Antiviral Use of Heteroaryl Derivative Compounds

Abstract

The present invention relates to the antiviral use of fused heteroaryl derivatives. The fused heteroaryl derivatives of the present invention exhibit excellent inhibitory activity against ANO6, and can therefore be useful as therapeutic agents for the treatment of viral infections or diseases associated with viral infections.

Description

[Technical Field]

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to antiviral uses of heteroaryl derivative compounds having ANO6 inhibitory activity. [Background technology]

[0002] Coronaviruses are enveloped RNA viruses that bind to host cells and transmit the viral genome to them. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is one of them. Belonging to the genus Beta-Coronavirus, coronaviruses possess a virion envelope and a class I viral fusion protein, the spike (S) glycoprotein. The S protein of SARS-CoV-2 is a key determinant of cellular tropism and mediates binding to angiotensin-converting enzyme 2 (ACE2), a viral entry receptor on host cells, which constitutes the initial step in the membrane fusion process. However, the process of viral-host membrane fusion has yet to be fully elucidated.

[0003] Anoctamin-6 (ANO6), also known as TMEM16F, binds Ca 2+ -activated Cl - Channel (CACC) and Ca 2+Phosphatidylserine is a cell membrane protein that functions as a phospholipid-dependent scramblase. Phosphatidylserine is an anionic phospholipid found primarily in the inner leaflet of the plasma membrane under normal conditions. Phosphatidylserine exposure on the outer surface of the plasma membrane plays a variety of physiological and pathological roles, including platelet aggregation, innate immunity, and cell death. This cell surface externalization of phosphatidylserine is mediated by the inactivation of lipid floppases, which create asymmetry in the membrane, or the activation of phospholipid scramblases such as ANO6, which enhance the translocation of anionic phospholipids. In particular, numerous studies have demonstrated that cell surface exposure of phosphatidylserine is associated with membrane fusion, not only with mammalian cell membranes but also with membrane fusion between enveloped viruses and host cell membranes, such as rhizogenesis, facilitating viral entry into host cells.

[0004] Therefore, there is a need to develop pharmaceuticals that can effectively improve or treat viral infections or viral infection-related diseases in which the functions of anoctamin-6 as an ion channel and phospholipid scramblase are involved by developing inhibitors of anoctamin-6 activity.

[0005] Against this background, the present inventors discovered that ANO6-mediated phosphatidylserine externalization in the host cell membrane is involved in the entry of enveloped viruses, and completed the present invention regarding the antiviral use of anoctamin-6 activity inhibitors. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] P. V''Kovski, A. Kratzel, S. Steiner, H. Stalder, V. Thiel, Nat Rev Microbiol 19, 155 (2021); [Non-patent document 2] Gordon, D.E., Jang, G.M., Bouhaddou, M. et al., Nature 583, 459―468 (2020); [Non-Patent Document 3] H. Yang, A. Kim, T. David, D. Palmer, T. Jin, J. Tien, F. Huang, T. Cheng, S. R. Coughlin, Y. N. Jan, L. Y. Jan, Cell 151, 111 (2012); [Non-Patent Document 4] A. Amara, J. Mercer, Nat Rev Microbiol 13, 461 (2015); [Non-Patent Document 5] D. A. Coil, A. D. Miller, J Virol 79, 11496 (2005); [Non-Patent Document 6] P. Younan, M. Iampietro, R. I. Santos, P. Ramanathan, V. L. Popov, A. Bukreyev, J Infect Dis 218, S335 (2018); [Non-Patent Document 7] E. Zaitseva, E. Zaitsev, K. Melikov, A. Arakelyan, M. Marin, R. Villasmil, L. B. Margolis, G. B. Melikyan, L. V. Chernomordik, Cell Host Microbe 22, 99 (2017). [[ID=​​​​​​​An object of the present invention is to provide a pharmaceutical use of a heteroaryl derivative compound having a novel structure, specifically to provide a use of the heteroaryl derivative compound as an active ingredient for treating or preventing a viral infection or a viral infection-related disease, or a method for treating or preventing a viral infection or a viral infection-related disease, comprising the step of administering the compound.

[0008] Another object of the present invention is to provide a composition for disinfecting or sterilizing an object contaminated with a virus, which comprises the heteroaryl derivative compound as an active ingredient, a use of the compound for disinfecting or sterilizing an object contaminated with a virus, or a method for disinfecting or sterilizing an object contaminated with a virus, which comprises administering the compound. [Means for solving the problem]

[0009] To achieve the above object, an embodiment of the present invention provides a novel pharmaceutical use of heteroaryl derivative compounds having a specific structure that inhibit ANO6 activity.

[0010] Medicinal uses of heteroaryl derivative compounds The present invention provides a compound represented by the following chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0011] [ka]

[0012] In the above Chemical Formula 1, Ring X is a 5- to 6-membered heteroaryl, a 5- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkenyl, wherein one or more H in the 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl ring is selected from -C 1-6 Alkyl, -benzyl, -C 1-6 Haloalkyl, -(CH2)nR e , -O-(CH2)nR e , or may be substituted with -halo}; Y1 to Y4 each independently represent CR Y or N; R Y -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -OR c , -C(=O)-R d , -(CH2)nR e , -O-(CH2)nR e , -S(=O)2-C 1-6 alkyl, -halo, or 5-6 membered heteroaryl, wherein one or more H in said 5-6 membered heteroaryl is -C 1-6 may be substituted with alkyl}; Ring A and ring B are each independently an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or multiple rings, and one or more H in the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -OR c , -C(=O)-R d , -(CH2)nR e , -O-(CH2)nR e , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be replaced by -C 1-6 optionally substituted with alkyl]}; L is -CH2-, -NR L -, -C≡C-NR L , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, -NR LC(=O)-, -S-, -S(=O)2-, -S(=O)2-NR L -, or -NR L -S(=O)2-; R L is -H or -C 1-6 is alkyl; Z is -H, -C 1-6 alkyl, -CN, -C2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein one or more H in said -C2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring is replaced with -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -OR c , -C(=O)-R d , -(CH2)nR e , -O-(CH2)nR e , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be replaced by -C 1-6 optionally substituted with alkyl]}; R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl; R c -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nR e , -benzyl, or heterocycloalkyl {wherein one or more H in the heterocycloalkyl ring is —C 1-6 may be substituted with alkyl}; R d -H, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-C 3-6cycloalkyl, or -NH-aryl; R e -C 1-6 Aminoalkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl, or heterocycloalkenyl is a single ring or multiple rings, and one or more H in said heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring is -C 1-6 may be substituted with alkyl}; n is 0, 1, 2, 3 or 4.

[0013] According to an embodiment of the present invention, [ka] may be in the following ranges: Ring X is a 5-membered heteroaryl {wherein one or more H in said 5-membered heteroaryl ring is —C 1-6 may be substituted with alkyl}; Y1 and Y4 each independently represent CR Y Y2 and Y3 are each independently CR Y or N {provided that when ring X is furan, thiophene, or thiazole, then either one of Y2 and Y3 is N}.

[0014] According to an embodiment of the present invention, [ka] may illustratively be in the following ranges: [ka] [ka] is.

[0015] According to embodiments of the present invention, L may illustratively be in the following ranges: [ka] is.

[0016] According to an embodiment of the present invention, the ring A may illustratively be in the following ranges: [ka] and; A1 to A4 are each independently CR or N; R is -CF3, -N(CH3)(CH3), -OH, -OCH3, -OCH2CH2-N(CH3)(CH3), -halo, [ka] is.

[0017] According to an embodiment of the present invention, the ring B may illustratively be in the following ranges: [ka] and; R is -methyl, -NO2, -NH2, -OCH3, -OH, or -halo.

[0018] According to embodiments of the present invention, Z may illustratively be in the following ranges: [ka] and; R is -H, -methyl, -CF3, -CN, -CH2-NH(CH3), -CH2-N(CH3)(CH3), -OCH3, -OH, -C(=O)-CH3, -C(=O)-OCH3, -C(=O)-OH, -C(=O)-Ot-butyl, -halo or [ka] is.

[0019] According to an embodiment of the present invention, the R e may illustratively be in the following ranges: [ka] is.

[0020] According to an embodiment of the present invention, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 1-1 below: [ka]

[0021] In the above Chemical Formula 1-1, X1 is CR1R2, NR3, O or S; X2 is CR4 or N; R1 to R4 are each independently -H or -C 1-6 is alkyl; Y1 to Y4 each independently represent CR Y or N; R Y -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -OR c , -C(=O)-R d , -S(=O)2-C 1-6 alkyl, -halo, or 5-6 membered heteroaryl, wherein one or more H in said 5-6 membered heteroaryl is -C 1-6 may be substituted with alkyl}; Ring A and ring B are each independently an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or multiple rings, and one or more H in the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -OR c , -C(=O)-R d , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be replaced by -C 1-6 optionally substituted with alkyl]}; L is -CH2-, -NR L -, -C≡C-NR L , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR L -, -NR L -C(=O)-, -S-, -S(=O)2-, -S(=O)2-NR L -or-NR L -S(=O)2-; R L is -H or -C 1-6 is alkyl; Z is -H, -CN, -C2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, where one or more H in the -C2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring is replaced with -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -OR c , -C(=O)-R d , -O-(CH2)nR e, -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be replaced by -C 1-6 optionally substituted with alkyl]}; R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl; R c -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nR e , -benzyl, or heterocycloalkyl {wherein one or more H in the heterocycloalkyl ring is —C 1-6 may be substituted with alkyl}; R d -H, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NH-C 3-6 cycloalkyl, or -NH-aryl; R e -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl, wherein one or more H in said heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring is replaced by —C 1-6 may be substituted with alkyl}; n is 0, 1, 2, 3 or 4.

[0022] According to an embodiment of the present invention, [ka] may be in the following ranges: X1 is NR3 or O; X2 is CR4 or N; R3 and R4 are each independently -H or -C 1-6 is alkyl; Y1 and Y4 each independently represent CR Y Y2 and Y3 are each independently CR Y or N {provided that when ring X1 is S, one of Y2 and Y3 is N, and when ring X1 is O and X2 is CR4, one of Y2 and Y3 is N}; R Y -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -OR c , -C(=O)-R d , -S(=O)2-C 1-6 alkyl, -halo, or 5-6 membered heteroaryl, wherein one or more H in said 5-6 membered heteroaryl is -C 1-6 may be substituted with alkyl}.

[0023] According to an embodiment of the present invention, the ring A may be in the following ranges: Ring A is phenyl, a 5- to 6-membered heteroaryl, or a 5- to 6-membered cycloalkyl, wherein one or more H in said phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered cycloalkyl ring is -C 1-6 Haloalkyl, -NO2, -NR a R b , -OR c , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be replaced by -C 1-6 may be substituted with alkyl]}.

[0024] According to an embodiment of the present invention, L may be in the following ranges: L is -NR L -, -C≡C-NR L , -O-, or -S(=O)2-; R L is -H or -C 1-6It is alkyl.

[0025] According to an embodiment of the present invention, the ring B may be in the following ranges: Ring B is phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl, wherein one or more H in said phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -NO2, -NR a R b , -OR c , or -halo}.

[0026] According to an embodiment of the present invention, the formula Z may be in the following ranges: Z is -CN, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl, where one or more H in the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -CN, -OR c , -C(=O)-R d , -(CH2)nR e , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H in the 5- to 6-membered heterocycloalkyl may be replaced by -C 1-6 and when ring B is phenyl, a 6-membered heteroaryl, or a 6-membered heterocycloalkyl, Z is attached in the p-position relative to L.

[0027] According to an embodiment of the present invention, the compound represented by Chemical Formula 1 may be selected from the group consisting of compounds listed in Table 1 below.

[0028] [Table 1-1]

[0029]

Table 1-2

[0030]

Table 1-3

[0031]

Table 1-4

[0032]

Table 1-5

[0033]

Table 1-6

[0034]

Table 1-7

[0035]

Table 1-8

[0036]

Table 1-9

[0037]

Table 1-10

[0038]

Table 1-11

[0039] In the present invention, "alkyl" may mean a straight or branched chain, acyclic, cyclic or combined saturated hydrocarbon, unless otherwise specified. For example, "C 1-6 "Alkyl" may mean alkyl containing 1 to 6 carbon atoms, and "C 1-4 "Alkyl" may mean alkyl containing 1 to 4 carbon atoms, and "C 1-3 "Alkyl" may refer to an alkyl containing 1 to 3 carbon atoms. Non-cyclic alkyl may include, by way of example only, methyl, ethyl, n-propyl, n-butyl, isopropyl, secondary (sec)-butyl, isobutyl, or tertiary (tert)-butyl. Cyclic alkyl may be used interchangeably herein with "cycloalkyl," and may include, by way of example only, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0040] In the present invention, "alkoxy" may refer to an alkyl ether group -(O-alkyl), where alkyl is as defined above. For example, "C 1-6 "Alkoxy" is C 1-6 Alkoxy containing alkyl, i.e., -(OC 1-6 alkyl), and "C 1-4 "Alkoxy" is C 1-4 Alkoxy containing alkyl, i.e., -(OC 1-4 alkyl), and "C 1-3 "Alkoxy" is C 1-3 Alkoxy containing alkyl, i.e., -(OC 1-3By way of example, alkoxy may include, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, and the like.

[0041] In the present invention, "halo" may be F, Cl, Br or I.

[0042] As used herein, "haloalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo, as defined herein. Examples of haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, independently substituted with one or more halogens, such as F, Cl, Br, or I.

[0043] As used herein, "hydroxyalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH). Examples of hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, each independently substituted with one or more -OH.

[0044] As used herein, "aminoalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with an amino (NR'R''), where R' and R'' are each independently hydrogen, C 1-6 R' and R'' may be selected from the group consisting of alkyl, and an N-protecting group (e.g., Boc), and each of the selected R' and R'' may be independently substituted or unsubstituted.

[0045] As used herein, "cycloalkyl" may refer to a hydrocarbon ring that does not contain heteroatoms (such as N, O, P, P(=O), or S) within the ring, and may be saturated or partially unsaturated. When unsaturated, it may be referred to as a cycloalkenyl. Unless otherwise specified, a cycloalkyl may be a single ring or multiple rings, such as a spiro ring, bridged ring, or fused ring.

[0046] In the present invention, "heterocycloalkyl" may refer to a ring containing one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. When unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise specified, a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring. In addition, "heterocycloalkyl of 3 to 12 atoms" may refer to a heterocycloalkyl containing 3 to 12 atoms forming a ring. Examples of heterocycloalkyl include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, and thiomorpholine-S-oxide. , thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane, and the like.

[0047] In the present invention, "arene" may refer to an aromatic hydrocarbon ring. The arene may be a single ring or multiple rings. The number of ring carbon atoms of the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinquebenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, and chrysene. In this specification, a residue obtained by removing one hydrogen atom from the above-mentioned "arene" is referred to as "aryl."

[0048] In the present invention, a "heteroarene" is a heteroatom and may be a ring containing one or more of O, N, P, Si, and S. The heteroarene may be a single ring or multiple rings. The number of ring carbon atoms in the heteroarene may be 2 or more and 30 or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a bicyclic or tricyclic structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, Examples of heteroarene include, but are not limited to, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran. The heteroarene includes tautomers when tautomeric structures are possible. In one embodiment of the present invention, the heteroarene may also include bicyclic heterocycloarenes including an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In this specification, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as a "heteroaryl."

[0049] In the present invention, "tautomers" refer to isomers that are in equilibrium with each other and undergo a transformation in molecular structure due to the migration of a proton.

[0050] In the present invention, the term "stereoisomer" refers to a compound having the same chemical or molecular formula but different in three dimensions. In this specification, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and their respective isomers, racemates, and mixtures thereof are also included within the scope of the present invention. For example, Chemical Formula 1 of the present invention does not specify the stereochemical structure, and therefore may include the stereoisomers of Chemical Formula 1. Unless otherwise specified, a solid bond connecting an asymmetric carbon atom [ka] is a solid wedge bond indicating the absolute arrangement of stereocenters [ka] or dotted wedge bond [ka] may include:

[0051] The compound of Chemical Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt." As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic acid addition salt of the compound, which has a concentration that is relatively non-toxic and harmless to patients and does not reduce the beneficial effect of the compound represented by Chemical Formula 1 due to side effects caused by the salt.

[0052] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess amount of aqueous acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Equal molar amounts of the compound and the acid or alcohol in water are heated, and the mixture is subsequently evaporated to dryness or the precipitated salt can be filtered off with suction.

[0053] In this case, the free acid may be an organic acid or an inorganic acid, and the inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid, and the organic acid may be methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, or hydroiodic acid, but is not limited to these.

[0054] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal salts or alkaline earth metal salts can be obtained, for example, by dissolving a compound in a solution of an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable for pharmaceutical purposes, but are not limited to these. Corresponding silver salts can also be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

[0055] Pharmaceutically acceptable salts of the present invention, unless otherwise specified, include salts of acidic or basic groups that may be present in the compounds of Formula 1. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelic acid, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, which may be prepared by salt preparation methods known in the art.

[0056] The compound represented by Chemical Formula 1 of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against ANO6 (anoctamin-6).

[0057] According to one embodiment of the present invention, the heteroaryl derivative represented by Chemical Formula 1 exhibits excellent inhibitory activity against ANO6 (anoctamin-6), and can therefore be useful for treating or preventing viral infections or viral infection-related diseases.

[0058] In the present invention, the viral infection or viral infection-related disease may be one or more virus-related diseases, disorders, or conditions selected from the group consisting of the common cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus 19 (COVID-19).

[0059] In the present invention, the virus can be an RNA virus.Specifically, the families include Coronaviridae, Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hypoviridae, Megabirnaviridae, Partitiviridae, and Picornaviridae. Cobirnaviridae, Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae, Picornaviridae viridae, Secoviridae, Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, Tymoviridae, Bornaviridae, Filoviridae, Paramyxoviridae, Phabdoviridae, The virus may be one or more viruses selected from the group consisting of Nyamiviridae, Caliciviridae, Flaviviridae, Luteoviridae, Togaviridae, Pneumoviridae, Arenaviridae, Deltaviridae, and Orthomyxoviridae.

[0060] According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing a viral infection or a viral infection-related disease, comprising, as an active ingredient, a compound represented by Chemical Formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The types of the viral infection or viral infection-related disease are as described above.

[0061] The pharmaceutical composition of the present invention may further contain one or more active ingredients exhibiting the same or similar pharmacological effects in addition to the compound represented by Chemical Formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0062] The pharmaceutical compositions of the present invention may be used for clinical administration and may be prepared so as to be administrable in a variety of oral and parenteral dosage forms.

[0063] In addition, according to one embodiment of the present invention, there is provided a method for treating or preventing a viral infection or a disease associated with a viral infection, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be an animal, including a human.

[0064] The term "therapeutically effective amount" used herein refers to an amount of a compound represented by Formula 1 that is effective in treating or preventing a viral infection or a viral infection-related disease. Specifically, "therapeutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment. The effective dose level can be determined based on factors well known in the medical field, including the type and severity of the individual, age, sex, type of disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment duration, concurrently used drugs, and other factors. The pharmaceutical compositions of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. They can be administered singly or multiple times. Taking all of the above factors into consideration, it is important to administer an amount that can achieve maximum efficacy with the minimum amount without side effects, and this can be easily determined by those skilled in the art. The dosage of the pharmaceutical compositions of the present invention can be determined by experts depending on various factors, such as the patient's condition, age, sex, and comorbidities. Because the active ingredients of the pharmaceutical compositions of the present invention are highly safe, they may be used at or above the determined dosage.

[0065] According to one embodiment of the present invention, there is provided a use of the compound represented by Chemical Formula 1, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt for use in the manufacture of a medicament for the treatment or prevention of a viral infection or a disease associated with a viral infection. The compound represented by Chemical Formula 1 for the manufacture of the medicament may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may be prepared as a combined preparation with other active ingredients to achieve a synergistic effect of the active ingredients.

[0066] In addition, according to one embodiment of the present invention, the heteroaryl derivative represented by Chemical Formula 1 exhibits excellent inhibitory activity against ANO6 (anoctamin-6), and therefore can be usefully used for sterilization or disinfection of virus-contaminated objects.

[0067] The term "sterilization" as used herein means any chemical or physical method for killing or removing microorganisms including viruses, and the term "disinfection" as used herein means any treatment for killing or inhibiting the activity of harmful microorganisms including viruses. The "subject contaminated with viruses" may be an animal, including a human.

[0068] The matters described in the uses, compositions, treatment methods, and sterilization methods of the present invention are equally applicable unless they contradict each other. [Effects of the Invention]

[0069] The heteroaryl derivative compounds of the present invention exhibit excellent inhibitory activity against ANO6 and can therefore be usefully used in the treatment or prevention of the above-mentioned viral infections or diseases associated with viral infections.

[0070] Furthermore, the heteroaryl derivative compounds of the present invention exhibit excellent inhibitory activity against ANO6, and therefore can be usefully used for sterilizing and disinfecting objects contaminated with the virus. [Brief explanation of the drawings]

[0071] [Figure 1] 1 is a graph showing the test results (inhibition rate) of the groups administered with Example Compounds 20 and 24 in Experimental Example 1. [Figure 2] 1 is a graph showing the test results (inhibition rate) of the Example Compound 25, 1 administration group in Experimental Example 1. [Figure 3] 1 is a graph showing the test results (inhibition rate) of the groups administered with Example Compounds 27 and 28 in Experimental Example 1. [Figure 4] 1 is a graph showing the test results (inhibition rate) of the groups administered with Example Compounds 23, 58, and 45 in Experimental Example 1. [Figure 5] 1 is a graph showing the test results (inhibition rate) of the group administered with Compound 21 of the Example in Experimental Example 1. [Figure 6] 1 is a graph showing the test results (inhibition rate) of the groups administered with Example Compounds 52 and 223 in Experimental Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0072] The present invention will be described in detail below with reference to Production Examples, Examples, and Experimental Examples, however, the following Production Examples, Examples, and Experimental Examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0073] [Production example] Production of main intermediate compounds Method a. Preparation of amine derivatives using Suzuki reaction (formula II-a) [ka]

[0074] Preparation Example 1: Synthesis of 5-(4-methylthiophen-3-yl)pyrimidin-2-amine [ka]

[0075] (4-Methylthiophen-3-yl)boronic acid (902 mg, 6.35 mmol), 5-bromopyrimidin-2-amine (850 mg, 4.88 mmol), Pd(PPh3)4 (282 mg, 0.244 mmol), and K2CO3 (2.03 g, 14.65 mmol) were dissolved in HO (80 mL) and DMF (10 mL) and stirred at 110 °C for 35 min in a microwave reactor. The Pd was removed by filtration through Celite, washed with brine, and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and hexane and filtered to give the title compound (496 mg, 53%) as a beige solid on the filter cake.

[0076] 1H NMR (400MHz, DMSO-d6) δ8.32(s, 2H), 7.48(d, J=3.3Hz, 1H), 7.29-7.27(m, 1H), 6.73(s, 2H), 2.22(s, 3H).

[0077] Preparation Example 2: Synthesis of 5-(pyrimidin-4-yl)pyridin-2-amine [ka]

[0078] 4-Chloropyrimidine hydrochloride (2 g, 13.25 mmol), (6-aminopyridin-3-yl)boronic acid (2.2 g, 15.9 mmol), Pd(dppf)Cl (0.485 g, 0.66 mmol), and KCO (11 g, 79.5 mmol) were dissolved in HO (13 mL) and 1,4-dioxane (26 mL) and refluxed at 110 °C for 17 h. The Pd was removed by filtration through Celite, washed with brine, and extracted with ethyl acetate. The organic layer was dried over NaSO and concentrated. The concentrated solution was purified by MPLC, slurried with ethyl acetate, and filtered to give the title compound (877 mg, 38%) as a gray solid on the filter cake.

[0079] 1 H NMR (400MHz, DMSO-d6) δ9.08 (d, J=1.0Hz, 1H), 8.82 (d, J=2.3Hz, 1H), 8.69 (d, J=5.5Hz, 1H), 8.18 (dd, J=2.4, 8.8Hz, 1H), 7.92 (dd, J=1.3, 5.5Hz, 1H), 6.66 (s, 2H), 6.54 (d, J=8.8Hz, 1H).

[0080] Preparation Example 3: Synthesis of 5-(4-fluoropyridin-2-yl)pyrimidin-2-amine

[0081] [ka]

[0082] 2-Bromo-4-fluoropyridine (5 g, 28.4 mmol), (2-aminopyrimidin-5-yl)boronic acid (4.7 g, 34.1 mmol), Pd(PPh3)4 (1.64 g, 1.42 mmol), and K2CO3 (11.8 g, 85.2 mmol) were dissolved in HO (30 mL) and 1,4-dioxane (60 mL) and refluxed at 100 °C for 6 h. The Pd was removed by filtration through Celite, washed with brine, and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to give the title compound (3.84 g, 71%) as a beige solid on the filter cake.

[0083] 1 H NMR (400MHz, DMSO-d6) δ8.96(s, 2H), 8.64-8.60(m, 1H), 7.86(dd, J=2.3, 11.2Hz, 1H), 7.25-7.18(m, 1H), 7.10(s, 2H).

[0084] Preparation Example 4: Synthesis of 5-(pyridin-2-yl)pyrimidin-2-amine [ka]

[0085] 2-Bromopyridine (1.7 mL, 18.0 mmol), (2-aminopyrimidin-5-yl)boronic acid (2.08 g, 15.0 mmol), Pd(PPh3)2Cl2 (1.05 g, 1.5 mmol), and Na2CO3 (4.77 g, 45.0 mmol) were dissolved in HO (18.75 mL) and 1,4-dioxane (56.25 mL) and refluxed at 110 °C for 23 h. After confirming completion of the reaction by LC-MS, the mixture was concentrated. The concentrated solution was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to give the title compound (1.71 g, 66.3%) as a pale yellow solid on the filter cake.

[0086] 1H NMR (400MHz, DMSO-d6) δ8.93(s, 2H), 8.61-8.58(m, 1H), 7.90-7.80(m, 2H), 7.31-7.26(m, 1H), 6.97(s, 2H).

[0087] Preparation Example 5: Synthesis of 4-(pyridin-2-yl)aniline [ka]

[0088] 2-Bromopyridine (1.16 mL, 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.19 g, 10 mmol), Pd(PPh)Cl (0.70 g, 1 mmol), and NaCO (3.18 g, 30 mmol) were dissolved in HO (12.5 mL) and 1,4-dioxane (37.5 mL) and refluxed at 100 °C for 21 h. Pd and HO were removed by filtration through Celite and MgSO, followed by concentration. The concentrated solution was purified by MPLC to give the title compound (1.57 g, 92%) as an orange solid.

[0089] 1 H NMR (400MHz, DMSO-d6) δ8.54-8.51(m, 1H), 7.81-7.72(m, 4H), 7.17-7.13(m, 1H), 6.66-6.60(m, 2H), 5.44(s, 2H).

[0090] Preparation Example 6: Synthesis of 4-(pyrimidin-5-yl)aniline [ka]

[0091] 5-Bromopyrimidine (1.91 g, 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.19 g, 10 mmol), Pd(PPh)Cl (0.70 g, 1 mmol), and NaCO (3.18 g, 30 mmol) were dissolved in HO (12.5 mL) and 1,4-dioxane (37.5 mL) and refluxed at 100 °C for 16 h. Pd and HO were removed by filtration through Celite and MgSO, followed by concentration. The concentrated solution was purified by MPLC to give the title compound (1.50 g, 87%) as a light brown solid.

[0092] 1 H NMR (400MHz, DMSO-d6) δ9.02(s, 1H), 9.01(s, 2H), 7.53-7.48(m, 2H), 6.71-6.66(m, 2H), 5.49(s, 2H).

[0093] Preparation Example 7: Synthesis of 4-(pyridin-4-yl)aniline [ka]

[0094] 4-Bromopyridine hydrochloride (2.33 g, 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.19 g, 10 mmol), Pd(PPh)Cl (0.70 g, 1 mmol), and NaCO (3.18 g, 30 mmol) were dissolved in HO (12.5 mL) and 1,4-dioxane (37.5 mL) and refluxed at 100 °C for 16 h. Pd and HO were removed by filtration through Celite and MgSO, followed by concentration. The concentrated solution was purified by MPLC to give the title compound (1.16 g, 67%) as a light brown solid.

[0095] 1 H NMR (400MHz, DMSO-d6) δ8.49-8.47(m, 2H), 7.58-7.52(m, 4H), 6.69-6.64(m, 2H), 5.53(s, 2H).

[0096] Preparation Example 8: Synthesis of 6-phenylpyridazin-3-amine [ka]

[0097] A solution of 6-chloropyridazin-3-amine (50.0 g, 386 mmol), phenylboronic acid (70.6 g, 579 mmol), XPhos (73.6 g, 154 mmol), and Na2CO3 (69.5 g, 656 mmol) in HO (25 mL) and 1,4-dioxane (250 mL) was degassed and purged with N2. Pd2(dba)3 (21.2 g, 23.2 mmol) was added to the mixture and stirred at reflux for 12 h at 100 °C. After confirming completion of the reaction by LC-MS, the mixture was washed with HO (500 mL) and extracted with ethyl acetate (250 mL x 4). The organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was purified by column chromatography to give the title compound (35.0 g, 53%) as a yellow solid.

[0098] 1 H NMR (400MHz, DMSO-d6) δ7.95(d, J=7.6Hz, 2H), 7.82(d, J=9.2Hz, 1H), 7.48(t, J=7.2Hz, 2H), 7.37(t, J=7.6Hz, 1H), 6.87(d, J=9.2Hz, 1H), 6.53(s, 2H).

[0099] Preparation Example 9: Synthesis of 4-(pyridazin-3-yl)aniline [ka]

[0100] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (63.8 g, 291 mmol), 3-chloropyridazine (30.0 g, 262 mmol), and aqueous CsCO solution (30 M, 29.1 mL, 873 mmol) were dissolved in toluene (180 mL), HO (40 mL), and EtOH (60 mL), followed by the addition of Pd(dppf)Cl (6.39 g, 8.73 mmol). The mixture was degassed and purged with N, then refluxed at 110 °C for 12 h. After confirming completion of the reaction by LC-MS, the mixture was diluted with HO (100 mL) and ethyl acetate (100 mL), and the suspension was filtered. The filter cake was dried in vacuo to give the title compound (42.0 g, 84%) as a black solid.

[0101] 1 H NMR (400MHz, DMSO-d6) δ9.00(d, J=4.8Hz, 1H), 8.00-7.98(m, 1H), 7.88(d, J=8.8Hz, 2H), 7.62-7.58(m, 1H), 6.68(d, J=8.8Hz, 2H), 5.59(s, 2H).

[0102] Preparation Example 10: Synthesis of 5-(pyridazin-3-yl)pyrimidin-2-amine [ka]

[0103] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (199.0 mg, 0.9 mmol), 3-chloropyridazine (114.5 mg, 1.0 mmol), and CsCO (963.2 mg, 3.0 mmol) were dissolved in toluene (3 mL), HO (0.7 mL), and EtOH (1 mL). Pd(dppf)Cl (5.17 mg, 0.04 mmol) was added and the mixture was refluxed at 110 °C for 16 h. After completion of the reaction was confirmed by LC-MS, the Pd was removed by filtration through Celite and the mixture was concentrated. The concentrated mixture was purified by MPLC to give the title compound (41 mg, 24%) as a brown solid.

[0104] 1 H NMR (400MHz, DMSO-d6) δ9.14(dd, J=1.4, 4.9Hz, 1H), 9.01(s, 2H), 8.16(dd, J=1.5, 8.8Hz, 1H), 7.73(dd, J=4.9, 8.8Hz, 1H), 7.15(s, 2H).

[0105] Production Example 11: Synthesis of [2,5'-bipyrimidine]-2'-amine [ka]

[0106] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (5.2 g, 23.7 mmol), 2-chloropyrimidine (2.8 g, 24.9 mmol), and K2CO3 (9.8 g, 71.1 mmol) were dissolved in 1,4-dioxane (40 mL) and HO (10 mL). Pd(dppf)Cl2 (867 mg, 1.18 mmol) was added and the mixture was refluxed at 90 °C for 64 h. After completion of the reaction was confirmed by LC-MS, the mixture was diluted with HO and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The residue was slurried in dichloromethane and filtered. Purification by MPLC afforded the title compound (520 mg, 13%) as a beige solid.

[0107] 1 H NMR (400MHz, DMSO-d6) δ9.14(dd, J=1.3, 4.8Hz, 1H), 8.99(s, 2H), 8.15(dd, J=1.3, 8.7Hz, 1H), 7.59-7.47(m, 1H), 7.14(s, 2H).

[0108] Preparation Example 12: Synthesis of 5-(3-fluorophenyl)pyridin-2-amine [ka]

[0109] 5-Bromopyridin-2-amine (900 mg, 5.2 mmol), (3-fluorophenyl)boronic acid (873 mg, 6.24 mmol), and K2CO3 (2.2 g, 15.6 mmol) were dissolved in DMF (10.4 mL) and HO (10.4 mL). Pd(PPh3)4 (301 mg, 0.26 mmol) was added and the mixture was refluxed at 140 °C for 12 h. After completion of the reaction was confirmed by LC-MS, the mixture was diluted with HO and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography. The residue was slurried in MTBE at room temperature for 1 h and filtered with MTBE. The filter cake was dried in vacuo to give the title compound (18.8 g, 35%) as a white solid.

[0110] 1 H NMR (400MHz, DMSO-d6) δ8.29(d, J=2.0Hz, 1H), 7.73(dd, J=8.8, 2.4Hz, 1H), 7.45-7.40(m, 3H), 7.09-7.04(m, 1H), 6.52(d, J=8.4Hz, 1H), 6.16(s, 2H).

[0111] Preparation Example 13: Synthesis of 4-(pyrimidin-4-yl)aniline [ka]

[0112] Step 1: Synthesis of 4-chloropyrimidine Pyrimidin-4-ol (10.0 g, 104 mmol) was dissolved in POCl (100 mL, 1.08 mol) and stirred in a pressure flask at 100 °C for 6 h. The mixture was concentrated to remove POCl, and ethyl acetate was slowly added and stirred for 30 min, then filtered with ethyl acetate. The filter cake was dried in vacuo to give the title compound (3.5 g, 30%) as a brown solid.

[0113] 1 H NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 8.07 (d, J=7.20Hz, 1H), 6.62 (d, J=7.60Hz, 1H).

[0114] Step 2: Synthesis of 4-(pyrimidin-4-yl)aniline 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.79 g, 17.3 mmol), 4-chloropyrimidine (1.80 g, 15.7 mmol), and CsCO (20.5 g, 62.9 mmol) were dissolved in toluene (12 mL), HO (3.6 mL), and EtOH (4 mL), followed by the addition of Pd(dppf)Cl (575 mg, 0.786 mmol). The mixture was refluxed at 100 °C for 12 h. After completion of the reaction was confirmed by TLC, the mixture was extracted with HO and ethyl acetate. The organic layer was washed with brine, dried over NaSO, concentrated, and purified by column chromatography to give the title compound (1.7 g, 63%) as a yellow solid.

[0115] 1 H NMR (400MHz, DMSO-d6) δ9.02(s, 1H), 8.62(d, J=5.20Hz, 1H), 7.94(d, J=8.80Hz, 2H), 7.83-7.79(m, 1H), 6.65(d, J=8.80Hz, 2H), 5.80(s, 2H).

[0116] Preparation Example 14: Synthesis of 4-(6-fluoropyridazin-3-yl)aniline [ka]

[0117] Step 1: Synthesis of 3-chloro-6-fluoropyridazine Pyridine (100 mL) was slowly added to pyridine / HF (200 mL) in a flask at -30 °C and stirred at the same temperature for 15 min. Then, tert-butyl nitrite (19.2 g, 185.26 mmol) dissolved in pyridine (100 mL) was added dropwise to the solution at -30 °C and stirred at the same temperature for another 15 min. The reaction mixture was added to ice water (2000 mL) and extracted with EA (200 mL × 3). The combined organic layer was washed with brine (2000 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (6 g, 48.88%) as a yellow solid.

[0118] MS: m / z = 133 (M+1, ESI+).

[0119] Step 2: Synthesis of 4-(6-fluoropyridazin-3-yl)aniline To a solution of 3-chloro-6-fluoropyridazine (3 g, 22.64 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (6.47 g, 29.53 mmol) in dioxane / HO (40 mL / 8 mL) was added NaCO (12.95 g, 45.30 mmol) and Pd(PPh) (2.61 g, 2.26 mmol). The reaction mixture was then stirred at 100 °C for 4 h under N. The reaction mixture was cooled to room temperature and poured into water (200 mL). The mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3.52 g, 82.24%) as a yellow solid.

[0120] 1 H NMR (400MHz, DMSO-d6) δ8.26(dd, J=9.3, 7.5Hz, 1H), 7.91-7.73(m, 2H), 7.62(dd, J=9.3, 1.7Hz, 1H), 6.71-6.62(m, 2H), 5.62(s, 2H).

[0121] MS: m / z = 190 (M+1, ESI+).

[0122] Preparation Example 15: Synthesis of 4-(4-(trifluoromethyl)pyridazin-3-yl)aniline [ka]

[0123] Step 1: Synthesis of 3-chloro-4-(trifluoromethyl)pyridazine To a mixture of 4-(trifluoromethyl)pyridazin-3(2H)-one (4 g, 24.38 mmol) in POCl (40 mL) was added DMF (0.5 mL) and stirred at 120 °C for 4 h. The reaction mixture was cooled to room temperature and poured into ice water (400 mL), followed by extraction with DCM (50 mL × 3). The combined organic layers were washed with Brine (200 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3 g, 67.87%) as a yellow solid.

[0124] 1 H NMR (400MHz, DMSO-d6) δ9.58 (d, J=5.0Hz, 1H), 8.30 (d, J=5.1Hz, 1H).

[0125] MS: m / z = 183 (M+1, ESI+).

[0126] Step 2: Synthesis of 4-(4-(trifluoromethyl)pyridazin-3-yl)aniline To a mixture of 3-chloro-4-(trifluoromethyl)pyridazine (3 g, 16.44 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.38 g, 21.47 mmol) in dioxane / HO (60 mL / 12 mL) was added CsCO (16.19 g, 49.64 mmol), and Pd(PPh) (1.92 g, 1.64 mmol). The reaction mixture was stirred at 100 °C under N for 4 h. The reaction mixture was cooled to room temperature and poured into water (500 mL). It was then extracted with EA (100 mL × 3). The combined organic layers were washed with Brine (500 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3 g, 76.92%) as a yellow solid.

[0127] 1 H NMR (400MHz, DMSO-d6) δ9.45 (d, J=5.0Hz, 1H), 8.11 (d, J=5.3Hz, 1H), 7.28 (d, J=8.4Hz, 2H), 6.76-6.57 (m, 2H), 5.57 (s, 2H).

[0128] MS: m / z = 240 (M+1, ESI+).

[0129] Preparation Example 16: Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate [ka]

[0130] Step 1: Synthesis of 6-(4-aminophenyl)pyridazine-4-carboxylic acid To a solution of methyl 6-chloropyridazine-4-carboxylate (6 g, 34.77 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (9.14 g, 41.72 mmol) in dioxane / HO (500 mL / 100 mL) was added CsCO (33.98 g, 104.31 mmol) and Pd(dppf)Cl (1.26 g, 1.74 mmol), and the reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was cooled to room temperature and poured into water (500 mL), followed by extraction with EA (80 mL × 3). The combined organic layers were washed with brine (500 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (12.1 g, crude) as a yellow solid.

[0131] MS: m / z=216 (M+1, ESI+).

[0132] Step 2: Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate To a solution of 6-(4-aminophenyl)pyridazine-4-carboxylic acid (12.1 g, 56.28 mmol) in MeOH (200 ml) at 0 °C, SOCl (13.39 g, 112.56 mmol) was added dropwise, and the reaction mixture was stirred at 70 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH 8 with aqueous NaHCO (500 mL) and then extracted with EA (80 mL × 3). The combined organic layers were washed with brine (400 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (4 g, 31.05%) as a yellow solid.

[0133] 1 H NMR (400MHz, DMSO-d6) δ9.33(d, J=2.0Hz, 1H), 8.28(d, J=2.0Hz, 1H), 7.95(d, J=8.4Hz, 2H), 6.70(d, J=8.4Hz, 2H), 5.72(s, 2H), 3.95(s, 3H).

[0134] MS: m / z = 230 (M+1, ESI+).

[0135] Preparation Example 17: Synthesis of 4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)aniline [ka]

[0136] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.3 mmol), 5-bromo-2-(4-methylpiperazin-1-yl)pyrimidine (593 mg, 2.3 mmol) in HO / toluene / EtOH (3 mL / 12 mL / 6 mL) was added CsCO (1.9 g, 5.7 mmol) and Pd(dppf)Cl (130 mg, 0.07 mmol), and the reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were dried over MgSO, concentrated under reduced pressure, and purified by MPLC. The crude mixture was solidified with DCM and hexane to give the title compound (232 mg, 38%) as a beige solid.

[0137] 1 H NMR (400MHz, DMSO-d6) δ8.58-8.54(m, 2H), 7.29(d, J=8.5Hz, 2H), 6.63(d, J= 8.5Hz, 2H), 5.21(s, 2H), 3.76-3.69(m, 4H), 2.39-2.32(m, 4H), 2.21(s, 3H).

[0138] Method b. Preparation of carboxylic acid derivatives using the Buchwald reaction (formula III-a) [ka]

[0139] Preparation Example 18: Synthesis of 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0140] Step 1: Synthesis of methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate 5-(4-Methylthiophen-3-yl)pyrimidin-2-amine (490 mg, 2.56 mmol), methyl 3-bromobenzoate (661 mg, 3.07 mmol), Pd(dba) (235 mg, 0.0256 mmol), BrettPhos (275 mg, 0.512 mmol), and CsCO (1.67 g, 5.12 mmol) were dissolved in 1,4-dioxane (13 mL) and stirred at 120 °C for 90 min in a microwave reactor. After confirming completion of the reaction by LC-MS, the mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over NaSO and concentrated. The concentrated mixture was slurried with ethyl acetate and hexane and filtered to give the title compound (364 mg, 44%) as a white solid on the filter cake.

[0141] 1 H NMR (400MHz, DMSO-d6) δ10.00(s, 1H), 8.64(s, 2H), 8.45(t, J=1.9Hz, 1H), 8.10-8.06(m, 1H), 7.64(d, J=3.3Hz, 1H), 7.58-7.55(m, 1H), 7.45(t, J=7.9Hz, 1H), 7.34-7.32(m, 1H), 3.87(s, 3H), 2.29(s, 3H).

[0142] Step 2: Synthesis of 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid Methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate (350 mg, 1.08 mmol) prepared in Step 1 and LiOH·HO (451 mg, 10.8 mmol) were dissolved in HO (4.5 mL) and 1,4-dioxane (21.5 mL) and stirred overnight at room temperature. Completion of the reaction was confirmed by LC-MS, and the mixture was acidified to pH 3 with 1N HCl (aq). It was then extracted with ethyl acetate and washed with brine. The organic layer was dried over NaSO and concentrated. The concentrated mixture was slurried with ethyl acetate and hexane and filtered to give the title compound (311 mg, 93%) as a white solid on the filter cake.

[0143] 1H NMR (400MHz, DMSO-d6) δ12.92(s, 1H), 9.97(s, 1H), 8.64(s, 2H), 8.44(t, J=1.8Hz, 1H), 8.05-8.01(m, 1H), 7.63(d, J=3.1Hz, 1H), 7.55(td, J=1.2, 7.6Hz, 1H), 7.42(t, J=7.9Hz, 1H), 7.34-7.32(m, 1H), 2.29(s, 3H).

[0144] Preparation Example 19: Synthesis of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0145] Step 1: Synthesis of methyl 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoate 5-(Pyridin-2-yl)pyrimidin-2-amine (861 mg, 5.0 mmol), methyl 3-bromobenzoate (2.69 g, 12.5 mmol), Pd(dba) (366 mg, 0.4 mmol), XPhos (405 mg, 0.85 mmol), and CsCO (3.26 g, 10.0 mmol) were dissolved in 1,4-dioxane (25 mL) and refluxed at 110 °C for 19.5 h. After confirming completion of the reaction by LC-MS, the Pd was removed by filtration through Celite and concentrated. The concentrated solution was purified by MPLC, concentrated, slurried with ethyl acetate, and filtered to give the title compound (829 mg, 54.1%) as a pale yellow solid on the filter cake.

[0146] 1 H NMR (400MHz, DMSO-d6) δ10.18(s, 1H), 9.21(s, 2H), 8.68-8.65(m, 1H), 8.49(t, J=1.9Hz, 1H), 8.11-8.07(m, 1H), 8.04-8.00(m, 1H), 7.93-7.88(m, 1H), 7.61-7.57(m, 1H), 7.48(t, J=7.9Hz, 1H), 7.39-7.35(m, 1H), 3.88(s, 3H).

[0147] Step 2: Synthesis of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid Methyl 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoate (820 mg, 0.59 mmol) prepared in Step 1 and LiOH HO (449 mg, 10.7 mmol) were dissolved in HO (8.9 mL) and THF (17.8 mL) and stirred at room temperature for 22 hours. 1N HCl (aq) was added to the reaction mixture to crystallize it, and the mixture was filtered to give the title compound (763 mg, 97.5%) as a white solid on the filter cake.

[0148] 1 H NMR (400MHz, DMSO-d6) δ12.91(s, 1H), 10.14(s, 1H), 9.21(s, 2H), 8.68-8.65(m, 1H), 8.47-8.45(m, 1H), 8.07-8 .03(m, 1H), 8.03-8.00(m, 1H), 7.92-7.87(m, 1H), 7.59-7.56(m, 1H), 7.44(t, J=7.9Hz, 1H), 7.38-7.34(m, 1H).

[0149] Preparation Example 20: Synthesis of 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid [ka]

[0150] Step 1: Synthesis of methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate 4-(Pyridin-2-yl)aniline (1.52 g, 8.93 mmol), methyl 3-bromobenzoate (2.88 g, 13.4 mmol), Pd(dba) (0.82 g, 0.89 mmol), BrettPhos (0.96 g, 1.79 mmol), and CsCO (11.64 g, 35.7 mmol) were dissolved in 1,4-dioxane (45 mL) and refluxed at 100 °C for 15 h. After filtration through Celite to remove Pd and concentration, the concentrated solution was purified by MPLC to give the title compound (1.36 g, 49%) as a yellow solid.

[0151] 1H NMR (400MHz, DMSO-d6) δ8.73-8.71(m, 1H), 8.61-8.59(m, 1H), 8.05-8.01(m, 2H), 7.91-7.87(m, 1H), 7.8 6-7.80(m, 1H), 7.74-7.71(m, 1H), 7.46-7.40(m, 3H), 7.28-7.24(m, 1H), 7.21-7.17(m, 2H), 3.85(s, 3H).

[0152] Step 2: Synthesis of 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid Methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate (1.35 g, 4.43 mmol) prepared in Step 1 and LiOH·HO (0.75 g, 17.74 mmol) were dissolved in HO (15 mL) and THF (30 mL) and stirred at room temperature for 117 hours. The mixture was acidified to pH 3 with 1N HCl (aq), extracted with ethyl acetate, washed with brine, and the organic layer was dried over MgSO and concentrated. The concentrated mixture was purified by MPLC to give the title compound (321 mg, 25%) as a pale yellow solid.

[0153] 1 H NMR (400MHz, DMSO-d6) δ12.93(s, 1H), 8.67(s, 1H), 8.61-8.60(m, 1H), 8.05-8.00(m, 2H), 7.90-7.86( m, 1H), 7.85-7.80(m, 1H), 7.73-7.71(m, 1H), 7.45-7.37(m, 3H), 7.28-7.24(m, 1H), 7.21-7.16(m, 2H).

[0154] Preparation Example 21: Synthesis of 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid [ka]

[0155] Step 1: Synthesis of methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate 4-(Pyrimidin-5-yl)aniline (1.45 g, 8.47 mmol), methyl 3-bromobenzoate (2.0 g, 9.32 mmol), Pd(dba) (0.62 g, 0.68 mmol), XPhos (0.69 g, 1.44 mmol), and CsCO (5.52 g, 16.94 mmol) were dissolved in 1,4-dioxane (43 mL) and refluxed at 100 °C for 16 h. The Pd was removed by filtration through Celite and concentrated. The concentrated solution was purified by MPLC, concentrated, slurried in acetone, and filtered to give the title compound (0.93 g, 36%) as a pale yellow solid on the filter cake.

[0156] 1 H NMR (400MHz, DMSO-d6) δ9.12(s, 3H), 8.75(s, 1H), 7.79-7.72(m, 3H), 7.50-7.36(m, 3H), 7.25-7.22(m, 2H), 3.85(s, 3H).

[0157] Step 2: Synthesis of 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid Methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate (0.90 g, 2.95 mmol) prepared in Step 1 and LiOH·HO (0.5 g, 11.8 mmol) were dissolved in HO (10 mL) and THF (20 mL) and stirred at room temperature for 64 hours. The mixture was acidified to pH 3 with 1N HCl (aq) and extracted with ethyl acetate. After washing with brine, the organic layer was dried over MgSO and concentrated. The concentrated mixture was purified by MPLC to give the title compound (706 mg, 82%) as a yellow solid.

[0158] 1 H NMR (400MHz, DMSO-d6) δ12.91(brs, 1H), 9.12-9.11(m, 3H), 8.70(s, 1H), 7.79-7.70(m, 3H), 7.49-7.33(m, 3H), 7.26-7.20(m, 2H).

[0159] Preparation Example 22: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid [ka]

[0160] Step 1: Synthesis of methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate 4-(Pyridin-4-yl)aniline (1.12 g, 6.58 mmol), methyl 3-bromobenzoate (1.56 g, 7.24 mmol), Pd(dba) (0.48 g, 0.53 mmol), XPhos (0.53 g, 1.12 mmol), and CsCO (4.29 g, 18.44 mmol) were dissolved in 1,4-dioxane (33 mL) and refluxed at 100 °C for 16 h. The Pd was removed by filtration through Celite and concentrated. The concentrated solution was purified by MPLC, concentrated, slurried in acetone, and filtered to give the title compound (0.79 g, 40%) as a white solid on the filter cake.

[0161] 1 H NMR (400MHz, DMSO-d6) δ8.79-8.77(m, 1H), 8.59-8.56(m, 2H), 7.80-7.76(m, 2H), 7.74-7 .71(m, 1H), 7.69-7.66(m, 2H), 7.48-7.41(m, 3H), 7.23-7.19(m, 2H), 3.86-3.85(m, 3H).

[0162] Step 2: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid Methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate (0.76 g, 2.5 mmol) prepared in Step 1 and LiOH·HO (0.42 g, 10 mmol) were dissolved in HO (8.5 mL) and THF (17 mL) and stirred at room temperature for 40 hours. The mixture was acidified to pH 3 with 1N HCl (aq), extracted with ethyl acetate, washed with brine, and the organic layer was dried over MgSO and concentrated. The concentrated mixture was slurried with ethyl acetate and acetone and filtered to give the title compound (244 mg, 34%) as a yellow solid.

[0163] 1H NMR (400MHz, DMSO-d6) δ12.99(brs, 1H), 9.24(s, 1H), 8.75(s, 2H), 8.23-8.16(m, 2 H), 7.99(d, J=8.8Hz, 2H), 7.79(s, 1H), 7.61-7.40(m, 3H), 7.26(d, J=42.4Hz, 2H).

[0164] Preparation Example 23: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid [ka]

[0165] Step 1: Synthesis of methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate A solution of methyl 3-bromobenzoate (35.9 g, 167 mmol), 6-phenylpyridazin-3-amine (30.0 g, 175 mmol), BrettPhos (18.0 g, 33.4 mmol), and Cs2CO3 (136 g, 417 mmol) in 1,4-dioxane (150 mL) was degassed and purged with N2. Pd2(dba)3 (4.58 g, 5.01 mmol) was added to the mixture and stirred at reflux at 100 °C for 6 h. After confirming completion of the reaction by LC-MS, the reaction solution was filtered. The filter cake was dried in vacuo and slurried in THF (300 mL) and MeOH (60 mL) at 25 °C for 12 h. The suspension was filtered, and the filtrate was concentrated to give the title compound (30.0 g, 98.3 mmol, 59%) as a yellow solid.

[0166] 1 H NMR (400MHz, DMSO-d6) δ8.65(s, 1H), 8.55(s, 1H), 8.07(d, J=6.0Hz, 1H), 7.97(d, J=5.6Hz) 3H), 7.49-7.47(m, 1H), 7.46-7.44(m, 4H), 7.44-7.42(m, 1H), 3.87(s, 3H).

[0167] Step 2: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid Methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate (20.0 g, 65.5 mmol) prepared in Step 1 and NaOH (2 M, 131 mL, 262 mmol) were dissolved in THF (100 mL) and MeOH (20 mL) and stirred at 50 °C for 12 hours. Completion of the reaction was confirmed by LC-MS, and the reaction solution was dried in vacuo. HO was added and the mixture was acidified to pH 3 with 1N HCl (aq). The suspension was filtered with HO, and the filter cake was dried in vacuo to give the title compound (10.0 g, 34.3 mmol, 52%) as a pale yellow solid.

[0168] 1 H NMR (400MHz, DMSO-d6) δ12.97(s, 1H), 9.60(s, 1H), 8.49(s, 1H), 8.08(t, J=9.2Hz, 4H), 7.55-7.46(m, 5H), 7.25(d, J=9.2Hz, 1H).

[0169] Preparation Example 24: Synthesis of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid [ka]

[0170] Step 1: Synthesis of methyl 3-((4-(pyridazin-3-yl)phenyl)amino)benzoate A solution of methyl 3-bromobenzoate (57.1 g, 265 mmol), 4-(pyridazin-3-yl)aniline (45.0 g, 263 mmol), BrettPhos (9.88 g, 18.4 mmol), CsCO (214 g, 657 mmol), and Pd(dba) (12.0 g, 13.1 mmol) in 1,4-dioxane (350 mL) was degassed, purged with N, and refluxed at 90 °C for 12 h. After confirming completion of the reaction by LC-MS, the reaction solution was diluted with HO, extracted with ethyl acetate, and washed with brine. The organic layer was dried over NaSO and concentrated. The mixture was purified by column chromatography to give the title compound (32.0 g, 40%) as a brown solid.

[0171] 1H NMR (400MHz, DMSO-d6) δ9.11(d, J=3.2Hz, 1H), 8.80(s, 1H), 8.14-8.09(m, 3H ), 7.75-7.69(m, 2H), 7.47-7.44(m, 3H), 7.23(d, J=8.4Hz, 2H), 3.85(s, 3H).

[0172] Step 2: Synthesis of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid Methyl 3-((4-(pyridazin-3-yl)phenyl)amino)benzoate (30.0 g, 98.3 mmol) prepared in Step 1 and LiOH·HO (8.25 g, 197 mmol) were dissolved in HO (60 mL) and MeOH (120 mL) and stirred at room temperature for 12 hours. Completion of the reaction was confirmed by LC-MS, and the reaction solution was dried in vacuo. HO was added and the mixture was acidified to pH 5-6 with 0.5 N HCl (aq). The suspension was filtered with HO, and the filter cake was dried in vacuo to give the title compound (25 g, 95%) as a brown solid.

[0173] 1 H NMR (400MHz, DMSO-d6) δ12.98(s, 1H), 9.12(d, J=4.0Hz, 1H), 8.79(s, 1H), 8.17-8.15(m, 1H), 8. 11-8.08(m, 2H), 7.74-7.72(m, 2H), 7.47-7.46(m, 1H), 7.41-7.40(m, 2H), 7.23(d, J=8.4Hz, 2H).

[0174] Preparation Example 25: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0175] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate A solution of 5-(3-fluorophenyl)pyrimidin-2-amine (30.0 g, 158 mmol), methyl 3-bromobenzoate (31.0 g, 144 mmol), XPhos (20.6 g, 43.3 mmol), and CsCO (141 g, 432 mmol) in 1,4-dioxane (210 mL) was degassed and purged with N. Pd(dba) (3.96 g, 4.32 mmol) was added to the mixture and stirred at reflux for 12 h at 100 °C. After confirming the completion of the reaction by TLC, the reaction solution was diluted with HO and the suspension was filtered with HO. The filter cake was dried under vacuum, THF was added, and the suspension was filtered with HO. The filtrate was purified by column chromatography to give the title compound (10.0 g, 22%) as a white solid.

[0176] 1 H NMR (400MHz, DMSO-d6) δ10.10(s, 1H), 8.93(s, 2H), 8.49(s, 1H), 8.05(dd, J=1.2Hz, 1H), 7.67-7.43(m, 5H), 7.20(s, 1H), 3.86(s, 3H).

[0177] Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoic acid Methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate (10 g, 30.9 mmol) prepared in Step 1 and NaOH (2 M, 30.9 mL) were dissolved in THF (70 mL) and MeOH (50 mL) and stirred at 50°C for 12 hours. Completion of the reaction was confirmed by TLC, and the reaction solution was dried in vacuo. HO was added and the mixture was acidified with 1N HCl (aq) to a pH of 1-2. The suspension was filtered with HO, and the filter cake was dried in vacuo to give the title compound (5.0 g, 52%) as a white solid.

[0178] 1 H NMR (400MHz, DMSO-d6) δ10.04(s, 1H), 8.92(s, 2H), 8.79(s, 1H), 8.46(s, 1H), 8. 00(d, J=8.0Hz, 1H), 7.66-7.50(m, 4H), 7.42(t, J=9.2Hz, 1H), 7.22-7.17(m, 1H).

[0179] Preparation Example 26: Synthesis of 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid [ka]

[0180] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoate A solution of 5-(3-fluorophenyl)pyridin-2-amine (20.0 g, 93.0 mmol), methyl 3-bromobenzoate (18.4 g, 97.6 mmol), XPhos (13.30 g, 27.9 mmol), and CsCO (90.9 g, 279 mmol) in 1,4-dioxane (100 mL) was degassed and purged with N. Pd(dba) (2.55 g, 2.79 mmol) was added to the mixture and stirred at reflux for 12 h at 100 °C. After confirming completion of the reaction by LC-MS, the reaction solution was filtered with ethyl acetate, and the organic layer was dried over NaSO and concentrated. The residue was slurried in MTBE at room temperature for 1 h and filtered with MTBE. The filter cake was dried in vacuo to give the title compound (16.5 g, 55%) as a white solid.

[0181] 1 H NMR (400MHz, DMSO-d6) δ9.51(s, 1H), 8.58(d, J=2.4Hz, 1H), 8.35(t, J=1.6Hz, 1H), 8.07-8.05(m, 1H), 7.98(dd, J=8.8, 2.4Hz, 1H), 7.55-7.40(m, 5H), 7.17-7.12(m, 1H), 6.93(d, J=8.4Hz, 1H), 3.86(s, 3H).

[0182] Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid Methyl 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoate (18 g, 55.8 mmol) prepared in Step 1 and NaOH (2 M, 55.8 mL) were dissolved in THF (18 mL) and MeOH (90 mL) and stirred at room temperature for 8 hours. The completion of the reaction was confirmed by LC-MS, and the reaction solution was concentrated and then HO was added. The residue was acidified to pH 5 with 6N HCl (aq). The suspension was filtered, and the filter cake was dried in vacuo to give the title compound (10.0 g, 58%) as a bright yellow solid.

[0183] 1 H NMR (400MHz, DMSO-d6) δ12.85(s, 1H), 9.49(s, 1H), 8.56(d, J=2.0Hz, 1H), 8.33-8.32( m, 1H), 7.99-7.95 (m, 2H), 7.54-7.36 (m, 5H), 7.15-7.10 (m, 1H), 6.93 (d, J=8.8Hz, 1H).

[0184] Preparation Example 27: Synthesis of 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid [ka]

[0185] Step 1: Synthesis of methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate A solution of 4-(pyrimidin-4-yl)aniline (1.70 g, 9.93 mmol), methyl 3-bromobenzoate (2.14 g, 9.93 mmol), BrettPhos (1.07 g, 1.99 mmol), and Cs2CO3 (8.09 g, 24.8 mmol) in 1,4-dioxane (15 mL) was degassed and purged with N2. Pd2(dba)3 (909 mg, 0.993 mmol) was added to the mixture and stirred at reflux for 12 h at 100 °C. After confirming completion of the reaction by TLC, the reaction solution was diluted with H2O, extracted with ethyl acetate, washed with brine, and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (1.30 g, 43%) as a yellow solid.

[0186] 1 H NMR (400MHz, DMSO-d6) δ9.13(s, 1H), 8.91(s, 1H), 8.74(d, J=5.20Hz, 1H), 8.15(d, J=8.80Hz, 2H), 7.96(d , J=5.20Hz, 1H), 7.76(s, 1H), 7.52-7.49(m, 1H), 7.46-7.43(m, 2H), 7.20(d, J=8.80Hz, 2H), 3.85(s, 3H).

[0187] Step 2: Synthesis of 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid Methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate (1.30 g, 4.26 mmol) prepared in Step 1 and KOH (478 mg, 8.52 mmol) were dissolved in HO (5 mL) and EtOH (7 mL) and stirred at 100 °C for 4 hours. Completion of the reaction was confirmed by TLC, and the reaction solution was added with HO, extracted with 2-MeTHF, and acidified to pH 5-6 with 0.5 N HCl (aq). The mixture was extracted with 2-MeTHF and washed with brine. The organic layer was dried over NaSO and concentrated. The residue was slurried in CHCN at room temperature for 12 hours to give the title compound (1.01 g, 81%) as a yellow solid.

[0188] 1 H NMR (400MHz, DMSO-d6) δ12.96(s, 1H), 9.13(s, 1H), 8.88(s, 1H), 8.74(d, J=5.60Hz, 1H), 8.15(d, J=8.8 0Hz, 2H), 7.97-7.94(m, 1H), 7.75(s, 1H), 7.52-7.48(m, 1H), 7.43-7.41(m, 2H), 7.20(d, J=8.80Hz, 2H).

[0189] Preparation Example 28: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid [ka]

[0190] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate 5-(3-Fluorophenyl)pyrimidin-2-amine (1.13 g, 6.0 mmol), methyl 3-chloro-4-methoxybenzoate (1.81 g, 9.00 mmol), XPhos (572 mg, 1.2 mmol), CsCO (3.90 g, 12.0 mmol), and Pd(dba) (824 mg, 0.90 mmol) were added to 1,4-dioxane (50 mL) and refluxed at 100 °C for 12 h. After confirming completion of the reaction by LC-MS, saturated NaHCO solution was added to the reaction solution, extracted with ethyl acetate, and concentrated. The residue was purified by MPLC to give the title compound (1.43 g, 68%) as an orange solid.

[0191] 1 H NMR (400MHz, DMSO) δ8.91(s, 2H), 8.73(s, 1H), 8.52(s, 1H), 7.76-7.59(m, 3H), 7.56-7.48(m, 1H), 7.24-7.17(m, 2H), 3.95(s, 3H), 3.84(s, 3H).

[0192] Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid Methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate (706 mg, 2.00 mmol) prepared in Step 1 and LiOH·HO (1.68 g, 40.0 mmol) were dissolved in HO (10 mL) and THF (20 mL) and stirred at 60 °C for 48 h. The reaction was confirmed to be complete by LC-MS, and the mixture was acidified to pH 2 with 1N HCl (aq). The suspension was filtered with HO and dried in vacuo to give the title compound (540 mg, 80%) as an orange solid.

[0193] 1 H NMR (400MHz, DMSO-d6) δ13.12(s, 1H), 8.80(s, 2H), 7.92(s, 1H), 7.81(d, J=8.1H) z, 1H), 7.66(d, J=8.9Hz, 1H), 7.61-7.48(m, 4H), 7.22-7.15(m, 1H), 3.56(s, 3H).

[0194] Preparation Example 29: Synthesis of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)aminobenzoic acid [ka]

[0195] Step 1: Synthesis of methyl 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate 5-(Pyridazin-3-yl)pyrimidin-2-amine (2.34 g, 13.5 mmol), methyl 3-bromobenzoate (3.05 g, 14.2 mmol), BrettPhos (870 mg, 1.6 mmol), CsCO (11.0 g, 33.8 mmol), and Pd(dba) (1.09 g, 1.35 mmol) were added to 1,4-dioxane (40 mL) and refluxed at 90 °C for 12 h. After completion of the reaction was confirmed by LC-MS, the reaction solution was diluted with HO, slurried with MeOH, and filtered. The resulting filter cake was slurried with dichloromethane and dried under vacuum to give the title compound (2.19 g, 53%) as a beige solid.

[0196] 1 H NMR (400MHz, DMSO-d6) δ10.30(s, 1H), 9.29(s, 2H), 9.22(dd, J=1.7, 5.0Hz, 1H), 8.50(s, 1H), 8.30(dd, J=1.4, 8.7Hz , 1H), 8.09(dd, J=1.2, 8.2Hz, 1H), 7.81(dd, J=4.9, 8.6Hz, 1H), 7.64-7.59(m, 1H), 7.49(t, =7.9Hz, 1H), 3.88(s, 3H).

[0197] Step 2: Synthesis of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid Methyl 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate (2.18 g, 7.09 mmol) prepared in Step 1 and LiOH·HO (1.20 g, 28.38 mmol) were dissolved in HO (20 mL) and THF (40 mL) and stirred at 60 °C for 13.5 h. The reaction was confirmed to be complete by LC-MS and neutralized with 1N HCl (aq). The suspension was filtered with HO to give the title compound (1.8 g, 84%) as a beige solid.

[0198] 1 H NMR (400MHz, DMSO-d6) δ12.96(s, 1H), 10.28(s, 1H), 9.29(d, J=2.5Hz, 2H), 9.25-9.21(m, 1H), 8.50-8.46( m, 1H), 8.33-8.28(m, 1H), 8.08-8.04(m, 1H), 7.85-7.79(m, 1H), 7.60(d, J=7.6Hz, 1H), 7.49-7.43(m, 1H).

[0199] Preparation Example 30: Synthesis of 3-([2,5'-bipyrimidin]-2'-ylamino)benzoic acid [ka]

[0200] Step 1: Synthesis of methyl 3-([2,5'-bipyrimidin]-2'-ylamino)benzoate [2,5'-Bipyrimidine]-2'-amine (500 mg, 2.9 mmol), methyl 3-bromobenzoate (627 mg, 2.91 mmol), BrettPhos (108 mg, 0.2 mmol), CsCO (2.35 g, 7.21 mmol), and Pd(dba) (116 mg, 0.14 mmol) were added to 1,4-dioxane (60 mL) and refluxed at 90 °C for 23 h. After completion of the reaction was confirmed by LC-MS, the reaction solution was added with HO and extracted with ethyl acetate. The organic layer was dried over MgSO and concentrated. The residue was purified by MPLC to give the title compound (180 mg, 20%) as a beige solid.

[0201] 1 H NMR (400MHz, DMSO-d6) δ10.34(s, 1H), 9.36(s, 2H), 8.90(d, J=4.9Hz, 2H), 8.44(t, J=1.8Hz, 1H), 8. 12(dd, J=1.3, 8.1Hz, 1H), 7.64-7.60(m, 1H), 7.50(d, J=7.9Hz, 1H), 7.48-7.44(m, 1H), 3.88(s, 3H).

[0202] Step 2: Synthesis of 3-([2,5'-bipyrimidin]-2'-ylamino)benzoic acid Methyl 3-([2,5'-bipyrimidin]-2'-ylamino)benzoate (180 mg, 0.59 mmol) prepared in Step 1 and LiOH·HO (49 mg, 1.17 mmol) were dissolved in HO (3 mL) and MeOH (6 mL) and stirred at 40 °C for 16 h. The completion of the reaction was confirmed by LC-MS, and the mixture was acidified to pH 2 with 1N HCl (aq). The suspension was filtered with HO, and the resulting filter cake was slurried in HO and dried in vacuo to give the title compound (110 mg, 64%) as a beige solid.

[0203] MS: m / z = 294 (M+1, ESI+).

[0204] Method a+b. Preparation of carboxylic acid derivatives using Suzuki and Buchwald reactions (formula III-a) [ka]

[0205] Preparation Example 31: Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid [ka]

[0206] Step 1: Synthesis of 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline To a solution of 4-bromo-3-nitroaniline (5 g, 23.04 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.78 g, 34.5 mmol) in dioxane (50 mL), KOAc (5.65 g, 57.60 mmol) and Pd(dppf)Cl (1.67 g, 2.30 mmol) were added, and the reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was cooled to room temperature and poured into water (300 mL). It was then extracted with EA (60 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3 g, 49.3%) as a yellow solid.

[0207] MS: m / z = 265 (M+1, ESI+).

[0208] Step 2: Synthesis of 3-nitro-4-(pyridazin-3-yl)aniline To a solution of 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3 g, 11.36 mmol) and 3-bromopyridazine (2.35 g, 14.77 mmol) in dioxane / HO (50 mL / 10 mL) was added CsCO (7.40 g, 22.72 mmol) and Pd(dppf)Cl (921 mg, 1.14 mmol), and the reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), followed by extraction with EA (60 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.1 g, 44.8%) as a yellow solid.

[0209] MS: m / z = 217 (M+1, ESI+).

[0210] Step 3: Synthesis of methyl 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoate To a solution of 3-nitro-4-(pyridazin-3-yl)aniline (1.1 g, 5.09 mmol) and methyl 3-bromobenzoate (1.29 g, 6.62 mmol) in dioxane / DMSO (50 mL / 4 mL) was added CsCO (3.02 g, 10.18 mmol), Brettphos (745 mg, 1.53 mmol), and Pd(dba) (636 mg, 0.76 mmol). The reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (300 mL). It was then extracted with EA (60 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (800 mg, 44.9%) as a pale yellow solid.

[0211] MS: m / z = 351 (M+1, ESI+).

[0212] Step 4: Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid To a solution of methyl 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoate (800 mg, 2.29 mmol) in THF / HO (20 mL / 4 mL) was added LiOH·HO (480 mg, 11.45 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N HCl(aq) (30 mL) and then extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, and concentrated in vacuo to give the title compound (700 mg, 91.14%) as a yellow solid.

[0213] 1 H NMR (400MHz, DMSO-d6) δ9.49(s, 1H), 9.18(s, 1H), 7.99(d, J=13.1Hz, 1H), 7.82 (s, 2H), 7.68(s, 1H), 7.63(d, J=2.2Hz, 1H), 7.58(d, J=6.8Hz, 1H), 7.48(s, 3H).

[0214] MS: m / z = 337 (M+1, ESI+).

[0215] Preparation Example 32: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid [ka]

[0216] Step 1: Synthesis of 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline To a solution of 4-bromo-3-methoxyaniline (5 g, 24.74 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.43 g, 37.11 mmol) in dioxane (50 mL) was added KOAc (6.06 g, 61.87 mmol) and Pd(dppf)Cl (898 mg, 1.21 mmol), and the reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was cooled to room temperature and poured into water (300 mL). It was then extracted with EA (60 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (2.4 g, 38.96%) as a yellow solid.

[0217] 1 H NMR (400MHz, DMSO-d6) δ7.25(d, J=7.8Hz, 1H), 6.15-6.07(m, 2H), 5.48(s, 2H), 3.64(d, J=6.2Hz, 3H), 1.22(s, 12H).

[0218] MS: m / z = 250 (M+1, ESI+).

[0219] Step 2: Synthesis of 3-methoxy-4-(pyridazin-3-yl)aniline To a solution of 3-bromopyridazine (1.99 g, 12.53 mmol) and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.4 g, 9.64 mmol) in dioxane / HO (50 mL / 10 mL) was added CsCO (6.28 g, 19.28 mmol) and Pd(dppf)Cl (697 mg, 0.96 mmol), and the reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), followed by extraction with EA (60 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.4 g, 72.27%) as a yellow solid.

[0220] MS: m / z=202 (M+1, ESI+).

[0221] Step 3: Synthesis of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate To a solution of 3-methoxy-4-(pyridazin-3-yl)aniline (1.4 g, 6.97 mmol) and methyl 3-bromobenzoate (1.95 g, 9.05 mmol) in dioxane (20 mL) was added CsCO (4.54 g, 13.94 mmol), Brettphos (697 mg, 1.30 mmol), and Pd(dba) (595 mg, 0.65 mmol). The reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (300 mL). It was then extracted with EA (60 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.1 g, 47.21%) as a pale yellow solid.

[0222] 1H NMR (400MHz, DMSO-d6) δ9.08 (dd, J=4.8, 1.6Hz, 1H), 8.84-8.68 (m, 1H), 8.15-7.94 (m, 1H), 7.81-7.74 (m, 2H), 7.64(dd, J=8.7, 4.9Hz, 1H), 7.51-7.39(m, 3H), 6.89-6.81(m, 2H), 3.86(s, 3H), 3.82(s, 3H).

[0223] MS: m / z=336 (M+1, ESI+).

[0224] Step 4: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid To a solution of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate (1.1 g, 3.28 mmol) in THF / HO (20 mL / 4 mL) was added LiOH·HO (689 mg, 16.42 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N HCl(aq) (20 mL) and then extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, and concentrated under reduced pressure to give the title compound (900 mg, 85.71%) as a yellow solid.

[0225] 1 H NMR (400MHz, DMSO-d6) δ9.33(dd, J=4.9, 1.4Hz, 1H), 8.68(d, J=8.9Hz, 1H), 8.28(dd, J=8.9 , 4.9Hz, 1H), 7.79(dd, J=12.9, 5.5Hz, 2H), 7.61-7.41(m, 3H), 6.89(dd, J=6.6, 2.1Hz, 2H).

[0226] MS: m / z = 322 (M+1, ESI+).

[0227] Preparation 33: Synthesis of 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0228] Step 1: Synthesis of 5-(6-fluoropyridin-2-yl)pyrimidin-2-amine To a solution of 2-bromo-6-fluoropyridine (3 g, 17.05 mmol) and (2-aminopyrimidin-5-yl)boronic acid (2.26 g, 16.23 mmol) in dioxane / HO (50 mL / 10 mL) was added CsCO (10.58 g, 32.46 mmol) and Pd(dppf)Cl (1.18 g, 1.62 mmol), and the reaction mixture was stirred at 100 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL), followed by extraction with EA (60 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3.10 g, 92.50%) as a brown solid.

[0229] MS: m / z = 191 (M+1, ESI+).

[0230] Step 2: Synthesis of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate To a solution of 5-(6-fluoropyridin-2-yl)pyrimidin-2-amine (3 g, 15.70 mmol) and methyl 3-bromobenzoate (3.39 g, 15.70 mmol) in dioxane (80 mL) was added CsCO (10.26 g, 31.40 mmol), Brettphos (847 mg, 1.57 mmol), and Pd(dba) (723 mg, 1.57 mmol). The reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (200 mL). It was then extracted with EA (80 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3.8 g, 71.96%) as a brown solid.

[0231] 1H NMR (400MHz, DMSO-d6) δ10.22(d, J=24.0Hz, 1H), 9.19(d, J=16.1Hz, 2H), 8.53-8.41(m, 1H), 8.15-8.01(m, 2H), 7.97(dd, J=7.5, 2.5Hz, 1H), 7.60(d, J=7.7Hz, 1H), 7.51-7.40(m, 1H), 7.18-7.08(m, 1H), 3.87(s, 3H).

[0232] MS: m / z = 325 (M+1, ESI+).

[0233] Step 3: Synthesis of 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid To a solution of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate (3.8 g, 11.73 mmol) in THF / HO (50 mL / 10 mL) was added LiOH·HO (2.46 g, 58.64 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N HCl(aq) (80 mL) and then extracted with EA (40 mL × 3). The combined organic layers were washed with brine (80 mL × 3), dried over NaSO, and concentrated in vacuo to give the title compound (3.2 g, 88.89%) as a brown solid.

[0234] 1 H NMR (400MHz, DMSO-d6) δ9.97(d, J=39.6Hz, 1H), 9.22-9.08(m, 2H), 8.30(d, J=14.8Hz, 1H), 8.06(q, J=8.1Hz, 1H), 7 .99-7.90(m, 1H), 7.85(d, J=8.0Hz, 1H), 7.59(d, J=7.5Hz, 1H), 7.29(t, J=7.8Hz, 1H), 7.10(dd, J=8.0, 2.2Hz, 1H).

[0235] MS: m / z = 311 (M+1, ESI+).

[0236] Preparation Example 34: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid [ka]

[0237] Step 1: Synthesis of 4-(6-fluoropyridin-2-yl)aniline To a solution of 2-chloro-6-fluoropyridine (1 g, 7.60 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 9.12 mmol) in dioxane / HO (50 mL / 10 mL) was added CsCO (4.95 g, 15.20 mmol) and Pd(dppf)Cl (616 mg, 0.76 mmol), and the reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was cooled to room temperature and poured into water (100 mL), followed by extraction with EA (60 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.4 g, 88.60%) as a brown solid.

[0238] MS: m / z = 189 (M+1, ESI+).

[0239] Step 2: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoate To a solution of 4-(6-fluoropyridin-2-yl)aniline (1.4 g, 7.45 mmol) and methyl 3-bromobenzoate (1.92 g, 8.94 mmol) in dioxane (30 mL) was added CsCO (4.84 g, 14.90 mmol), Brettphos (403 mg, 0.75 mmol), and Pd(dba) (687 mg, 0.75 mmol), and the reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). It was then extracted with EA (40 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.1 g, 45.83%) as a brown solid.

[0240] 1H NMR (400MHz, DMSO-d6) δ8.78(s, 1H), 8.04-7.95(m, 3H), 7.83(dd, J=7.6, 2.7Hz, 1H), 7.73(s, 1H) ), 7.51-7.39(m, 3H), 7.19(d, J=8.8Hz, 2H), 7.01(dd, J=8.0, 2.8Hz, 1H), 3.84(d, J=9.8Hz, 3H).

[0241] MS: m / z = 323 (M+1, ESI+).

[0242] Step 3: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid To a solution of methyl 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoate (1.1 g, 3.42 mmol) in THF / HO (25 mL / 5 mL) was added LiOH·HO (718 mg, 17.10 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N HCl(aq) (40 mL) and then extracted with EA (15 mL × 3). The combined organic layers were washed with brine (60 mL × 3), dried over NaSO, and concentrated in vacuo to give the title compound (900 mg, 85.70%) as a yellow solid.

[0243] 1 H NMR (400MHz, DMSO-d6) δ8.68(s, 1H), 8.13-8.00(m, 3H), 7.90(ddd, J=21.2, 7.6, 2.5Hz, 1H), 7.79(s, 1H), 7.76-7.63(m, 1H), 7.57-7.49(m, 1H), 7.48-7.38(m, 2H), 7.28-7.10(m, 2H), 7.05(dd, J=8.0, 2.7Hz, 1H).

[0244] MS: m / z = 309 (M+1, ESI+).

[0245] Preparation Example 35: Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid [ka]

[0246] Step 1: Synthesis of methyl 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoate To a solution of 4-(pyrazin-2-yl)aniline (150 mg, 0.88 mmol), methyl 5-bromo-2-(dimethylamino)benzoate (271 mg, 1.05 mmol) in 1,4-dioxane (9 mL) was added Pd(dba) (71 mg, 0.0876 mmol), Brettphos (235 mg, 0.438 mmol), and CsCO (563 mg, 1.75 mmol). The mixture was stirred in a microwave oven at 150 °C for 2 h. The reaction mixture was cooled to room temperature and poured into water, followed by extraction with DCM. The combined organic layers were washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (173 mg, 57%) as a yellow solid.

[0247] 1 H NMR (400MHz, DMSO-d6) δ9.13(d, J=1.6Hz, 1H), 8.62-8.57(m, 1H), 8.45(d, J=2.5Hz, 1H), 8.38(s, 1H), 8.04-7 .97(m, 2H), 7.34(d, J=2.8Hz, 1H), 7.26(dd, J=2.8, 8.8Hz, 1H), 7.07-6.98(m, 3H), 3.81(s, 3H), 2.72(s, 6H).

[0248] Step 2: Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid To a solution of methyl 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoate (130 mg, 0.37 mmol) in HO / THF / MeOH (1 mL / 3 mL / 1 mL) was added LiOH·HO (94 mg, 2.24 mmol), and the reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was acidified to pH 3 with 1 N HCl (aq). The solid was then filtered with HO. The filtrate was solidified with DCM and MeOH to give the title compound (82 mg, 66%) as a yellow solid.

[0249] 1H NMR (400MHz, DMSO-d6) δ9.20(d, J=1.6Hz, 1H), 8.93(s, 1H), 8.66-8.64(m, 1H), 8.52(d, J=2.5Hz, 1H) , 8.13-8.07(m, 2H), 7.82-7.76(m, 2H), 7.45(dd, J=2.8, 8.8Hz, 1H), 7.26-7.21(m, 2H), 2.96(s, 6H).

[0250] Preparation Example 36: Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0251] Step 1: Synthesis of ethyl 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate To a solution of 5-(pyridazin-3-yl)pyrimidin-2-amine (400 mg, 2.31 mmol), ethyl 3-bromo-4-(4-methylpiperazin-1-yl)benzoate (907 mg, 2.77 mmol) in 1,4-dioxane (20 mL) was added Pd(dba) (467 mg, 0.58 mmol), Brettphos (620 mg, 1.15 mmol), and CsCO (1483 mg, 4.62 mmol). The reaction mixture was stirred in a microwave oven at 150 °C for 6 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (388 mg, 40%) as a brown solid.

[0252] MS: m / z = 420 (M+1, ESI+).

[0253] Step 2: Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid To a solution of ethyl 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate (387 mg, 0.95 mmol) in HO / THF / MeOH (1.5 mL / 9 mL / 3 mL) was added LiOH·HO (240 mg, 5.73 mmol), and the reaction mixture was stirred at 60 °C for 6 h. The reaction mixture was acidified to pH 3 with 1N HCl (aq) and then extracted with DCM. The combined organic layers were concentrated under reduced pressure. The residue was filtered and washed with MeOH to give the title compound (285 mg, 78%) as a yellow solid.

[0254] 1 H NMR (400MHz, DMSO-d6) δ10.79(s, 1H), 9.30(s, 2H), 9.24(dd, J=4.9, 1.5Hz, 1H), 8.86(s, 1H), 8.76(d, J=2.0Hz, 1H), 8.35(d d, J=1.5, 8.7Hz, 1H), 7.89-7.81(m, 1H), 7.70(dd, J=2.0, 8.3Hz, 1H), 7.29(d, J=8.3Hz, 1H), 3.38-3.11(m, 8H), 2.84(m, 3H).

[0255] Method c. Preparation of carboxylic acid derivatives using other methods (formula III-a) [ka]

[0256] Production Example 37: Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid [ka]

[0257] Step 1: Synthesis of methyl (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylate To a solution of 3-chloro-6-phenylpyridazine (0.5 g, 2.6 mmol) and methyl (1s,4s)-4-aminobicyclo[2.2.1]heptane-1-carboxylate (0.578 g, 3.4 mol) in n-butanol (10 mL) in a sealed tube, trifluoroacetic acid (0.148 g, 13 mmol) was added and the mixture was refluxed at 150 °C for 72 hours. After confirming completion of the reaction by TLC, the reaction solution was cooled to room temperature, diluted with HO, extracted with ethyl acetate, washed with brine, and the organic layer was dried over NaSO and concentrated. The residue was purified by column chromatography to yield the title compound (170 mg, 20%) as a white solid.

[0258] 1 H NMR (400MHz, methanol-d4) δ7.87 (d, J=7.6Hz, 2H), 7.72 (d, J=9.6, 1H), 7.50-7.40 (m, 3H), 6.95(d, J=9.6, 1H), 3.67(s, 3H), 2.25-2.10(m, 6H), 2.03-1.94(m, 2H), 1.83-1.78(m, 2H).

[0259] Step 2: Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid Methyl (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylate (1.4 g, 4.3 mol) prepared in Step 1 and LiOH·HO (0.541 g, 12.9 mol) were dissolved in HO (5 mL) and THF (10 mL) and stirred at room temperature for 6 h. The reaction was confirmed to be complete by TLC, and the mixture was acidified to pH 4 with 2N HCl (aq). The suspension was filtered with HO, and the filter cake was dried in vacuo to give the title compound (1.05 g, 80%) as a pale yellow solid.

[0260] 1H NMR (400MHz, DMSO-d6) δ12.15(s, 1H), 7.98(d, J=7.2Hz, 2H), 7.87(d, J=9.2Hz, 1H), 7 .51-7.43(m, 4H), 7.00(d, J=9.2Hz, 1H), 2.13-2.04(m, 6H), 1.83(m, 2H), 1.70(m, 2H).

[0261] Preparation Example 38: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid [ka]

[0262] Step 1: Synthesis of ethyl 3-aminoadamantane-1-carboxylate hydrochloride To a solution of 3-aminoadamantane-1-carboxylic acid hydrochloride (20.0 g, 86.3 mmol) in EtOH (140 mL), SOCl2 (10.3 g, 86.3 mmol) was added and the mixture was refluxed and stirred at 80°C for 4 hours. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated. Petroleum ether was added to the residue, and the pressure was reduced three times until a precipitate formed. The residue was then slurried in petroleum ether at room temperature for 30 minutes and filtered to obtain the title compound (21.0 g, 94%) as a white solid.

[0263] 1 H NMR (400MHz, DMSO-d6) δ8.28(s, 3H), 4.06(q, J=7.2Hz, 2H), 2.18(s, 2H), 1.90(s, 2H), 1.77(s, 6H), 1.67-1.55(m, 4H), 1.17(t, J=7.2Hz, 3H).

[0264] Step 2: Synthesis of ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-1-carboxylate Ethyl 3-aminoadamantane-1-carboxylate hydrochloride (21.0 g, 80.8 mmol) prepared in Step 1 and K2CO3 (33.5 g, 243 mmol) were added to a solution of 3,6-dichloropyridazine (24.1 g, 162 mmol) in DMF (147 mL), and the mixture was refluxed at 135 °C for 12 hours. After completion of the reaction was confirmed by TLC, the reaction solution was diluted with HO, extracted with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (1.80 g, 7%) as a white solid.

[0265] 1 H NMR (400MHz, CDCl3) δ8.28(s, 3H), 4.06(q, J=7.2Hz, 2H), 2.18(s, 2H), 1.90(s, 2H), 1.77(s, 6H), 1.67-1.55(m, 4H), 1.17(t, J=7.2Hz, 3H).

[0266] Step 3: Synthesis of ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylate Phenylboronic acid (719 mg, 5.90 mmol) and Na2CO3 (2.84 g, 26.8 mmol) were added to a solution of ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-1-carboxylate (1.80 g, 5.36 mmol) prepared in Step 2 in DME (9 mL) and HO (1.8 mL). Pd(PPh3)2Cl2 (376 mg, 0.536 mmol) was added to the mixture, which was then degassed and purged with N2, and refluxed at 80 °C for 12 h. After confirming completion of the reaction by TLC, the reaction solution was diluted with HO, extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography and prep-HPLC to give the title compound (800 mg, 40%) as a white solid.

[0267] 1H NMR (400MHz, CDCl3) δ7.97(d, J=7.2Hz, 2H), 7.56(d, J=9.6Hz, 1H), 7.48-7.44(m 2H), 7.42-7.40(m 1H), 6.70(d, J=9.2Hz, 1H), 4.15-4.09(m, 2H), 2.33(s, 2H), 2.28(s, 2H), 2.19( s, 3H), 1.90(q, J=12Hz, 3H), 1.75-1.70(m, 2H), 1.59(s, 2H), 1.29-1.23(m, 3H).

[0268] Step 4: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid Ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylate (800 mg, 2.12 mmol) prepared in Step 3 and LiOH·HO (445 mg, 10.6 mmol) were dissolved in HO (1.6 mL) and EtOH (3.2 mL) and refluxed at 45 °C for 12 h. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove the EtOH. The residue was acidified to pH 5 with citric acid (aq). The suspension was filtered with HO, and the filter cake was dried in vacuo to give the title compound (450 mg, 60%) as a white solid.

[0269] 1 H NMR (400MHz, DMSO-d6) δ12.11(s, 1H), 7.96(d, J=7.2Hz, 2H), 7.75(d, J=9.2Hz, 1H), 7.48-7.44(m, 2H), 7.40-7.38(m, 1H), 6 .90(d, J=9.6Hz, 1H), 6.60(s, 1H), 2.26(s, 2H), 2.18-2.16(m, 4H), 2.05-2.03(m, 2H), 1.82-1.79(s, 4H), 1.66-1.63(m, 2H).

[0270] Preparation Example 39: Synthesis of 3-((4-phenylpiperazin-1-yl)methyl)benzoic acid [ka]

[0271] Step 1: Synthesis of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate 1-Phenylpiperazine (648 mg, 4.0 mmol), methyl 3-(bromomethyl)benzoate (458 mg, 2.0 mmol), and K2CO3 (552 mg, 4.0 mmol) were dissolved in THF (18 mL) and stirred at room temperature for 39.5 hours. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated. The residue was slurried with ethyl acetate and filtered. The filter cake was purified by MPLC to give the title compound (532 mg, 85%) as a white solid.

[0272] MS: m / z = 311 (M+1, ESI+).

[0273] Step 2: Synthesis of 3-((4-phenylpiperazin-1-yl)methyl)benzoic acid To a solution of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate (310 mg, 1.0 mmol) prepared in Step 1 in MeOH (10 mL) and HO (2 mL) was added LiOH·HO (422 mg, 10.0 mmol), followed by stirring at 65 °C for 2 h. After confirming completion of the reaction by LC-MS, the mixture was neutralized to pH 6 with 6N HCl (aq). The suspension was slurried with HO and filtered to give the title compound (221 mg, 75%) as a white solid.

[0274] MS: m / z = 297 (M+1, ESI+).

[0275] Preparation Example 40: Synthesis of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid [ka]

[0276] Step 1: Synthesis of 4-(pyridazin-3-yl)phenol To a solution of (4-hydroxyphenyl)boronic acid (2.5 g, 18.13 mmol) and 3-bromopyridazine (3.75 g, 23.56 mmol) in dioxane / HO (50 mL / 10 mL) was added CsCO (11.81 g, 36.26 mmol) and Pd(dppf)Cl (1.31 g, 1.81 mmol), and the reaction mixture was stirred at 100 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), followed by extraction with EA (60 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.9 g, 61.29%) as a yellow solid.

[0277] 1 H NMR (400MHz, CDCl3) δ7.65-7.31 (m, 3H), 7.26 (dd, J=15.2, 5.7Hz, 2H), 6.97-6.76 (m, 2H).

[0278] MS: m / z = 173 (M+1, ESI+).

[0279] Step 2: Synthesis of methyl 3-(4-(pyridazin-3-yl)phenoxy)benzoate To a solution of 4-(pyridazin-3-yl)phenol (1.6 g, 9.30 mmol) and (3-(methoxycarbonyl)phenyl)boronic acid (2.17 g, 12.09 mmol) in DCM (30 mL) was added Cu(CFSO) (6.73 g, 18.60 mmol) and TEA (2.82 g, 27.90 mmol), and the reaction mixture was stirred at 40 °C under N for 72 h. The reaction mixture was cooled to room temperature and poured into water (150 mL), followed by extraction with DCM (30 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (650 mg, 22.41%) as a yellow solid.

[0280] MS: m / z=307 (M+1, ESI+).

[0281] Step 3: Synthesis of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid To a solution of methyl 3-(4-(pyridazin-3-yl)phenoxy)benzoate (650 mg, 2.12 mmol) in THF / HO (20 mL / 4 mL) was added LiOH·HO (445 mg, 10.62 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N HCl(aq) (20 mL) and then extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, and concentrated under reduced pressure to give the title compound (600 mg, 96.77%) as a yellow solid.

[0282] MS: m / z=293 (M+1, ESI+).

[0283] Method d. Preparation of benzimidazole derivatives using cyclization reaction (formula IV-a) [ka]

[0284] Preparation Example 41: Synthesis of 2-(3-bromophenyl)-6-fluoro-1H-benzo[d]imidazole [ka]

[0285] 3-Bromobenzoic acid (10.0 g, 49.8 mmol) and 4-fluorobenzene-1,2-diamine (6.27 g, 49.8 mmol) were dissolved in polyphosphoric acid (75 mL) and stirred at reflux at 190 °C for 5 hours. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature and basified with 2N KOH (aq) to pH 9. The suspension was slurried with HO, filtered, and dried in vacuo to give the title compound (10.5 g, 71%) as a purple solid.

[0286] 1 H NMR (400MHz, DMSO-d6) δ13.2(s, 1H), 8.35(s, 1H), 8.16(d, J=6.4Hz, 1H), 7.54-7.50(m, 4H), 7.09(s, 1H).

[0287] Preparation Example 42: Synthesis of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)aniline [ka]

[0288] 3-Aminobenzoic acid (411 mg, 3.0 mmol) and 4,5-dichlorobenzene-1,2-diamine (531 mg, 3.0 mmol) were dissolved in polyphosphoric acid (10 mL) and refluxed at 200 °C for 1 hour. After confirming the completion of the reaction by LC-MS, the mixture was cooled to room temperature and neutralized to pH 6 with 2N NaOH (aq). The suspension was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated, then separated by MPLC. The mixture was slurried with ethyl acetate and diethyl ether and filtered to give the title compound (190 mg, 68%) as a dark pink solid.

[0289] 1 H NMR (400MHz, DMSO-d6) δ13.07(s, 1H), 7.91(s, 1H), 7.70(s, 1H), 7.41(t, J=1.9Hz, 1H), 7.27(d, J=8.0Hz, 1H), 7.19(t, J=7.8Hz, 1H), 6.73-6.70(m, 1H), 5.37(s, 2H).

[0290] Method e. Preparation of amine derivatives using the Steel reaction (formula II-a) [ka]

[0291] Method e+b. Preparation of carboxylic acid derivatives using the Steel and Buchwald reactions (formula III-a) [ka]

[0292] Preparation 43: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid [ka]

[0293] Step 1: Synthesis of 5-(pyrimidin-4-yl)pyridin-2-amine To a solution of 4-(tributylstannyl)pyrimidine (4 g, 10.84 mmol) and 5-bromopyridin-2-amine (1.55 g, 7.06 mmol) in toluene (60 mL) was added Pd(PPh3)4 (1.25 g, 1.08 mmol), and the reaction mixture was stirred at 120 °C under N2 for 48 h. The reaction mixture was cooled to room temperature and poured into water (100 mL), followed by extraction with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.10 g, 58.9%) as a yellow solid.

[0294] MS: m / z = 173 (M+1, ESI+).

[0295] Step 2: Synthesis of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate To a solution of 5-(pyrimidin-4-yl)pyridin-2-amine (1 g, 5.81 mmol) and methyl 3-bromobenzoate (1.63 g, 7.56 mmol) in dioxane / DMSO (15 mL / 3 mL) was added CsCO (3.79 g, 11.62 mmol), Brettphos (936 mg, 1.74 mmol), and Pd(dba) (1.59 g, 1.74 mmol). The reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). It was then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (800 mg, 44.9%) as a pale yellow solid.

[0296] MS: m / z=307 (M+1, ESI+).

[0297] Step 3: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid To a solution of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate (800 mg, 2.61 mmol) in THF / HO (10 mL / 2 mL) was added LiOH·HO (547 mg, 13.04 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N HCl(aq) (20 mL) and then extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, and concentrated in vacuo to give the title compound (700 mg, 91.7%) as a pale yellow solid.

[0298] 1 H NMR (400MHz, DMSO-d6) δ9.73(s, 1H), 9.25-9.13(m, 1H), 9.07(d, J=2.3Hz, 1H), 8.78(d, J=5.4Hz, 1H), 8. 48-8.28(m, 3H), 8.11-7.96(m, 2H), 7.54(t, J=10.1Hz, 1H), 7.40(t, J=7.9Hz, 1H), 6.99(d, J=8.8Hz, 1H).

[0299] MS: m / z=293 (M+1, ESI+).

[0300] Preparation 44: Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid [ka]

[0301] Step 1: Synthesis of 3-chloro-6-(pyridin-2-yl)pyridazine To a solution of 2-(tributylstannyl)pyridine (14 g, 38.03 mmol) and 3,6-dichloropyridazine (7.4 g, 49.44 mmol) in toluene (200 mL) was added Pd(PPh3)4 (2.2 g, 1.90 mmol), and the reaction mixture was stirred at 120 °C under N2 for 48 h. The reaction mixture was cooled to room temperature and poured into water (500 mL), followed by extraction with EA (100 mL × 3). The combined organic layers were washed with brine (500 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3.2 g, 43.9%) as a yellow solid.

[0302] 1 H NMR (400MHz, DMSO-d6) δ8.77(t, J=8.7Hz, 1H), 8.55(dd, J=19.6, 8.5Hz, 2H), 8.05(dd, J=11.8, 5.4Hz, 2H), 7.66-7.54(m, 1H).

[0303] MS: m / z = 192 (M+1, ESI+).

[0304] Step 2: Synthesis of 6-(pyridin-2-yl)pyridazin-3-amine A mixture of 3-chloro-6-(pyridin-2-yl)pyridazine (3.2 g, 16.7 mmol) in NH.sub.3 HO (35 mL) was stirred at 120.degree. C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the title compound (3 g, crude) as a white solid.

[0305] MS: m / z = 173 (M+1, ESI+).

[0306] Step 3: Synthesis of methyl 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoate To a solution of 6-(pyridin-2-yl)pyridazin-3-amine (2 g, 11.62 mmol) and methyl 3-bromobenzoate (5 g, 23.23 mmol) in dioxane (50 mL) was added CsCO (7.6 g, 23.23 mmol), Brettphos (623 mg, 1.16 mmol), and Pd(dba) (532 mg, 0.58 mmol), and the reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (500 mL), followed by extraction with EA (80 mL × 3). The combined organic layers were washed with brine (500 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.1 g, 30.38%) as a yellow solid.

[0307] MS: m / z=307 (M+1, ESI+).

[0308] Step 4: Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid To a solution of methyl 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoate (1.1 g, 3.59 mmol) in THF / HO (12 mL / 3 mL) was added LiOH·HO (301 mg, 7.18 mmol), and the reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N HCl(aq) (100 mL) and then extracted with EA (40 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated in vacuo to give the title compound (900 mg, 85.71%) as a yellow solid.

[0309] 1 H NMR (400MHz, DMSO-d6) δ9.74(s, 1H), 8.70(d, J=4.1Hz, 1H), 8.59-8.43(m, 2H), 8.36(d , J=9.3Hz, 1H), 8.12-7.92(m, 2H), 7.54(dd, J=39.6, 7.6Hz, 3H), 7.30(d, J=9.3Hz, 1H).

[0310] MS: m / z=293 (M+1, ESI+).

[0311] Method f. Preparation of benzimidazole derivatives using cyclization (Acetic acid) (Formula IV-a) [ka]

[0312] Preparation Example 45: Synthesis of 2-(2-bromopyridin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole [ka]

[0313] To a solution of 2-bromoisonicotinic acid (5.00 g, 24.75 mmol) and TBTU (11.92 g, 37.12 mmol) in DCM (300 mL) was added 4-(trifluoromethyl)benzene-1,2-diamine (5.67 g, 32.18 mmol) and DIEA (9.60 g, 74.25 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (200 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give a yellow solid, N-(2-amino-5-(trifluoromethyl)phenyl)-2-bromoisonicotinamide (4.4 g, 49.4%). MS: m / z = 362 (M+1, ESI+). Then, a mixture of N-(2-amino-5-(trifluoromethyl)phenyl)-2-bromoisonicotinamide (4.4 g, 12.22 mmol) in AcOH (50 mL) was stirred at 110° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (3.0 g, 71.56%) as a white solid.

[0314] 1H NMR (400MHz, DMSO-d6) δ13.78(s, 1H), 8.62(d, J=5.1Hz, 1H), 8.36(s, 1H), 8.18( dd, J=5.1, 1.2Hz, 1H), 8.06(s, 1H), 7.87(d, J=8.3Hz, 1H), 7.61(d, J=8.2Hz, 1H).

[0315] MS: m / z = 343 (M+1, ESI+).

[0316] Preparation Example 46: Synthesis of 2-(3-bromophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole [ka]

[0317] To a solution of 3-bromobenzoic acid (16.5 g, 82.09 mmol) and HATU (37.4 g, 98.51 mmol) in DCM (300 mL) was added 4-(trifluoromethyl)benzene-1,2-diamine (15.17 g, 86.20 mmol) and DIEA (31.77 g, 246.27 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (800 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (800 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give a yellow solid, N-(2-amino-4-(trifluoromethyl)phenyl)-3-bromobenzamide (21 g, 71.19%). MS: m / z = 360 (M+1, ESI+). Then, a mixture of N-(2-amino-4-(trifluoromethyl)phenyl)-3-bromobenzamide (21 g, 58.50 mmol) in AcOH (200 mL) was stirred at 110° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (16 g, 80.21%) as a yellow solid.

[0318] 1H NMR (400MHz, DMSO-d6) δ13.47(s, 1H), 8.40(s, 1H), 8.22(d, J=7.5Hz, 1H), 8.0 5(s, 1H), 7.88(d, J=13.1Hz, 1H), 7.76(d, J=7.9Hz, 1H), 7.56(t, J=7.4Hz, 2H).

[0319] MS: m / z = 341 (M+1, ESI+).

[0320] Method g. Preparation of benzimidazole derivatives using Mitsunobu reaction and cyclization (Formular IV-b) [ka]

[0321] Preparation Example 47: Synthesis of 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethan-1-amine [ka]

[0322] Step 1: Synthesis of methyl 5-bromo-2-(2-(dimethylamino)ethoxy)benzoate To a solution of methyl 5-bromo-2-hydroxybenzoate (300 mg, 1.30 mmol), 2-(dimethylamino)ethan-1-ol (0.13 mL, 1.30 mmol) in toluene (3 mL) was added PPh3 (375 mg, 1.43 mmol) and DIAD (0.28 mL, 1.43 mmol), and the reaction mixture was stirred at 80 °C for 7 h. The reaction mixture was cooled to room temperature and poured into water, followed by extraction with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (258 mg, 66%) as a yellow oil.

[0323] 1H NMR (400MHz, DMSO-d6) δ7.74(d, J=2.6Hz, 1H), 7.68(dd, J=2.7, 8.9Hz, 1H), 7.15(d, J =8.9Hz, 1H), 4.11(t, J=5.7Hz, 2H), 3.78(s, 3H), 2.62(t, J=5.7Hz, 2H), 2.21(s, 6H).

[0324] Step 2: Synthesis of 5-bromo-2-(2-(dimethylamino)ethoxy)benzoic acid To a solution of methyl 5-bromo-2-(2-(dimethylamino)ethoxy)benzoate (200 mg, 0.662 mmol) in HO / THF (1 mL / 4 mL) was added 1N NaOH (2 mL), and the reaction mixture was stirred at 60° C. for 5 h. The reaction mixture was acidified to pH 3 with 1N HCl (aq) and then extracted with DCM. The combined organic layers were dried over MgSO and concentrated in vacuo to give the title compound (245 mg, >100%) as a white solid.

[0325] 1 H NMR (400MHz, DMSO-d6) δ7.80(d, J=2.6Hz, 1H), 7.72(dd, J=2.7, 8.9Hz, 1H), 7.19(d, J=8.9Hz, 1H), 4.46-4.42(m, 2H), 3.52-3.48(m, 2H), 2.87(s, 6H).

[0326] Step 3: Synthesis of 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethan-1-amine To a solution of 5-bromo-2-(2-(dimethylamino)ethoxy)benzoic acid (130 mg, 0.451 mmol), benzene-1,2-diamine (54 mg, 0.496 mmol) in DCM (5 mL) was added EDCI (95 mg, 0.496 mmol), HOBt (122 mg, 0.902 mmol), and TEA (0.189 mL, 1.354 mmol), and the reaction mixture was stirred at room temperature for 96 h. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 °C for 8 h. The reaction mixture was washed with NaHCO3(aq) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (69 mg, 42%) as a yellow solid.

[0327] 1 H NMR (400MHz, DMSO-d6) δ13.26(s, 1H), 8.38(d, J=2.6Hz, 1H), 7.69-7.52(m, 3H), 7.32(d, J =8.8Hz, 1H), 7.27-7.19(m, 2H), 4.40(t, J=5.3Hz, 2H), 2.83(t, J=5.3Hz, 2H), 2.43(s, 6H).

[0328] Preparation Example 48: Synthesis of 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole [ka]

[0329] Step 1: Synthesis of methyl 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate To a solution of methyl 5-bromo-2-hydroxybenzoate (300 mg, 1.30 mmol), 2-(4-methylpiperazin-1-yl)ethan-1-ol (0.187 mL, 1.30 mmol) in toluene (3 mL) was added PPh3 (375 mg, 1.43 mmol) and DIAD (0.28 mL, 1.43 mmol), and the reaction mixture was stirred at 80 °C for 7 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (341 mg, 73%) as a yellow oil.

[0330] 1 H NMR (400MHz, DMSO-d6) δ7.74(d, J=2.6Hz, 1H), 7.68(dd, J=2.6, 8.9Hz, 1H), 7.16(d, J=9 .0Hz, 1H), 4.13(t, J=5.6Hz, 2H), 2.68(t, J=5.6Hz, 2H), 2.47-2.21(m, 8H), 2.14(s, 3H).

[0331] Step 2: Synthesis of 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoic acid To a solution of methyl 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate (290 mg, 0.812 mmol) in HO / THF (2 mL / 8 mL) was added 1N NaOH (2.4 mL), and the reaction mixture was stirred at 60° C. for 5 h. The reaction mixture was acidified to pH 3 with 1N HCl (aq) and then extracted with DCM. The combined organic layers were dried over MgSO and concentrated under reduced pressure to give the title compound (223 mg, 80%) as a white solid.

[0332] 1 H NMR (400MHz, DMSO-d6) δ11.11(s, 1H), 7.79(d, J=2.6Hz, 1H), 7.71(dd, J=2.7, 8 .9Hz, 1H), 7.17(d, J=8.9Hz, 1H), 4.38(s, 2H), 3.33-3.05(m, 10H), 2.79(s, 3H).

[0333] Step 3: Synthesis of 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole To a solution of 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoic acid (130 mg, 0.379 mmol), benzene-1,2-diamine (45 mg, 0.417 mmol) in DCM was added EDCI (80 mg, 0.417 mmol), HOBt (102 mg, 0.758 mmol), and TEA (0.158 mL, 1.136 mmol), and the reaction mixture was stirred at room temperature for 96 h. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 °C for 8 h. The reaction mixture was washed with NaHCO3 (aq) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (67 mg, 43%) as a yellow solid.

[0334] 1H NMR (400MHz, DMSO-d6) δ12.11(s, 1H), 8.39(d, J=2.6Hz, 1H), 7.71-7.61(m, 3H), 7.32-7.22(m, 3H) , 4.40(t, J=5.5Hz, 2H), 2.85(t, J=5.5Hz, 2H), 2.66-2.54(m, 4H), 2.45-2.35(m, 4H), 2.15(s, 3H).

[0335] Preparation Example 49: Synthesis of 2-(5-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]imidazole [ka]

[0336] Step 1: Synthesis of methyl 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoate To a solution of methyl 5-bromo-2-hydroxybenzoate (300 mg, 1.30 mmol), 1-methylpiperidin-4-ol (0.153 mL, 1.30 mmol) in toluene (3 mL) was added PPh3 (375 mg, 1.43 mmol) and DIAD (0.28 mL, 1.43 mmol), and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (224 mg, 52%) as a yellow oil.

[0337] 1 H NMR (400MHz, CDCl3) δ7.89(d, J=2.6Hz, 1H), 7.51(dd, J=2.6, 8.9Hz, 1H), 6.87(d, J=8.9Hz, 1H), 4.42(s, 1H), 3.89(s, 3H), 2.70-2.59(m, 2H), 2.43-2.34(m, 2H), 2.32(s, 3H), 2.03-1.86(m, 4H).

[0338] Step 2: Synthesis of 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoic acid To a solution of methyl 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoate (223 mg, 0.680 mmol) in HO / THF (1.5 mL / 6 mL) was added 1N NaOH (2.0 mL), and the reaction mixture was stirred at 60° C. for 5 h. The reaction mixture was acidified to pH 3 with 1N HCl (aq) and then extracted with DCM. The combined organic layers were dried over MgSO and concentrated in vacuo to give the title compound (121 mg, 56%) as a brown oil.

[0339] 1 H NMR (400MHz, DMSO-d6) δ7.79(d, J=2.6Hz, 1H), 7.68(dd, J=2.7, 8.9Hz, 1H), 7.24(d, J=9.0Hz, 1H), 4.95-4.70(m, 1H), 4.18-3.98(m, 2H), 3.27-3.21(m, 2H), 2.72(s, 3H), 2.19-1.95(m, 4H).

[0340] Step 3: Synthesis of 2-(5-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]imidazole To a solution of 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoic acid (65 mg, 0.207 mmol), benzene-1,2-diamine (25 mg, 0.228 mmol) in DCM (2 mL) was added EDCI (44 mg, 0.228 mmol), HOBt (56 mg, 0.414 mmol), and TEA (0.087 mL, 0.621 mmol), and the reaction mixture was stirred at room temperature for 93 h. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 °C for 8 h. The reaction mixture was washed with NaHCO3(aq) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (23 mg, 28%) as a yellow solid.

[0341] 1H NMR (400MHz, DMSO-d6) δ11.86(s, 1H), 8.26(d, J=2.6Hz, 1H), 7.69-7.57(m, 3H), 7.31(d, J=9.0Hz, 1 H), 7.26-7.18(m, 2H), 4.66-4.48(m, 1H), 2.79-2.57(m, 3H), 2.24-2.11(m, 4H), 2.03-1.85(m, 4H).

[0342] Method H. Preparation of Carboxylic Acid Derivatives Using Amide Coupling Reaction [ka]

[0343] Preparation Example 50: Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid [ka]

[0344] Step 1: Synthesis of methyl (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylate To a solution of (1R,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (0.060 mL, 0.449 mmol), 4-(pyrazin-2-yl)aniline (64 mg, 0.374 mmol) in DCM (4 mL) was added HBTU (213 mg, 0.561 mmol) and DIPEA (0.326 mL, 1.869 mmol), and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with NaHCO3 (aq) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was solidified with EA and hexane to give the title compound (100 mg, 90%) as a beige solid.

[0345] 1H NMR (400MHz, DMSO-d6) δ10.64(s, 1H), 9.22(d, J=1.6Hz, 1H), 8.70-8.66(m, 1H), 8.56(d, J=2.5Hz, 1H), 8.14-8.09( m, 2H), 7.77-7.72(m, 2H), 3.66(s, 3H), 2.42-2.35(m, 1H), 2.07-2.01(m, 1H), 1.44-1.37(m, 1H), 1.37-1.31(m, 1H).

[0346] Step 2: Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid To a solution of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylate (89 mg, 0.299 mmol) in HO / THF (1 mL / 3 mL) was added 1N NaOH (0.9 mL) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was acidified to pH 3 with 1N HCl (aq) and then extracted with DCM. The combined organic layers were dried over MgSO and concentrated under reduced pressure to give the title compound (61 mg, 71%) as a beige solid.

[0347] 1 H NMR (400MHz, DMSO-d6) δ12.63(s, 1H), 10.64(s, 1H), 9.23(d, J=1.5Hz, 1H), 8.72-8.66(m, 1H), 8.56(d, J=2 .5Hz, 1H), 8.17-8.09(m, 2H), 7.78-7.71(m, 2H), 2.40-2.29(m, 1H), 1.99-1.89(m, 1H), 1.41-1.27(m, 2H).

[0348] [Example] Preparation of the compound represented by formula 1 according to the present invention Method A. Preparation by amide reaction and cyclization reaction [ka]

[0349] Example 1: Synthesis of 6-phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine [ka]

[0350] 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (1.75 g, 6.0 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (1.11 g, 6.3 mmol), and TBTU (2.89 g, 9.0 mmol) were dissolved in DMF (20 mL). DIPEA (2.09 mL, 12.0 mmol) was added and the mixture was stirred at room temperature overnight. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove the DMF, and acetic acid (20 mL) was added and stirred at reflux at 120 °C for 3 hours. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to give the title compound (154 mg, 42%) as a white solid.

[0351] Example 2: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine [ka]

[0352] 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (524 mg, 1.8 mmol), benzene-1,2-diamine (162 mg, 1.5 mmol), and TBTU (963 mg, 3.0 mmol) were dissolved in DMF (20 mL), followed by the addition of DIPEA (0.784 mL, 4.5 mmol) and stirring at room temperature overnight. After confirming completion of the reaction by LC-MS, the mixture was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and acetic acid (20 mL) was added and stirred at reflux for 5 hours at 120 °C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to give the title compound (154 mg, 42%) as a white solid.

[0353] Example 5: Synthesis of 5,6-dichloro-2-(3-((4-phenylpiperazin-1-yl)methyl)phenyl)-1H-benzo[d]imidazole [ka]

[0354] 3-((4-Phenylpiperazin-1-yl)methyl)benzoic acid (221 mg, 0.747 mmol), 4,5-dichlorobenzene-1,2-diamine (217 mg, 0.821 mmol), and TBTU (360 mg, 1.12 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.260 mL, 1.49 mmol) and stirring at room temperature for 2.5 hours. After confirming completion of the reaction by LC-MS, the mixture was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and acetic acid (5 mL) was added and stirred at reflux for 1.5 hours at 120 °C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was purified by MPLC to give the title compound (190 mg, 43%) as a pale yellow solid.

[0355] Example 6: Synthesis of 6-phenyl-N-(3-(6-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine [ka]

[0356] 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (73 mg, 0.25 mmol), 4-(trifluoromethoxy)benzene-1,2-diamine (48 mg, 0.25 mmol), and TBTU (160 mg, 0.5 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.130 mL, 0.75 mmol) and stirring at room temperature overnight. After confirming completion of the reaction by LC-MS, the mixture was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and acetic acid (5 mL) was added and stirred at reflux for 2 hours at 120 °C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to give the title compound (16 mg, 14%) as a white solid.

[0357] Example 7: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine [ka]

[0358] 3-((6-Phenylpyridazin-3-yl)amino)benzoic acid (96 mg, 0.33 mmol), 4,5-dichlorobenzene-1,2-diamine (53 mg, 0.3 mmol), and TBTU (193 mg, 0.6 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.157 mL, 0.9 mmol) and stirring at 50 °C overnight. After confirming completion of the reaction by LC-MS, the mixture was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and acetic acid (5 mL) was added and stirred at reflux at 120 °C overnight. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was purified by MPLC to give the title compound (45 mg, 35%) as a white solid.

[0359] Example 11: Synthesis of N-(3-(7-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine [ka]

[0360] 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (250 mg, 0.859 mmol), 3-bromo-5-fluorobenzene-1,2-diamine (176 mg, 0.859 mmol), and TBTU (551 mg, 1.72 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.450 mL, 2.58 mmol) and stirring overnight at room temperature. After confirming completion of the reaction by TLC, the mixture was diluted with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (5 mL) was added and stirred at reflux for 2 hours at 120 °C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, filtered and dried with dichloromethane to give the title compound (45 mg, 11%) as a white solid.

[0361] Example 14: Synthesis of 5-phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine [ka]

[0362] 3-((5-phenylpyrimidin-2-yl)amino)benzoic acid (873 mg, 3.0 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (528 mg, 3.0 mmol), and TBTU (1.93 g, 6.0 mmol) were dissolved in DMF (30 mL), followed by the addition of DIPEA (1.569 mL, 9.0 mmol) and stirring at room temperature overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and acetic acid (5 mL) was added and stirred at reflux for 4 hours at 120 °C. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, filtered and dried with dichloromethane to give the title compound (475 mg, 37%) as a white solid.

[0363] Example 18: Synthesis of 5-(3-fluorophenyl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridin-2-amine [ka]

[0364] 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid (616 mg, 2.0 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (352 mg, 2.0 mmol), and TBTU (1.28 g, 4.0 mmol) were dissolved in DMF (20 mL), followed by the addition of DIPEA (1.045 mL, 6.0 mmol) and stirring at room temperature overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and acetic acid (20 mL) was added and stirred at reflux for 2 hours at 120 °C. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, filtered and dried with dichloromethane to give the title compound (69 mg, 8%) as a white solid.

[0365] Example 20: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridin-2-yl)phenyl)aniline [ka]

[0366] 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid (100 mg, 0.34 mmol), benzene-1,2-diamine (37 mg, 0.34 mmol), and TBTU (133 mg, 0.41 mmol) were dissolved in DMF (10 mL), followed by the addition of DIPEA (0.180 mL, 1.03 mmol) and stirring at 60 °C overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (10 mL) was added and stirred at reflux for 1 hour at 120 °C. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and ethyl acetate, and filtered to give the title compound (51 mg, 41%) as a white solid.

[0367] Example 21: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [ka]

[0368] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (437 mg, 1.5 mmol), benzene-1,2-diamine (162 mg, 1.5 mmol), and TBTU (722 mg, 1.5 mmol) were dissolved in DMF (10 mL), followed by the addition of DIPEA (0.523 mL, 3.0 mmol) and stirring at 60 °C overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (10 mL) was added and stirred at reflux at 120 °C for 1 hour. After confirming the completion of the reaction by TLC, the solution was cooled to room temperature. The solution was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, slurried in dichloromethane, and filtered to give the title compound (103 mg, 19%) as a pale yellow solid.

[0369] Example 23: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline [ka]

[0370] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (232 mg, 0.8 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (141 mg, 0.8 mmol), and TBTU (283 mg, 0.88 mmol) were dissolved in DMF (10 mL), followed by the addition of DIPEA (0.279 mL, 1.6 mmol) and stirring at 60 °C overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (10 mL) was added and stirred at reflux for 1 hour at 120 °C. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane / ethyl acetate and filtered to give the title compound (190 mg, 55%) as a beige solid.

[0371] Example 24: Synthesis of N-(4-(pyrimidin-4-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline [ka]

[0372] 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid (437 mg, 1.5 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (264 mg, 1.5 mmol), and TBTU (578 mg, 1.8 mmol) were dissolved in DMF (10 mL), followed by the addition of DIPEA (0.523 mL, 3.0 mmol) and stirring at 60 °C overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (10 mL) was added and stirred at reflux for 1 hour at 120 °C. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to give the title compound (167 mg, 26%) as a beige solid.

[0373] Example 25: Synthesis of 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [ka]

[0374] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (437 mg, 1.5 mmol), 4-fluorobenzene-1,2-diamine (246 mg, 1.5 mmol), and TBTU (530 mg, 1.65 mmol) were dissolved in DMF (10 mL), followed by the addition of DIPEA (0.523 mL, 3.0 mmol) and stirring at 60 °C overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (10 mL) was added and stirred at reflux for 1 hour at 120 °C. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and ethyl acetate, and filtered to give the title compound (250 mg, 44%) as a beige solid.

[0375] Example 30: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrimidin-5-yl)phenyl)aniline [ka]

[0376] 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid (146 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol), and TBTU (177 mg, 0.55 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.174 mL, 1.0 mmol) and stirring at room temperature overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (5 mL) was added and stirred at reflux for 2 hours at 120 °C. The completion of the reaction was confirmed by LC-MS, and the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane / ethyl acetate and filtered to give the title compound (35 mg, 19%) as a beige solid.

[0377] Example 32: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)aniline [ka]

[0378] 3-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid (146 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol), and TBTU (177 mg, 0.55 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.174 mL, 1.0 mmol) and stirring overnight at room temperature. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (5 mL) was added and stirred at reflux for 2 hours at 120 °C. The completion of the reaction was confirmed by LC-MS, and the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane / ethyl acetate and filtered to give the title compound (19 mg, 10%) as a beige solid.

[0379] Example 34: Synthesis of N-((1s,4s)-4-(1H-benzo[d]imidazol-2-yl)bicyclo[2.2.1]heptan-1-yl)-6-phenylpyridazin-3-amine [ka]

[0380] (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid (102 mg, 0.33 mmol), benzene-1,2-diamine (36 mg, 0.33 mmol), and TBTU (116 mg, 0.36 mmol) were dissolved in DMF (5 mL). DIPEA (0.115 mL, 0.66 mmol) was added and the mixture was stirred at room temperature overnight. After confirming completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed at 120 °C for 4 hours. After confirming completion of the reaction by TLC, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane / diethyl ether / ethyl acetate and filtered to give the title compound (41 mg, 33%) as a beige solid.

[0381] Example 35: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)adamantan-1-yl)-6-phenylpyridazin-3-amine [ka]

[0382] 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid (115 mg, 0.33 mmol), benzene-1,2-diamine (36 mg, 0.33 mmol), and TBTU (116 mg, 0.36 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.115 mL, 0.66 mmol) and stirring overnight at room temperature. After confirming completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 4 hours. After confirming completion of the reaction by TLC, the reaction solution was concentrated, slurried in dichloromethane / ethyl acetate, and filtered to give the title compound (100 mg, 72%) as a white solid.

[0383] Example 38: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(3-fluorophenyl)-N-methylpyrimidin-2-amine [ka]

[0384] 3-((5-(3-Fluorophenyl)pyrimidin-2-yl)(methyl)amino)benzoic acid (162 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol), and TBTU (177 mg, 0.5 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.174 mL, 1.0 mmol) and stirring overnight at room temperature. After confirming the completion of the reaction by LC-MS, the reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove the DMF, and acetic acid (5 mL) was added and stirred at reflux for 2 hours at 120 °C. After confirming the completion of the reaction by LC-MS, the solution was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was purified by MPLC to give the title compound (80 mg, 42%) as a beige solid.

[0385] Example 39: Synthesis of N-(5-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenyl)-5-(3-fluorophenyl)pyrimidin-2-amine [ka]

[0386] 3-((5-(3-Fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid (170 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol), and TBTU (177 mg, 0.5 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.174 mL, 1.0 mmol) and stirring at room temperature overnight. After confirming completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 2 hours. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to give the title compound (80 mg, 39%) as a beige solid.

[0387] Example 43: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-methylthiophen-3-yl)pyrimidin-2-amine [ka]

[0388] 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid (100 mg, 0.32 mmol), benzene-1,2-diamine (38 mg, 0.35 mmol), and TBTU (124 mg, 0.39 mmol) were dissolved in DMF (2.1 mL), followed by the addition of DIPEA (67 μL, 0.39 mmol) and stirring at room temperature overnight. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove DMF, and acetic acid (2.9 mL) was added and stirred at reflux at 100 °C for 3 hours. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was purified by MPLC to give the title compound (91 mg, 74%) as a yellow foam.

[0389] Example 44: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine [ka]

[0390] 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (130 mg, 0.44 mmol), benzene-1,2-diamine (48 mg, 0.44 mmol), and TBTU (171 mg, 0.53 mmol) were dissolved in DMF (4 mL). DIPEA (0.155 mL, 0.89 mmol) was added and the mixture was stirred at 60 °C for 20 hours. After confirming completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 1 hour. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with saturated NaHCO3 solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to give the title compound (86 mg, 54%) as a beige solid.

[0391] Example 46: Synthesis of 3-(1H-imidazolo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [ka]

[0392] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (291 mg, 1.0 mmol), pyridine-3,4-diamine (109 mg, 1.0 mmol), and TBTU (385 mg, 1.2 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.348 mL, 2.0 mmol) and stirring at 60°C for 7.5 hours. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 16 hours. After confirming the completion of the reaction by LC-MS, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and acidified to pH 2 with 1N HCl (aq), extracted with dichloromethane, and concentrated. The concentrated solution was slurried with dichloromethane / diethyl ether / ethyl acetate and filtered to give the title compound (84 mg, 23%) as a beige solid.

[0393] Example 48: Synthesis of N-(3-(1H-imidazolo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine [ka]

[0394] 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (100 mg, 0.34 mmol), pyridine-3,4-diamine (37 mg, 0.34 mmol), and TBTU (132 mg, 0.41 mmol) were dissolved in DMF (3.4 mL), followed by the addition of DIPEA (0.12 mL, 0.68 mmol) and stirring at room temperature for 21 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was concentrated to remove the DMF, and acetic acid (2 mL) was added and stirred at reflux for 18 hours at 100°C. After confirming completion of the reaction by LC-MS, the reaction mixture was concentrated to remove the acetic acid. After extraction with ethyl acetate and washing with brine, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was purified by MPLC and concentrated, then slurried with a small amount of MeOH and filtered to give the title compound (7 mg, 5.6%) as a beige solid as a filter cake.

[0395] Example 51: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine [ka]

[0396] 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (146 mg, 0.5 mmol), 4-fluorobenzene-1,2-diamine (63 mg, 0.5 mmol), and TBTU (176 mg, 0.55 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.174 mL, 1.0 mmol) and stirring at 60 °C for 16 hours. After confirming completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 19 hours. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with 1N NaOH solution and extraction with ethyl acetate, the organic layer was dried over MgSO and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to give the title compound (77 mg, 40%) as a white solid.

[0397] Example 52: Synthesis of 5-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine [ka]

[0398] 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (200 mg, 0.68 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (120 mg, 0.68 mmol), and TBTU (263 mg, 0.82 mmol) were dissolved in DMF (7 mL). DIPEA (238 μL, 1.36 mmol) was added and the mixture was stirred at room temperature for 2 hours and at 50 °C for 17 hours. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove the DMF, and acetic acid (8 mL) was added and stirred at reflux for 18 hours at 110 °C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature and concentrated to remove the acetic acid. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was slurried with dichloromethane and filtered to give the title compound (91 mg, 31%) as a brown solid as the filter cake.

[0399] Example 54: Synthesis of N-(3-(1H-imidazolo[4,5-c]pyridin-2-yl)phenyl)-6-phenylpyridazin-3-amine [ka]

[0400] 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (200 mg, 0.68 mmol), pyridine-3,4-diamine (75 mg, 0.69 mmol), and TBTU (263 mg, 0.82 mmol) were dissolved in DMF (7 mL), followed by the addition of DIPEA (238 μL, 1.36 mmol) and stirring at room temperature for 67 hours. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove the DMF, and acetic acid (6 mL) was added and stirred at reflux for 17 hours at 110 °C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature and concentrated. The pH was adjusted to 8 using saturated NaHCO3 solution, 1N HCl (aq), and water, followed by extraction with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was slurried with ethyl acetate, filtered, and the filter cake was lyophilized to give the title compound (144 mg, 58%) as a beige solid.

[0401] Example 55: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyridin-2-amine [ka]

[0402] 3-((5-(pyridazin-3-yl)pyridin-2-yl)amino)benzoic acid (100 mg, 0.34 mmol), 4-fluorobenzene-1,2-diamine (48 mg, 0.38 mmol), and TBTU (132 mg, 0.41 mmol) were dissolved in DMF (4 mL), followed by the addition of DIPEA (119 μL, 0.68 mmol) and stirring at room temperature for 17 hours. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove the DMF, and acetic acid (4 mL) was added and stirred at reflux for 4 hours at 110 °C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. The resulting solid was slurried with ethyl acetate and filtered to obtain the title compound (48 mg, 37%) as a brown solid on the filter cake.

[0403] Example 58: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-[2,3′-bipyridine]-6′-amine [ka]

[0404] 3-([2,3'-bipyridin]-6'-ylamino)benzoic acid (190 mg, 0.65 mmol), 4-fluorobenzene-1,2-diamine (82 mg, 0.65 mmol), and TBTU (230 mg, 0.72 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.227 mL, 1.3 mmol) and stirring at 60 °C for 1 h. After confirming completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 1 h. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. After washing with 1N NaOH solution and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to give the title compound (80 mg, 32%) as a white solid.

[0405] Example 61: Synthesis of methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0406] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (500 mg, 1.72 mmol), methyl 3,4-diaminobenzoate (314 mg, 1.89 mmol), and TBTU (661 mg, 2.06 mmol) were dissolved in DMF (17 mL), followed by the addition of DIPEA (0.6 mL, 3.4 mmol) and stirring at room temperature for 17 hours. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove DMF, and acetic acid (17 mL) was added and stirred at reflux for 2 hours at 110°C. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. The resulting solid was slurried with ethyl acetate and filtered. The resulting filter cake was lyophilized to afford the title compound (476 mg, 65%) as a yellow solid.

[0407] Example 64: Synthesis of N-(3-(6-chloro-1H-imidazolo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine [ka]

[0408] 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (146 mg, 0.5 mmol), 6-chloropyridin-3,4-amine (72 mg, 0.5 mmol), and TBTU (177 mg, 0.55 mmol) were dissolved in DMF (5 mL), followed by the addition of DIPEA (0.174 mL, 1.0 mmol) and stirring at 60°C for 18 hours. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 130°C for 25 hours. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated. MeOH was added to the residue, concentrated, and the residue was separated by MPLC, slurried in dichloromethane, and filtered to give the title compound (80 mg, 32%) as a yellow solid.

[0409] Example 78: Synthesis of methyl 2-(3-((4-(pyrimidin-2-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate [ka]

[0410] 3-((4-(pyrimidin-2-yl)phenyl)amino)benzoic acid (3.5 g, 12.0 mmol), methyl 3,4-diaminobenzoate (2.2 g, 13.2 mmol), and TBTU (4.6 g, 14.4 mmol) were dissolved in DMF (40 mL), followed by the addition of DIPEA (3.1 mL, 24.0 mmol) and stirring at 60 °C for 3 hours. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (40 mL) was added, and the mixture was refluxed and stirred at 120 °C for 1 hour. After confirming the completion of the reaction by LC-MS, the mixture was cooled to room temperature. The mixture was slurried with saturated NaHCO3 solution and ethyl acetate and filtered. The resulting filter cake was slurried with dichloromethane and filtered to give the title compound (4.5 g, 89%) as a beige solid.

[0411] Example 79: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazolo[4,5-c]pyridin-2-yl)aniline [ka]

[0412] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (200 mg, 0.69 mmol), 6-(trifluoromethyl)pyridine-3,4-diamine (134 mg, 0.76 mmol), and TBTU (265 mg, 0.83 mmol) were dissolved in DMF (7 mL). DIPEA (239 μL, 1.37 mmol) was added and the mixture was stirred at room temperature for 362 hours, followed by stirring at 40 °C for 16 hours. After confirming completion of the reaction by LC-MS, the mixture was concentrated to remove the DMF, and acetic acid (7 mL) was added. The mixture was refluxed and stirred at 110 °C for 111 hours. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrated solution was slurried with ethyl acetate, filtered, and the filter cake was reslurried with 10% MeOH in DCM to give the title compound (79 mg, 27%) as a dark beige solid on the filter cake.

[0413] Example 91: Synthesis of 3-(1-methyl-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-3-yl)phenyl)aniline [ka]

[0414] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (200 mg, 0.69 mmol), N 11,2-Methylbenzene-1,2-diamine (92 mg, 0.76 mmol) and TBTU (265 mg, 0.83 mmol) were dissolved in DMF (7 mL), followed by the addition of DIPEA (239 μL, 1.37 mmol). The reaction mixture was stirred at room temperature for 24 hours. After confirming completion of the reaction by LC-MS, the reaction mixture was concentrated to remove the DMF, and acetic acid (7 mL) was added. The mixture was then refluxed and stirred at 110°C for 30 hours. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrate was separated by MPLC, slurried with ethyl acetate, and filtered to give the title compound (92 mg, 36%) as a beige solid.

[0415] Example 200: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-(pyrimidin-2-yl)pyridazin-3-amine [ka]

[0416] To a solution of 3-((6-(pyrimidin-2-yl)pyridazin-3-yl)amino)benzoic acid (350 mg, 1.19 mmol) and T3P (760 mg, 2.39 mmol) in DMF (10 mL) was added benzene-1,2-diamine (167 mg, 1.55 mmol) and DIEA (461 mg, 3.57 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a yellow solid, N-(2-aminophenyl)-3-((6-(pyrimidin-2-yl)pyridazin-3-yl)amino)benzamide (400 mg, crude). The crude product was dissolved in AcOH (5 mL) and stirred for 16 h at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to give the title compound (35 mg, 8.04%) as a yellow solid.

[0417] Example 213: Synthesis of 2-(3-(4-(pyridazin-3-yl)phenoxy)phenyl)-1H-benzo[d]imidazole [ka]

[0418] To a solution of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid (600 mg, 2.05 mmol) and HATU (1.17 g, 3.44 mmol) in DMF (20 mL) was added benzene-1,2-diamine (288 mg, 2.67 mmol) and DIEA (1.32 g, 10.25 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give N-(2-aminophenyl)-3-(4-(pyridazin-3-yl)phenoxy)benzamide (600 mg, crude). The crude product was dissolved in AcOH (10 mL) and stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was recrystallized from EA to give the title compound (160 mg, 47.97%) as a white solid.

[0419] Example 214: Synthesis of 5-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)thiazol-2-amine [ka]

[0420] To a solution of 2-((4-(pyridazin-3-yl)phenyl)amino)thiazole-5-carboxylic acid (950 mg, 3.18 mmol) and HATU (1.45 g, 3.82 mmol) in DMF (50 ml), benzene-1,2-diamine (379 mg, 3.50 mmol) and DIEA (1.23 g, 9.55 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (400 mg, 30.77%) as a brown solid.

[0421] Example 218: Synthesis of 3-(6-bromo-1H-imidazo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [ka]

[0422] To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (900 mg, 4.80 mmol) and TBTU (1.85 g, 5.76 mmol) in DMF (15 mL) was added 6-bromopyridine-3,4-diamine (1.46 g, 1.03 mmol) and DIEA (1.86 g, 14.4 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a yellow solid, N-(4-amino-6-bromopyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (1.6 g, crude). The crude product was dissolved in AcOH (30 mL) and stirred for 36 h at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to give the title compound (80 mg, 5.33%) as a beige solid.

[0423] Example 222: Synthesis of 3-(6-(benzyloxy)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [ka]

[0424] To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (300 mg, 1.03 mmol) and TBTU (397 mg, 1.24 mmol) in DMF (15 mL) was added 4-(benzyloxy)benzene-1,2-diamine (232 mg, 1.08 mmol) and DIEA (402 mg, 3.09 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a yellow solid, N-(3-aminopyridin-2-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (400 mg, crude). The crude product was dissolved in AcOH (10 mL) and stirred for 36 h at 120° C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then purified by prep-HPLC to give the title compound (35 mg, 17.5%) as a yellow solid.

[0425] Example 232: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazol[4,5-c]pyridin-2-yl)aniline [ka]

[0426] Step 1: Synthesis of 2-chloro-6-(trifluoromethoxy)pyridine 1-oxide To a stirred solution of 2-chloro-6-(trifluoromethoxy)pyridine (10 g, 58.94 mmol) in DCM (500 mL) at 0 °C, urea hydrogen peroxide (19.41 g, 206.31 mmol) and TFAA (24.76 g, 117.89 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (500 mL) and extracted with DCM (80 mL × 3). The combined organic layers were washed with brine (500 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (600 mg, 4.78%) as a yellow oil.

[0427] 1 H NMR (400MHz, DMSO-d6) δ7.91 (dd, J=8.3, 1.8Hz, 1H), 7.77 (dd, J=8.3, 1.0Hz, 1H), 7.47 (t, J=8.3Hz, 1H).

[0428] MS: m / z = 214 (M+1, ESI+).

[0429] Step 2: Synthesis of 2-chloro-4-nitro-6-(trifluoromethoxy)pyridine 1-oxide To a solution of 2-chloro-6-(trifluoromethoxy)pyridine 1-oxide (550 mg, 2.58 mmol) in HSO / HNO (8 mL / 4 mL) at 0° C. was added KNO (391 mg, 3.86 mmol), and the reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water (50 mL), followed by extraction with EA (15 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (445 mg, 66.83%) as a yellow oil.

[0430] 1 H NMR (400MHz, DMSO-d6) δ8.87 (d, J=3.1Hz, 1H), 8.67 (d, J=3.0Hz, 1H).

[0431] MS: m / z = 259 (M+1, ESI+).

[0432] Step 3: Synthesis of 2-chloro-6-(trifluoromethoxy)pyridin-4-amine To a solution of 2-chloro-4-nitro-6-(trifluoromethoxy)pyridine 1-oxide (445 mg, 1.72 mmol) in AcOH (10 mL) was added Fe (288 mg, 5.16 mmol). The mixture was then stirred at 45 °C for 3 h. The reaction mixture was cooled to room temperature and poured into water (50 mL), followed by extraction with EA (15 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (160 mg, 43.73%) as a yellow solid.

[0433] MS: m / z=213 (M+1, ESI+).

[0434] Step 4: Synthesis of 2-chloro-3-nitro-6-(trifluoromethoxy)pyridin-4-amine To a solution of 2-chloro-6-(trifluoromethoxy)pyridin-4-amine (160 mg, 0.75 mmol) in HSO (5 mL) was added KNO (152 mg, 1.51 mmol), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was cooled to room temperature and poured into water (50 mL), followed by extraction with EA (15 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (175 mg, 90.3%) as a yellow solid.

[0435] 1 H NMR (400MHz, DMSO-d6) δ7.74(s, 2H), 6.59(s, 1H).

[0436] MS: m / z = 257 (M+1, ESI+).

[0437] Step 5: Synthesis of 6-(trifluoromethoxy)pyridine-3,4-diamine To a solution of 2-chloro-3-nitro-6-(trifluoromethoxy)pyridin-4-amine (175 mg, 0.68 mmol) in MeOH (5 mL) was added Pd / C (36 mg, 0.34 mmol), and the reaction mixture was stirred at room temperature for 16 h and filtered. The filtrate was purified by column chromatography to give the title compound (60 mg, 45.72%) as a brown solid.

[0438] 1 H NMR (400MHz, DMSO-d6) δ7.29(s, 1H), 6.21(s, 1H), 5.85(s, 2H), 4.64(s, 2H).

[0439] MS: m / z = 194 (M+1, ESI+).

[0440] Step 6: Synthesis of N-(4-(pyrazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)aniline To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (82 mg, 0.28 mmol) and HATU (129 mg, 0.34 mmol) in DMF (10 mL) was added 6-(trifluoromethoxy)pyridine-3,4-diamine (60 mg, 0.31 mmol) and DIEA (110 mg, 0.85 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a brown solid, N-(4-amino-6-(trifluoromethoxy)pyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (95 mg, 78.68%). MS: m / z = 467 (M+1, ESI+). The brown solid obtained above was dissolved in AcOH (2 mL) and stirred in a microwave at 120 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from MeOH to give the title compound (10 mg, 12.24%) as a pale white solid.

[0441] Example 234: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)aniline [ka]

[0442] To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (550 mg, 1.89 mmol) and HATU (862 mg, 2.27 mmol) in DMF (50 ml) was added 5-(trifluoromethyl)pyridine-2,3-diamine (368 mg, 2.08 mmol) and DIEA (732 mg, 5.66 mmol), and the reaction mixture was stirred at 50° C. for 48 h. The reaction mixture was poured into water (500 mL) and extracted with EA (80 mL × 3). The combined organic layer was washed with brine (500 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a brown solid, N-(2-amino-5-(trifluoromethyl)pyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (700 mg, crude). MS: m / z = 451 (M+1, ESI+). The crude product was dissolved in AcOH (10 mL) and stirred at 120° C. for 48 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to give the title compound (45 mg, 5.51%) as a yellow solid.

[0443] Example 244: Synthesis of 5-(pyridin-2-yl)-N-(3-(5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)pyrimidin-2-amine [ka]

[0444] To a solution of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (650 mg, 2.21 mmol) and T3P (850 mg, 2.67 mmol) in DMF (30 mL) was added 6-(trifluoromethyl)pyridine-2,3-diamine (414 mg, 2.34 mmol), DIEA (863 mg, 6.68 mmol) and DMAP (134 mg, 1.11 mmol), and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give N-(2-amino-6-(trifluoromethyl)pyridin-3-yl)-3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide (800 mg, crude). MS: m / z = 452 (M + 1, ESI +). The crude product was dissolved in AcOH (8 mL) and stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from MeOH to give the title compound (330 mg, 34.23%) as a beige solid.

[0445] Example 250: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)-5-(trifluoromethyl)aniline [ka]

[0446] To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)-5-(trifluoromethyl)benzoic acid (940 mg, 2.62 mmol) and HATU (1.19 g, 3.14 mmol) in DMF (15 mL) was added benzene-1,2-diamine (340 mg, 3.14 mmol) and DIEA (1.01 g, 7.86 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a pale white solid, N-(2-aminophenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)-5-(trifluoromethyl)benzamide (1.2 g, crude). The crude product was dissolved in AcOH (25 mL) and stirred for 16 h at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to give the title compound (190 mg, 16.52%) as a pale white solid.

[0447] Example 252: Synthesis of N-(4-(6-fluoropyridin-2-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline [ka]

[0448] To a solution of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid (500 mg, 1.70 mmol) and HATU (775 mg, 2.05 mmol) in DMF (15 mL) was added 4-(trifluoromethyl)benzene-1,2-diamine (300 mg, 2.05 mmol) and DIEA (665 mg, 5.11 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a brown solid, N-(2-amino-5-(trifluoromethyl)phenyl)-3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzamide (800 mg, crude). The crude product was dissolved in AcOH (20 mL) and stirred for 16 h at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA / MeOH to give the title compound (130 mg, 16.95%) as a white solid.

[0449] Example 279: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine [ka]

[0450] Step 1: Synthesis of N1-methyl-4-nitrobenzene-1,3-diamine To a solution of 5-fluoro-2-nitroaniline (5 g, 32.03 mmol) and methanamine hydrochloride (4.33 g, 64.06 mmol) in NMP (100 mL) was added DIEA (20.66 g, 160.14 mmol), and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature and poured into water (500 mL), followed by extraction with EA (100 mL × 3). The combined organic layer was washed with brine (500 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (4 g, 74.77%) as a yellow solid.

[0451] MS: m / z = 168 (M+1, ESI+).

[0452] Step 2: Synthesis of N4-methylbenzene-1,2,4-triamine N in DCM (10 mL) 1 To a solution of 4-methyl-4-nitrobenzene-1,3-diamine (500 mg, 2.99 mmol), Pd / C (50 mg) was added, and the reaction mixture was stirred at 25 °C under H for 6 h and filtered. The filtrate was concentrated under reduced pressure to give the title compound (500 mg, crude) as a brown solid.

[0453] MS: m / z = 138 (M+1, ESI+).

[0454] Step 3: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (817 mg, 2.81 mmol) and HATU (1.60 g, 4.21 mmol) in DMF (20 mL) was added N 4 N-methylbenzene-1,2,4-triamine (500 mg, 3.65 mmol) and DIEA (1.09 g, 8.42 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (200 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a yellow solid, N-(2-amino-5-(methylamino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (250 mg, crude). This crude product was dissolved in AcOH (20 mL) and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from MeOH to give the title compound (8 mg, 0.56%) as a yellow solid.

[0455] Example 280: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine [ka]

[0456] Step 1: Synthesis of N-benzyl-N-methyl-3,4-dinitroaniline To a solution of 4-fluoro-1,2-dinitrobenzene (10 g, 53.73 mmol) and N-methyl-1-phenylmethanamine (8.47 g, 69.85 mmol) in THF (100 mL) was added TEA (10.86 g, 107.46 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (300 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (9 g, 58.44%) as a yellow solid.

[0457] MS: m / z = 288 (M+1, ESI+).

[0458] Step 2: Synthesis of N4-benzyl-N4-methylbenzene-1,2,4-triamine To a solution of N-benzyl-N-methyl-3,4-dinitroaniline (9 g, 31.35 mmol) in MeOH (100 mL) was added Pd / C (1 g), and the reaction mixture was stirred at 25 °C under H for 16 h. Filtration and concentration of the filtrate under reduced pressure afforded the title compound (1.2 g, 16.9%) as a brown solid.

[0459] 1 H NMR (400MHz, DMSO-d6) δ7.31-7.20 (m, 5H), 6.14 (d, J=2.4Hz, 1H), 5.92 (dd, J=8. 4, 2.8Hz, 1H), 5.76(s, 1H), 4.33(s, 2H), 4.29(s, 2H), 3.84(s, 2H), 2.72(s, 3H).

[0460] MS: m / z = 228 (M+1, ESI+).

[0461] Step 3: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (1.40 g, 4.81 mmol) and T3P (2.74 g, 7.21 mmol) in DMF (20 mL) was added N4 -Benzyl-N 4 N-methylbenzene-1,2,4-triamine (1.2 g, 5.28 mmol) and DIEA (1.86 g, 14.42 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (200 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give a yellow solid, N-(2-amino-5-(benzyl(methyl)amino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (1.4 g, crude). This crude product was dissolved in AcOH (20 mL) and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from EA to give the title compound (36 mg, 6.8%) as a pale white solid.

[0462] Example 288: Synthesis of N-(3-(6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine [ka]

[0463] Step 1: Synthesis of 4-(2-morpholinoethoxy)-2-nitroaniline To a solution of 4-amino-3-nitrophenol (2 g, 12.98 mmol) and 2-morpholinoethan-1-ol (1.87 g, 14.27 mmol) in EA (150 mL) at room temperature, PPh3 (4.08 g, 15.57 mmol) and DEAD (3.39 g, 19.47 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature and poured into water (800 mL). It was then extracted with EA (300 mL × 3). The combined organic layers were washed with brine (800 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (2 g, 55.5%) as a black oil.

[0464] Step 2: Synthesis of 4-(2-morpholinoethoxy)benzene-1,2-diamine To a solution of 4-(2-morpholinoethoxy)-2-nitroaniline (1 g, 3.74 mmol) in MeOH (10 mL) was added Pd / C (100 mg), and the reaction mixture was stirred for 16 h at 50° C. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (800 mg, 85.83%) as a brown solid.

[0465] Step 3: Synthesis of N-(3-(6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine To a solution of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (300 mg, 1.02 mmol) and HATU (467 mg, 1.23 mmol) in DMF (10 mL) was added 4-(2-morpholinoethoxy)benzene-1,2-diamine (316 mg, 1.33 mmol) and DIEA (397 mg, 3.07 mmol), and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a brown solid, N-(2-amino-5-(2-morpholinoethoxy)phenyl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzamide (600 mg, crude). The crude product was dissolved in AcOH (5 mL) and stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-column chromatography to give the title compound (160 mg, 21.95%) as a white solid.

[0466] Example 300: Synthesis of N-(3-(6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrazin-2-amine [ka]

[0467] To a solution of 3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzoic acid (270 mg, 0.92 mmol) and HATU (422 mg, 1.11 mmol) in DMF (10 mL) was added 4-(difluoromethoxy)benzene-1,2-diamine (177 mg, 1.02 mmol) and DIEA (358 mg, 2.77 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a yellow solid, N-(2-amino-5-(difluoromethoxy)phenyl)-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzamide (500 mg, crude). The crude product was dissolved in AcOH (5 mL) and stirred for 16 h at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from MeOH to give the title compound (170 mg, 38.55%) as a yellow solid.

[0468] Example 303: Synthesis of N-(3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(thiazol-4-yl)pyrimidin-2-amine [ka]

[0469] To a solution of 3-((5-(thiazol-4-yl)pyrimidin-2-yl)amino)benzoic acid (600 mg, 2.05 mmol) and HATU (935 mg, 2.45 mmol) in DMF (30 mL) was added 6-chloropyridine-3,4-diamine (353 mg, 2.45 mmol) and DIEA (793 mg, 6.15 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a yellow solid, N-(5-amino-2-chloropyridin-4-yl)-3-((5-(thiazol-4-yl)pyrimidin-2-yl)amino)benzamide (700 mg, crude). The crude product was dissolved in AcOH (10 mL) and stirred for 72 h at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to give the title compound (50 mg, 6.13%) as a yellow solid.

[0470] Example 158: Synthesis of (1R,2R)-2-(6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)cyclopropane-1-carboxamide [ka]

[0471] To a solution of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid (20 mg, 0.0706 mmol), 4-fluorobenzene-1,2-diamine (10 mg, 0.0777 mmol) in DCM (1 mL) was added HBTU (40 mg, 0.106 mmol) and DIPEA (0.037 mL, 0.212 mmol), and the reaction mixture was stirred at room temperature for 22 h. The reaction mixture was concentrated under reduced pressure, AcOH (1 mL) was added, and the residue was stirred at 100 °C for 22 h. The reaction mixture was washed with NaHCO3(aq) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (4.4 mg, 17%) as a yellow solid.

[0472] Example 167: Synthesis of 2-(1H-benzo[d]imidazol-2-yl)-N1,N1-dimethyl-N4-(4-(pyrazin-2-yl)phenyl)benzene-1,4-diamine [ka]

[0473] To a solution of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid (50 mg, 0.150 mmol), benzene-1,2-diamine (16 mg, 0.150 mmol) in DCM (1.5 mL) was added HBTU (68 mg, 0.179 mmol) and DIPEA (0.052 mL, 0.299 mmol), and the reaction mixture was stirred at room temperature for 7 h. The reaction mixture was concentrated under reduced pressure, AcOH (1.5 mL) was added, and the residue was stirred at 100 °C for 20 h. The reaction mixture was washed with NaHCO3(aq) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (25 mg, 41%) as a yellow solid.

[0474] Example 176: Synthesis of N-(2-(4-methylpiperazin-1-yl)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine [ka]

[0475] To a solution of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (150 mg, 0.383 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (67 mg, 0.383 mmol) in DMF (4 mL) was added HBTU (174 mg, 0.460 mmol) and DIPEA (0.134 mL, 0.766 mmol), and the reaction mixture was stirred at 60 °C for 22 h. The reaction mixture was concentrated under reduced pressure, AcOH (1.5 mL) was added, and the residue was stirred at 100 °C for 7 h. The reaction mixture was washed with NaHCO3(aq) and then extracted with DCM, and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (61 mg, 30%) as a beige solid.

[0476] Example 328: Synthesis of 5-(pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)pyrazin-2-amine [ka]

[0477] To a solution of 3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzoic acid (300 mg, 1.03 mmol) and 6-(trifluoromethyl)pyridine-3,4-diamine (182 mg, 1.13 mmol) in DMF (10 mL) was added HATU (472 mg, 1.24 mmol) and DIEA (399 mg, 3.09 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a yellow solid, N-(5-amino-2-(trifluoromethyl)pyridin-4-yl)-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzamide (350 mg, crude). The crude product was dissolved in AcOH (5 mL) and stirred for 2 h at 150° C. under microwave irradiation. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from MeOH to give the title compound (78 mg, 16.46%) as a yellow solid.

[0478] Example 329: Synthesis of N-(3-(6-(difluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine [ka]

[0479] To a solution of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (300 mg, 1.03 mmol) and 6-(difluoromethoxy)pyridine-3,4-diamine (198 mg, 1.13 mmol) in DMF (10 mL) was added HATU (472 mg, 1.24 mmol) and DIEA (399 mg, 3.09 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a yellow solid, N-(5-amino-2-(difluoromethoxy)pyridin-4-yl)-3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide (400 mg, crude). The crude product was dissolved in AcOH (6 mL) and stirred under microwave irradiation at 160° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to give the title compound (34 mg, 7.2%) as a yellow solid.

[0480] Method B. Preparation using the Buchwald reaction [ka]

[0481] Example 69: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-2-yl)pyridin-2-amine [ka]

[0482] 5-(Pyrimidin-2-yl)pyridin-2-amine (100 mg, 0.58 mmol), 2-(3-bromophenyl)-1H-benzo[d]imidazole (174 mg, 0.64 mmol), Pd(dba) (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol), and CsCO (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 120 °C for 2 h in a microwave reactor. After completion of the reaction was confirmed by LC-MS, the reaction mixture was purified by MPLC, concentrated, slurried in dichloromethane, and filtered to give the title compound (85 mg, 40.2%) as a beige solid on the filter cake.

[0483] Example 72: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-4-yl)pyridin-2-amine [ka]

[0484] 5-(Pyrimidin-4-yl)pyridin-2-amine (100 mg, 0.58 mmol), 2-(3-bromophenyl)-6-fluoro-1H-benzo[d]imidazole (186 mg, 0.64 mmol), Pd(dba) (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol), and CsCO (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 120 °C for 2 h in a microwave reactor. After adding Pd(dba) (106 mg, 0.116 mmol) and BrettPhos (124 mg, 0.232 mmol), the mixture was stirred at 120 °C for an additional 1 h in a microwave reactor. After confirming the completion of the reaction by LC-MS, the reaction solution was purified by MPLC to give the title compound (37 mg, 17%) as a yellow solid.

[0485] Example 73: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-fluoropyridin-2-yl)pyrimidin-2-amine [ka]

[0486] 5-(4-Fluoropyridin-2-yl)pyrimidin-2-amine (100 mg, 0.53 mmol), 2-(3-bromophenyl)-1H-benzo[d]imidazole (158 mg, 0.58 mmol), Pd(dba) (241 mg, 0.26 mmol), BrettPhos (282 mg, 0.53 mmol), and CsCO (343 mg, 1.05 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 120 °C for 1 h in a microwave reactor. After adding Pd(dba) (120 mg, 0.13 mmol) and BrettPhos (141 mg, 0.26 mmol), the mixture was stirred at 120 °C for an additional 1 h in a microwave reactor. After confirming the completion of the reaction by LC-MS, the reaction solution was purified by MPLC to give the title compound (30 mg, 15%) as a white solid.

[0487] Example 16: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine [ka]

[0488] 2-Chloropyrimidine (334 mg, 3.0 mmol), 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)aniline (831 mg, 3.0 mmol), Pd(dba) (275 mg, 0.3 mmol), BrettPhos (242 mg, 0.45 mmol), and CsCO (2.9 g, 9.0 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 150 °C for 40 min in a microwave reactor. After completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature. After removing the Pd by filtration through Celite, the mixture was separated by MPLC, slurried in dichloromethane / ethyl acetate, and filtered to give the title compound (180 mg, 17%) as a beige solid.

[0489] Example 75: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-3-(pyrimidin-5-yl)aniline [ka]

[0490] 3-(Pyrimidin-5-yl)aniline (99 mg, 0.58 mmol), 2-(3-bromophenyl)-1H-benzo[d]imidazole (174 mg, 0.64 mmol), Pd(dba) (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol), and CsCO (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 120 °C for 2 h in a microwave reactor. After confirming completion of the reaction by LC-MS, the reaction mixture was purified by MPLC, concentrated, slurried with ethyl acetate, and filtered to give the title compound (115 mg, 54.5%) as a white solid on the filter cake.

[0491] Example 77: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-phenylpyrimidin-5-amine [ka]

[0492] 2-Phenylpyrimidin-5-amine (103 mg, 0.60 mmol), 2-(3-bromophenyl)-1H-benzo[d]imidazole (164 mg, 0.60 mmol), Pd(dba) (49 mg, 0.053 mmol), BrettPhos (64 mg, 0.12 mmol), and CsCO (391 mg, 1.2 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 120 °C for 1.5 h in a microwave reactor. After completion of the reaction was confirmed by LC-MS, the mixture was cooled to room temperature. After washing with H2O and extraction with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The residue was separated by MPLC, slurried in dichloromethane / hexane, and filtered to give the title compound (21 mg, 9%) as a white solid.

[0493] Example 113: Synthesis of 6-(1-methyl-4-piperidyl)-N-[3-[6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl]phenyl]pyridazin-3-amine [ka]

[0494] To a solution of 6-(1-methyl-4-piperidyl)pyridazin-3-amine (100 mg, 0.52 mmol) and 2-(3-bromophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (213 mg, 0.62 mmol) in dioxane (5 mL) was added Pd(dba) (47.6 mg, 0.052 mmol), BrettPhos (69.8 mg, 0.13 mmol), and NaOtBu (100 mg, 1.04 mmol). The reaction mixture was stirred at 150 °C under microwave irradiation for 1.5 h. After completion of the reaction was confirmed by LC-MS, the mixture was cooled to ambient temperature. The reaction mixture was washed with brine, extracted with 10% MeOH in DCM, dried over NaSO, and concentrated under reduced pressure. The residue was slurried in ethyl acetate / hexane and concentrated under reduced pressure. The residue was slurried in DCM and filtered to give the title compound (81 mg, 34%) as a white solid.

[0495] Example 261: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-amine [ka]

[0496] To a solution of 2-(2-bromopyridin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1.45 g, 4.24 mmol) and 4-(pyridazin-3-yl)aniline (943 mg, 5.51 mmol) in dioxane / DMSO (30 mL / 6 mL) was added t-BuOK (950 mg, 8.48 mmol) and Ruphos-Pd G3 (706 mg, 0.85 mmol). The reaction mixture was stirred at 120 °C under N for 16 h. The reaction mixture was cooled to room temperature and poured into water (200 mL). It was then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (48 mg, 2.6%) as a yellow solid.

[0497] Example 265: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(6-fluoropyridazin-3-yl)phenyl)aniline [ka]

[0498] To a solution of 4-(6-fluoropyridazin-3-yl)aniline (100 mg, 0.53 mmol) and 2-(3-bromophenyl)-1H-benzo[d]imidazole (188 mg, 0.69 mmol) in dioxane (5 mL) was added CsCO (346 mg, 1.06 mmol), Brettphos (142 mg, 0.27 mmol), and Pd(dba) (247 mg, 0.27 mmol). The reaction mixture was stirred at 120 °C under microwave irradiation for 4 h. The reaction mixture was cooled to room temperature and poured into water (50 mL). It was then extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (20 mg, 9.90%) as a pale yellow solid.

[0499] Example 154: Synthesis of N-(4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline [ka]

[0500] To a solution of 4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)aniline (56 mg, 0.206 mmol), 2-(3-bromophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (85 mg, 0.248 mmol) in 1,4-dioxane (3 mL) was added Pd(dba) (42 mg, 0.0516 mmol), BrettPhos (55 mg, 0.103 mmol), and CsCO (133 mg, 0.413 mmol). The reaction mixture was stirred in a microwave at 150 °C for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified with DCM and hexane to give the title compound (10 mg, 9%) as a beige solid.

[0501] Example 168: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-(2-(dimethylamino)ethoxy)-N-(4-(pyrazin-2-yl)phenyl)aniline [ka]

[0502] To a solution of 4-(pyrazin-2-yl)aniline (15 mg, 0.0916 mmol), 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethan-1-amine (30 mg, 0.0833 mmol) in 1,4-dioxane (1 mL) was added Pd(dba) (7 mg, 0.0083 mmol), BrettPhos (22 mg, 0.0416 mmol), and CsCO (53 mg, 0.167 mmol), and the reaction mixture was stirred in a microwave at 150 °C for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (6 mg, 16%) as a yellow solid.

[0503] Example 169: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(4-(pyrazin-2-yl)phenyl)aniline [ka]

[0504] To a solution of 4-(pyrazin-2-yl)aniline (14 mg, 0.0795 mmol), 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole (30 mg, 0.0722 mmol) in 1,4-dioxane (1 mL) was added Pd(dba) (6 mg, 0.0072 mmol), BrettPhos (19 mg, 0.0361 mmol), and CsCO (46 mg, 0.145 mmol), and the reaction mixture was stirred in a microwave at 150 °C for 2 h. The reaction mixture was purified. The crude mixture was solidified with EA and hexane to give the title compound (12 mg, 31%) as a yellow solid.

[0505] Example 172: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-((1-methylpiperidin-4-yl)oxy)-N-(4-(pyrazin-2-yl)phenyl)aniline [ka]

[0506] To a solution of 4-(pyrazin-2-yl)aniline (11 mg, 0.0626 mmol), 2-(5-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]imidazole (22 mg, 0.0570 mmol) in 1,4-dioxane (1 mL) was added Pd(dba) (5 mg, 0.0057 mmol), BrettPhos (15 mg, 0.0285 mmol), and CsCO (37 mg, 0.114 mmol), and the reaction mixture was stirred in a microwave at 150 °C for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (4 mg, 16%) as a yellow solid.

[0507] Example 177: Synthesis of N-(2-((1-methylpiperidin-4-yl)oxy)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine [ka]

[0508] To a solution of 5-(pyridazin-3-yl)pyrimidin-2-amine (77 mg, 0.444 mmol), 2-(3-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (184 mg, 0.404 mmol) in 1,4-dioxane (4 mL) was added Pd(dba) (33 mg, 0.0404 mmol), BrettPhos (108 mg, 0.202 mmol), and CsCO (259 mg, 0.808 mmol), and the reaction mixture was stirred in a microwave at 150 °C for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (6 mg, 16%) as a yellow solid.

[0509] Example 178: Synthesis of N-(3-((1-methylpiperidin-4-yl)oxy)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrazin-3-yl)pyrimidin-2-amine [ka]

[0510] To a solution of 5-(pyridazin-3-yl)pyrimidin-2-amine (39 mg, 0.223 mmol), 2-(3-bromo-5-((1-methylpiperidin-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (92 mg, 0.203 mmol) in 1,4-dioxane (2 mL) was added Pd(dba) (16 mg, 0.0203 mmol), BrettPhos (54 mg, 0.101 mmol), and CsCO (130 mg, 0.405 mmol), and the reaction mixture was stirred in a microwave at 150 °C for 3 h. The reaction mixture was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (10 mg, 9%) as a pink solid.

[0511] Example 179: Synthesis of N-(3-(2-(dimethylamino)ethoxy)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine [ka]

[0512] To a solution of 5-(pyridazin-3-yl)pyrimidin-2-amine (111 mg, 0.642 mmol), 2-(3-bromo-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenoxy)-N,N-dimethylethan-1-amine (250 mg, 0.584 mmol) in 1,4-dioxane (6 mL) was added Pd(dba) (47 mg, 0.0584 mmol), BrettPhos (157 mg, 0.292 mmol), and CsCO (375 mg, 1.168 mmol), and the reaction mixture was stirred in a microwave at 160 °C for 3 h. The reaction mixture was purified by MPLC. The crude mixture was solidified with EA and hexane to give the title compound (58 mg, 19%) as a yellow solid.

[0513] Example 311: Synthesis of 5-(5-((methylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine [ka]

[0514] Step 1: Synthesis of tert-butyl methyl ((6-(2-((3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)pyrimidin-5-yl)pyridin-3-yl)methyl)carbamate To a solution of tert-butyl ((6-(2-aminopyrimidin-5-yl)pyridin-3-yl)methyl)(methyl)carbamate (320 mg, 1.86 mmol) and 2-(3-bromophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (395 mg, 1.77 mmol) in dioxane (8 mL) was added Pd(dba) (146 mg, 0.16 mmol), Brettphos (170 mg, 0.32 mmol), and t-BuONa (305 mg, 3.17 mmol), and the reaction mixture was stirred at 130 °C for 4 h under microwave irradiation. The reaction mixture was cooled to room temperature and poured into water (30 mL), followed by extraction with DCM (10 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (700 mg, crude) as a yellow solid.

[0515] MS: m / z = 576 (M+1, ESI+).

[0516] Step 2: Synthesis of 5-(5-((methylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine To a mixture of tert-butyl methyl ((6-(2-((3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)pyrimidin-5-yl)pyridin-3-yl)methyl)carbamate (320 mg, 1.86 mmol) in EA (8 mL) was added 3 M HCl in ethyl acetate (2 mL), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to give the title compound (70 mg, 8.93%) as a white solid.

[0517] Example 321: Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate [ka]

[0518] Step 1: Synthesis of 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylic acid To a solution of methyl 4'-amino-[1,1'-biphenyl]-3-carboxylate (320 mg, 1.41 mmol) and 2-(3-bromophenyl)-1H-benzo[d]imidazole (571 mg, 1.93 mmol) in dioxane (4 mL) was added Pd(dba) (128 mg, 0.141 mmol), Brettphos (75 mg, 0.141 mmol), and t-BuONa (269 mg, 2.82 mmol). The reaction mixture was stirred at 130 °C for 4 h under microwave irradiation. The reaction mixture was cooled to room temperature and poured into water (20 mL). It was then extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (110 mg, 19.30%) as a yellow solid.

[0519] Step 2: Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate To a solution of 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylic acid (110 mg, 0.27 mmol) in MeOH (10 mL) at 0 °C was added SOCl (64 mg, 0.54 mmol) dropwise, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (30 mg, 32.26%) as a white solid.

[0520] Method C. Preparation of Carboxylic Acid Derivatives by Hydrolysis Example 62: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0521] Methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.12 mmol) prepared in Example 61 and LiOH·HO (50 mg, 1.186 mmol) were dissolved in 1,4-dioxane (1 mL) and HO (0.2 mL) and stirred at room temperature for 1.5 hours, then refluxed and stirred at 50°C for 19 hours. After confirming the completion of the reaction by LC-MS, the pH was adjusted to 5 with 1N HCl solution and extracted with ethyl acetate. The organic layer was dried over NaSO and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to obtain the title compound (13 mg, 27%) as a yellow solid on the filter cake.

[0522] Method D. Preparation of Amide Derivatives by Amide Ligation Example 65: Synthesis of N-isopropyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide [ka]

[0523] 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.12 mmol) prepared in Example 62, propan-2-amine (9 mg, 0.013 mmol), and TBTU (47 mg, 0.15 mmol) were dissolved in DMF (2 mL), and then DIPEA (13 μL, 0.69 mmol) was added and stirred at room temperature for 67 hours. After confirming the completion of the reaction by LC-MS, the mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to obtain the title compound (8.4 mg, 15%) as a beige solid on the filter cake.

[0524] Example 66: Synthesis of N-cyclohexyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide [ka]

[0525] 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.12 mmol) prepared in Example 62, cyclohexanamine (15 mg, 0.017 mmol), and TBTU (47 mg, 0.15 mmol) were dissolved in DMF (2 mL), and then DIPEA (13 μL, 0.69 mmol) was added and stirred at room temperature for 17 hours. After confirming completion of the reaction by LC-MS, the mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was slurried with dichloromethane and filtered to obtain the title compound (41 mg, 68%) as a beige solid on the filter cake.

[0526] Method E. Preparation by amide reaction and cyclization followed by additional reaction [ka]

[0527] Example 40: Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-2-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)phenol [ka]

[0528] N-(5-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenyl)-5-(3-fluorophenyl)pyrimidin-2-amine (41 mg, 0.10 mmol) prepared in Example 39 was dissolved in dichloromethane, and BBr3 in hexane (1 M, 0.2 mL, 0.2 mmol) was added at 0 °C. The mixture was stirred at room temperature for 8 hours. After confirming the completion of the reaction by LC-MS, the residue was slurried in dichloromethane and filtered to obtain the title compound (21 mg, 9%) as a beige solid.

[0529] Example 93: Synthesis of 3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [ka]

[0530] To a solution of methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate (102 mg, 0.24 mmol) prepared in Example 61 and N-hydroxyacetamidine (24 mg, 0.32 mmol) in DMSO (0.5 mL) was added NaOH (16 mg, 0.45 mmol), and the reaction mixture was stirred at room temperature for 49 hours. After completion of the reaction was confirmed by LC-MS, the mixture was washed with brine. After extraction with 10% MeOH in DCM, the precipitated solid was slurried again with ethyl acetate and filtered to give the title compound (16 mg, 22%) as a beige solid.

[0531] Method F. Preparation by Other Reactions [ka]

[0532] Example 122: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole [ka]

[0533] Step 1: Synthesis of 2-(3-iodophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 3-iodobenzaldehyde (1-1, 3 g, 12.9 mmol) in DMF (20 mL) was added 4-(trifluoromethyl)benzene-1,2-diamine (1-2, 2.06 g, 11.7 mmol) and oxone (5.03 g, 8.19 mmol). After stirring the mixture at room temperature for 2 h, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE: EtOAc = 10:1) to give the title compound (1-3, 3.7 g, 81%) as a white solid.

[0534] 1 H-NMR (400MHz, DMSO-d6)δ: 13.45(s, 1H), 8.59(s, 1H), 8.24(d, J=7.6Hz, 1H), 8.05-7.75(m, 3H), 7.56(d, J=6.4Hz, 1H), 7.40(t, J=8.0Hz, 1H).

[0535] 19 F-NMR (377MHz, DMSO-d6): δ-58.91. Step 2: Synthesis of 2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole A mixture of 2-(3-iodophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-3, 1 g, 2.57 mmol), 4-bromobenzenethiol (1-4, 400 mg, 2.14 mmol), CuI (408 mg, 2.14 mmol), L-proline (246 mg, 2.14 mmol), and KPO (1.36 g, 6.42 mmol) in 1,4-dioxane (10 mL) was degassed and refilled with N (three times). The mixture was heated to 100 °C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 4:1) to give the title compound (1-5, 1.02 g, 88%) as a white solid.

[0536] MS: m / z = 449 (M+1, ESI+).

[0537] Step 3: Synthesis of 2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-5, 800 mg, 1.78 mmol) in CHCl3 (20 mL) was added mCPBA (645 mg, 3.75 mmol), and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give the title compound (1-6, 652 mg, 76%) as a white solid.

[0538] 1 H-NMR (400MHz, DMSO-d6) δ13.68(s, 1H), 8.81(s, 1H), 8.52(d, J=8.0Hz, 1H), 8.14(d, J=8.0Hz, 1H), 8 .10(s, 0.5H), 7.98(d, J=8.4Hz, 2H), 7.90-7.85(m, 4H), 7.79(d, J=8.0Hz, 0.5H), 7.60-7.55(m, 1H).

[0539] 19 F-NMR (377MHz, DMSO-d6): δ -58.94, -59.01.

[0540] Step 4: Synthesis of 2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole A mixture of 2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-6, 350 mg, 0.73 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1-7, 278 mg, 1.1 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), and KOAc (214 mg, 2.19 mmol) in 1,4-dioxane (10 mL) was degassed and refilled with N2 (three times). The mixture was heated to 100 °C overnight. LC-MS confirmed the reaction was complete. After cooling, the product was used immediately in the next reaction.

[0541] MS: m / z = 529 (M+1, ESI+).

[0542] Step 5: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-8, 0.73 mmol) in 1,4-dioxane (10 mL) was added 3-bromopyridazine (1-9, 139 mg, 0.87 mmol), HO (1 mL), KCO (302 mg, 2.19 mmol), and Pd(dppf)Cl (22 mg, 0.03 mmol). The mixture was degassed and refilled with N (three times) before being heated to 100 °C overnight. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 1:2) to give the title compound (150 mg, 42%) as a white solid.

[0543] Example 123: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4-oxadiazol-2-amine [ka]

[0544] Step 1: Synthesis of pyridazine-3-carbohydrazide Pyridazine-3-carboxylic acid (2-0, 1.0 g, 8 mmol) was dissolved in DCM (20 mL) at 0 °C. SOCl (1.2 g, 9.6 mmol) and one drop of DMF were added to the solution. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was dissolved in DCM (20 mL), and then NH NHBoc (1.2 g, 8.8 mmol) and DIEA (2 g, 16 mmol) were added. The mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and aqueous NaHCO (50 mL). The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated in vacuo. Subsequently, the crude product was dissolved in ethyl acetate (10 mL). HCl / 1,4-dioxane (4 mol / L, 10 mL) was added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and aqueous NaHCO3 (100 mL). The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (2-1, 790 mg, 71%) as a white solid.

[0545] MS: m / z = 139 (M+1, ESI+).

[0546] Step 2: Synthesis of 2-(3-nitrophenyl)-1H-benzo[d]imidazole Benzene-1,2-diamine (2-2, 3.2 g, 30 mmol) was dissolved in DMF (30 mL). 3-Nitrobenzaldehyde (2-3, 5 g, 33 mmol) was added, followed by Oxone (12.8 g, 21 mmol). The mixture was stirred at room temperature for 2 h, after which HPLC analysis confirmed the reaction was complete. The reaction was quenched with aqueous KCO (1 M, 10 mL), and HO (120 mL) was added dropwise to the mixture with vigorous stirring. The resulting precipitate was collected by filtration, washed with HO, and dried to give the title compound (2-4, 7.5 g, crude), which was used in the next step without further addition.

[0547] MS: m / z = 240 (M+1, ESI+).

[0548] Step 3: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)aniline A mixture of 2-(3-nitrophenyl)-1H-benzo[d]imidazole (2-4, 7.5 g, crude) and 750 mg of Pd / C in MeOH (100 mL) was stirred at room temperature under a H atmosphere for 16 hours. The reaction mixture was then filtered through Celite and subsequently washed with MeOH. The combined filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 60:1) to give the title compound (2-5, 3.8 g, 61%) as a yellow solid.

[0549] MS: m / z = 210 (M+1, ESI+).

[0550] Step 4: Synthesis of 2-(3-isothiocyanatophenyl)-1H-benzo[d]imidazole To a solution of 3-(1H-benzo[d]imidazol-2-yl)aniline (2-5, 0.7 g, 3.3 mmol) in THF (10 mL) was added O-phenylcarbonochloridothioate (2-6, 633 mg, 3.7 mmol). The resulting mixture was stirred at room temperature under N atmosphere for 2 h, and then 1N NaOH solution (10 mL) was added. The resulting mixture was stirred at room temperature under N atmosphere for 16 h, then diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title compound (2-7, 180 mg, 22%) as a yellow solid.

[0551] MS: m / z = 252 (M+1, ESI+).

[0552] Step 5: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-(pyridazine-3-carbonyl)hydrazine-1-carbothioamide A mixture of 2-(3-isothiocyanatophenyl)-1H-benzo[d]imidazole (2-7, 180 mg, 0.7 mmol) and pyridazine-3-carbohydrazide (2-1, 97 mg, 0.7 mmol) in EtOH (30 mL) was stirred at room temperature under a N atmosphere for 16 h. The resulting precipitate was collected by filtration, washed with EtOH, and dried. The residue was purified by prep-HPLC to give the title compound (2-8, 190 mg, 70%) as a yellow solid.

[0553] MS: m / z = 390 (M+1, ESI+).

[0554] Step 6: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4-oxadiazol-2-amine To a solution of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-(pyridazine-3-carbonyl)hydrazine-1-carbothioamide (2-8, 100 mg, 0.25 mmol) in DMSO (3 mL) was added EDCI (72 mg, 0.37 mmol). The resulting mixture was stirred at room temperature under a N atmosphere for 16 h. The reaction was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (50 mg, 56%) as a white solid.

[0555] Example 124: Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline [ka]

[0556] Step 1: Synthesis of 2-(3-nitrophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 4-(trifluoromethyl)benzene-1,2-diamine (3-2, 821 mg, 4.7 mmol) in DMF (10 mL) was added 3-nitrobenzaldehyde (3-1, 774 mg, 5.1 mmol), followed by oxone (2.0 g, 3.3 mmol). The mixture was stirred at room temperature for 2 h, after which LCMS analysis confirmed the reaction was complete. The reaction was quenched with aqueous KCO (1 M, 25 mL), and HO (60 mL) was added dropwise to the mixture with vigorous stirring. The resulting precipitate was collected by filtration, washed with HO, and dried to give the title compound (3-3, 1.5 g, crude), which was used in the next step without further purification.

[0557] MS: m / z = 308 (M+1, ESI+).

[0558] Step 2: Synthesis of 3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline A mixture of 2-(3-nitrophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (3-3, 1.5 g, crude) and 150 mg of Pd / C in MeOH (30 mL) was stirred at room temperature under a H atmosphere for 2 hours. The reaction mixture was then filtered through Celite and subsequently washed with MeOH. The combined filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 60:1) to give the title compound (3-4, 410 mg, 31%) as a brown solid.

[0559] MS: m / z = 278 (M+1, ESI+).

[0560] Step 3: Synthesis of 3-chloro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridazine A flame-dried flask was charged with PdCl(dppf) (250 mg, 0.3 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (3-5, 2.1 g, 8.0 mmol), 3,6-dichloropyridazine (3-6, 1.0 g, 6.7 mmol), and KCO (2.8 g, 20.1 mmol). The flask was opened and refilled with N. 1,4-Dioxane / HO (3:1, 30 mL) was added via syringe. The reaction mixture was heated at 80 °C for 16 h. After complete disappearance of the starting material, as monitored by TLC, the mixture was allowed to cool to room temperature. The reaction mixture was diluted with HO and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 2:1) to give the title compound (3-7, 1.2 g, 71%) as a pale white solid.

[0561] MS: m / z=253 (M+1, ESI+).

[0562] Step 4: Synthesis of 3-(1,4-dioxaspiro[4.5]decan-8-yl)pyridazine A mixture of 3-chloro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridazine (3-7, 1.2 g, 4.7 mmol) and 200 mg of Pd / C in MeOH (20 mL) was stirred at room temperature under an H atmosphere for 16 hours. The reaction mixture was then filtered through Celite and subsequently washed with MeOH. The combined filtrate was concentrated to give the title compound (3-8, 0.95 g, crude) as a yellow solid, which was used in the next step without further purification.

[0563] MS: m / z=221 (M+1, ESI+).

[0564] Step 5: Synthesis of 4-(pyridazin-3-yl)cyclohexanone To a stirred solution of 3-(1,4-dioxaspiro[4.5]decan-8-yl)pyridazine (3-8, 0.95 g, crude) in THF (20 mL) was added 1N HCl (aq) (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After confirming the disappearance of the starting material by TLC, the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=60:1) to afford the title compound (3-9, 480 mg, 57%) as a white solid.

[0565] MS: m / z = 177 (M+1, ESI+).

[0566] Step 6: Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline To a solution of 3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline (3-4, 150 mg, 0.54 mmol), 4-(pyridazin-3-yl)cyclohexanone (3-9, 95 mg, 0.54 mmol), and HOAc (65 mg, 1.1 mmol) in DCE (10 mL) was added sodium triacetoxyborohydride (229 mg, 1.1 mmol). The resulting mixture was stirred at room temperature under a N atmosphere for 16 h. The reaction was quenched with aqueous NaHCO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (78 mg, mixture of two isomers, 31%) as a white solid.

[0567] 19 F NMR (376MHz, DMSO-d6): δ-58.78. Example 125: Synthesis of 1-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidin-4-amine [ka]

[0568] Step 1: Synthesis of 8-(pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (4-1, 1.4 g, 9.8 mmol), 3-bromopyridazine (4-2, 2.3 g, 14.7 mmol), and K2CO3 (2.7 g, 19.6 mmol) in 30 mL of DMF was stirred at 100 °C for 16 h and monitored by TLC. After the reaction was complete, the mixture was cooled and 100 mL of water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (4-3, 2.5 g, crude), which was used without further purification.

[0569] MS: m / z=222 (M+1, ESI+).

[0570] Step 2: Synthesis of 1-(pyridazin-3-yl)piperidin-4-one To a stirred solution of 8-(pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4-3, 2.5 g, crude) in THF (20 mL) was added 1N HCl (aq) (10 mL) at room temperature. The resulting mixture was stirred at 70 °C for 2 h. After TLC confirmed the reaction was complete, it was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 60:1) to give the title compound (4-4, 490 mg, 27%) as a brown oil.

[0571] MS: m / z = 178 (M+1, ESI+).

[0572] Step 3: Synthesis of 1-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidin-4-amine To a solution of 1-(pyridazin-3-yl)piperidin-4-one (4-4, 100 mg, 0.56 mmol), 3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline (4-5, 155 mg, 0.56 mmol), and HOAc (67 mg, 1.1 mmol) in DCE (10 mL) was added sodium triacetoxyborohydride (239 mg, 1.1 mmol). The resulting mixture was stirred at room temperature under a N atmosphere for 16 h. The reaction was quenched with aqueous NaHCO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (77 mg, 31%) as a white solid.

[0573] 19 F NMR (376MHz, DMSO-d6): δ-58.81. Example 312: Synthesis of 5-(5-((dimethylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine [ka]

[0574] To a mixture of 5-(5-((methylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine (100 mg, 0.17 mmol) prepared in Example 311 in formic acid (5 mL) was added formaldehyde (5 mL) and the reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to give the title compound (17 mg, 13.82%) as a white solid.

[0575] Example 317: Synthesis of 6-(piperidin-4-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2yl)phenyl)piperazin-3-amine [ka]

[0576] To a mixture of tert-butyl 4-(6-((3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)pyridazin-3-yl)piperidine-1-carboxylate (200 mg, 0.37 mmol) in EA (8 mL) was added 3 M HCl in ethyl acetate (4 mL), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to give the title compound (23 mg, 8.07%) as a white solid.

[0577] Other compounds of the above examples were prepared using Methods A through F.

[0578] The chemical structures, NMR and LC-MS analysis results of the compounds of Examples 1 to 336 are summarized in Table 2 below. [Table 2-1]

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

[0579] Experimental Example 1: Efficacy test of thrombus formation inhibitors (ferric chloride-induced carotid artery thrombosis model) 1. Experimental materials and equipment Isoflurane solution (Hana Pharm), iron(III) chloride (FeCl3, Sigma-Aldrich, cat. #157740), dimethyl sulfoxide (DMSO, Sigma-Aldrich, cat. #D5879), poly(ethylene glycol), average Mn 400 (PEG400, Sigma-Aldrich, cat. #202398), hydroxypropyl-beta-cyclodextrin (HP-β-CD, TCI, cat. #H0979)

[0580] 2. Experimental Animals Eight-week-old male SD rats (Sprague-Dawley rats, Orient Bio) were acclimated for two weeks before the experiment. The number of animals was confirmed upon acquisition, and general symptoms and weight measurements were performed. Laboratory records provided by the animal supplier were retained as basic test data. All animals were observed for general symptoms once daily during the quarantine and acclimation periods. They were housed in polycarbonate cages (278W x 420L x 200H mm) under sterile conditions, with a temperature of 22±3°C, relative humidity of 30-70%, ventilation rate of 10-15 times per hour, and a 12-hour day / night cycle (illumination of 150-300 Lux). The cages were changed once a week, and drinking bottles were changed at least twice a week. The animals were given solid feed for laboratory animals (Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C, Envigo RMS, Inc., USA) in a feeder and given free access.

[0581] After the final quarantine, the animals were separated into groups based on the results of ranked weight measurements so that the average weights of each group were distributed as evenly as possible. The remaining animals after group separation were excluded from the study and euthanized by inhaling carbon dioxide (CO2) gas.

[0582] 3. Experimental Procedure 3-1. Preparation of control and test substances The required amounts of control substance 1 (rivaroxaban), control substance 2 (edoxaban), and test substances were weighed, and DMSO equivalent to 5% of the required solution was added. The solution was sonicated for 2 minutes to confirm dissolution. PEG400 equivalent to 50% was then added and sonicated for 2 minutes. Then, 20% HP-β-CD in distilled water equivalent to 45% was added and sonicated for 2 minutes to completely dissolve the substance. The test substances were prepared immediately before administration to the test animals.

[0583] 3-2. Preparation of inducer (50% FeCl3 solution) The required amount of inducer was weighed, added with water for injection, and vortexed, and then water for injection was added to prepare the required volume.

[0584] 3-3. Administration of test substance The test substance was administered orally at a volume of 10 mL / kg using a disposable syringe connected to an oral administration probe 2 hours before thrombosis induction. The control substance was administered orally at a volume of 10 mL / kg using a disposable syringe connected to an oral administration probe 25 minutes or 2 hours before thrombosis induction. The normal control and negative control groups were orally administered the same volume of vehicle (5% DMSO, 50% PEG400, 45% (20% HP-β-CD in distilled water)).

[0585] 3-4. Thrombus induction and measurement of vessel weight The test animals were anesthetized with Ifran solution and the carotid artery was exposed. 2 A Whatman No. 1 filter paper was placed on the carotid artery for 10 minutes. After 10 minutes, the paper was removed and the remaining FeCl3 in the blood vessel was washed with PBS. After leaving it for 20 minutes, the blood vessel was separated. 2 The Whatman No. 1 filter paper from each individual was treated in the same manner. 20 minutes after removing the Whatman No. 1 filter paper, both ends of the vessel were tied with a 4-0 silk ligature and the vessel was separated. The length of the vessel and the length of the ligature were the same for all individuals. After removing the ligature, the vessel was gently touched to Kimwipes to remove any oozing blood from the vessel, and the weight was measured. The vessel was then photographed and its length was measured using the Image J program.

[0586] 3-5. End of exam The test was completed after measuring and photographing the weight and length of the blood vessels. The test results were expressed as an inhibition rate (%) calculated using the index (blood vessel weight (mg) / blood vessel length (mm)) as follows:

number

[0587] The test results (inhibition rate, %) for the groups administered with the compound of each example are presented in Figures 1 to 6, and the compounds of the examples presented in each figure are as shown in Table 3 below. [Table 3]

[0588] Experimental Example 2: Lactic Acid C2 Assay (Measurement of the Externalization Sclera-Brease Function of Phosphatidylserine) 1. Materials and Equipment Ionomycin (Alomonelab, cat. #I-700), DAPI (Sigma-Aldrich, cat. #D8417), paraformaldehyde (Biosesang, cat. #P2031), Lionheart FX automated fluorescence microscope (BioTek), Gen5 TM Software program (BioTek), Image J analysis software program.

[0589] 2.Cell culture Fisher rat thyroid (FRT) cells expressing human ANO6 (variant 5; GenBank accession no. NP_001191732.1) were cultured in DMEM / Ham's F-12 (1:1) medium supplemented with 10% fetal bovine serum, 2 mM L-549 glutamine, 100 units / mL penicillin, and 100 μg / mL streptomycin at 37°C in 5% CO2.

[0590] 3. Test Method FRT cells (2 × 10 ) expressing human ANO6 (variant 5) 4Cells (cells / well) were cultured in a 96-well microplate for 24 hours. After incubation, each well was treated with compound at different concentrations (50 nM, 100 nM, 1 μM) dissolved in DMSO at 1% v / v and incubated for 10 minutes. Ionomycin was then added to each well to a final concentration of 10 μM and incubated for 10 minutes, followed by washing with 200 μL of PBS. Following washing, 50 μL of lactadherin-C2 (Lact-C2)-GFP in DMEM medium was added to each well to a final concentration of 500 nM to stain phosphatidylserine, and the wells were incubated for 10 minutes at 37°C. After incubation, the wells were washed with 200 μL of PBS and fixed with 4% paraformaldehyde for 5 minutes at room temperature. For morphological analysis, cells were incubated in DAPI solution for 15 minutes and then washed with PBS. The fluorescence intensity of Lact-C2-GFP bound to phosphatidylserine on the cell surface was measured using an automated fluorescence microscope. Quantitative analysis of the fluorescence intensity of Lact-C2-GFP was performed using Gen5 TM , the Image J analysis program was used.

[0591] The inhibitory activity (%) of phosphatidylserine externalization by compounds was calculated using the following analytical method. After subtracting background fluorescence from the measured Lact-C2-GFP fluorescence values, the fluorescence values ​​of the ionomycin-untreated group and the ionomycin-treated group in the same row as each test group in a 96-well microplate were calculated. To calculate the inhibitory activity (%) of compounds, the group untreated with compound and ionomycin was set to 100% inhibitory activity, and the group treated with ionomycin alone was set to 0% inhibitory activity, and the relative inhibitory activity was calculated. The test was repeated three times to derive the results, and the average values ​​were classified according to the following ranges and are shown in Table 4 below (A: >60% inhibition, B: 30-60% inhibition, N / A: test not progressed). [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0592] Experimental Example 3: Measurement of cell viability 1. Materials and Equipment Vero cell line (Ministry of Food and Drug Safety, Republic of Korea, serial number: VERO01WCB-1201), Calu-3 cell line (Korean Cell Line Bank, Republic of Korea, KCLB#30055), CellTiter 96 (trademark registered) AQueous One Solution Cell Proliferation Assay kit (Promega, cat.# G3582), Infinite M200 microplate reader (Tecan).

[0593] 2.Cell culture Vero cells were cultured in DMEM medium supplemented with 10% fetal bovine serum, 100 units / mL penicillin, and 100 μg / mL streptomycin at 37° C. in 5% CO 2 .

[0594] Calu-3 cells were cultured in MEM medium supplemented with 10% fetal bovine serum, 2.2 g / L sodium bicarbonate, 1% 100 units / mL penicillin, and 100 μg / mL streptomycin at 37°C in 5% CO2.

[0595] 3. Test Method Vero or Calu-3 cells were cultured in 96-well microplates for 24 hours to reach 20% confluency. After incubation, each well was treated with 1, 3, or 10 μM compounds in DMSO at 0.5% v / v and incubated at 37°C for 48 hours. After incubation, 100 μL of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay solution (CellTiter 96™ AQueous One Solution Cell Proliferation Assay Kit (Promega)) mixed with DMEM medium at a 1:5 ratio was dispensed into each well of the 96-well microplate and incubated at 37°C for 1 hour. Absorbance at 490 nm and 690 nm was then measured using an Infinite M200 instrument.

[0596] The cell viability (%) following compound treatment was calculated using the following analytical method. After subtracting the background absorbance value at 690 nm from the measured absorbance value at 490 nm, the cell viability of each test group was calculated by setting the viability of the DMSO-treated group (not treated with any compound) as 100%, and then calculating the relative viability (%) for each compound. Two to six replicate tests were performed to derive the results, and the average values ​​of the results were classified according to the following ranges, as shown in Table 5 (A: ≥80% survival, B: 50-80% survival, N / A: not tested). [Table 5-1] [Table 5-2] [Table 5-3]

[0597] Experimental Example 4: Virus replication test 1. Experimental materials and equipment Severe acute respiratory syndrome coronavirus type 2: NCCP-43343 or NCCP-43388 (National Pathogen Resource Bank, Republic of Korea), Calu-3 cells (Korea Cell Line Bank, Republic of Korea, KCLB#30055), Vero cells (Korea Food and Drug Administration, Republic of Korea), Minimum Essential Medium (MEM, HyClone #SH30024.01, Logan, UT), fetal bovine serum (FBS, HyClone #SH30084.03), penicillin-streptomycin (HyClone #SV300010), phosphate-buffered saline (PBS, HyClone, Logan, UT), QIAamp Viral RNA Mini kit (QIAGEN #52906, Valencia, CA), Luna® Universal One-Step RT-qPCR Kit (New England) BioLabs® Inc., Ipswich, MA), severe acute respiratory syndrome coronavirus type 2 nsp targeting forward primer, 5'-TGG GGY TTT ACR GGT AAC CT-3'; severe acute respiratory syndrome coronavirus type 2 nsp targeting reverse primer, 5'-AAC RCG CTT AAC AAA GCA CTC-3'; probe, 5'-56-FAM-TAG TTG TGA / ZEN / TGC WAT CAT GAC TAG-3IABkFQ-3' (Chu, DK, Wet et al., 2020), on an Applied Biosystem Quantstudio 3 detection system (Applied Biosystems, Waltham, MA).

[0598] 2.Cell culture Calu-3 (or Vero) cells were cultured in MEM medium supplemented with 10% fetal bovine serum, 2.2 g / L sodium bicarbonate, and 1% penicillin-streptomycin at 37°C in 5% CO2.

[0599] 3. Test Method Clinically isolated severe acute respiratory syndrome coronavirus type 2 (SAR-2) strain NCCP-43343 (or NCCP-43388) was used. To evaluate the efficacy of nine drugs against viral infection, Calu-3 (or Vero) cells were infected with NCCP-43343 (or NCCP-43388) (0.01 MOI) for 1 hour after pre-infection with the drug. After washing with PBS to remove uninfected virus, the cells were re-infected with MEM medium containing 2% fetal bovine serum and then incubated for 48 hours. After washing with PBS to remove uninfected virus, the cells were re-infected with MEM medium containing 2% fetal bovine serum and then incubated for 48 hours. All viral infection experiments were conducted in the Yonsei University Medical Center Biosafety Committee's Level 3 facility (IBC 2020-003) and approved by the Yonsei University Medical Center's Life Safety Committee. To measure the amount of replicated severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus, viral RNA secreted into the cell culture medium was extracted using the QIAamp Viral RNA Mini kit. For amplification, 2 μL of extracted RNA was mixed with 10 μL of 2X Luna Universal One-Step Reaction Mix, 0.4 μL of 10 μM primers, 0.2 μL of 10 μM probe, and 1 μL of 20X Luna WarmStart® RT Enzyme Mix, and then RNase-free water was added to bring the total volume to 20 μL. Forty amplifications were performed using the conditions described in the manufacturer's protocol and monitored in real time using an Applied Biosystems Quantstudio 3 detection system. A standard curve was derived from qRT-PCR values ​​using serially diluted virus.

[0600] The inhibitory activity (%) for the nine test drugs was calculated as follows.

[0601] (1) The measured values ​​of the test drug minus the measured values ​​of the negative control group (DMSO) were converted into a relative percentage. In other words, the value of the negative control group was fixed at 0%. The formula for calculating inhibitory activity is as follows: Inhibitory activity (%) = [negative control group - test drug group] ÷ [negative control group] × 100 (2) The experiment was repeated twice and the average was calculated.

[0602] The results of the analysis are shown in Table 6, where "A" denotes compounds that exhibited inhibitory activity of more than 60%, and "B" denotes compounds that exhibited inhibitory activity of 30 to 60%. [Table 6]

Claims

1. A pharmaceutical composition for treating or preventing a virus-related disease, disorder or condition, comprising a compound represented by the following chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above Chemical Formula 1, Ring X is a 5- to 6-membered heteroaryl, a 5- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkenyl, wherein one or more H in said 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl ring is —C １－６ Alkyl, -benzyl, -C １－６ Haloalkyl, -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ or -halo}; Y １ Or Y ４ are each independently CR Ｙ or N; R Ｙ is -H, -C １－６ Alkyl, —C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ , -S(=O) ２ -C １－６ alkyl, -halo, or 5- to 6-membered heteroaryl, wherein one or more H in said 5- to 6-membered heteroaryl is —C １－６ optionally substituted with alkyl; Ring A and ring B are each independently an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or multiple rings, and one or more H in the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring is selected from -C １－６ Alkyl, -C １－６ Aminoalkyl, —C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl]}; L is -CH ２ -, -NR Ｌ -, -C≡C-NR Ｌ , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR Ｌ -, -NR Ｌ C(=O)-, -S-, -S(=O) ２ -, -S(=O) ２ -NR Ｌ - or -NR Ｌ -S(=O) ２ - and; R Ｌ is -H or -C １－６ is alkyl; Z is -H, -C １－６ Alkyl, -CN, -C ２ alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {said -C ２ One or more H in an alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring may be replaced by —C １－６ Alkyl, -C １－６ Aminoalkyl, —C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl]}; R ａ and R ｂ are each independently —H, —C １－６ alkyl, or -benzyl; R ｃ is -H, -C １－６ Alkyl, —C １－６ Haloalkyl, -(CH ２ ) n-R ｅ , -benzyl, or heterocycloalkyl, wherein one or more H in the heterocycloalkyl ring is —C １－６ optionally substituted with alkyl; R ｄ is -H, -OH, -O-C １－６ Alkyl, —NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) (C １－６ alkyl), —NH—C ３－６ cycloalkyl, or -NH-aryl; R ｅ is -C １－６ Aminoalkyl, —NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) (C １－６ alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl, or heterocycloalkenyl is a single ring or multiple rings, and one or more H in said heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring is -C １－６ optionally substituted with alkyl; n is 0, 1, 2, 3 or 4.

2. The compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 1-1 below: 【Chemistry 2】 In the above Chemical Formula 1-1, X １ is CR １ R ２ , N.R. ３ , O or S; X ２ is CR ４ or N; R １ Or R ４ are each independently —H or —C １－６ is alkyl; Y １ Or Y ４ are each independently CR Ｙ or N; R Ｙ is -H, -C １－６ Alkyl, —C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -S(=O) ２ -C １－６ alkyl, -halo, or 5- to 6-membered heteroaryl, wherein one or more H in said 5- to 6-membered heteroaryl is —C １－６ optionally substituted with alkyl; Ring A and ring B are each independently an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or multiple rings, and one or more H in the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ Aminoalkyl, —C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl]}; L is -CH ２ -, -NR Ｌ -, -C≡C-NR Ｌ , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR Ｌ -, -NR Ｌ -C(=O)-, -S-, -S(=O) ２ -, -S(=O) ２ -NR Ｌ - or -NR Ｌ -S(=O) ２ - and; R Ｌ is -H or -C １－６ is alkyl; Z is -H, -CN, -C ２ alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein the —C ２ One or more H in an alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring may be replaced by —C １－６ Alkyl, -C １－６ Aminoalkyl, —C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , —O—(CH ２ ) n-R ｅ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl]}; R ａ and R ｂ are each independently —H, —C １－６ alkyl, or -benzyl; R ｃ is -H, -C １－６ Alkyl, —C １－６ Haloalkyl, -(CH ２ ) n-R ｅ , -benzyl, or heterocycloalkyl, wherein one or more H in the heterocycloalkyl ring is —C １－６ optionally substituted with alkyl; R ｄ is -H, -OH, -O-C １－６ Alkyl, —NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) (C １－６ alkyl), —NH—C ３－６ cycloalkyl, or -NH-aryl; R ｅ is -NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) (C １－６ alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl, wherein one or more H in said heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring is —C １－６ optionally substituted with alkyl; n is 0, 1, 2, 3 or 4; The pharmaceutical composition of claim 1.

3. X １ is NR ３ or O; X ２ is CR ４ or N; R ３ and R ４ are each independently —H or —C １－６ is alkyl; Y １ and Y ４ are each independently CR Ｙ and Y ２ and Y ３ are each independently CR Ｙ or N {wherein ring X １ If S, then Y ２ and Y ３ one of the rings is N; １ is O and X ２ is CR ４ If Y ２ and Y ３ one of which is N}; R Ｙ is -H, -C １－６ Alkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -S(=O) ２ -C １－６ alkyl, -halo, or 5- to 6-membered heteroaryl, wherein one or more H in said 5- to 6-membered heteroaryl is —C １－６ optionally substituted with alkyl; The pharmaceutical composition of claim 2.

4. Ring A is phenyl, a 5- to 6-membered heteroaryl, or a 5- to 6-membered cycloalkyl, wherein one or more H in said phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered cycloalkyl ring is —C １－６ Haloalkyl, -NO ２ , -NR ａ R ｂ , -OR ｃ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl]}; The pharmaceutical composition of claim 2.

5. L is -NR Ｌ -, -C≡C-NR Ｌ , —O—, or —S(═O) ２ - and; R Ｌ is -H or -C １－６ is alkyl; The pharmaceutical composition of claim 2.

6. Ring B is phenyl, a 5- to 6-membered heteroaryl, or a 5- to 6-membered heterocycloalkyl, wherein one or more H in said phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl ring is —C １－６ Alkyl, -C １－６ Haloalkyl, -NO ２ , -NR ａ R ｂ , -OR ｃ or -halo}; The pharmaceutical composition of claim 2.

7. Z is —CN, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl, wherein one or more H in said phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl ring is —C １－６ Alkyl, -C １－６ Haloalkyl, —CN, —OR ｃ , —C(═O)—R ｄ , -(CH ２ ) n-R ｅ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl, and when Ring B is phenyl, a 6-membered heteroaryl, or a 6-membered heterocycloalkyl, Z is attached in the p-position relative to L; The pharmaceutical composition of claim 2.

8. 2. The pharmaceutical composition of claim 1, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the virus-related disease, disorder, or condition is one or more selected from the group consisting of the common cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus 19 (COVID-19).

10. The pharmaceutical composition of claim 9 , wherein the virus is an RNA virus.

11. The RNA viruses include Coronaviridae, Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hypoviridae, Megabirnaviridae, Partitiviridae, and Picornaviridae. (Picobirnaviridae), Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae, Picornaviridae viridae), Secoviridae, Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, Tymoviridae, Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Niyami 11. The pharmaceutical composition of claim 10, wherein the virus is selected from the group consisting of Nyamiviridae, Caliciviridae, Flaviviridae, Luteoviridae, Togaviridae, Pneumoviridae, Arenaviridae, Deltaviridae, and Orthomyxoviridae.

12. A composition for disinfecting or sterilizing an object contaminated with a virus, comprising a compound represented by the following chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above Chemical Formula 1, Ring X is a 5- to 6-membered heteroaryl, a 5- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkenyl, wherein one or more H in said 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl ring is —C １－６ Alkyl, -benzyl, -C １－６ Haloalkyl, -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ or -halo}; Y １ Or Y ４ are each independently CR Ｙ or N; R Ｙ is -H, -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ , -S(=O) ２ -C １－６ alkyl, -halo, or 5- to 6-membered heteroaryl, wherein one or more H in said 5- to 6-membered heteroaryl is —C １－６ optionally substituted with alkyl; Ring A and ring B are each independently an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or multiple rings, and one or more H in the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring is selected from -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl]}; L is -CH ２ -, -NR Ｌ -, -C≡C-NR Ｌ , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR Ｌ -, -NR Ｌ C(=O)-, -S-, -S(=O) ２ -, -S(=O) ２ -NR Ｌ - or -NR Ｌ -S(=O) ２ - and; R Ｌ is -H or -C １－６ is alkyl; Z is -H, -C １－６ Alkyl, -CN, -C ２ alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {said -C ２ One or more H in an alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring may be replaced by —C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, —C １－６ Haloalkyl, —CN, —NO ２ , -NR ａ R ｂ , -OR ｃ , —C(═O)—R ｄ , -(CH ２ ) n-R ｅ , —O—(CH ２ ) n-R ｅ , -halo, or 5- to 6-membered heterocycloalkyl, wherein one or more H of the 5- to 6-membered heterocycloalkyl may be —C １－６ optionally substituted with alkyl]}; R ａ and R ｂ are each independently —H, —C １－６ alkyl, or -benzyl; R ｃ is -H, -C １－６ Alkyl, -C １－６ Haloalkyl, -(CH ２ ) n-R ｅ , -benzyl, or heterocycloalkyl, wherein one or more H in the heterocycloalkyl ring is —C １－６ optionally substituted with alkyl; R ｄ is -H, -OH, -O-C １－６ Alkyl, —NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) (C １－６ alkyl), —NH—C ３－６ cycloalkyl, or -NH-aryl; R ｅ is -C １－６ Aminoalkyl, —NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) (C １－６ alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl, or heterocycloalkenyl is a single ring or multiple rings, and one or more H in said heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring is -C １－６ optionally substituted with alkyl; n is 0, 1, 2, 3 or 4.

13. Use of a compound represented by Chemical Formula 1 according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment or prevention of a viral infection or a disease associated with a viral infection.

14. A method for treating or preventing a viral infection or a disease associated with a viral infection, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula 1 according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

15. 13. Use of the compound represented by formula 1, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt as claimed in claim 12, for use in the manufacture of a medicament for use in disinfecting or sterilizing a virus-contaminated subject.

16. A method for sterilizing or disinfecting a virus-contaminated subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Chemical Formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof as described in claim 12.

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