-3-carboxamide).

[1255] Preparation of N-(6-(4-(Difluoromethyl)piperidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide -pr ne DMSO

[1256] [Step 1]

[1257] Compound 6-(4-(Difluoromethyl)piperidin-1-yl)pyridazin-3-amine (6-(4-

[1258] (Difluoromethyl)piperidin-1-yl)pyridazin-3-amine) was obtained in the same manner as in step 1 of Example 141, except that 4-(difluoromethyl)piperidine was used.

[1259] [Step 2] Compound N-(6-(4-

[1260] (Difluoromethyl)piperidin-1-yl)pyridazin-3-amine) was obtained in the same manner as in step 2 of Example 141, except that 6-(4-(difluoromethyl)piperidin-1-yl)pyridazin-3-amine was used.

[1261] (Difluoromethyl)piperidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(4-

[1262] (di f luoromethyl )piper idin-l-yl )pyr idazin— 3— yl )thiazole— 4— carboxamide) was obtained. Example 192

[1263] Preparation of N-(6-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide L-prine DMF DMSO

[1264] [Step 1]

[1265] Compound 6-(3-) was prepared in the same manner as in step 1 of Example 141, except that 3-(trifluoromethyl)pyrrolidine was used.

[1266] (trifluoromethyl)pyrrolidin-1-yl)pyridazin-3-amine (6-(3-

[1267] (tr if luoromethyl )pyrrol idin-l-yl )pyr idazin-3-amine)-^ obtained. [Step 2]

[1268] 6-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridazin-3-amine(6-(3-

[1269] Compound N-(6-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide (ci-(6-(3-(trif luoromethyl )pyrrol idin-l-yl )pyr idazin— 3— yl)thiazole— 4— carboxamide) was obtained in the same manner as in step 2 of Example 141, except that (trifluoromethyl)pyrrolidin-1-yl)pyridazin-3-amine) was used. Example 193

[1270] 2- (3-fluoropyridin-2-yl)- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)acetamide ( 2- ( 3- f 1 uoropyr idi n- 2- y 1 ) - N- (6- (4-

[1271] (trif luoromethyl )phenyl )pyr idazin— 3— yl )acetamide)

[1272] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[1273] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1274] (trifluoromethyl)phenyl)pyridazin— 3— amine) was obtained. [Step 2]

[1275] Compound was prepared in the same manner as in step 2 of Example 14, except that 2-(3-fluoropyridin-2-yl)acetic acid was used.

[1276] 2- (3 -fluoropyridin- 2 -yl)- N- (6- (4- (trifluoromethyl)phenyl)pyridazin- 3-yl)acetamide ( 2— ( 3- f 1 uoropyr idi n- 2- y 1 ) - N- (6- (4-

[1277] (tri f luoromethyl )phenyl )pyridazin- 3- yl )acetamide) was obtained. Example 194

[1278] Preparation of N-(6-(2-fluoro-5-(methylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[1279] [Step 1]

[1280] (2-fluoro-5-(methylcarbamoyl)phenyl)boronic acid ((2-f luoro-5-

[1281] 3-(6-aminopyridazin-3-yl)-4-fluoro-N-methylbenzamide was obtained by the same method as in step 1 of Example 12, except that (methyl carbamoyl )phenyl )boronic acid) was used. [Step 2]

[1282] Compound N-(6-(2-fluoro-5-) was prepared in the same manner as in step 2 of Example 12, except that 3-(6-aminopyridazin-3-yl)-4-fluoro-N-methylbenzamide (3-(6-am i nopyr i daz i n-3-y 1 )— 4— f 1 uor oN-me t hy 1 benz amide), thiazole-4-carboxylic acid was used.

[1283] (Methylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (ci-(6-(2-£11101'0-5- (methylcarbamoyl)phenyl)pyridazin— 3— yl) thiazole— 4— carboxamide) was obtained. Example 195

[1284] Preparation of (S)-N-(6-(3-(2,2,2-trifluoroethyl)pyrrolidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide

[1285] [Step 1]

[1286] (S)-6-(3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride was prepared in the same manner as in step 1 of Example 141, except that (S)-3-(2,2,2-trif luoroethyl)pyrrol idine hydrochloride was used. [Step 2]

[1287] (S)-6-(3-(2,2,2-Trifluoroethyl)pyrrolidin-1-yl)pyridazin-3-amine was used except for the preparation of compound (S)-N-(6-(3-(2,2,2-trifluoroethyl)pyrrolidin-1-yl)pyridazin-3-yl)thiazole-4-carboxamide in the same manner as in Step 2 of Example 141. Example 196

[1288] Preparation of N-(6-(3-(isopropylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide (N-(6-(3-(isopropyl carbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide)

[1289] [Step 1]

[1290] (3-(Isopropylcarbamoyl)phenyl)boronic acid ((3-

[1291] (isopropyl carbamoyl)phenyl)boronic acid) was used except for the preparation of

[1292] 3-(6-Aminopyridazin-3-yl)-N-isopropylbenzamide was obtained in the same manner as in Step 1 of Example 12. [Step 2]

[1293] The compound N-(6-(3-(isopropylcarbamoyl)phenyl)pyridazin-3-yl)thiazole-4-carboxamide was obtained in the same manner as in step 2 of Example 12, except that 3-(6-aminopyridazin-3-yl)-N-isopropylbenzamide, thiazole-4-carboxylic acid, was used. Example 197

[1294] Preparation of N-(6-(5-(cyclopropylcarbamoyl)-2-fluorophenyl)pyridazin-3-yl)thiazole-4-carboxamide

[1295] [Step 1]

[1296] (5-(cyclopropylcarbamoyl)-2-fluorophenyl)boronic acid ( (5-

[1297] 3-(6-aminopyridazin-3-yl)- was prepared in the same manner as in step 1 of Example 12, except that ( eye 1 opr opy 1 car bamoy 1 )-2- f luorophenyl )boronic acid) was used.

[1298] N-Cyclopropyl-4-fluorobenzamide (3-(6-aminopyr idazin-3- yl)-N- cyclopropyl-4- f 1 fluorobenz am i de ) was obtained. [Step 2]

[1299] 3-(6-Aminopyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide, except using thiazole-4-carboxylic acid, was prepared in the same manner as in Step 2 of Example 12 to obtain the compound N-(6-(5-(cyclopropylcarbamoyl)-2-fluorophenyl)pyridazin-3-yl)thiazole-4-carboxamide. Example 198

[1300] (cyclopropylcarbamoyl)-2-fluorophenyl)pyridazin—3—yl)thiazole—4—carboxamide)# was obtained. Example 198

[1301] Preparation of N-(6-(3-((N,N-dimethylsulfamoyl)amino)phenyl)pyridazin-3-yl)thiazole-4-carboxamide

[1302] [Step 1]

[1303] (3-((N,N-dimethylsulfamoyl)amino)phenyl)boronic acid was used, and (3-(6-aminopyridazin-3-yl)phenyl)-N,N-dimethylsulfamide was obtained in the same manner as in Step 1 of Example 12.

[1304] [Step 2]

[1305] The compound N-(6-(3-((N,N-dimethylsulfamoyl)amino)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(ci-(6-(3-((N,N-dimethylsulfamoyl)amino)phenyl)pyridazin-3-yl)thiazole-4-carboxamide(thi-(6-(3-

[1306] ( ( N , N— di me t hy 1 su 1 f amoy 1 )amino) pheny 1 ) pyr idazin— 3— yl )thiazole— 4— carboxamide) was obtained. Example 199

[1307] N-(6-(3-(methylcarbamoyl)phenyl)pyridazin-3-yl)furan-3-carboxamide(cy-(6-

[1308] Preparation of (3-(methyl carbamoyl)phenyl)pyr idazin—3—yl)furan—3—carboxamide) , water

[1309] [Step 1] The compound 3-(6-aminopyridazin-3-yl)-N-methylbenzamide (3-(6-aminopyridazin-3-yl)-N-methylbenzamide) was obtained in the same manner as in Step 1 of Example 103.

[1310] [Step 2] Compound N-(6-(3-) was prepared in the same manner as in Step 2 of Example 103, except that furan-3-carboxylic acid was used.

[1311] (Methylcarbamoyl)phenyl)pyridazin-3-yl)furan-3-carboxamide (ci-(6-(3-(methylcarbamoyl)i)henyl)pyridazin— 3— yl)furan— 3— carboxamide) was obtained. 200

[1312] Preparation of N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)furan-3-carboxamide

[1313] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 141.

[1314] (Trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4-

[1315] (trif luoromethyl)piperidin— 1— yl)pyridazin— 3— amine) was obtained.

[1316] [Step 2] Compound N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)furan-3-carboxamide (N-(6-(4-

[1317] (trifluoromethyl)piperidine (n—l—yl)pyridazin— 3— yl)furan— 3— carboxamide) was obtained. Example 201

[1318] 3-fluoro-N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide (3-fluoro-N-(6-(4-(trif luoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide)

[1319] [Step 1] Compound 6-(4-

[1320] (trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4-

[1321] (tr if luoromethyl)piper idin— 1— yl)pyr idazin— 3— amine) was obtained.

[1322] [Step 2]

[1323] Compound 3-fluoro-N-(6-(4-) was prepared in the same manner as in step 2 of Example 141, except that 3-fluoropicolinic acid was used.

[1324] (trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)picolinamide (3-fluoro-N-(6-(4—(tri f luoromethyl )piperidin—l— yl )pyridazin— 3— yl )pi col inamide) was obtained. Example 202

[1325] 2- (6-fluoropyridin-2-yl)- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)acetamide ( 2- ( 6- f 1 uoropyr idi n- 2- y 1 ) - N- (6- (4-

[1326] Preparation of (tri f luoromethyl ) phenyl ) pyr idazin— 3— yl ) acetamide)

[1327] 1,4-Dioxane DMF water

[1328] [Step 1] Compound 6-(4-) was prepared in the same manner as in Step 1 of Example 14.

[1329] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1330] (tri f luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[1331] [Step 2]

[1332] Compound prepared in the same manner as in step 2 of Example 14, except that 2-(6-fluoropyridin-2-yl)acetic acid was used.

[1333] 2- (6-fluoropyridin-2-yl)- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)acetamide ( 2- ( 6- f 1 uoropyr idi n- 2- y 1 ) - N- (6- (4-

[1334] (tri f luoromethyl )phenyl )pyridazin-3-yl )acetamide)# was obtained. Example 203

[1335] 2- (5-fluoropyridin-2-yl)- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)acetamide ( 2- ( 5- f 1 uoropyr idi n- 2- y 1 ) - N- (6- (4-

[1336] (tr if luoromethyl ) phenyl ) pyr idazin— 3— yl ) acetamide) water

[1337] [Step 1] Compound 6- (4 -) was prepared in the same manner as in Step 1 of Example 14.

[1338] (trifluoromethyl)phenyl)pyridazin-3-amine(6-(4-

[1339] (tr if luoromethyl )phenyl )pyr idazin— 3— amine) was obtained.

[1340] [Step 2]

[1341] Compound prepared in the same manner as in step 2 of Example 14, except that 2-(5-fluoropyridin-2-yl)acetic acid was used.

[1342] 2- (5-fluoropyridin-2-yl)- N- (6- (4- (trifluoromethyl)phenyl)pyridazin-3-yl)acetamide ( 2- ( 5- f 1 uoropyr idi n- 2- y 1 ) - N- (6- (4-

[1343] (tr if luoromethyl ) phenyl ) pyr i daz i n-3-y 1 ) acet amide)# obtained. Example 204

[1344] Preparation of N-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide (N-(6-(2-ch 1 oro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)picolinamide) water

[1345] [Step 1]

[1346] (2-chloro-4-(trifluoromethyl)phenyl)boronic acid ( (2-chloro-4-

[1347] Compound 6-(2-chloro-4-) was prepared in the same manner as in step 1 of Example 12, except that (tr if luoromethyl )phenyl )boronic acid) was used.

[1348] (Trifluoromethyl)phenyl)pyridazin-3-amine(6-(2-(±101'0-4-

[1349] (tr if luoromethyl )phenyl )pyr idaz in— 3— amine) was obtained.

[1350] [Step 2]

[1351] Compound N-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-amine) was obtained by the same method as in step 2 of Example 12, except that picolinic acid was used. Example 205

[1352] Preparation of 3-fluoro- N- (6- (4- (trifluoromethyl)piperidin- 1-yl)pyridazin- 3-yl)thiophene- 2-carboxamide (3- f luoro- N- (6- (4- (tri f luoromethyl )piperidin- 1- yl )pyridazin- 3- yl )thiophene- 2-carboxamide)

[1353] [Step 1] Compound 6-(4-) in the same manner as step 1 of Example 141

[1354] (Trifluoromethyl)piperidin-1-yl)pyridazin-3-amine(6-(4-

[1355] (tri f luoromethyl )piperidin— 1— yl )pyridazin— 3— amine) was obtained.

[1356] [Step 2]

[1357] Compound 3-fluoro-N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)thiophene-2-carboxamide was obtained in the same manner as in step 2 of Example 141, except that 3-fluorothiophene-2-carboxylic acid was used. The NMR of each of the compounds of the examples prepared in the above preparation examples is as follows.

[1358] [Table 3] <Old NMR> Experimental Example Experimental Example 1: HEK293 Luciferase Assay

[1359] [Validation of compounds that inhibit IL-2 gene expression by NR2F6]

[1360] A HEK293 cell line stably expressing the IL-2 luciferase reporter was constructed. The cell line was transfected with a plasmid expressing NR2F6 or an empty vector to confirm the IL-2 transcriptional repression activity of NR2F6. The cell line expressing NR2F6 was treated with compounds, and then a luciferase assay was performed and luminescence was measured using a luminometer. The results are shown in Table 4.

[1361] [Table 4]

[1362]

[1363]

[1364]

[1365]

[1366] A: IC50 < luM (less than luM)

[1367] B: luM <IC5o < lOuM (luM 초과 lOuM 이하)

[1368] C: lOuM < IC50 (greater than lOuM)

[1369] (nd: not detected) The compounds according to the present invention showed excellent activity in inhibiting IL-2 transcriptional repression by NR2F6, and therefore, it can be seen that they can be useful in the prevention or treatment of NR2F6-related diseases and cancer by increasing IL-2 gene expression through NR2F6 inhibition.

Claims

【Scope of Claims】 【 Claim 11 A compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, [Chemical Formula I] In the above chemical formula I, Ai is a 3-8 membered heterocycloalkyl having one or more heteroatoms selected from C1-C8 cycloalkyl, N, 0 and , a 6-14 membered aryl or a 5-12 membered heteroaryl having one or more heteroatoms selected from N, 0 and , wherein one or more groups of Ai are each independently C1-C6 alkyl, C1-C5 alkoxy, a 6-14 membered aryl, a 5-12 membered heteroaryl having one or more heteroatoms selected from N, 0 and , - NR1R2, - C(=O)Ri, - C(=O)ORi, -S(=0)2RI, -C(=N)OHRI, -NHC(=O)RI, -C(=O)NHRI, -C1-C4 alkylene- OH, -CN, -OH, - CF2H, -Can be substituted or unsubstituted with CFS or halogen, Ri and R2 are each independently H, 0, -0H, or C1-C6 alkyl, 362 Li is C1-C6 alkylene, -C(=O)NH-, -C1-C6 alkylene - C(=O)NH- , - C(=O)NH- Cl- C6 alkylene-, -NHC(=O)-, -NH-NHC=O, - NH(C=O)- NH- , - NHC(=O)- Cl- C6 alkylene-, -C1-C6 alkylene- NHC(=O)_, -S(=0)2NH-, -NHS(=0)2-, -NH-, -S(=0)2-, -NHC(=O)O-, -C(=0)0-, -C(=0)-, or - 0-, wherein one or more of the groups of Li are each independently substituted with C1-C6 alkyl, C3-C6 cycloalkyl, - Cl- C4 alkylene- OH, -CN, -0H or halogen. or may be unsubstituted, A2 is C1-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and , 6-14 membered aryl, 5-8 membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and 、 / 12-membered heteroaryl or x2 (wherein m is 0, 1, 2, 3, 4 or 5, and Xi and X2 are each independently C, N, CH or NH), wherein one or more of the above A2 may be independently substituted or unsubstituted with Ra or - L2- Ra, L2 is C1-C6 alkylene, - C(=O)NH- , -C1-C6 alkylene - C(=O)NH- , - C(=O)NH- Cl- C6 alkylene- , -NHC(=O)- , -NH-NHC=O, - NH(C=O)- NH- , - NHC(=O)- Cl- C6 alkylene- , -C1-C6 alkylene- NHC(=O)- , -C1-C6 alkylene- NH- , - NH- Cl- C6 alkylene- , -S(=0)2NH- , -NHS(=0)2- , -NH- , -S(=0)2- , -NHC(=O)O- , -C(=0)0- , -C(=0)- , or -0-, 363 Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and S, 3- to 8-member heterocycloalkenyl containing one or more heteroatoms selected from N, O and S, 6- to 14-member aryl or 5- to 12-member heteroaryl containing one or more heteroatoms selected from N, O and S, wherein one or more substituents of the Ra are each independently -ORb, -C(=O)Rb, -C(=O)ORb, -SRb, S(=O)2Rb, -NRbRc, -C(=O)NRbRc, -NRbC(=O)Rc, -S(=O)2NRbRc, -NRbS(=O)2Rc, -C1-C4 alkylene-NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and S, 6- to 14-member aryl, 5- to 12-member heteroaryl containing one or more heteroatoms selected from N, O and S, -C1-C4 alkylene-OH, -C1-C4 alkylene-CF3, -CN, -OH, -CF2H, -CF3 or halogen, and may be substituted or unsubstituted, Rb and Rc are each independently H, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and S, 6- to 14-member aryl, 5- to 12-member heteroaryl containing one or more heteroatoms selected from N, O and S, -C1-C4 alkylene-OH, -CN, -OH, -CF2H, -CF3 or halogen, wherein one or more substituents of the Rb and Rc are each independently C1-C6 alkyl, C1-C8 cycloalkyl, 6- to 14-member aryl, -NRdRe, -CF3 or halogen, and may be substituted or unsubstituted, A compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, wherein Rd and Re are each independently H or C1-C6 alkyl, and halogen is F, Cl, Br, or I. 【

2. In claim 1, in the chemical formula I, Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , wherein one or more of Ai is independently C1-C6 alkyl, C1-C5 alkoxy, a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , - NR1R2, -C1-C4 alkylene- 0H, -CN, -OH, -CF2H, -CFS or halogen, which may be substituted or unsubstituted, Ri and R2 are each independently H or 0, Li is - C(=O)NH-, -C1-C6 alkylene - C(=O)NH-, - C(=O)NH- Cl- C6 alkylene-, - NHC(=O)-, -NHC(=O)-C1-C6 alkylene-, -C1-C6 alkylene- NHC(=O)-, -S(=0)2NH-, - NHS(=0)2 -or - NHC(=O)O-, wherein one or more of the groups of Li are each independently C1-C6 alkyl, C3-C6 Cycloalkyl, - Cl- C4 alkylene- OH, -CN, -OH or may be substituted or unsubstituted with halogen, A2 is a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, 0 and (At this time, m is 0, 1, 2, 3, 4 or 5, and Xi and X2 is each independently C, N, CH or NH), wherein one or more of the above A2 may be independently substituted or unsubstituted with Ra or - L2- Ra, L2 is -C1-C6 alkylene- NH-, -NH-C1-C6 alkylene-, -S(=0)2NH-, -NHS(=0)2-, - NH- or - 0-, Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from N, O and S, 3- to 8-membered heterocycloalkenyl containing one or more heteroatoms selected from N, O and S, 6- to 14-membered aryl or 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and S, wherein one or more substituents of said Ra are each independently -ORb, -C(=O)Rb, -C(=O)ORb, -SRb, S(=O)2Rb, -NRbRc, -C(=O)NRbRc, -NRbC(=O)Rc, -S(=O)2NRbRc, - NRbS(=O)2Rc, -C1-C4 alkylene-NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from N, O and S, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and S, -C1- C4 alkylene-OH, -C1-C4 alkylene-CF3, -CN, -OH, -CF2H, -CF3 or halogen, and may be substituted or unsubstituted, Rb and Rc are each independently H, C1-C6 alkyl, C1-C5 alkoxy, C-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from N, O and S, 6- to 14-membered aryl, 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and S, -C1-C4 alkylene-OH, -CN, -OH, -CF2H, -CF3 or halogen, wherein one or more substituents of said Rb and Rc are each independently C1-C6 alkyl, C1-C8 cycloalkyl, 6- to 14-membered aryl, -NRdRe, -CF3 or halogen, and may be substituted or unsubstituted, A compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, wherein Rd and Re are each independently H or C1-C6 alkyl, and halogen is F, Cl, Br, or I.

3. In the first paragraph, in the chemical formula I, Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , wherein one or more of Ai is independently C1-C6 alkyl, C1-C5 alkoxy, a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , - NR1R2, -C1-C4 alkylene- 0H, -CN, -OH, -CF2H, -CFS or halogen, which may be substituted or unsubstituted, Ri and R2 are each independently H or 0, Li is - NHC(=O)- , -NHC(=O)-C1-C6 alkylene-, -C1-C6 alkylene- NHC(=O)- , - NHS(=0)2 - or - NHC(=O)O-, A2 is a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, 0 and (At this time, the above m is 3, 4 or 5, and Xi and X2 are each independently C, N, CH or NH), wherein one or more of the above A2 may be independently substituted or unsubstituted with Ra or - L2- Ra, L2 is -C1-C6 alkylene- NH-, - NHS(=0)2-, -NH- or - 0-, Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, N, 0 and A 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from , a 3- to 8-membered heterocycloalkenyl containing one or more heteroatoms selected from N, O and , a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, O and , wherein one or more substituents of Ra are each independently -ORb, -C(=O)Rb, -C(=O)ORb, -SRb, -NRbRc, -C(=O)NRbRc, -NRbC(=O)Rc, -S(=O)2NRbRc, -NRbS(=O)2Rc, -C1-C4 alkylene-NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, a 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from N, O and , a 6- to 14-membered aryl, -C1-C4 alkylene-CF3, -CN, -OH, -CF2H, -CF3 or halogen, and may be substituted or unsubstituted, Rb and Rc are each independently H, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, a 3- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from N, O and , a 6- to 14-membered aryl, -CF3 or halogen, wherein one or more substituents of Rb and Rc are each independently C1-C6 alkyl, C1-C8 cycloalkyl, a 6- to 14-membered aryl, -NRdRe, -CF3 or halogen, and may be substituted or unsubstituted, Rd and Re are each independently H or C1-C6 alkyl, and halogen is F, Cl, Br or I, 369 a compound, its stereoisomers, its pharmaceutically acceptable salts or their solvates or hydrates. 【 According to claim 4, in claim 1, the formula I is represented by the following formula la, formula lb or formula Ic, [chemical formula la] [Chemical formula Ic] In the above chemical formula la, Xi, X2, X3, X4 and X5 are each independently C, N, CH, or Pa, wherein CH and or Pa may each independently be substituted or unsubstituted with Ra or -L『 Ra, and in the above chemical formula lb, Xi, X2 and X3 are each independently C, N, CH, or Pa, wherein CH and or Pa's H are each independently Ra or A compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, wherein in the chemical formula Ic, Xi and X2 are each independently C, N, CH, or Pa, wherein the CH and or Pa groups may each be independently substituted or unsubstituted with Ra or - L2- Ra, and m is 0, 1, 2, 3, 4, or 5, and in each of the chemical formulas la, lb, and Ic, Ai, Li, L2, and Ra are each the same as defined in the chemical formula I.

5. 371 In the fourth paragraph, the chemical formula I is represented by the chemical formula la, and in the chemical formula la, X1, X2, X3, X4 and X5 are each independently C, N, CH, or P, wherein CH and or P may each be independently substituted or unsubstituted with Ra or - L『 Ra, Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , wherein one or more of Ai is independently C1-C6 alkyl, C1-C5 alkoxy, a 6- to 14-membered aryl, a 5- to 12-membered heteroaryl comprising one or more heteroatoms selected from N, 0 and , - NR1R2, -C1-C4 alkylene- 0H, -CN, -OH, -CF2H, -CFS or halogen, which may be substituted or unsubstituted, Ri and R2 are each independently H or 0, Li is - NHC(=O)- , -NHC(=O)-C1-C6 alkylene-, -C1-C6 alkylene- NHC(=O)- , - NHS(=0)2 - or - NHC(=O)O-, L2 is -C1-C6 alkylene- NH-, - NHS(=0)2-, -NH- or - 0-, Ra is H, halogen, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, a 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and S, a 3- to 8-member heterocycloalkenyl containing one or more heteroatoms selected from N, O and S, a 6- to 14-member aryl or a 5- to 12-member heteroaryl containing one or more heteroatoms selected from N, O and S, wherein one or more substituents of Ra are each independently -ORb, -C(=O)Rb, -C(=O)ORb, -SRb, -NRbRc, -C(=O)NRbRc, -NRbC(=O)Rc, -S(=O)2NRbRc, -NRbS(=O)2Rc, -C1-C4 alkylene-NRbC(=O)Rc, C1-C6 alkyl, C1-C5 alkoxy, a 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and S, a 6- to 14-member aryl, -C1-C4 alkylene-CF3, -CN, -OH, -CF2H, -CF3 or halogen, and may be substituted or unsubstituted, Rb and Rc are each independently H, C1-C6 alkyl, C1-C5 alkoxy, C1-C8 cycloalkyl, a 3- to 8-member heterocycloalkyl containing one or more heteroatoms selected from N, O and S, a 6- to l4-member aryl, -CF3 or halogen, wherein one or more substituents of Rb and Rc are each independently C1-C6 alkyl, C1-C8 cycloalkyl, a 6- to 14-member aryl, -NRdRe, -CF3 or halogen, and may be substituted or unsubstituted, 372 Rd and Re are each independently H or C1-C6 alkyl, and halogen is F, Cl, Br or I, a compound, its stereoisomers, its pharmaceutically acceptable salts or their solvates or hydrates. Claim 6 According to claim 4, the formula I is represented by the formula lb, and in the formula lb, 【 ' 373 ​ X1, X2 and X3 are each independently N, CH, or P, wherein CH and or P may each independently be substituted or unsubstituted with Ra, Ai is a 5- to 12-membered heteroaryl group containing one or more heteroatoms selected from N, 0, and wherein one or more of Ai may be independently substituted or unsubstituted with C1-C6 alkyl, Li is - NHC(=O)-, Ra is H,_C1-C8cycloalkyl or 6- to 14-membered aryl, a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. 【

7. In claim 4, the chemical formula I is represented by the chemical formula Ic, and in the chemical formula Ic, m is 4, X1 and X2 are each independently C or N, 374 Ai is a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl containing one or more heteroatoms selected from N, 0 and wherein one or more of Ai may be independently substituted or unsubstituted with C1-C6 alkyl, C1-C5 alkoxy or -0H, Li is - NHC(=O)-, a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof. 【

8. A compound selected from the compounds shown in the table below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof: 【A pharmaceutical composition for the prevention or treatment of NR2F6-related diseases, comprising a compound according to any one of claims 1 to 8, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof; or a compound selected from the compounds shown in the table below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof: 407

10. A pharmaceutical composition according to claim 9, wherein the NR2F6-related disease includes cancer.

11. A pharmaceutical composition according to claim 10, wherein the cancer comprises a cancer selected from the group consisting of ovarian cancer, colon cancer, and melanoma.

12. A method for preventing or treating an NR2F6-related disease, comprising administering an effective amount of a pharmaceutical composition according to any one of claims 9 to 11.

13. Use of a pharmaceutical composition according to any one of claims 9 to 11 for the manufacture of a medicament for the prevention or treatment of a disease associated with NR2F6.

14. Use of a pharmaceutical composition according to any one of claims 9 to 11 for the prevention or treatment of NR2F6-related diseases. 441

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