Heteroaryl derivative compounds and uses thereof

Abstract

The present invention relates to fused heteroaryl derivatives and uses thereof. The fused heteroaryl derivative of the present invention can exhibit an excellent inhibitory activity against Annotermin-6 (ANO6), and can be usefully used as a therapeutic agent against thrombus or thrombus-related diseases.

Description

Technical Field

[0001] The present invention relates to a heteroaryl derivative compound and its medical use. Specifically, the present invention relates to a heteroaryl derivative compound having inhibitory activity on Annotamine-6 ​​(ANO6). Background Art

[0002] Annotamine-6 ​​(ANO6 / TMEM16F) is encoded by the TMEM16F gene, is a member of the transmembrane protein family belonging to the Annotamine family, and is expressed in various cells. Annotamine-6 ​​protein is crucial for phosphatidylserine present in the cell membrane to be exposed to the outside of the cell membrane dependent on calcium ions to participate in coagulation, bone formation and T cell activation. Specifically, when platelets are activated, Annotamine-6 ​​exposes phosphatidylserine to activate the coagulation system. In addition, phosphatidylserine is exposed to the outside of the cell membrane through Annotamine-6, thereby acting as a cell activation signal in various cells and participating in cell proliferation and death, and therefore plays an important role in the development and progression of various diseases including hemorrhagic diseases and cancer.

[0003] Therefore, there is a need to develop a composition that can effectively improve or treat diseases such as thromboembolic diseases, inflammatory diseases or cancers involving Annotamine-6 ​​as an ion channel and phospholipid protease through the development of inhibitors of Annotamine-6 ​​activity. Summary of the invention

[0004] Problem that the invention aims to solve

[0005] The object of the present invention is to provide a heteroaryl derivative having a novel structure, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0006] Another object of the present invention is to provide a method for preparing heteroaryl derivative compounds.

[0007] Another object of the present invention is to provide a medical use of a heteroaryl derivative compound; specifically, to provide a pharmaceutical composition for treating or preventing thrombosis or thrombosis-related diseases, the pharmaceutical composition comprising a heteroaryl derivative compound as an active ingredient, and the use of the compound for treating or preventing thrombosis or thrombosis-related diseases; or to provide a method for treating or preventing thrombosis or thrombosis-related diseases, the method comprising administering the compound.

[0008] Means used to solve problems

[0009] In order to achieve the above object, a specific embodiment of the present invention provides a heteroaryl derivative compound having a specific structure that inhibits the activity of Annotamine-6 ​​(ANO6).

[0010] Heteroaryl derivative compounds

[0011] The present invention provides a compound represented by the following Chemical Formula 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0012] [Chemical formula 1]

[0013]

[0014] In the above chemical formula 1,

[0015] Ring X is a 5-6 membered heteroaryl, a 5-6 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl, wherein at least one H in the 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl ring can be substituted by -C 1-6 Alkyl, -benzyl, -C 1-6 Haloalkyl, -(CH2)nR e 、-O-(CH2)nR e or -halogen substitution;

[0016] Y1 to Y4 are each independently CR Y or N;

[0017] R Y -H, -C 1-6 Alkyl, -C 1-6 Amine alkyl, -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 at least one H in the 5-6 membered heteroaryl ring can be -C 1-6 Alkyl substitution;

[0018] Ring A and Ring B are each independently aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is monocyclic or polycyclic, and at least one H in the aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring can be replaced by -C 1-6 Alkyl, -C 1-6 Amine alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b 、-OR c , -C(=O)-R d 、-(CH2)nRe 、-O-(CH2)nR e , -halogen or 5-6 membered heterocycloalkyl, wherein at least one H in the 5-6 membered heterocycloalkyl can be substituted by -C 1-6 Alkyl substitution;

[0019] 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-;

[0020] R L -H or -C 1-6 alkyl;

[0021] Z is -H, -C 1-6 Alkyl, -CN, -C2 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein at least one H in the -C2 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring may be substituted by -C 1-6 Alkyl, -C 1-6 Amine alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b , -ORc, -C(=O)-R d 、-(CH2)nR e 、-O-(CH2)nR e , -halogen or 5-6 membered heterocycloalkyl, wherein at least one H in the 5-6 membered heterocycloalkyl can be substituted by -C 1-6 Alkyl substitution;

[0022] R a and R b are independently -H, -C 1-6 Alkyl or -benzyl;

[0023] R c -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nR e , -benzyl or heterocycloalkyl, wherein at least one H in the heterocycloalkyl ring can be -C 1-6 Alkyl substitution;

[0024] 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;

[0025] R e For -C 1-6 Amine alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), heteroaryl, heterocycloalkyl or heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl or heterocycloalkenyl is monocyclic or polycyclic, and at least one H in the heteroaryl, heterocycloalkyl or heterocycloalkenyl ring can be substituted by -C 1-6 Alkyl substitution; and

[0026] n is 0, 1, 2, 3 or 4.

[0027] According to one embodiment of the present invention, The range is:

[0028] Ring X is a 5-membered heteroaryl group, wherein at least one H in the 5-membered heteroaryl group can be 1-6 Alkyl substitution; and

[0029] Y1 and Y4 are each independently CR Y , and Y2 and Y3 are each independently CR Y or N, wherein when ring X is furan, thiophene or thiazole, one of Y2 and Y3 is N.

[0030] According to one embodiment of the present invention, For example, it can be in the following range:

[0031]

[0032]

[0033] According to an embodiment of the present invention, L may be, for example, in the following range:

[0034]

[0035] According to one embodiment of the present invention, ring A may be, for example, in the following range:

[0036]

[0037] A1 to A4 are each independently CR or N; and

[0038] R is -CF3, -N(CH3)(CH3), -OH, -OCH3, -OCH2CH2-N(CH3)(CH3), -halogen,

[0039] According to one embodiment of the present invention, ring B may be, for example, in the following range:

[0040] and

[0041] R is -methyl, -NO2, -NH2, -OCH3, -OH or -halogen.

[0042] According to one embodiment of the present invention, Z may be, for example, in the following range:

[0043] and

[0044] 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)-O-tert-butyl, -halogen or

[0045] According to one embodiment of the present invention, Re may be, for example, in the following range:

[0046]

[0047] According to an embodiment of the present invention, the compound represented by Chemical Formula 1 may be a compound represented by the following Chemical Formula 1-1:

[0048] [Chemical formula 1-1]

[0049]

[0050] In the above chemical formula 1-1,

[0051] X1 is CR1R2, NR3, O or S;

[0052] X2 is CR4 or N;

[0053] R1 to R4 are each independently -H or -C 1-6 alkyl;

[0054] Y1 to Y4 are each independently CR Y or N;

[0055] R Y -H, -C 1-6 Alkyl, -C1-6 Amine alkyl, -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, -halogen or 5-6 membered heteroaryl, wherein at least one H in the 5-6 membered heteroaryl can be -C 1-6 Alkyl substitution;

[0056] Ring A and Ring B are each independently aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein at least one H in the aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring may be replaced by -C 1-6 Alkyl, -C 1-6 Amine alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b 、-OR c , -C(=O)-R d , -halogen or 5-6 membered heterocycloalkyl, wherein at least one H in the 5-6 membered heterocycloalkyl ring can be substituted by -C 1-6 Alkyl substitution;

[0057] 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-;

[0058] R L -H or -C 1-6 alkyl;

[0059] Z is -H, -CN, -C2 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein at least one H in the -C2 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring may be substituted by -C 1-6 Alkyl, -C 1-6 Amine alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b 、-OR c , -C(=O)-Rd 、-O-(CH2)nR e , -halogen or 5-6 membered heterocycloalkyl, wherein at least one H in the 5-6 membered heterocycloalkyl can be substituted by -C 1-6 Alkyl substitution;

[0060] R a and R b are independently -H, -C 1-6 Alkyl or -benzyl;

[0061] R c -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -(CH2)nR e , -benzyl or heterocycloalkyl, wherein at least one H in the heterocycloalkyl ring can be -C 1-6 Alkyl substitution;

[0062] 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; and

[0063] R e For -C 1-6 Amine alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), heteroaryl, heterocycloalkyl or heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl or heterocycloalkenyl is monocyclic or polycyclic, and at least one H in the heteroaryl, heterocycloalkyl or heterocycloalkenyl ring can be substituted by -C 1-6 Alkyl substitution; and

[0064] n is 0, 1, 2, 3 or 4.

[0065] According to one embodiment of the present invention, Available in the following ranges:

[0066] X1 is NR3 or O;

[0067] X2 is CR4 or N;

[0068] R3 and R4 are each independently -H or -C 1-6 alkyl;

[0069] Y1 and Y4 are each independently CR Y , Y2 and Y3 are each independently CR Yor N, wherein when ring X1 is S, one of Y2 and Y3 is N, and when X1 is O and X2 is CR4, one of Y2 and Y3 is N; and

[0070] 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, -halogen or 5-6 membered heteroaryl, wherein at least one H in the 5-6 membered heteroaryl can be -C 1-6 Alkyl substitution.

[0071] According to one embodiment of the present invention, ring A may be within the following range:

[0072] Ring A is phenyl, 5-6 membered heteroaryl or 5-6 membered cycloalkyl, wherein at least one H in the phenyl, 5-6 membered heteroaryl or 5-6 membered cycloalkyl ring can be -C 1-6 Haloalkyl, -NO2, -NR a R b 、-OR c , -halogen or 5-6 membered heterocycloalkyl, wherein at least one H in the heterocycloalkyl may be substituted by -C 1-6 Alkyl substitution.

[0073] According to one embodiment of the present invention, L may be within the following range:

[0074] L is -NR L -、-C≡C-NR L , -O- or -S(=O)2-; and

[0075] R L -H or -C 1-6 alkyl.

[0076] According to one embodiment of the present invention, ring B may be within the following range:

[0077] Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl, wherein at least one H in the phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl ring can be substituted by -C 1-6 Alkyl, -C 1-6 Haloalkyl, -NO2, -NR a R b 、-OR c or -halogen substituted.

[0078] According to one embodiment of the present invention, Z may be within the following range:

[0079] Z is -CN, phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl, wherein at least one H in the phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl may be -C 1-6 Alkyl, -C 1-6 Haloalkyl, -CN, -OR c , -C(=O)-R d 、-(CH2)nR e , -halogen or 5-6 membered heterocycloalkyl, wherein at least one H in the 5-6 membered heterocycloalkyl can be substituted by -C 1-6 Alkyl substitution, wherein Z is attached to the para position relative to L when Ring B is phenyl, 6-membered heteroaryl or 6-membered heterocycloalkyl.

[0080] 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 described below.

[0081] [Table 1]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089] Unless otherwise specified, the term "alkyl" as used herein may refer to a straight or branched chain acyclic, cyclic or saturated hydrocarbon to which carbon atoms are attached. 1-6 "Alkyl" may refer to an alkyl group containing 1 to 6 carbon atoms, "C 1-4 "Alkyl" may refer to an alkyl group containing 1 to 4 carbon atoms, and "C 1-3 The term "alkyl" may refer to an alkyl group having 1 to 3 carbon atoms. Acyclic alkyl groups may include, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, secondary butyl, isobutyl, tertiary butyl, and the like, but are not limited thereto. In the present specification, cyclic alkyl may be used interchangeably with "cycloalkyl" and may include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, but are not limited thereto.

[0090] In the present invention, "alkoxy" may refer to -(O-alkyl) as an alkyl ether group, wherein the alkyl group is the same as defined above. For example, "C 1-6 "Alkoxy" may refer to a group containing C 1-6 Alkoxy of alkyl, i.e. -(OC 1-6 Alkyl), "C 1-4 "Alkoxy" may refer to a group containing C 1-4 Alkoxy of alkyl, i.e. -(OC 1-4 Alkyl) and "C 1-3 "Alkoxy" may refer to a group containing C 1-3 Alkoxy of alkyl, i.e. -(OC 1-3 Alkyl). For example, alkoxy groups may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, and the like.

[0091] In the present invention, "halo" may be F, Cl, Br or I.

[0092] In the present invention, the term "haloalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with at least one halo as defined herein. Examples of haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with at least one halogen (such as F, Cl, Br or I).

[0093] In the present specification, the term "hydroxyalkyl" may refer to a straight or branched alkyl (hydrocarbon) having a carbon atom substituted with a hydroxyl group (OH). Examples of hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with at least one -OH group.

[0094] In the present specification, the term "aminoalkyl" may refer to a straight or branched alkyl (hydrocarbon) having a carbon atom substituted by an amino group -(NR'R"). Here, R' and R" may be independently selected from hydrogen, C 1-6 The group consisting of an alkyl group and an N protecting group (such as Boc), and the selected R' and R" may be independently substituted or unsubstituted.

[0095] In the present invention, "cycloalkyl" may refer to a hydrocarbon ring that does not contain heteroatoms (N, O, P, P(=O), S or the like) in the ring and may be saturated or partially unsaturated. Here, when unsaturated, the cycloalkyl may be referred to as a cycloalkenyl group. Unless otherwise specified, the cycloalkyl may be monocyclic or polycyclic, such as a spirocyclic, bridged or fused ring.

[0096] In the present invention, "heterocycloalkyl" may refer to a ring containing at least one selected from N, O, P, P(=O) and S in the ring and may be saturated or partially unsaturated. In this article, when unsaturated, heterocycloalkyl may be referred to as heterocycloolefin. Unless otherwise specified, heterocycloalkyl may be monocyclic or polycyclic, such as spirocyclic, bridged or fused rings. In addition, "3 to 12 membered heterocycloalkyl" may refer to heterocycloalkyl containing 3 to 12 atoms forming the ring. Examples of heterocycloalkyl groups may include, but are not limited to, pyrrolidine, piperidine, imidazoline, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, alkane, 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.

[0097] In the present invention, "aromatic hydrocarbon" may refer to an aromatic hydrocarbon ring. The aromatic hydrocarbon may be monocyclic or polycyclic. The number of ring carbon atoms in the aromatic hydrocarbon may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of aromatic hydrocarbons may include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, biphenyl, triphenyl, tetraphenyl, pentphenyl, hexaphenyl, diphenyl, pyrene, benzophenone, In the present specification, a moiety obtained by removing one hydrogen atom from the above “arene” is referred to as “aryl group”.

[0098] In the present invention, "heteroaromatic hydrocarbon" may be a ring containing one or more of O, N, P, Si and S as a heterogeneous element. The heteroaromatic hydrocarbon may be monocyclic or polycyclic. The number of ring carbon atoms of the heteroaromatic hydrocarbon may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroaromatic hydrocarbon may be a monocyclic heteroaromatic hydrocarbon or a polycyclic heteroaromatic hydrocarbon. The polycyclic heteroaromatic hydrocarbon may have, for example, a bicyclic or tricyclic structure. Examples of heteroaromatic hydrocarbons may include, but are not limited to, thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, Oxadiazole, triazole, pyridine, bipyridine, triazole Acridinium, pyridazine, pyrazine, quinoline, quinazoline, quinol Phenoline, coffee Tie Pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, 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, dibenzofuran and the like. If the heteroaromatic hydrocarbon can be tautomers, the heteroaromatic hydrocarbon can include tautomers. In one embodiment of the present invention, the heteroaromatic hydrocarbon can also include a bicyclic heteroaromatic hydrocarbon containing an aromatic hydrocarbon ring fused to a heterocycloalkyl ring or a heteroaromatic hydrocarbon fused to a cycloalkyl ring. In the present specification, a moiety obtained by removing one hydrogen atom from the above “heteroarene” is referred to as a “heteroaryl group”.

[0099] In the present invention, the term "tautomer" refers to isomers which are in equilibrium with each other and whose molecular structures are switched by proton transfer.

[0100] In the present invention, the term "stereoisomer" refers to a compound of the present invention having the same chemical formula or molecular formula but different in spatial arrangement. In this specification, stereoisomers include optical isomers, mirror isomers, non-mirror isomers, cis / trans isomers, rotational isomers and hysteresis isomers. Each of these isomers, racemates and mixtures thereof is also included in the scope of the present invention. For example, because stereochemistry is not specified, Chemical Formula I of the present invention may include stereoisomers of Chemical Formula 1. Unless otherwise specified, the solid line bond connected to the asymmetric carbon atom is May include solid wedge-shaped keys or dotted wedge key It indicates the absolute arrangement of stereocenters.

[0101] The compound represented by 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 from a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" as used herein refers to a concentration having an effective effect that is relatively non-toxic and harmless to patients, and includes any organic or inorganic acid addition salt of the compound represented by Chemical Formula 1, wherein the side effects caused by such salts do not reduce the beneficial effects of the compound.

[0102] Acid addition salts are prepared by known methods, for example by dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Here, the acid or alcohol aqueous solution and equimolar amounts of the compound can be heated and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.

[0103] Here, an organic acid or an inorganic acid can be used as a free acid, wherein the inorganic acid can be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid or the like, and the organic acid can 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, carbonic acid, vanillic acid or hydroiodic acid or the like. However, the organic acid and the inorganic acid are not limited thereto.

[0104] In addition, a base can be used to prepare a pharmaceutically acceptable metal salt. For example, an alkali metal salt or an alkaline earth metal salt is obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. Here, sodium, potassium or calcium salts are particularly suitable as metal salts of pharmaceutical form, but the metal salts are not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0105] Unless otherwise specified, the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound represented by the above Chemical Formula 1. For example, the pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxyl groups, and may include other pharmaceutically acceptable salts of amine groups, such as hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (methanesulfonate / mesylate) and p-toluenesulfonate (p-toluenesulfonate / tosylate) and the like, which may be prepared by salt preparation methods known in the art.

[0106] Uses of heteroaryl derivative compounds

[0107] The present invention provides a compound represented by the following Chemical Formula 1, its tautomer, its stereoisomer or its pharmaceutically acceptable salt:

[0108] [Chemical formula 1]

[0109]

[0110] Chemical Formula 1 is the same as defined above.

[0111] 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 Annotermin-6 (ANO6).

[0112] According to one embodiment of the present invention, the heteroaryl derivative represented by Chemical Formula 1 can exhibit excellent inhibitory activity against Annotamine-6 ​​(ANO6), and thus can be effectively used for treating or preventing thrombosis or thrombosis-related diseases.

[0113] In the present invention, thrombosis or thrombosis-related diseases may be at least one disease selected from the group consisting of: acute myocardial infarction; atrial fibrillation; unstable angina; chronic stable angina; transient ischemic attack; stroke; peripheral vascular disease; preeclampsia; eclampsia; deep vein thrombosis; embolism; cancer-related thrombosis; disseminated intravascular coagulation; thrombotic thrombocytopenia; and thrombotic complications or restenotic complications occurring after invasive procedures such as angioplasty, carotid endarterectomy, coronary artery bypass graft (CABG) surgery, vascular graft surgery, stent placement, and insertion of intravascular devices and prostheses.

[0114] According to one embodiment of the present invention, the present invention provides a pharmaceutical composition for treating or preventing thrombosis or thrombosis-related diseases, comprising a compound represented by Chemical Formula 1 as described above as an active ingredient, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The types of thrombosis or thrombosis-related diseases are as described above.

[0115] The pharmaceutical composition of the present invention may further comprise at least one active ingredient exhibiting the same or similar efficacy other than the compound represented by Chemical Formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0116] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared for administration in various oral and parenteral dosage forms.

[0117] In addition, according to one embodiment of the present invention, a method for treating or preventing thrombosis or thrombosis-related diseases is provided, comprising: administering to an individual in need thereof a therapeutically effective amount of a compound represented by Chemical Formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The individual may be a mammal, including a human.

[0118] The term "therapeutically effective amount" used in the present invention refers to the amount of the compound represented by Chemical Formula 1 that effectively treats or prevents thrombosis or thrombosis-related diseases. Specifically, "pharmaceutically effective amount" refers to an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose can be determined by the type and severity of the individual, age, gender, disease type, drug activity, sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, including concomitant drugs and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, or can be administered sequentially or simultaneously with commercially available therapeutic agents. In addition, the pharmaceutical composition of the present invention can be administered in a single dose or in multiple doses. Taking all of the above factors into account, it is important to administer an amount that can achieve the maximum effect with the minimum amount and without side effects, which can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by experts depending on various factors, such as the patient's condition, age, gender, complications and the like. Since the pharmaceutical composition of the present invention achieves an excellent safety of the active ingredient, the active ingredient can be used even in excess of the intended administration dose.

[0119] In addition, according to one embodiment of the present invention, the present invention provides the use of a compound represented by Chemical Formula 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, which is used to manufacture a medicament for treating or preventing thrombosis or thrombosis-related diseases. The compound represented by Chemical Formula 1 used to manufacture the medicament can be mixed with an acceptable adjuvant, diluent, carrier and the like, and can be prepared into a combined preparation with other active agents to produce a synergistic effect with the active ingredient.

[0120] Unless the contents contradict each other, the contents described in the uses, compositions and methods of treatment of the present invention are equally applicable.

[0121] Effects of the Invention

[0122] The heteroaryl derivative compounds of the present invention can exhibit excellent inhibitory activity against ANO6 and can be effectively used for treating or preventing thrombosis or thrombosis-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0123] Figure 1 It is a graph showing the inhibition rate of the compound 20 and 24 administration groups according to Experimental Example 1.

[0124] Figure 2 Graph showing the inhibition rate of the compound 25 and 1 administration group according to Experimental Example 1.

[0125] Figure 3 It is a graph showing the inhibition rate of the compound 27 and 28 administration group according to Experimental Example 1.

[0126] Figure 4 It is a graph showing the inhibition rates of the groups to which compounds 23, 58 and 45 were administered according to Experimental Example 1.

[0127] Figure 5 Graph showing the inhibition rate of the Compound 21-administered group according to Experimental Example 1.

[0128] Figure 6 It is a graph showing the inhibition rate of the compound 52 and 223 administration group according to Experimental Example 1. DETAILED DESCRIPTION

[0129] Hereinafter, the present invention will be described in detail with reference to preparation examples, examples and experimental examples. However, the following preparation examples, examples and experimental examples are only for illustrating the present invention, and the content of the present invention is not limited to these examples.

[0130] [Preparation Example] Preparation of main intermediate compounds

[0131] Method a. Preparation of amine derivatives (Formula II-a) using Suzuki reaction

[0132]

[0133] Preparation Example 1: Synthesis of 5-(4-methylthiophen-3-yl)pyrimidin-2-amine

[0134]

[0135] (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 H2O (80 mL) and DMF (10 mL) and stirred in a microwave reactor at 110°C for 35 min. Pd was removed by filtration through celite, then the residue was washed with brine solution and extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and hexanes and filtered to obtain the title compound (496 mg, 53%) as a beige solid in the form of a filter cake.

[0136] 1 H 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).

[0137] Preparation Example 2: Synthesis of 5-(pyrimidin-4-yl)pyridin-2-amine

[0138]

[0139] 4-Chloropyrimidine hydrochloride (2 g, 13.25 mmol), (6-aminopyridin-3-yl)boronic acid (2.2 g, 15.9 mmol), Pd(dppf)Cl2 (0.485 g, 0.66 mmol) and K2CO3 (11 g, 79.5 mmol) were dissolved in H2O (13 mL) and 1,4-dioxane (26 mL), then stirred at reflux for 17 h at 110°C. Pd was removed by filtration through celite, then the residue was washed with brine solution and extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was purified by MPLC, then slurried with ethyl acetate and filtered to obtain the title compound (877 mg, 38%) as a gray solid in the form of a filter cake.

[0140] 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).

[0141] Preparation Example 3: Synthesis of 5-(4-fluoropyridin-2-yl)pyrimidin-2-amine

[0142]

[0143] 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 H2O (30 mL) and 1,4-dioxane (60 mL), then stirred at reflux for 6 hours at 100°C. Pd was removed by filtration through celite, then the residue was washed with brine solution and extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to obtain the title compound (3.84 mg, 71%) as a beige solid in the form of a filter cake.

[0144] 1H 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).

[0145] Preparation Example 4: Synthesis of 5-(pyridin-2-yl)pyrimidin-2-amine

[0146]

[0147] 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 H2O (18.75 mL) and 1,4-dioxane (56.25 mL), then stirred at 110 °C for 23 hours under reflux. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was concentrated. The concentrated solution was washed with brine solution and extracted with ethyl acetate, and the organic layer was dried over MgSO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to obtain the title compound (1.71 g, 66.3%) in the form of a filter cake as a light yellow solid.

[0148] 1 H 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).

[0149] Preparation Example 5: Synthesis of 4-(pyridin-2-yl)aniline

[0150]

[0151] 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(PPh3)2Cl2 (0.70 g, 1 mmol) and Na2CO3 (3.18 g, 30 mmol) were dissolved in H2O (12.5 mL) and 1,4-dioxane (37.5 mL), and the mixture was stirred at 100°C under reflux for 21 hours. After removing Pd and H2O by filtration through celite and MgSO4, the reaction mixture was concentrated. The concentrated solution was purified by MPLC to obtain the title compound (1.57 g, 92%) as an orange solid.

[0152] 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).

[0153] Preparation Example 6: Synthesis of 4-(pyrimidin-5-yl)aniline

[0154]

[0155] 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(PPh3)2Cl2 (0.70 g, 1 mmol) and Na2CO3 (3.18 g, 30 mmol) were dissolved in H2O (12.5 mL) and 1,4-dioxane (37.5 mL), and the mixture was stirred at 100°C under reflux for 16 hours. After removing Pd and H2O by filtration through celite and MgSO4, the reaction mixture was concentrated. The concentrated solution was purified by MPLC to obtain the title compound (1.50 g, 87%) as a light brown solid.

[0156] 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).

[0157] Preparation Example 7: Synthesis of 4-(pyridin-4-yl)aniline

[0158]

[0159] 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(PPh3)2Cl2 (0.70 g, 1 mmol) and Na2CO3 (3.18 g, 30 mmol) were dissolved in H2O (12.5 mL) and 1,4-dioxane (37.5 mL), and the mixture was stirred at 100°C under reflux for 16 hours. After removing Pd and H2O by filtration through celite and MgSO4, the reaction mixture was concentrated. The concentrated solution was purified by MPLC to obtain the title compound (1.16 g, 67%) as a light brown solid.

[0160] 1H 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).

[0161] Preparation Example 8: Synthesis of 6-phenylpyridazine-3-amine

[0162]

[0163] 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) were dissolved in H2O (25 mL) and 1,4-dioxane (250 mL), and the dissolved solution was degassed and purged with N2. Pd2(dba)3 (21.2 g, 23.2 mmol) was added to the mixed solution, and the reaction mixture was stirred at reflux for 12 hours at 100°C. After the completion of the reaction was confirmed by LC-MS, the reaction mixture was washed with H2O (500 mL), extracted with ethyl acetate (250 mL×4), and the organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (35.0 g, 53%) as a yellow solid.

[0164] 1 H NMR (400MHz, DMSO-d6) δ7.95 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 9.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.53 (s, 2H).

[0165] Preparation Example 9: Synthesis of 4-(pyridazin-3-yl)aniline

[0166]

[0167] 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 Cs2CO3 (30 M, 29.1 mL, 873 mmol) aqueous solution were dissolved in toluene (180 mL), H2O (40 mL) and EtOH (60 mL), and then Pd(dppf)Cl2 (6.39 g, 8.73 mmol) was added. The mixed solution was degassed and purged with N2, and the reaction mixture was stirred at reflux for 12 hours at 110°C. After the completion of the reaction was confirmed by LC-MS, the mixture was diluted with H2O (100 mL) and ethyl acetate (100 mL), and the suspension was filtered. The filter cake was dried under vacuum to obtain the title compound (42.0 g, 84%) as a black solid.

[0168] 1 H NMR (400MHz, DMSO-d6) δ9.00 (d, J = 4.8 Hz, 1H), 8.00-7.98 (m, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.62-7.58 (m, 1H), 6.68 (d, J = 8.8 Hz, 2H), 5.59 (s, 2H).

[0169] Preparation Example 10: Synthesis of 5-(pyridazin-3-yl)pyrimidin-2-amine

[0170]

[0171] 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 Cs2CO3 (963.2 mg, 3.0 mmol) were dissolved in toluene (3 mL), H2O (0.7 mL) and EtOH (1 mL), and then Pd(dppf)Cl2 (5.17 mg, 0.04 mmol) was added. The reaction mixture was stirred at reflux for 16 hours at 110 °C. After the reaction was completed as confirmed by LC-MS, Pd was removed by diatomaceous earth filtration and the reaction mixture was concentrated. The concentrated mixture was purified by MPLC to obtain the title compound (41 mg, 24%) as a brown solid.

[0172] 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).

[0173] Preparation Example 11: Synthesis of [2,5'-bipyrimidine]-2'-amine

[0174]

[0175] 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 H2O (10 mL), and then Pd(dppf)Cl2 (867 mg, 1.18 mmol) was added. The reaction mixture was stirred at 90 °C under reflux for 64 hours. After the completion of the reaction was confirmed by LC-MS, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated, and the residue was then slurried with dichloromethane and filtered. The filtrate was purified by MPLC to obtain the title compound (520 mg, 13%) as a beige solid.

[0176] 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).

[0177] Preparation Example 12: Synthesis of 5-(3-fluorophenyl)pyridin-2-amine

[0178]

[0179] 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 H2O (10.4 mL), followed by the addition of Pd(PPh3)4 (301 mg, 0.26 mmol), and the mixture was stirred at reflux for 12 h at 140 °C. After completion of the reaction was confirmed by LC-MS, the reaction mixture was diluted with H2O 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 with MTBE at room temperature for 1 h and filtered through MTBE. The filter cake was dried under vacuum to obtain the title compound (18.8 g, 35%) as a white solid.

[0180] 1H NMR (400MHz, DMSO-d6) δ8.29 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.45-7.40 (m, 3H), 7.09-7.04 (m, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.16 (s, 2H).

[0181] Preparation Example 13: Synthesis of 4-(pyrimidin-4-yl)aniline

[0182]

[0183] Step 1: Synthesis of 4-chloropyrimidine

[0184] Pyrimidin-4-ol (10.0 g, 104 mmol) was dissolved in POCl (100 mL, 1.08 mol) and stirred at 100 ° C. in a pressure flask for 6 hours. The mixture was concentrated to remove POCl, and then ethyl acetate was slowly added to the mixture, stirred for 30 minutes, and then filtered with ethyl acetate. The filter cake was dried under vacuum to obtain the title compound (3.5 g, 30%) as a brown solid.

[0185] 1 H NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 8.07 (d, J = 7.20Hz, 1H), 6.62 (d, J = 7.60Hz, 1H).

[0186] Step 2: Synthesis of 4-(pyrimidin-4-yl)aniline

[0187] 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 Cs2CO3 (20.5 g, 62.9 mmol) were dissolved in toluene (12 mL), H2O (3.6 mL) and EtOH (4 mL), followed by the addition of Pd(dppf)Cl2 (575 mg, 0.786 mmol). The mixed solution was stirred at 100° C. under reflux for 12 hours. After the completion of the reaction was confirmed by TLC, the reaction product was extracted with H2O and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to obtain the title compound (1.7 g, 63%) as a yellow solid.

[0188] 1H 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).

[0189] Preparation Example 14: Synthesis of 4-(6-fluoropyridazin-3-yl)aniline

[0190]

[0191] Step 1: Synthesis of 3-chloro-6-fluoropyridazine

[0192] In a flask, pyridine (100 mL) was slowly added to pyridine / HF (200 mL) at -30 ° C and stirred at this temperature for 15 minutes. Then, a mixture of tributyl nitrite (19.2 g, 185.26 mmol) dissolved in pyridine (100 mL) was added dropwise to the above solution at -30 ° C and stirred at this temperature for another 15 minutes. The reaction mixture was poured into ice water (2000 mL), then extracted with EA (200 mL×3), the combined organic layers were washed with brine (2000 mL×3), dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (6 g, 48.88%) as a yellow solid.

[0193] MS: m / z=133 (M+1, ESI+).

[0194] Step 2: Synthesis of 4-(6-fluoropyridazin-3-yl)aniline

[0195] 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 / H2O (40 mL / 8 mL) was added Na2CO3 (12.95 g, 45.30 mmol) and Pd(PPh3)4 (2.61 g, 2.26 mmol). The reaction mixture was then stirred at 100°C under N2 for 4 h. The reaction mixture was cooled to room temperature and poured into water (200 mL), then 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. The residue was purified by column chromatography to obtain the title compound (3.52 g, 82.24%) as a yellow solid.

[0196] 1H 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).

[0197] MS: m / z=190 (M+1, ESI+).

[0198] Preparation Example 15: Synthesis of 4-(4-trifluoromethyl)pyridazin-3-yl)aniline

[0199]

[0200] Step 1: Synthesis of 3-chloro-4-(trifluoromethyl)pyridazine

[0201] 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 hours. The reaction mixture was cooled to room temperature and poured into ice water (400 mL), 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 obtain the title compound (3 g, 67.87%) as a yellow solid.

[0202] 1 H NMR (400MHz, DMSO-d6) δ9.58 (d, J = 5.0 Hz, 1H), 8.30 (d, J = 5.1 Hz, 1H).

[0203] MS: m / z=183 (M+1, ESI+).

[0204] Step 2: Synthesis of 4-(4-(trifluoromethyl)pyridazin-3-yl)aniline

[0205] To a mixture of 3-chloro-4-(trifluoromethyl)pyridazine (3 g, 16.44 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.38 g, 21.47 mmol) in dioxane / H2O (60 mL / 12 mL) was added Cs2CO3 (16.19 g, 49.64 mmol) and Pd(PPh3)4 (1.92 g, 1.64 mmol), the reaction mixture was stirred at 100°C under N2 for 4 h. The reaction mixture was cooled to room temperature and poured into water (500 mL), then extracted 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 obtain the title compound (3 g, 76.92%) as a yellow solid.

[0206] 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).

[0207] MS: m / z=240 (M+1, ESI+).

[0208] Preparation Example 16: Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate

[0209]

[0210] Step 1: Synthesis of 6-(4-aminophenyl)pyridazine-4-carboxylic acid

[0211] 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 / H2O (500 mL / 100 mL) was added Cs2CO3 (33.98 g, 104.31 mmol) and Pd(dppf)Cl2 (1.26 g, 1.74 mmol), the reaction mixture was stirred at 100°C under N2 for 2 hours. The reaction mixture was cooled to room temperature and poured into water (500 mL), then extracted with EA (80 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 obtain the title compound (12.1 g, crude product) as a yellow solid.

[0212] MS: m / z = 216 (M+1, ESI+)

[0213] Step 2: Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate

[0214] To a solution of 6-(4-aminophenyl)pyridazine-4-carboxylic acid (12.1 g, 56.28 mmol) in MeOH (200 mL) was added SOCl2 (13.39 g, 112.56 mmol) dropwise at 0°C, and the reaction mixture was then stirred at 70°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was acidified to pH 8 with NaHCO3 (aqueous solution, 500 mL), then extracted with EA (80 mL×3), and the combined organic layers were washed with brine (400 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (4 g, 31.05%) as a yellow solid.

[0215] 1 H NMR (400MHz, DMSO-d6) δ9.33 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.72 (s, 2H), 3.95 (s, 3H).

[0216] MS: m / z=230 (M+1, ESI+).

[0217] Preparation Example 17: Synthesis of 4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)aniline

[0218]

[0219] 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 H2O / toluene / EtOH (3 mL / 12 mL / 6 mL) was added Cs2CO3 (1.9 g, 5.7 mmol) and Pd(dppf)Cl2 (130 mg, 0.07 mmol), the reaction mixture was stirred at 90°C for 4 hours. The reaction mixture was poured into water and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure and purified by MPLC. The crude mixture was solidified using DCM and hexanes to obtain the title compound (232 mg, 38%) as a beige solid.

[0220] 1H NMR (400MHz, DMSO-d) 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).

[0221] Method b. Preparation of carboxylic acid derivatives (Formula III-a) using Buchwald reaction

[0222]

[0223] Preparation Example 18: Synthesis of 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid

[0224]

[0225] Step 1: Synthesis of methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate

[0226] 5-(4-Methylthiophen-3-yl)pyrimidin-2-amine (490 mg, 2.56 mmol), methyl 3-bromobenzoate (661 mg, 3.07 mmol), Pd2(dba)3 (235 mg, 0.0256 mmol), BrettPhos (275 mg, 0.512 mmol) and Cs2CO3 (1.67 g, 5.12 mmol) were dissolved in 1,4-dioxane (13 mL) and stirred in a microwave reactor at 120°C for 90 minutes. After the reaction was confirmed to be complete by LC-MS, the mixture was washed with brine solution and extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to obtain the title compound (364 mg, 44%) as a white solid in the form of a filter cake.

[0227] 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).

[0228] Step 2: Synthesis of 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid

[0229] The methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate (350 mg, 1.08 mmol) prepared in step 1 above and LiOH.HO (451 mg, 10.8 mmol) were dissolved in HO (4.5 mL) and 1,4-dioxane (21.5 mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the reaction product was acidified to pH 3 with 1N-HCl (aq.), extracted with ethyl acetate and washed with brine. The organic layer was then dried over NaSO and concentrated. The concentrated mixture was slurried with ethyl acetate and hexanes and filtered to obtain the title compound (311 mg, 93%) as a white solid in the form of a filter cake.

[0230] 1 H 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).

[0231] Preparation Example 19: Synthesis of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid

[0232]

[0233] Step 1: Synthesis of methyl 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoate

[0234] 5-(Pyridin-2-yl)pyrimidin-2-amine (861 mg, 5.0 mmol), methyl 3-bromobenzoate (2.69 g, 12.5 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), XPhos (405 mg, 0.85 mmol) and Cs2CO3 (3.26 g, 10.0 mmol) were dissolved in 1,4-dioxane (25 mL), and the mixture was stirred at reflux for 19.5 hours at 110 °C. After the reaction was confirmed to be complete by LC-MS, Pd was removed by diatomaceous earth filtration and the reaction mixture was concentrated. The concentrated solution was purified by MPLC, concentrated, slurried with ethyl acetate and filtered to obtain the title compound (829 mg, 54.1%) as a light yellow solid in the form of a filter cake.

[0235] 1H 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).

[0236] Step 2: Synthesis of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid

[0237] Methyl 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoate (820 mg, 0.59 mmol) prepared in step 1 above and LiOH.HO (449 mg, 10.7 mmol) were dissolved in HO (8.9 mL) and THF (17.8 mL), and the reaction mixture was stirred at room temperature for 22 hours. 1N-HCl (aq.) was added to the reaction mixture for crystallization and filtered to give the title compound (763 mg, 97.5%) as a white solid in the form of a filter cake.

[0238] 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).

[0239] Preparation Example 20: Synthesis of 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid

[0240]

[0241] Step 1: Synthesis of methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate

[0242] 4-(Pyridin-2-yl)aniline (1.52 g, 8.93 mmol), methyl 3-bromobenzoate (2.88 g, 13.4 mmol), Pd2(dba)3 (0.82 g, 0.89 mmol), BrettPhos (0.96 g, 1.79 mmol) and Cs2CO3 (11.64 g, 35.7 mmol) were dissolved in 1,4-dioxane (45 mL), and the mixture was stirred under reflux at 100° C. for 15 h. After removing Pd by filtration through celite, the reaction product was concentrated, and the concentrated solution was purified by MPLC to obtain the title compound (1.36 g, 49%) as a yellow solid.

[0243] 1 H 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).

[0244] Step 2: Synthesis of 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid

[0245] Methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate (1.35 g, 4.43 mmol) prepared in step 1 above and LiOH.HO (0.75 g, 17.74 mmol) were dissolved in HO (15 mL) and THF (30 mL), and the reaction mixture was stirred at room temperature for 117 hours. The reaction product was acidified to pH 3 with 1N-HCl(aq), extracted with ethyl acetate and washed with brine. The organic layer was then dried over MgSO and concentrated. The concentrated mixture was purified by MPLC to obtain the title compound (321 mg, 25%) as a pale yellow solid.

[0246] 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).

[0247] Preparation Example 21: Synthesis of 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid

[0248]

[0249] Step 1: Synthesis of methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate

[0250] 4-(Pyrimidin-5-yl)aniline (1.45 g, 8.47 mmol), methyl 3-bromobenzoate (2.0 g, 9.32 mmol), Pd2(dba)3 (0.62 g, 0.68 mmol), XPhos (0.69 g, 1.44 mmol) and Cs2CO3 (5.52 g, 16.94 mmol) were dissolved in 1,4-dioxane (43 mL), and the mixture was stirred at reflux for 16 h at 100 °C. Pd was removed by filtration through celite, and the reaction mixture was concentrated. The concentrated solution was purified by MPLC, concentrated, then slurried with acetone and filtered to obtain the title compound (0.93 g, 36%) as a light yellow solid in the form of a filter cake.

[0251] 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).

[0252] Step 2: Synthesis of 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid

[0253] Methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate (0.90 g, 2.95 mmol) prepared in step 1 above and LiOH.HO (0.5 g, 11.8 mmol) were dissolved in HO (10 mL) and THF (20 mL), and the reaction mixture was stirred at room temperature for 64 h. After acidification to pH 3 with 1N-HCl(aq), the mixture was extracted with ethyl acetate. The extract was 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 (706 mg, 82%) as a yellow solid.

[0254] 1 H NMR (400MHz, DMSO-d6) δ12.91(br s,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).

[0255] Preparation Example 22: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid

[0256]

[0257] Step 1: Synthesis of methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate

[0258] 4-(Pyridin-4-yl)aniline (1.12 g, 6.58 mmol), methyl 3-bromobenzoate (1.56 g, 7.24 mmol), Pd2(dba)3 (0.48 g, 0.53 mmol), XPhos (0.53 g, 1.12 mmol) and Cs2CO3 (4.29 g, 18.44 mmol) were dissolved in 1,4-dioxane (33 mL) and stirred at 100 °C under reflux for 16 hours. Pd was removed by filtration through celite, and the reaction mixture was concentrated. The concentrated solution was purified by MPLC, concentrated, then slurried with acetone and filtered to obtain the title compound (0.79 g, 40%) as a white solid in the form of a filter cake.

[0259] 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).

[0260] Step 2: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid

[0261] Methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate (0.76 g, 2.5 mmol) prepared in step 1 above and LiOH.HO (0.42 g, 10 mmol) were dissolved in HO (8.5 mL) and THF (17 mL), and the reaction mixture was stirred at room temperature for 40 h. The reaction product was acidified to pH 3 with 1N-HCl(aq), extracted with ethyl acetate and washed with brine. The organic layer was then dried over MgSO4 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.

[0262] 1H NMR(400MHz,DMSO-d6)δ12.99(br s,1H),9.24(s,1H),8.75(s,2H),8.23-8.16(m,2H),7.99(d,J=8.8Hz,2H),7.79(s,1H),7.61-7.40(m,3H),7.26(d,J=42.4Hz,2H).

[0263] Preparation Example 23: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid

[0264]

[0265] Step 1: Synthesis of methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate

[0266] Methyl 3-bromobenzoate (35.9 g, 167 mmol), 6-phenylpyridazine-3-amine (30.0 g, 175 mmol), BrettPhos (18.0 g, 33.4 mmol) and Cs2CO3 (136 g, 417 mmol) were dissolved in 1,4-dioxane (150 mL), and the dissolved solution was degassed and purged with N2. Pd2(dba)3 (4.58 g, 5.01 mmol) was added to the mixed solution, and the reaction mixture was stirred at 100°C under reflux for 6 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was filtered. The filter cake was dried under vacuum and slurried with THF (300 mL) and MeOH (60 mL) at 25°C for 12 hours. The suspension was filtered and the filtrate was concentrated to obtain the title compound (30.0 g, 98.3 mmol, 59%) as a yellow solid.

[0267] 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).

[0268] Step 2: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid

[0269] Methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate (20.0 g, 65.5 mmol) prepared in step 1 above and NaOH (2M, 131 mL, 262 mmol) were dissolved in THF (100 mL) and MeOH (20 mL), and the reaction mixture was stirred at 50° C. for 12 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was dried under vacuum, and H2O was added, followed by acidification to pH 3 with 1N-HCl (aq). The suspension was filtered with H2O, and the filter cake was dried under vacuum to obtain the title compound (10.0 g, 34.3 mmol, 52%) as an off-white solid.

[0270] 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).

[0271] Preparation Example 24: Synthesis of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid

[0272]

[0273] Step 1: Synthesis of methyl 3-((4-(pyridazin-3-yl)phenyl)amino)benzoate

[0274] 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), Cs2CO3 (214 g, 657 mmol) and Pd2(dba)3 (12.0 g, 13.1 mmol) were dissolved in 1,4-dioxane (350 mL), and the dissolved solution was degassed and purged with N2, then stirred at 90°C under reflux for 12 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was diluted with H2O, extracted with ethyl acetate and washed with brine. Then, the organic layer was dried over Na2SO4 and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (32.0 g, 40%) as a brown solid.

[0275] 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).

[0276] Step 2: Synthesis of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid

[0277] The 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 the reaction mixture was stirred at room temperature for 12 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was dried under vacuum, and HO was added, followed by acidification to pH 5 to 6 with 0.5N-HCl (aq.). The suspension was filtered with HO, and the filter cake was dried under vacuum to obtain the title compound (25 g, 95%) as a brown solid.

[0278] 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).

[0279] Preparation Example 25: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoic acid

[0280]

[0281] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate

[0282] 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 Cs2CO3 (141 g, 432 mmol) were dissolved in 1,4-dioxane (210 mL), and the dissolved solution was degassed and purged with N2. Pd2(dba)3 (3.96 g, 4.32 mmol) was added to the mixed solution, and the reaction mixture was stirred at 100 °C under reflux for 12 hours. After the completion of the reaction was confirmed by TLC, the reaction solution was diluted with H2O and the suspension was filtered with H2O. The filter cake was dried under vacuum, and then THF was added and the suspension was filtered with THF. The filtrate was purified by column chromatography to obtain the title compound (10.0 g, 22%) as a white solid.

[0283] 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).

[0284] Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoic acid

[0285] Methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate (10 g, 30.9 mmol) prepared in step 1 above and NaOH (2M, 30.9 mL) were dissolved in THF (70 mL) and MeOH (50 mL), and the reaction mixture was then stirred at 50° C. for 12 h. After the reaction was confirmed to be complete by TLC, the reaction solution was dried under vacuum, and H2O was added, followed by acidification to pH 1 to 2 with 1N-HCl (aq). The suspension was filtered with H2O, and the filter cake was dried under vacuum to obtain the title compound (5.0 g, 52%) as a white solid.

[0286] 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).

[0287] Preparation Example 26: Synthesis of 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid

[0288]

[0289] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoate

[0290] 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 Cs2CO3 (90.9 g, 279 mmol) were dissolved in 1,4-dioxane (100 mL), and the dissolved solution was degassed and purged with N2. Pd2(dba)3 (2.55 g, 2.79 mmol) was added to the mixed solution, and the reaction mixture was stirred at 100 °C under reflux for 12 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was filtered with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The residue was slurried with MTBE at room temperature for 1 hour and filtered through MTBE. The filter cake was dried under vacuum to obtain the title compound (16.5 g, 55%) as a white solid.

[0291] 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).

[0292] Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid

[0293] Methyl 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoate (18 g, 55.8 mmol) prepared in step 1 above and NaOH (2M, 55.8 mL) were dissolved in THF (18 mL) and MeOH (90 mL), and the reaction mixture was then stirred at room temperature for 8 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated and then H2O was added. The residue was acidified to pH 5 with 6N-HCl (aq.). The suspension was filtered and the filter cake was dried under vacuum to obtain the title compound (10.0 g, 58%) as a bright yellow solid.

[0294] 1H 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).

[0295] Preparation Example 27: Synthesis of 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid

[0296]

[0297] Step 1: Synthesis of methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate

[0298] 4-(Pyrimidin-4-ylaniline) (1.70 g, 9.93 mmol), methyl 3-bromobenzoate (2.14 g, 9.93 mmol), BrettPhos (1.07 g, 1.99 mmol), Cs2CO3 (8.09 g, 24.8 mmol) were dissolved in 1,4-dioxane (15 mL), and the dissolved solution was degassed and purged with N2. Pd2(dba)3 (909 mg, 0.993 mmol) was added to the mixed solution, followed by stirring at 100 ° C under reflux for 12 hours. After the reaction was confirmed to be complete by TLC, the reaction solution was diluted with H2O, extracted with ethyl acetate and washed with brine. Then, the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography to obtain the title compound (1.30 g, 43%) as a yellow solid.

[0299] 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).

[0300] Step 2: Synthesis of 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid

[0301] Methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate (1.30 g, 4.26 mmol) prepared in step 1 above and KOH (478 mg, 8.52 mmol) were dissolved in H2O (5 mL) and EtOH (7 mL), and the reaction mixture was stirred at 100°C for 4 hours. After the reaction was confirmed to be complete by TLC, H2O was added to the reaction solution, followed by extraction with 2-MeTHF and acidification with 0.5N-HCl (aq.) to pH 5 to 6. The mixed solution was extracted with 2-MeTHF, washed with brine, and the organic layer was dried over Na2SO4 and concentrated. The residue was slurried with CH3CN at room temperature for 12 hours to obtain the title compound (1.01 g, 81%) as a yellow solid.

[0302] 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).

[0303] Preparation Example 28: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid

[0304]

[0305] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate

[0306] 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), Cs2CO3 (3.90 g, 12.0 mmol) and Pd2(dba)3 (824 mg, 0.90 mmol) were added to 1,4-dioxane (50 mL) and stirred at 100° C. under reflux for 12 hours. After the completion of the reaction was confirmed by LC-MS, a saturated solution of NaHCO3 was added to the reaction solution, which was then extracted with ethyl acetate and concentrated. The residue was purified by MPLC to obtain the title compound (1.43 g, 68%) as an orange solid.

[0307] 1H 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).

[0308] Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid

[0309] Methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate (706 mg, 2.00 mmol) prepared in step 1 above and LiOH.H2O (1.68 g, 40.0 mmol) were dissolved in H2O (10 mL) and THF (20 mL), and the reaction mixture was then stirred at 60°C for 48 hours. The reaction was confirmed complete by LC-MS, and the reaction product was acidified to pH 2 with 1N-HCl (aq.). The suspension was filtered with H2O and dried under vacuum to obtain the title compound (540 mg, 80%) as an orange solid.

[0310] 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).

[0311] Preparation Example 29: Synthesis of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)aminobenzoic acid

[0312]

[0313] Step 1: Synthesis of methyl 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate

[0314] 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), Cs2CO3 (11.0 g, 33.8 mmol) and Pd2(dba)3 (1.09 g, 1.35 mmol) were added to 1,4-dioxane (40 mL) and stirred at 90°C under reflux for 12 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was diluted with H2O, slurried with MeOH and filtered. The resulting filter cake was slurried with dichloromethane and dried in vacuo to obtain the title compound (2.19 g, 53%) as a beige solid.

[0315] 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).

[0316] Step 2: Synthesis of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid

[0317] Methyl 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate (2.18 g, 7.09 mmol) prepared in step 1 above and LiOH.HO (1.20 g, 28.38 mmol) were dissolved in HO (20 mL) and THF (40 mL), and the reaction mixture was stirred at 60° C. for 13.5 hours. The reaction was confirmed to be complete by LC-MS, and the reaction product was neutralized with 1N-HCl (aq). The suspension was filtered with HO to obtain the title compound (1.8 g, 84%) as a beige solid.

[0318] 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).

[0319] Preparation Example 30: Synthesis of 3-([2,5'-bipyrimidine]-2'-ylamino)benzoic acid

[0320]

[0321] Step 1: Synthesis of methyl 3-([2,5'-bipyrimidinyl]-2'-ylamino)benzoate

[0322] [2,5'-Bipyrimidine]-2'-amine (500 mg, 2.9 mmol), methyl 3-bromobenzoate (627 mg, 2.91 mmol), BrettPhos (108 mg, 0.2 mmol), Cs2CO3 (2.35 g, 7.21 mmol) and Pd2(dba)3 (116 mg, 0.14 mmol) were added to 1,4-dioxane (60 mL) and stirred at 90° C. under reflux for 23 hours. After the completion of the reaction was confirmed by LC-MS, H2O was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The residue was purified by MPLC to obtain the title compound (180 mg, 20%) as a beige solid.

[0323] 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).

[0324] Step 2: Synthesis of 3-([2,5'-bipyrimidinyl]-2'-ylamino)benzoic acid

[0325] Methyl 3-([2,5'-bipyrimidine]-2'-ylamino)benzoate (180 mg, 0.59 mmol) prepared in step 1 above and LiOH.HO (49 mg, 1.17 mmol) were dissolved in HO (3 mL) and MeOH (6 mL), and the reaction mixture was stirred at 40° C. for 16 h. The reaction was confirmed to be complete by LC-MS, and the reaction product was acidified to pH 2 with 1N-HCl (aq). The suspension was filtered with HO, the resulting filter cake was slurried with HO, and the filter cake was dried in vacuo to obtain the title compound (110 mg, 64%) as a beige solid.

[0326] MS: m / z=294 (M+1, ESI+).

[0327] Method a+b. Preparation of carboxylic acid derivatives (Formula III-a) using Suzuki reaction and Buchwald reaction

[0328]

[0329] Preparation Example 31: Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid

[0330]

[0331] Step 1: Synthesis of 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0332] To a solution of 4-bromo-3-nitrobenzene (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) were added KOAc (5.65 g, 57.60 mmol) and Pd(dppf)Cl2 (1.67 g, 2.30 mmol), the reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), then extracted with EA (60 mL×3), the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (3 g, 49.3%) as a yellow solid.

[0333] MS: m / z=265 (M+1, ESI+).

[0334] Step 2: Synthesis of 3-nitro-4-(pyridazin-3-yl)aniline

[0335] 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 / H2O (50 mL / 10 mL) was added Cs2CO3 (7.40 g, 22.72 mmol) and Pd(dppf)Cl2 (921 mg, 1.14 mmol), the reaction mixture was stirred at 100°C under N2 for 2 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), then extracted with EA (60 mL×3), the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.1 g, 44.8%) as a yellow solid.

[0336] MS: m / z=217 (M+1, ESI+).

[0337] Step 3: Synthesis of methyl 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoate

[0338] 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 Cs2CO3 (3.02 g, 10.18 mmol), Brettphos (745 mg, 1.53 mmol) and Pd2(dba)3 (636 mg, 0.76 mmol), the reaction mixture was stirred at 120°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), then extracted with EA (60 mL×3), the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (800 mg, 44.9%) as a light yellow solid.

[0339] MS: m / z=351 (M+1, ESI+).

[0340] Step 4: Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid

[0341] To a solution of methyl 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoate (800 mg, 2.29 mmol) in THF / H2O (20 mL / 4 mL) was added LiOH.H2O (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), then extracted with EA (10 mL×3), the combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (700 mg, 91.14%) as a yellow solid.

[0342] 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).

[0343] MS: m / z=337 (M+1, ESI+).

[0344] Preparation Example 32: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid

[0345]

[0346] Step 1: Synthesis of 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0347] 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) were added KOAc (6.06 g, 61.87 mmol) and Pd(dppf)Cl2 (898 mg, 1.21 mmol), the reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), then extracted with EA (60 mL×3), the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (2.4 g, 38.96%) as a yellow solid.

[0348] 1 H NMR (400MHz, DMSO-d6) δ7.25 (d, J = 7.8 Hz, 1H), 6.15-6.07 (m, 2H), 5.48 (s, 2H), 3.64 (d, J = 6.2 Hz, 3H), 1.22 (s, 12H).

[0349] MS: m / z=250 (M+1, ESI+).

[0350] Step 2: Synthesis of 3-methoxy-4-(pyridazin-3-yl)aniline

[0351] 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 / H2O (50 mL / 10 mL) was added Cs2CO3 (6.28 g, 19.28 mmol) and Pd(dppf)Cl2 (697 mg, 0.96 mmol), the reaction mixture was stirred at 100°C under N2 for 2 hours. The reaction mixture was cooled to room temperature and poured into water (300 mL), then extracted with EA (60 mL×3), the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.4 g, 72.27%) as a yellow solid.

[0352] MS: m / z=202 (M+1, ESI+).

[0353] Step 3: Synthesis of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate

[0354] 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) were added Cs2CO3 (4.54 g, 13.94 mmol), Brettphos (697 mg, 1.30 mmol) and Pd2(dba)3 (595 mg, 0.65 mmol), the reaction mixture was stirred at 120°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), then extracted with EA (60 mL×3), the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.1 g, 47.21%) as a light yellow solid.

[0355] 1 H 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).

[0356] MS: m / z=336 (M+1, ESI+).

[0357] Step 4: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid

[0358] To a solution of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate (1.1 g, 3.28 mmol) in THF / H2O (20 mL / 4 mL) was added LiOH.H2O (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), then extracted with EA (10 mL×3), the combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (900 mg, 85.71%) as a yellow solid.

[0359] 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).

[0360] MS: m / z=322 (M+1, ESI+).

[0361] Preparation Example 33: Synthesis of 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid

[0362]

[0363] Step 1: Synthesis of 5-(6-fluoropyridin-2-yl)pyrimidin-2-amine

[0364] 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 / H2O (50 mL / 10 mL) were added Cs2CO3 (10.58 g, 32.46 mmol) and Pd(dppf)Cl2 (1.18 g, 1.62 mmol), the reaction mixture was stirred at 100°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL), then extracted with EA (60 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 obtain the title compound (3.10 g, 92.50%) as a brown solid.

[0365] MS: m / z=191 (M+1, ESI+).

[0366] Step 2: Synthesis of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate

[0367] 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) were added Cs2CO3 (10.26 g, 31.40 mmol), Brettphos (847 mg, 1.57 mmol) and Pd2(dba)3 (723 mg, 1.57 mmol), the reaction mixture was stirred at 120°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (200 mL), then extracted with EA (80 mL×3), the combined organic layers were washed with brine (200 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (3.8 g, 71.96%) as a brown solid.

[0368] 1 H 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).

[0369] MS: m / z=325 (M+1, ESI+).

[0370] Step 3: Synthesis of 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid

[0371] To a solution of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate (3.8 g, 11.73 mmol) in THF / H2O (50 mL / 10 mL) was added LiOH·H2O (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), then extracted with EA (40 mL×3), the combined organic layers were washed with brine (80 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (3.2 g, 88.89%) as a brown solid.

[0372] 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).

[0373] MS: m / z=311 (M+1, ESI+).

[0374] Preparation Example 34: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid

[0375]

[0376] Step 1: Synthesis of 4-(6-fluoropyridin-2-yl)aniline

[0377] 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 / H2O (50 mL / 10 mL) was added Cs2CO3 (4.95 g, 15.20 mmol) and Pd(dppf)Cl2 (616 mg, 0.76 mmol), the reaction mixture was stirred at 100°C under N2 for 2 h. The reaction mixture was cooled to room temperature and poured into water (100 mL), then extracted with EA (60 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 obtain the title compound (1.4 g, 88.60%) as a brown solid.

[0378] MS: m / z = 189 (M+1, ESI+)

[0379] Step 2: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoate

[0380] 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) were added Cs2CO3 (4.84 g, 14.90 mmol), Brettphos (403 mg, 0.75 mmol) and Pd2(dba)3 (687 mg, 0.75 mmol), the reaction mixture was stirred at 120°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL), then extracted with EA (40 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 obtain the title compound (1.1 g, 45.83%) as a brown solid.

[0381] 1 H 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).

[0382] MS: m / z=323 (M+1, ESI+).

[0383] Step 3: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid

[0384] To a solution of methyl 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoate (1.1 g, 3.42 mmol) in THF / H2O (25 mL / 5 mL) was added LiOH·H2O (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), then extracted with EA (15 mL×3), the combined organic layers were washed with brine (60 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (900 mg, 85.70%) as a yellow solid.

[0385] 1H 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).

[0386] MS: m / z=309 (M+1, ESI+).

[0387] Preparation Example 35: Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid

[0388]

[0389] Step 1: Synthesis of methyl 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoate

[0390] 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 Pd2(dba)3 (71 mg, 0.0876 mmol), Brettphos (235 mg, 0.438 mmol) and Cs2CO3 (563 mg, 1.75 mmol). The mixture was stirred in a microwave at 150 °C for 2 h. The reaction mixture was cooled to room temperature and poured into water, then extracted with DCM, and the combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC. The crude mixture was solidified using EA and hexanes to obtain the title compound (173 mg, 57%) as a yellow solid.

[0391] 1 H NMR(400MHz,DMSO-d)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).

[0392] Step 2: Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid

[0393] To a solution of methyl 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoate (130 mg, 0.37 mmol) in H2O / THF / MeOH (1 mL / 3 mL / 1 mL) was added LiOH.H2O (94 mg, 2.24 mmol), and the reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq.). The solid was then filtered using H2O. The filtrate was solidified using DCM and MeOH to give the title compound (82 mg, 66%) as a yellow solid.

[0394] 1 H NMR(400MHz,DMSO-d)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).

[0395] Preparation Example 36: Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid

[0396]

[0397] Step 1: Synthesis of ethyl 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate

[0398] 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 Pd2(dba)3 (467 mg, 0.58 mmol), Brettphos (620 mg, 1.15 mmol) and Cs2CO3 (1483 mg, 4.62 mmol), the reaction mixture was stirred at 150 °C in microwave for 6 h. The reaction mixture was cooled to room temperature and poured into water, then 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. The crude mixture was solidified using EA and hexanes to obtain the title compound (388 mg, 40%) as a brown solid.

[0399] MS: m / z=420 (M+1, ESI+).

[0400] Step 2: Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid

[0401] 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 H2O / THF / MeOH (1.5 mL / 9 mL / 3 mL) was added LiOH.H2O (240 mg, 5.73 mmol), and the reaction mixture was stirred at 60°C for 6 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq.) and then extracted with DCM, and 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.

[0402] 1 H NMR (400MHz, DMSO-d) 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(dd ,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).

[0403] Method c. Preparation of carboxylic acid derivatives (Formula III-a) using other methods

[0404]

[0405] Preparation Example 37: Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

[0406]

[0407] Step 1: Synthesis of methyl (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0408] In a sealed tube, 3-chloro-6-phenylpyridazine (0.5 g, 2.6 mmol) and (1s, 4s)-4-aminobicyclo[2.2.1]heptane-1-carboxylic acid methyl ester (0.578 g, 3.4 mol) were dissolved in n-butanol (10 mL), and trifluoroacetic acid (0.148 g, 13 mmol) was added to the solution. Then, the resulting mixture was stirred at 150 ° C under reflux for 72 hours. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled at room temperature, 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 obtain the title compound (170 mg, 20%) as a white solid.

[0409] 1 H NMR (400 MHz, methanol-d4) δ 7.87 (d, J = 7.6 Hz, 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).

[0410] Step 2: Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

[0411] The (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid methyl ester (1.4 g, 4.3 mol) prepared in step 1 above 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 hours. The reaction was confirmed to be complete by TLC, and the reaction product was acidified to pH 4 with 2N-HCl (aq.). The suspension was filtered with HO, and the filter cake was dried under vacuum to obtain the title compound (1.05 g, 80%) as an off-white solid.

[0412] 1 H 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).

[0413] Preparation Example 38: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid

[0414]

[0415] Step 1: Synthesis of ethyl 3-aminoadamantane-1-carboxylate hydrochloride

[0416] To 3-amino adamantane-1-formyl hydrochloride (20.0g, 86.3mmol) was dissolved in EtOH (140mL) solution SOCl2 (10.3g, 86.3mmol), and stirred at 80°C under reflux for 4 hours. After the reaction was completed by LC-MS, the reaction solution was concentrated. Petroleum ether was added to the residue and the pressure was reduced until precipitation occurred. After repeating this process three times, the resulting product was made into a slurry with petroleum ether at room temperature for 30 minutes and filtered to obtain the title compound (21.0g, 94%) as a white solid.

[0417] 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).

[0418] Step 2: Synthesis of ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-1-carboxylate

[0419] 3-Aminoadamantane-1-carboxylic acid ethyl ester hydrochloride (21.0 g, 80.8 mmol) prepared in step 1 above and K2CO3 (33.5 g, 243 mmol) were added to a solution of 3,6-dichloropyridazine (24.1 g, 162 mmol) dissolved in DMF (147 mL), followed by stirring at 135° C. under reflux for 12 hours. After the reaction was confirmed to be complete by TLC, the reaction solution was diluted with H2O, extracted with ethyl acetate and washed with brine. Then, the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography to obtain the title compound (1.80 g, 7%) as a white solid.

[0420] 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).

[0421] Step 3: Synthesis of ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylate

[0422] To a solution of ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-1-carboxylate (1.80 g, 5.36 mmol) prepared in step 2 above dissolved in DME (9 mL) and H2O (1.8 mL) was added phenylboronic acid (719 mg, 5.90 mmol) and Na2CO3 (2.84 g, 26.8 mmol). Pd(PPh3)2Cl2 (376 mg, 0.536 mmol) was added to the mixed solution, which was then degassed and purged with N2, and the mixture was stirred at 80°C under reflux for 12 hours. After completion of the reaction was confirmed by TLC, the reaction solution was diluted with H2O, extracted with ethyl acetate and washed with brine. Then, the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography and preparative HPLC to obtain the title compound (800 mg, 40%) as a white solid.

[0423] 1 H 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).

[0424] Step 4: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid

[0425] Ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylate (800 mg, 2.12 mmol) prepared in step 3 above and LiOH.HO (445 mg, 10.6 mmol) were dissolved in HO (1.6 mL) and EtOH (3.2 mL), and the reaction mixture was stirred at reflux for 12 h at 45 °C. After completion of the reaction was confirmed by LC-MS, EtOH was removed by concentration. The residue was acidified to pH 5 with citric acid (aq). The suspension was filtered with HO, and the filter cake was dried under vacuum to obtain the title compound (450 mg, 60%) as a white solid.

[0426] 1H 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).

[0427] Preparation Example 39: Synthesis of 3-((4-phenylpiperazin-1-yl)methyl)benzoic acid

[0428]

[0429] Step 1: Synthesis of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate

[0430] 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 the reaction was confirmed to be complete by TLC, the reaction solution was concentrated. The residue was slurried with ethyl acetate and filtered, and the filter cake was purified by MPLC to obtain the title compound (532 mg, 85%) as a white solid.

[0431] MS: m / z=311 (M+1, ESI+).

[0432] Step 2: Synthesis of 3-((4-phenylpiperazin-1-yl)methyl)benzoic acid

[0433] To a solution of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate (310 mg, 1.0 mmol) prepared in step 1 above dissolved in MeOH (10 mL) and H2O (2 mL) was added LiOH.H2O (422 mg, 10.0 mmol) and stirred at 65°C for 2 h. The reaction was confirmed complete by LC-MS, and the reaction product was neutralized to pH 6 with 6N-HCl (aq). The suspension was slurried with H2O and filtered to give the title compound (221 mg, 75%) as a white solid.

[0434] MS: m / z=297 (M+1, ESI+).

[0435] Preparation Example 40: Synthesis of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid

[0436]

[0437] Step 1: Synthesis of 4-(pyridazin-3-yl)phenol

[0438] 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 / H2O (50 mL / 10 mL) was added Cs2CO3 (11.81 g, 36.26 mmol) and Pd(dppf)Cl2 (1.31 g, 1.81 mmol), the reaction mixture was stirred at 100°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (300 mL), then extracted with EA (60 mL×3), the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.9 g, 61.29%) as a yellow solid.

[0439] 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).

[0440] MS: m / z=173 (M+1, ESI+).

[0441] Step 2: Synthesis of methyl 3-(4-(pyridazin-3-yl)phenoxy)benzoate

[0442] 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(CF3SO3)2 (6.73 g, 18.60 mmol) and TEA (2.82 g, 27.90 mmol), and the reaction mixture was stirred at 40°C under N2 for 72 h. The reaction mixture was cooled to room temperature and poured into water (150 mL), then extracted with DCM (30 mL×3), the combined organic layers were washed with brine (150 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (650 mg, 22.41%) as a yellow solid.

[0443] MS: m / z=307 (M+1, ESI+).

[0444] Step 3: Synthesis of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid

[0445] To a solution of methyl 3-(4-(pyridazin-3-yl)phenoxy)benzoate (650 mg, 2.12 mmol) in THF / H2O (20 mL / 4 mL) was added LiOH.H2O (445 mg, 10.62 mmol), and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was acidified to pH 2 with 2N-HCl (aq.) (20 mL), then extracted with EA (10 mL×3), and the combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain the title compound (600 mg, 96.77%) as a yellow solid.

[0446] MS: m / z=293 (M+1, ESI+).

[0447] Method d. Preparation of benzimidazole derivatives (Formula IV-a) using cyclization

[0448]

[0449] Preparation Example 41: Synthesis of 2-(3-bromophenyl)-6-fluoro-1H-benzo[d]imidazole

[0450]

[0451] 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 190° C. under reflux for 5 hours. The reaction was confirmed to be complete by TLC, and the reaction product was cooled to room temperature and basified to pH 9 with 2N-KOH (aq.). The suspension was slurried with H2O, filtered and dried in vacuo to obtain the title compound (10.5 g, 71%) as a purple solid.

[0452] 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).

[0453] Preparation Example 42: Synthesis of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)aniline

[0454]

[0455] 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 stirred at 200 ° C. under reflux for 1 hour. The reaction was confirmed to be complete by LC-MS, and the reaction product 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, separated by MPLC, slurried with ethyl acetate and diethyl ether and filtered to obtain the title compound (190 mg, 68%) as a dark pink solid.

[0456] 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).

[0457] Method e. Preparation of amine derivatives (Formula II-a) using Stille reaction

[0458]

[0459] Method e+b. Preparation of carboxylic acid derivatives (Formula III-a) using Stiller reaction and Buchwald reaction

[0460]

[0461] Preparation Example 43: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid

[0462]

[0463] Step 1: Synthesis of 5-(pyrimidin-4-yl)pyridin-2-amine

[0464] 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 for 48 h under N2. The reaction mixture was cooled to room temperature and poured into water (100 mL), then extracted with EA (30 mL×3), and 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 obtain the title compound (1.10 g, 58.9%) as a yellow solid.

[0465] MS: m / z=173 (M+1, ESI+).

[0466] Step 2: Synthesis of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate

[0467] 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 Cs2CO3 (3.79 g, 11.62 mmol), Brettphos (936 mg, 1.74 mmol) and Pd2(dba)3 (1.59 g, 1.74 mmol), the reaction mixture was stirred at 120°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL), then 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. The residue was purified by column chromatography to obtain the title compound (800 mg, 44.9%) as a light yellow solid.

[0468] MS: m / z=307 (M+1, ESI+).

[0469] Step 3: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid

[0470] To a solution of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate (800 mg, 2.61 mmol) in THF / H2O (10 mL / 2 mL) was added LiOH·H2O (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), then extracted with EA (10 mL×3), and the combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (700 mg, 91.7%) as a pale yellow solid.

[0471] 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).

[0472] MS: m / z=293 (M+1, ESI+).

[0473] Preparation Example 44: Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid

[0474]

[0475] Step 1: Synthesis of 3-chloro-6-(pyridin-2-yl)pyridazine

[0476] 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 hours. The reaction mixture was cooled to room temperature and poured into water (500 mL), then extracted with EA (100 mL×3), and 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 obtain the title compound (3.2 g, 43.9%) as a yellow solid.

[0477] 1H 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).

[0478] MS: m / z=192 (M+1, ESI+).

[0479] Step 2: Synthesis of 6-(pyridin-2-yl)pyridazin-3-amine

[0480] A mixture of 3-chloro-6-(pyridin-2-yl)pyridazine (3.2 g, 16.7 mmol) in NH3.H2O (35 mL) was stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (3 g, crude product) as a white solid.

[0481] MS: m / z = 173 (M+1, ESI+)

[0482] Step 3: Synthesis of methyl 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoate

[0483] 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) were added Cs2CO3 (7.6 g, 23.23 mmol), Brettphos (623 mg, 1.16 mmol) and Pd2(dba)3 (532 mg, 0.58 mmol), the reaction mixture was stirred at 120°C under N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (500 mL), then extracted with EA (80 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 obtain the title compound (1.1 g, 30.38%) as a yellow solid.

[0484] MS: m / z=307 (M+1, ESI+).

[0485] Step 4: Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid

[0486] To a solution of methyl 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoate (1.1 g, 3.59 mmol) in THF / H2O (12 mL / 3 mL) was added LiOH.H2O (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), then extracted with EA (40 mL×3), and the combined organic layers were washed with brine (100 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (900 mg, 85.71%) as a yellow solid.

[0487] 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).

[0488] MS: m / z=293 (M+1, ESI+).

[0489] Method f. Preparation of benzimidazole derivatives (acetic acid) (Formula IV-a) using cyclization reaction

[0490]

[0491] Preparation Example 45: Synthesis of 2-(2-bromopyridin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0492]

[0493] 4-(Trifluoromethyl)benzene-1,2-diamine (5.67 g, 32.18 mmol) and DIEA (9.60 g, 74.25 mmol) were added 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), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL), then extracted with DCM (50 mL×3), and the combined organic layers were washed with brine (200 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(2-amino-5-(trifluoromethyl)phenyl)-2-bromoisonicotinamide (4.4 g, 49.4%) as a yellow solid. MS: m / z=362 (M+1, ESI+). And a mixture of N-(2-amino-5-(trifluoromethyl)phenyl)-2-bromoisonicotinamide (4.4 g, 12.22 mmol) in AcOH (50 mL) was stirred for 16 h at 110° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (3.0 g, 71.56%) as a white solid.

[0494] 1 H 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).

[0495] MS: m / z=343 (M+1, ESI+).

[0496] Preparation Example 46: Synthesis of 2-(3-bromophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0497]

[0498] 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), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (800 mL), then extracted with DCM (100 mL×3), the combined organic layers were washed with brine (800 mL×3), dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain N-(2-amino-4-(trifluoromethyl)phenyl)-3-bromobenzamide (21 g, 71.19%) as a yellow solid. MS: m / z=360 (M+1, ESI+). And a mixture of N-(2-amino-4-(trifluoromethyl)phenyl)-3-bromobenzamide (21 g, 58.50 mmol) in AcOH (200 mL) was stirred for 16 h at 110° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (16 g, 80.21%) as a yellow solid.

[0499] 1 H 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).

[0500] MS: m / z=341 (M+1, ESI+).

[0501] Method g. Preparation of benzimidazole derivatives (acetic acid) (Formula IV-b) using Mitsunobu reaction and cyclization reaction

[0502]

[0503] Preparation Example 47: Synthesis of 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethan-1-amine

[0504]

[0505] Step 1: Synthesis of methyl 5-bromo-2-(2-(dimethylamino)ethoxy)benzoate

[0506] 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 hours. The reaction mixture was cooled to room temperature and poured into water, then extracted with DCM, and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (258 mg, 66%) as a yellow oil.

[0507] 1 H NMR(400MHz,DMSO-d)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).

[0508] Step 2: Synthesis of 5-bromo-2-(2-(dimethylamino)ethoxy)benzoic acid

[0509] To a solution of methyl 5-bromo-2-(2-(dimethylamino)ethoxy)benzoate (200 mg, 0.662 mmol) in H2O / 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), then extracted with DCM, and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound (245 mg, >100%) as a white solid.

[0510] 1 H NMR (400MHz, DMSO-d) δ7.80 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 2.7, 8.9 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H), 4.46-4.42 (m, 2H), 3.52-3.48 (m, 2H), 2.87 (s, 6H).

[0511] Step 3: Synthesis of 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethan-1-amine

[0512] 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 hours. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 ° C for 8 hours. The reaction mixture was washed with NaHCO 3 (aq.) and then extracted with DCM, and the combined organic layers were dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (69 mg, 42%) as a yellow solid.

[0513] 1 H NMR(400MHz, DMSO-d)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).

[0514] Preparation Example 48: Synthesis of 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole

[0515]

[0516] Step 1: Synthesis of methyl 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate

[0517] 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 hours. The reaction mixture was cooled to room temperature and poured into water, then 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 obtain the title compound (341 mg, 73%) as a yellow oil.

[0518] 1H NMR (400MHz, DMSO-d) 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).

[0519] Step 2: Synthesis of 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoic acid

[0520] To a solution of methyl 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate (290 mg, 0.812 mmol) in H2O / THF (2 mL / 8 mL) was added 1N-NaOH (2.4 mL), and the reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq.) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound (223 mg, 80%) as a white solid.

[0521] 1 H NMR (400MHz, DMSO-d) 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).

[0522] Step 3: Synthesis of 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole

[0523] 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 were 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 hours. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 ° C for 8 hours. The reaction mixture was washed with NaHCO 3 (aq.), then extracted with DCM, and the combined organic layers were dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (67 mg, 43%) as a yellow solid.

[0524] 1 H NMR(400MHz,DMSO-d)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).

[0525] Preparation Example 49: Synthesis of 2-(5-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]imidazole

[0526]

[0527] Step 1: Synthesis of methyl 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoate

[0528] 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 hours. The reaction mixture was cooled to room temperature and poured into water, then 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 obtain the title compound (224 mg, 52%) as a yellow oil.

[0529] 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).

[0530] Step 2: Synthesis of 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoic acid

[0531] To a solution of methyl 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoate (223 mg, 0.680 mmol) in H2O / THF (1.5 mL / 6 mL) was added 1N-NaOH (2.0 mL) and the reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq.) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound (121 mg, 56%) as a brown oil.

[0532] 1 H NMR(400MHz,DMSO-d)δ7.79(d,J=2.6Hz,1H),7.68(dd,J=2.7,8.9Hz,1H),7.24(d,J=9.0Hz,1 H),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).

[0533] Step 3: Synthesis of 2-(5-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]imidazole

[0534] 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 hours. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 ° C for 8 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 purified by MPLC to obtain the title compound (23 mg, 28%) as a yellow solid.

[0535] 1 H NMR(400MHz,DMSO-d)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).

[0536] Method h. Synthesis of carboxylic acid derivatives using amide coupling reaction

[0537]

[0538] Preparation Example 50: Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid

[0539]

[0540] Step 1: Synthesis of methyl (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylate

[0541] 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, and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was solidified using EA and hexanes to obtain the title compound (100 mg, 90%) as a beige solid.

[0542] 1 H NMR (400MHz, DMSO-d) 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).

[0543] Step 2: Synthesis of (1,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid

[0544] To a solution of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylate (89 mg, 0.299 mmol) in H2O / THF (1 mL / 3 mL) was added 1N-NaOH (0.9 mL) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq) and then extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under pressure to obtain the title compound (61 mg, 71%) as a beige solid.

[0545] 1 H NMR (400MHz, DMSO-d) 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).

[0546] [Example] Preparation of the compound represented by Chemical Formula 1 according to the present invention

[0547] Method A. Preparation via amide reaction and cyclization reaction

[0548]

[0549] Example 1: Synthesis of 6-phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine

[0550]

[0551] 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), to which DIPEA (2.09 mL, 12.0 mmol) was then added, followed by stirring at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (20 mL) was added thereto, followed by stirring at reflux for 3 hours at 120 ° C. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to obtain the title compound (154 mg, 42%) as a white solid.

[0552] Example 2: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine

[0553]

[0554] 3-((6-phenylpyridazine-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 the mixture was stirred at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, followed by the addition of acetic acid (20 mL), and the mixture was stirred at reflux for 5 hours at 120 ° C. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to obtain the title compound (154 mg, 42%) as a white solid.

[0555] Example 5: Synthesis of 5,6-dichloro-2-(3-((4-phenylpiperazin-1-yl)methyl)phenyl)-1H-benzo[d]imidazole

[0556]

[0557] 3-((4-phenylpiperazine-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 the mixture was stirred at room temperature for 2.5 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was washed with 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, followed by the addition of acetic acid (5 mL), and the mixture was stirred at reflux at 120 ° C for 1.5 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over Na2SO4 and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (190 mg, 43%) as a light yellow solid.

[0558] Example 6: Synthesis of 6-phenyl-N-(3-(6-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine

[0559]

[0560] 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), and DIPEA (0.130 mL, 0.75 mmol) was added thereto, followed by stirring at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was washed with 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and then acetic acid (5 mL) was added, and the mixture was stirred at reflux for 2 hours at 120 ° C. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO3 solution and extracted with ethyl acetate, and then 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 as a white solid (16 mg, 14%).

[0561] Example 7: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine

[0562]

[0563] 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 the mixture was stirred at 50 ° C overnight. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was washed with 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, followed by the addition of acetic acid (5 mL), and the mixture was stirred at 120 ° C overnight under reflux. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over Na2SO4 and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (45 mg, 35%) as a white solid.

[0564] Example 11: Synthesis of N-(3-(7-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine

[0565]

[0566] 3-((6-phenylpyridazine-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), and then DIPEA (0.450 mL, 2.58 mmol) was added, and stirred at room temperature overnight. After the reaction was confirmed to be complete by TLC, the resulting mixture was diluted with 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and then acetic acid (5 mL) was added, and the mixture was stirred at reflux for 2 hours at 120 ° C. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate, and then the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, filtered with dichloromethane, and dried to give the title compound (45 mg, 11%) as a white solid.

[0567] Example 14: Synthesis of 5-phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

[0568]

[0569] 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), and then DIPEA (1.569 mL, 9.0 mmol) was added thereto, followed by stirring at room temperature overnight. The reaction solution was washed with a 5% aqueous solution of LiCl and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and then acetic acid (5 mL) was added, and the mixture was stirred at reflux for 4 hours at 120 ° C. After the reaction was confirmed to be complete by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and then the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, filtered with dichloromethane, and dried to obtain the title compound (475 mg, 37%) as a white solid.

[0570] Example 18: Synthesis of 5-(3-fluorophenyl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridin-2-amine

[0571]

[0572] 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), and then DIPEA (1.045 mL, 6.0 mmol) was added thereto, followed by stirring at room temperature overnight. The reaction solution was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, and then acetic acid (20 mL) was added, and the mixture was stirred at reflux for 2 hours at 120 ° C. After the reaction was confirmed to be complete by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and then the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, filtered with dichloromethane, and dried to obtain the title compound (69 mg, 8%) as a white solid.

[0573] Example 20: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridin-2-yl)phenyl)aniline

[0574]

[0575] 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 the mixture was stirred at 60 ° C overnight. The reaction solution was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate, and the organic layer was concentrated to remove DMF, and acetic acid (10 mL) was added thereto, followed by stirring at 120 ° C under reflux for 1 hour. After the reaction was confirmed to be complete by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO3 solution and extracted with ethyl acetate, and then 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 obtain the title compound (51 mg, 41%) as a white solid.

[0576] Example 21: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

[0577]

[0578] 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 the mixture was stirred at 60 ° C overnight. The reaction solution was washed with 5% aqueous LiCl and extracted with ethyl acetate, and the organic layer was concentrated to remove DMF, and acetic acid (10 mL) was added thereto, followed by stirring at 120 ° C under reflux for 1 hour. After the reaction was confirmed to be complete by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and then the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to obtain the title compound (103 mg, 19%) as a light yellow solid.

[0579] Example 23: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0580]

[0581] 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 the mixture was stirred at 60° C. overnight. The reaction solution was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate, and the organic layer was concentrated to remove DMF, and acetic acid (10 mL) was added thereto, followed by stirring at 120° C. under reflux for 1 hour. After the completion of the reaction was confirmed by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO 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.

[0582] Example 24: Synthesis of N-(4-(pyrimidin-4-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0583]

[0584] 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 the mixture was stirred at 60° C. overnight. The reaction solution was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate, and the organic layer was concentrated to remove DMF, and acetic acid (10 mL) was added thereto, followed by stirring at 120° C. under reflux for 1 hour. After the completion of the reaction was confirmed by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and then the organic layer was dried over MgSO 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.

[0585] Example 25: Synthesis of 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

[0586]

[0587] 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 the mixture was stirred at 60° C. overnight. The reaction solution was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate, and the organic layer was concentrated to remove DMF, and acetic acid (10 mL) was added thereto, followed by stirring at 120° C. under reflux for 1 hour. After the completion of the reaction was confirmed by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and ethyl acetate, and filtered to give the title compound as a beige solid (250 mg, 44%).

[0588] Example 30: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrimidin-5-yl)phenyl)aniline

[0589]

[0590] 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 the mixture was stirred at room temperature overnight. The reaction solution was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate, and the organic layer was concentrated to remove DMF, and acetic acid (5 mL) was added thereto, followed by stirring at 120° C. under reflux for 2 hours. After the completion of the reaction was confirmed by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and then the organic layer was dried over MgSO and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane / ethyl acetate, and filtered to obtain the title compound (35 mg, 19%) as a beige solid.

[0591] Example 32: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)aniline

[0592]

[0593] 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 the mixture was stirred at room temperature overnight. The reaction solution was washed with a 5% aqueous LiCl solution and extracted with ethyl acetate, and the organic layer was concentrated to remove DMF, and acetic acid (5 mL) was added thereto, followed by stirring at 120° C. under reflux for 2 hours. After the completion of the reaction was confirmed by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and then the organic layer was dried over MgSO and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane / ethyl acetate, and filtered to obtain the title compound (19 mg, 10%) as a beige solid.

[0594] Example 34: Synthesis of N-((1s,4s)-4-(1H-benzo[d]imidazol-2-yl)bicyclo[2.2.1]hept-1-yl)-6-phenylpyridazin-3-amine

[0595]

[0596] In DMF (5 mL), (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, and DIPEA (0.115 mL, 0.66 mmol) was then added thereto, followed by stirring at room temperature overnight. After the completion of the reaction was confirmed by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 120° C. under reflux for 4 hours. After the completion of the reaction was confirmed by TLC, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO 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.

[0597] Example 35: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)adamantan-1-yl)-6-phenylpyridazin-3-amine

[0598]

[0599] 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), and then DIPEA (0.115 mL, 0.66 mmol) was added thereto, followed by stirring at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 120° C. under reflux for 4 hours. After the reaction was confirmed to be complete by TLC, the reaction solution was concentrated, slurried with dichloromethane / ethyl acetate, and filtered to obtain the title compound (100 mg, 72%) as a white solid.

[0600] Example 38: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(3-fluorophenyl)-N-methylpyrimidin-2-amine

[0601]

[0602] 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 the mixture was stirred at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was washed with a 5% aqueous LiCl solution, extracted with ethyl acetate, and the organic layer was concentrated to remove DMF. Then, acetic acid (5 mL) was added thereto, followed by stirring at 120° C. under reflux for 2 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and then the organic layer was dried over MgSO and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (80 mg, 42%) as a beige solid.

[0603] Example 39: Synthesis of N-(5-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenyl)-5-(3-fluorophenyl)pyrimidin-2-amine

[0604]

[0605] 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 the mixture was stirred at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 120 ° C. under reflux for 2 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to obtain the title compound (80 mg, 39%) as a beige solid.

[0606] Example 43: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-methylthiophen-3-yl)pyrimidin-2-amine

[0607]

[0608] 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 the mixture was stirred at room temperature overnight. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (2.9 mL) was added thereto, followed by stirring at 100° C. under reflux for 3 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over NaSO and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (91 mg, 74%) as a yellow foam.

[0609] Example 44: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine

[0610]

[0611] 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), followed by the addition of DIPEA (0.155 mL, 0.89 mmol), and the mixture was stirred at 60 ° C for 20 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 120 ° C for 1 hour under reflux. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with saturated NaHCO3 solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO4 and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to obtain the title compound (86 mg, 54%) as a beige solid.

[0612] Example 46: Synthesis of 3-(1H-imidazo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

[0613]

[0614] 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 the mixture was stirred at 60 ° C for 7.5 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 120 ° C for 16 hours under reflux. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The reaction solution was washed with saturated NaHCO3 solution, 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 obtain the title compound (84 mg, 23%) as a beige solid.

[0615] Example 48: Synthesis of N-(3-(1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine

[0616]

[0617] 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 the mixture was stirred at room temperature for 21 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (2 mL) was added thereto, followed by stirring at reflux at 100 ° C for 18 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated to remove acetic acid. The resulting product was extracted with ethyl acetate and washed with brine, and the organic layer was dried over MgSO4 and concentrated. The concentrated solution was purified by MPLC, concentrated, then slurried with a small amount of MeOH and filtered to obtain the title compound (7 mg, 5.6%) as a beige solid in the form of a filter cake.

[0618] Example 51: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine

[0619]

[0620] 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 the mixture was stirred at 60 ° C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 120 ° C for 19 hours under reflux. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with 1N-NaOH solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO4 and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to obtain the title compound (77 mg, 40%) as a white solid.

[0621] Example 52: Synthesis of 5-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

[0622]

[0623] 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), followed by the addition of DIPEA (238 μL, 1.36 mmol), and the mixture was stirred at room temperature for 2 hours and at 50° C. for 17 hours. After the completion of the reaction was confirmed by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (8 mL) was added thereto, followed by stirring at 110° C. under reflux for 18 hours. After the completion of the reaction was confirmed by LC-MS, the mixture was cooled to room temperature and concentrated to remove acetic acid. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over NaSO and concentrated. The concentrated solution was slurried with dichloromethane and filtered to afford the title compound as a tan solid as a filter cake (91 mg, 31%).

[0624] Example 54: Synthesis of N-(3-(1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-6-phenylpyridazin-3-amine

[0625]

[0626] 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 the mixture was stirred at room temperature for 67 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (6 mL) was added thereto, followed by stirring at reflux for 17 hours at 110°C. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature and concentrated. The resulting concentrate was adjusted to pH 8 with saturated NaHCO3 solution, 1N-HCl (aq.) and water, extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was slurried with ethyl acetate and filtered, and the resulting filter cake was lyophilized to give the title compound as a beige solid (144 mg, 58%).

[0627] Example 55: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyridin-2-amine

[0628]

[0629] 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 the mixture was stirred at room temperature for 17 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (4 mL) was added thereto, followed by stirring at reflux for 4 hours at 110°C. After the reaction was confirmed to be complete by LC-MS, the resulting 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 in the form of a filter cake.

[0630] Example 58: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-[2,3'-bipyridyl]-6'-amine

[0631]

[0632] 3-([2,3'-bipyridine]-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 the mixture was stirred at 60 ° C for 1 hour. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 120 ° C for 1 hour under reflux. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with 1N-NaOH solution and extracted with ethyl acetate, and the organic layer was then dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to obtain the title compound (80 mg, 32%) as a white solid.

[0633] Example 61: Synthesis of methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate

[0634]

[0635] 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 the mixture was stirred at room temperature for 17 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (17 mL) was added thereto, followed by stirring at reflux for 2 hours at 110°C. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The resulting solid was slurried with ethyl acetate and filtered, and the resulting filter cake was lyophilized to obtain the title compound (476 mg, 65%) as a yellow solid.

[0636] Example 64: Synthesis of N-(3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine

[0637]

[0638] 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 the mixture was stirred at 60° C. for 18 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was concentrated, and acetic acid (5 mL) was added thereto, followed by stirring at 130° C. under reflux for 25 hours. After the completion of the reaction was confirmed by LC-MS, the reaction solution was concentrated. MeOH was added to the residue, and the resulting mixture was concentrated, separated by MPLC, slurried with dichloromethane and filtered to obtain the title compound (80 mg, 32%) as a yellow solid.

[0639] Example 78: Synthesis of methyl 2-(3-((4-(pyrimidin-2-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate

[0640]

[0641] 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 the mixture was stirred at 60 ° C for 3 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and acetic acid (40 mL) was added thereto, followed by stirring at 120 ° C for 1 hour under reflux. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The resulting mixture was slurried with saturated NaHCO3 solution and ethyl acetate and filtered. The resulting filter cake was slurried with dichloromethane and filtered to obtain the title compound (4.5 g, 89%) as a beige solid.

[0642] Example 79: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-2-yl)aniline

[0643]

[0644] 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), followed by the addition of DIPEA (239 μL, 1.37 mmol), and the mixture was stirred at room temperature for 362 hours and at 40° C. for 16 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (7 mL) was added thereto, followed by stirring at 110° C. under reflux for 111 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over NaSO and concentrated. The concentrated solution was slurried with ethyl acetate and filtered, and the resulting filter cake was further slurried with 10% MeOH in DCM to afford the title compound as a dark beige solid in the form of a filter cake (79 mg, 27%).

[0645] Example 91: Synthesis of 3-(1-methyl-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-3-yl)phenyl)aniline

[0646]

[0647] 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (200 mg, 0.69 mmol), N 1 -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), and the mixture was stirred at room temperature for 24 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was concentrated to remove DMF, and acetic acid (7 mL) was added thereto, followed by stirring at reflux for 30 hours at 110 ° C. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with a saturated NaHCO solution and extracted with ethyl acetate, and the organic layer was then dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, slurried with ethyl acetate and filtered to obtain the title compound (92 mg, 36%) as a beige solid.

[0648] Example 200: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-(pyrimidin-2-yl)pyridazin-3-amine

[0649]

[0650] 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 hours. The reaction mixture was poured into water (100 mL), then extracted with EA (30 mL×3), and the combined organic layers were washed with brine (100 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(2-aminophenyl)-3-((6(pyrimidin-2-yl)pyridazin-3-yl)amino)benzamide (400 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (5 mL) and stirred at 120° C. for 16 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure, the residue was recrystallized with EA to give the title compound (35 mg, 8.04%) as a yellow solid.

[0651] Example 213: Synthesis of 2-(3-(4-(pyridazin-3-yl)phenoxy)phenyl)-1H-benzo[d]imidazole

[0652]

[0653] 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 hours. The reaction mixture was poured into water (100 mL), then extracted with EA (30 mL×3), and the combined organic layers were washed with brine (100 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(2-aminophenyl)-3-(4-(pyridazin-3-yl)phenoxy)benzamide (600 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (10 mL) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure, the residue was recrystallized from EA to give the title compound (160 mg, 47.97%) as a white solid.

[0654] Example 214: Synthesis of 5-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)thiazol-2-amine

[0655]

[0656] 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) were added benzene-1,2-diamine (379 mg, 3.50 mmol) and DIEA (1.23 g, 9.55 mmol), and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was poured into water (100 mL), then extracted with EA (30 mL×3), the combined organic layers were washed with brine (100 mL×3), dried over Na 2 SO 4 and concentrated under reduced pressure, the residue was purified by column chromatography to obtain the title compound (400 mg, 30.77%) as a brown solid.

[0657] Example 218: Synthesis of 3-(6-bromo-1H-imidazo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

[0658]

[0659] 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) were 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 hours. The reaction mixture was poured into water (150 mL), then extracted with EA (40 mL×3), and the combined organic layers were washed with brine (150 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(4-amino-6-bromopyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (1.6 g, crude product) as a yellow solid. This crude product was dissolved in AcOH (30 mL) and stirred at 120° C. for 36 h. The reaction mixture was cooled to rt and concentrated under reduced pressure, the residue was recrystallized with EA to give the title compound (80 mg, 5.33%) as a beige solid.

[0660] Example 222: Synthesis of 3-(6-(Benzyloxy)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

[0661]

[0662] 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 hours. The reaction mixture was poured into water (150 mL), then extracted with EA (30 mL×3), and the combined organic layers were washed with brine (150 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(3-aminopyridin-2-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (400 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (10 mL) and stirred at 120° C. for 36 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by preparative HPLC to obtain the title compound (35 mg, 17.5%) as a yellow solid.

[0663] Example 232: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)aniline

[0664]

[0665] Step 1: Synthesis of 2-chloro-6-(trifluoromethoxy)pyridine 1-oxide

[0666] To a stirred solution of 2-chloro-6-(trifluoromethoxy)pyridine (10 g, 58.94 mmol) in DCM (500 mL) was added urea peroxide (19.41 g, 206.31 mmol) and TFAA (24.76 g, 117.89 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (500 mL), then extracted with DCM (80 mL×3), the combined organic layers were washed with brine (500 mL×3), dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (600 mg, 4.78%) as a yellow oil.

[0667] 1 H NMR (400MHz, DMSO-d6) δ7.91 (dd, J = 8.3, 1.8 Hz, 1H), 7.77 (dd, J = 8.3, 1.0 Hz, 1H), 7.47 (t, J = 8.3 Hz, 1H).

[0668] MS: m / z=214 (M+1, ESI+).

[0669] Step 2: Synthesis of 2-chloro-4-nitro-6-(trifluoromethoxy)pyridine 1-oxide

[0670] To a solution of 2-chloro-6-(trifluoromethoxy)pyridine 1-oxide (550 mg, 2.58 mmol) in H2SO4 / HNO3 (8 mL / 4 mL) was added KNO3 (391 mg, 3.86 mmol) at 0°C, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), then extracted with EA (15 mL×3), the combined organic layers were washed with brine (50 mL×3), dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (445 mg, 66.83%) as a yellow oil.

[0671] 1 H NMR (400MHz, DMSO-d6) δ 8.87 (d, J = 3.1 Hz, 1H), 8.67 (d, J = 3.0 Hz, 1H).

[0672] MS: m / z=259 (M+1, ESI+).

[0673] Step 3: Synthesis of 2-chloro-6-(trifluoromethoxy)pyridin-4-amine

[0674] 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 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), then extracted with EA (15 mL×3), the combined organic layers were washed with brine (50 mL×3), dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (160 mg, 43.73%) as a yellow solid.

[0675] MS: m / z=213 (M+1, ESI+).

[0676] Step 4: Synthesis of 2-chloro-3-nitro-6-(trifluoromethoxy)pyridin-4-amine

[0677] To a solution of 2-chloro-6-(trifluoromethoxy)pyridin-4-amine (160 mg, 0.75 mmol) in H2SO4 (5 mL) was added KNO3 (152 mg, 1.51 mmol), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), then extracted with EA (15 mL×3), the combined organic layers were washed with brine (50 mL×3), dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (175 mg, 90.3%) as a yellow solid.

[0678] 1 H NMR (400MHz, DMSO-d6) δ7.74 (s, 2H), 6.59 (s, 1H).

[0679] MS: m / z=257 (M+1, ESI+).

[0680] Step 5: Synthesis of 6-(trifluoromethoxy)pyridine-3,4-diamine

[0681] 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. The filtrate was filtered and purified by column chromatography to give the title compound (60 mg, 45.72%) as a brown solid.

[0682] 1H NMR (400MHz, DMSO-d6) δ7.29(s,1H),6.21(s,1H),5.85(s,2H),4.64(s,2H).

[0683] MS: m / z=194 (M+1, ESI+).

[0684] Step 6: Synthesis of N-(4-(pyrazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)aniline

[0685] 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) were added 6-(trifluoromethoxy)pyridine-3,4-diamine (60 mg, 0.31 mmol) and DIEA (110 mg, 0.85 mmol), the reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (100 mL), then extracted with DCM (30 mL x 3), the combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4 and concentrated under reduced pressure to give N-(4-amino-6-(trifluoromethoxy)pyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (95 mg, 78.68%) as a brown solid. MS: m / z=467 (M+1, ESI+). The brown solid obtained above was dissolved in AcOH (2 mL) and stirred under microwave at 120° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with MeOH to obtain the title compound (10 mg, 12.24%) as an off-white solid.

[0686] Example 234: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)aniline

[0687]

[0688] 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) were 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 hours. The reaction mixture was poured into water (500 mL), then extracted with EA (80 mL×3), and the combined organic layers were washed with brine (500 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(2-amino-5-(trifluoromethyl)pyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (700 mg, crude product) as a brown solid. MS: m / z=451 (M+1, ESI+). This crude product was dissolved in AcOH (10 mL) and stirred at 120° C. for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography to obtain the title compound (45 mg, 5.51%) as a yellow solid.

[0689] Example 244: Synthesis of 5-(pyridin-2-yl)-N-(3-(5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)pyrimidin-2-amine

[0690]

[0691] 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) were 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), the reaction mixture was stirred at 50 ° C for 16 hours. The reaction mixture was poured into water (100 mL), then extracted with DCM (40 mL×3), the combined organic layers were washed with brine (100 mL×3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(2-amino-6-(trifluoromethyl)pyridin-3-yl)-3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide (800 mg, crude product) as a yellow solid. MS: m / z=452 (M+1, ESI+). This crude product was dissolved in AcOH (8 mL) and stirred at 120 ° C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with MeOH to obtain the title compound as a beige solid (330 mg, 34.23%).

[0692] Example 250: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)-5-(trifluoromethyl)aniline

[0693]

[0694] 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 ( The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (150 mL), then 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 obtain N-(2-aminophenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)-5-(trifluoromethyl)benzamide (1.2 g, crude product) as an off-white solid. This crude product was dissolved in AcOH (25 mL) and stirred at 120°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with EA to obtain the title compound (190 mg, 16.52%) as an off-white solid.

[0695] Example 252: Synthesis of N-(4-(6-fluoropyridin-2-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0696]

[0697] 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 ( The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (150 mL), then 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 obtain N-(2-amino-5-(trifluoromethyl)phenyl)-3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzamide (800 mg, crude product) as a brown solid. This crude product was dissolved in AcOH (20 mL) and stirred at 120° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA / MeOH to obtain the title compound (130 mg, 16.95%) as a white solid.

[0698] Example 279: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine

[0699]

[0700] Step 1: Synthesis of N1-methyl-4-nitrobenzene-1,3-diamine

[0701] To a solution of 5-fluoro-2-nitroaniline (5 g, 32.03 mmol) and methylamine 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 hours. The reaction mixture was cooled to room temperature and poured into water (500 mL), then extracted with EA (100 mL×3), and the combined organic layers were washed with brine (500 mL×3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (4 g, 74.77%) as a yellow solid.

[0702] MS: m / z=168 (M+1, ESI+).

[0703] Step 2: Synthesis of N4-toluene-1,2,4-triamine

[0704] To N 1To a solution of 1-methyl-4-nitrobenzene-1,3-diamine (500 mg, 2.99 mmol) in DCM (10 mL) was added Pd / C (50 mg), the reaction mixture was stirred under H2 at 25°C for 6 h. Filtered and the filtrate was concentrated under reduced pressure to give the title compound (500 mg, crude) as a brown solid.

[0705] MS: m / z=138 (M+1, ESI+).

[0706] Step 3: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine

[0707] 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 -toluene-1,2,4-triamine (500 mg, 3.65 mmol) and DIEA (1.09 g, 8.42 mmol), the reaction mixture was stirred at 50 ° C for 16 hours. The reaction mixture was poured into water (200 mL), then 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 obtain N-(2-amino-5-(methylamino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (250 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (20 mL) and stirred at 90 ° C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with MeOH to obtain the title compound (8 mg, 0.56%) as a yellow solid.

[0708] Example 280: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine

[0709]

[0710] Step 1: Synthesis of N-benzyl-N-methyl-3,4-dinitroaniline

[0711] To a solution of 4-fluoro-1,2-dinitrobenzene (10 g, 53.73 mmol) and N-methyl-1-phenylmethylamine (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 hours. The reaction mixture was poured into water (300 mL), then extracted with EA (100 mL×3), and the combined organic layers were washed with brine (300 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (9 g, 58.44%) as a yellow solid.

[0712] MS: m / z=288 (M+1, ESI+).

[0713] Step 2: Synthesis of N4-benzyl-N4-toluene-1,2,4-triamine

[0714] 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), the reaction mixture was stirred under H2 at 25°C for 16 h. Filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.2 g, 16.9%) as a brown solid.

[0715] 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).

[0716] MS: m / z=228 (M+1, ESI+).

[0717] Step 3: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine

[0718] 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 N 4 -Benzyl-N 4-toluene-1,2,4-triamine (1.2 g, 5.28 mmol) and DIEA (1.86 g, 14.42 mmol), the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water (200 mL), then 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 N-(2-amino-5-(benzyl(methyl)amino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (1.4 g, crude product) as a yellow solid. This crude product was dissolved in AcOH (20 mL) and stirred at 90°C for 16 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure, the residue was recrystallized with EA to give N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine (36 mg, 6.8%) as an off-white solid.

[0719] Example 288: Synthesis of N-(3-(6-(2-(N-morpholinyl)ethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine

[0720]

[0721] Step 1: Synthesis of 4-(2-(N-morpholinyl)ethoxy)-2-nitroaniline

[0722] To a solution of 4-amino-3-nitrophenol (2 g, 12.98 mmol) and 2-(N-morpholinyl)ethan-1-ol (1.87 g, 14.27 mmol) in EA (150 mL) was added PPh3 (4.08 g, 15.57 mmol) and DEAD (3.39 g, 19.47 mmol) at room temperature, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature and poured into water (800 mL), then extracted with EA (300 mL×3), and 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 obtain the title compound (2 g, 55.5%) as a black oil.

[0723] Step 2: Synthesis of 4-(2-(N-morpholinyl)ethoxy)benzene-1,2-diamine

[0724] To a solution of 4-(2-(N-morpholinyl)ethoxy)-2-nitroaniline (1 g, 3.74 mmol) in MeOH (10 mL) was added Pd / C (100 mg) and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (800 mg, 85.83%) as a brown solid.

[0725] Step 3: Synthesis of N-(3-(6-(2-(N-morpholinyl)ethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine

[0726] 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-(N-morpholinyl)ethoxy)benzene-1,2-diamine (316 mg, 1.33 mmol) and DIEA ( The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water (100 mL), then 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 obtain N-(2-amino-5-(2-(N-morpholinyl)ethoxy)phenyl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzamide (600 mg, crude product) as a brown solid. This crude product was dissolved in AcOH (5 mL) and stirred at 120°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography to obtain the title compound (160 mg, 21.95%) as a white solid.

[0727] Example 300: Synthesis of N-(3-(6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrazin-2-amine

[0728]

[0729] 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) were added 4-(difluoromethoxy)benzene-1,2-diamine (177 mg, 1.02 mmol) and DIEA (The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water (100 mL), then 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 obtain N-(2-amino-5-(difluoromethoxy)phenyl)-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzamide (500 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (5 mL) and stirred at 120°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with MeOH to obtain the title compound (170 mg, 38.55%) as a yellow solid.

[0730] Example 303: Synthesis of N-(3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(thiazol-4-yl)pyrimidin-2-amine

[0731]

[0732] 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 ( The reaction mixture was stirred at 50 ° C for 16 hours. The reaction mixture was poured into water (100 mL), then 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 obtain N-(5-amino-2-chloropyridin-4-yl)-3-((5-(thiazol-4-yl)pyrimidin-2-yl)amino)benzamide (700 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (10 mL) and stirred at 120 ° C for 72 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with EA to obtain the title compound (50 mg, 6.13%) as a yellow solid.

[0733] Example 158: Synthesis of (1R,2R)-2-(6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)cyclopropane-1-carboxamide

[0734]

[0735] 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 hours. The reaction mixture was concentrated under reduced pressure, AcOH (1 mL) was added, and the residue was stirred at 100 °C for 22 hours. The reaction mixture was washed with NaHCO3 (aq.), then extracted with DCM, and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (4.4 mg, 17%) as a yellow solid.

[0736] Example 167: Synthesis of 2-(1H-benzo[d]imidazol-2-yl)-N1,N1-dimethyl-N4-(4-(pyrazin-2-yl)phenyl)benzene-1,4-diamine

[0737]

[0738] 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 hours. The reaction mixture was concentrated under reduced pressure, AcOH (1.5 mL) was added, and the residue was stirred at 100 °C for 20 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 purified by MPLC to obtain the title compound (25 mg, 41%) as a yellow solid.

[0739] 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

[0740]

[0741] 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), the reaction mixture was stirred at 60 ° C for 22 hours. The reaction mixture was concentrated under reduced pressure, AcOH (1.5 mL) was added, and the residue was stirred at 100 ° C for 7 hours. The reaction mixture was washed with NaHCO 3 (aq.) and then extracted with DCM, the combined organic layers were dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC. The crude mixture was solidified using EA and hexanes to obtain the title compound (61 mg, 30%) as a beige solid.

[0742] Example 328: Synthesis of 5-(pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)pyrazin-2-amine

[0743]

[0744] 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 ( The reaction mixture was stirred at 50 ° C for 16 hours. The reaction mixture was poured into water (100 mL), then 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 obtain N-(5-amino-2-(trifluoromethyl)pyridin-4-yl)-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzamide (350 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (5 mL) and stirred at 150 ° C for 2 hours under microwave. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with MeOH to obtain the title compound (78 mg, 16.46%) as a yellow solid.

[0745] Example 329: Synthesis of N-(3-(6-(difluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine

[0746]

[0747] 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 ( The reaction mixture was stirred at 50 ° C for 16 hours. The reaction mixture was poured into water (100 mL), then 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 obtain N-(5-amino-2-(difluoromethoxy)pyridin-4-yl)-3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide (400 mg, crude product) as a yellow solid. This crude product was dissolved in AcOH (6 mL) and stirred at 160 ° C for 2 hours under microwave. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography to obtain the title compound (34 mg, 7.2%) as a yellow solid.

[0748] Method B. Preparation using the Buchwald reaction

[0749]

[0750] Example 69: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-2-yl)pyridin-2-amine

[0751]

[0752] 5-(Pyrimidin-2-yl)pyridin-2-amine (100 mg, 0.58 mmol), 2-(3-bromophenyl)-1H-benzo[d]imidazole (174 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) and Cs2CO3 (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was then stirred in a microwave reactor at 120° C. for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was purified by MPLC, concentrated, slurried with dichloromethane and filtered to obtain the title compound (85 mg, 40.2%) as a beige solid in the form of a filter cake.

[0753] Example 72: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-4-yl)pyridin-2-amine

[0754]

[0755] 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), Pd2(dba)3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) and Cs2CO3 (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was then stirred at 120° C. in a microwave reactor for 2 hours. Pd2(dba)3 (106 mg, 0.116 mmol) and BrettPhos (124 mg, 0.232 mmol) were added, and the mixture was further stirred at 120° C. in a microwave reactor for 1 hour. After the reaction was confirmed to be complete by LC-MS, the reaction solution was purified by MPLC to obtain the title compound (37 mg, 17%) as a yellow solid.

[0756] Example 73: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-fluoropyridin-2-yl)pyrimidin-2-amine

[0757]

[0758] 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), Pd2(dba)3 (241 mg, 0.26 mmol), BrettPhos (282 mg, 0.53 mmol) and Cs2CO3 (343 mg, 1.05 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was then stirred at 120° C. in a microwave reactor for 1 hour. Pd2(dba)3 (120 mg, 0.13 mmol) and BrettPhos (141 mg, 0.26 mmol) were added, and the mixture was further stirred at 120° C. in a microwave reactor for 1 hour. After the reaction was confirmed to be complete by LC-MS, the reaction solution was purified by MPLC to obtain the title compound (30 mg, 15%) as a white solid.

[0759] Example 16: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

[0760]

[0761] 2-Chloropyrimidine (334 mg, 3.0 mmol), 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)aniline (831 mg, 3.0 mmol), Pd2(dba)3 (275 mg, 0.3 mmol), BrettPhos (242 mg, 0.45 mmol) and Cs2CO3 (2.9 g, 9.0 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was then stirred in a microwave reactor at 150 °C for 40 min. After the reaction was confirmed to be complete by TLC, the resulting mixture was cooled to room temperature. After removing Pd by filtration through celite, the resulting mixture was separated by MPLC, slurried with dichloromethane / ethyl acetate and filtered to obtain the title compound (180 mg, 17%) as a beige solid.

[0762] Example 75: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-3-(pyrimidin-5-yl)aniline

[0763]

[0764] 3-(Pyrimidin-5-yl)aniline (99 mg, 0.58 mmol), 2-(3-bromophenyl)-1H-benzo[d]imidazole (174 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) and Cs2CO3 (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and then stirred in a microwave reactor at 120° C. for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was purified by MPLC, concentrated, slurried with ethyl acetate and filtered to obtain the title compound (115 mg, 54.5%) as a white solid in the form of a filter cake.

[0765] Example 77: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-phenylpyrimidin-5-amine

[0766]

[0767] 2-Phenylpyrimidin-5-amine (103 mg, 0.60 mmol), 2-(3-bromophenyl)-1H-benzo[d]imidazole (164 mg, 0.60 mmol), Pd2(dba)3 (49 mg, 0.053 mmol), BrettPhos (64 mg, 0.12 mmol) and Cs2CO3 (391 mg, 1.2 mmol) were dissolved in 1,4-dioxane (3 mL) and then stirred at 120 °C in a microwave reactor for 1.5 hours. After the reaction was confirmed to be complete by LC-MS, the resulting mixture was cooled to room temperature. The mixture was washed with H2O and extracted with ethyl acetate, and the organic layer was then dried over MgSO4 and concentrated. The residue was separated by MPLC, slurried with dichloromethane / hexanes and filtered to obtain the title compound (21 mg, 9%) as a white solid.

[0768] Example 113: Synthesis of 6-(1-methyl-4-piperidinyl)-N-[3-[6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl]phenyl]pyridazin-3-amine

[0769]

[0770] To a solution of 6-(1-methyl-4-piperidinyl)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 Pd2(dba)3 (47.6 mg, 0.052 mmol), BrettPhos (69.8 mg, 0.13 mmol) and NaOtBu (100 mg, 1.04 mmol) and the reaction mixture was stirred at 150 °C under microwave for 1.5 hours. After completion of the reaction as confirmed by LC-MS, the resulting mixture was cooled to room temperature. The reaction mixture was washed with brine, then extracted with 10% MeOH in DCM, dried over Na2SO4 and concentrated under reduced pressure. The residue was slurried with ethyl acetate / hexanes and concentrated under reduced pressure. The residue was slurried in DCM and filtered to give the title compound as a white solid (81 mg, 34%).

[0771] Example 261: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-amine

[0772]

[0773] 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 N2 for 16 h. The reaction mixture was cooled to room temperature and poured into water (200 mL), then extracted with DCM (50 mL×3), the combined organic layers were washed with brine (200 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (48 mg, 2.6%) as a yellow solid.

[0774] Example 265: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(6-fluoropyridazin-3-yl)phenyl)aniline

[0775]

[0776] 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 Cs2CO3 (346 mg, 1.06 mmol), Brettphos (142 mg, 0.27 mmol) and Pd2(dba)3 (247 mg, 0.27 mmol), the reaction mixture was stirred at 120°C under microwave for 4 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), then extracted with DCM (15 mL×3), the combined organic layers were washed with brine (50 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (20 mg, 9.90%) as a light yellow solid.

[0777] 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

[0778]

[0779] 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 Pd2(dba)3 (42 mg, 0.0516 mmol), BrettPhos (55 mg, 0.103 mmol) and Cs2CO 3( 133 mg, 0.413 mmol). The reaction mixture was stirred at 150 °C in microwave for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified using DCM and hexanes to obtain the title compound (10 mg, 9%) as a beige solid.

[0780] Example 168: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-(2-(dimethylamino)ethoxy)-N-(4-(pyrazin-2-yl)phenyl)aniline

[0781]

[0782] 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) were added Pd2(dba)3 (7 mg, 0.0083 mmol), BrettPhos (22 mg, 0.0416 mmol) and Cs2CO 3( 53 mg, 0.167 mmol), the reaction mixture was stirred at 150° C. in microwave for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexanes to give the title compound (6 mg, 16%) as a yellow solid.

[0783] 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

[0784]

[0785] 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 Pd2(dba)3 (6 mg, 0.0072 mmol), BrettPhos (19 mg, 0.0361 mmol) and Cs2CO 3( 46 mg, 0.145 mmol), the reaction mixture was stirred at 150° C. in microwave for 2 h. The reaction mixture was purified. The crude mixture was solidified using EA and hexanes to give the title compound (12 mg, 31%) as a yellow solid.

[0786] Example 172: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-((1-methylpiperidin-4-yl)oxy)-N-(4-(pyrazin-2-yl)phenyl)aniline

[0787]

[0788] 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 Pd2(dba)3 (5 mg, 0.0057 mmol), BrettPhos (15 mg, 0.0285 mmol) and Cs2CO3 (37 mg, 0.114 mmol), the reaction mixture was stirred at 150 °C in microwave for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexanes to give the title compound (4 mg, 16%) as a yellow solid.

[0789] 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

[0790]

[0791] 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 Pd2(dba)3 (33 mg, 0.0404 mmol), BrettPhos (108 mg, 0.202 mmol) and Cs2CO3 (259 mg, 0.808 mmol) and the reaction mixture was stirred at 150 °C in microwave for 2 h. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexanes to give the title compound (6 mg, 16%) as a yellow solid.

[0792] 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

[0793]

[0794] 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 Pd2(dba)3 (16 mg, 0.0203 mmol), BrettPhos (54 mg, 0.101 mmol) and Cs2CO3 (130 mg, 0.405 mmol) and the reaction mixture was stirred at 150 °C in microwave for 3 h. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexanes to give the title compound (10 mg, 9%) as a pink solid.

[0795] 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

[0796]

[0797] 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 Pd2(dba)3 (47 mg, 0.0584 mmol), BrettPhos (157 mg, 0.292 mmol) and Cs2CO3 (375 mg, 1.168 mmol), the reaction mixture was stirred at 160 °C in microwave for 3 h. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexanes to give the title compound (58 mg, 19%) as a yellow solid.

[0798] 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

[0799]

[0800] 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

[0801] 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) were added Pd2(dba)3 (146 mg, 0.16 mmol), Brettphos (170 mg, 0.32 mmol) and t-BuONa (305 mg, 3.17 mmol), the reaction mixture was stirred under microwave at 130 °C for 4 h. The reaction mixture was cooled to room temperature and poured into water (30 mL), then extracted with DCM (10 mL x 3), the combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (700 mg, crude) as a yellow solid.

[0802] MS: m / z=576 (M+1, ESI+).

[0803] 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

[0804] 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 3M 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.

[0805] Example 321: Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate

[0806]

[0807] Step 1: Synthesis of 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylic acid

[0808] 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 Pd2(dba)3 (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 under microwave for 4 hours. The reaction mixture was cooled to room temperature and poured into water (20 mL), then extracted with DCM (10 mL×3), the combined organic layers were washed with brine (20 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (110 mg, 19.30%) as a yellow solid.

[0809] Step 2: Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate

[0810] 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) was added SOCl2 (64 mg, 0.54 mmol) dropwise at 0°C and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (30 mg, 32.26%) as a white solid.

[0811] Method C. Preparation of carboxylic acid derivatives via hydrolysis

[0812] Example 62: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0813]

[0814] Methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.12 mmol) and LiOH·H2O (50 mg, 1.186 mmol) prepared in Example 61 above were dissolved in 1,4-dioxane (1 mL) and H2O (0.2 mL), stirred at room temperature for 1.5 hours, and stirred at reflux for 19 hours at 50°C. After the reaction was confirmed to be complete by LC-MS, the reaction solution was adjusted to pH 5 with 1N-HCl solution, extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to obtain the title compound (13 mg, 27%) as a yellow solid in the form of a filter cake.

[0815] Method D. Preparation of amide derivatives via amide linkage reaction

[0816] Example 65: Synthesis of N-isopropyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide

[0817]

[0818] 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.12 mmol), propan-2-amine (9 mg, 0.013 mmol), and TBTU (47 mg, 0.15 mmol) prepared in Example 62 above were dissolved in DMF (2 mL), followed by the addition of DIPEA (13 μL, 0.69 mmol), and the mixture was stirred at room temperature for 67 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was washed with brine solution and extracted with ethyl acetate, and 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 in the form of a filter cake.

[0819] Example 66: Synthesis of N-cyclohexyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide

[0820]

[0821] 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.12 mmol), cyclohexylamine (15 mg, 0.017 mmol) and TBTU (47 mg, 0.15 mmol) prepared in Example 62 above were dissolved in DMF (2 mL), followed by the addition of DIPEA (13 μL, 0.69 mmol), and the mixture was stirred at room temperature for 17 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was washed with brine solution and extracted with ethyl acetate, and 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 in the form of a filter cake.

[0822] Method E. Preparation via amide reaction and cyclization followed by further reaction

[0823] Example 40: Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-2-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)phenol

[0824]

[0825] 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 above was dissolved in dichloromethane and BBr3 in hexanes (1 M, 0.2 mL, 0.2 mmol) was added at 0°C. The mixture was then stirred at room temperature for 8 hours. After the reaction was confirmed to be complete by LC-MS, the residue was slurried with dichloromethane and filtered to obtain the title compound (21 mg, 9%) as a beige solid.

[0826] Example 93: 3-(6-(3-methyl-1,2,4- Synthesis of oxadiazole-5-yl)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

[0827]

[0828] 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) and N-hydroxyacetamidine (24 mg, 0.32 mmol) prepared in Example 61 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 resulting mixture was washed with brine. After extraction with a solution of 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.

[0829] Method F. Preparation by other reactions

[0830]

[0831] Example 122: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0832]

[0833] Step 1: Synthesis of 2-(3-iodophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0834] 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 potassium hydrogen persulfate (5.03 g, 8.19 mmol). After the mixture was stirred at room temperature for 2 hours, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to obtain the title compound (1-3, 3.7 g, 81%) as a white solid.

[0835] 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).

[0836] 19 F-NMR (377MHz, DMSO-d6): δ-58.91.

[0837] Step 2: Synthesis of 2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0838] A mixture of 2-(3-iodophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-3, 1 g, 2.57 mmol), 4-bromothiophenol (1-4, 400 mg, 2.14 mmol), CuI (408 mg, 2.14 mmol), L-proline (246 mg, 2.14 mmol) and K3PO4 (1.36 g, 6.42 mmol) in 1,4-dioxane (10 mL) was degassed and backfilled with N2 (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 obtain the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to obtain the title compound (1-5, 1.02 g, 88%) as a white solid.

[0839] MS: m / z=449 (M+1, ESI+).

[0840] Step 3: Synthesis of 2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0841] To a solution of 2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-5, 800 mg, 1.78 mmol) in CHCl (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 obtain the title compound (1-6, 652 mg, 76%) as a white solid.

[0842] 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).

[0843] 19 F-NMR (377MHz, DMSO-d6): δ-58.94,-59.01.

[0844] 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

[0845] 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 backfilled with N2 (three times). The mixture was heated to 100 °C overnight. LCMS showed the reaction was complete. After cooling, the product was used directly in the next step.

[0846] MS: m / z=529 (M+1, ESI+).

[0847] Step 5: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0848] 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 prepared in the previous step in 1,4-dioxane (10 mL) (1-8, 0.73 mmol) was added 3-bromopyridazine (1-9, 139 mg, 0.87 mmol), H2O (1 mL), K2CO3 (302 mg, 2.19 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol). The mixture was degassed and backfilled with N2 (three times) and then 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 obtain the title compound (150 mg, 42%) as a white solid.

[0849] Example 123: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4-oxadiazol-2-amine

[0850]

[0851] Step 1: Synthesis of pyridazine-3-carboxylic acid hydrazide

[0852] Pyridazine-3-carboxylic acid (2-0) (1.0 g, 8 mmol) was dissolved in DCM (20 mL) at 0 °C. SOCl2 (1.2 g, 9.6 mmol) and a drop of DMF were added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in DCM (20 mL), followed by the addition of NH2NHBoc (1.2 g, 8.8 mmol) and DIEA (2 g, 16 mmol). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was distributed between ethyl acetate (100 mL) and NaHCO3 aqueous solution (50 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 crude product was then 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 hours. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and aqueous NaHCO3 solution (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 obtain the title compound (2-1, 790 mg, 71%) as a white solid.

[0853] MS: m / z=139 (M+1, ESI+).

[0854] Step 2: Synthesis of 2-(3-nitrophenyl)-1H-benzo[d]imidazole

[0855] 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 potassium persulfate (12.8 g, 21 mmol). The mixture was stirred at room temperature for 2 hours, after which HPLC analysis indicated that the reaction was complete. The reactants were quenched by K2CO3 aqueous solution (1 M, 10 mL), and then H2O (120 mL) was added dropwise to the mixture under vigorous stirring. The resulting precipitate was collected by filtration, washed with H2O and dried to obtain the title compound (2-4, 7.5 g, crude product), which was used in the next step without further purification.

[0856] MS: m / z=240 (M+1, ESI+).

[0857] Step 3: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)aniline

[0858] A mixture of 2-(3-nitrophenyl)-1H-benzo[d]imidazole (2-4, 7.5 g, crude product) and 750 mg of Pd / C in MeOH (100 mL) was stirred at room temperature under H2 atmosphere for 16 hours. The reaction mixture was then filtered through celite and then washed with MeOH. The combined filtrate was concentrated and the residue was purified by silica gel column chromatography (DCM:MeOH=60:1) to obtain the title compound (2-5, 3.8 g, 61%) as a yellow solid.

[0859] MS: m / z = 210 (M+1, ESI+)

[0860] Step 4: Synthesis of 2-(3-isothiocyanatophenyl)-1H-benzo[d]imidazole

[0861] 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-phenyl chlorothioate (2-6, 633 mg, 3.7 mmol). The resulting mixture was stirred at room temperature for 2 hours under N2 atmosphere and then 1N NaOH solution (10 mL) was added. The resulting mixture was stirred at room temperature under N2 atmosphere for 16 hours, then diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to obtain the title compound (2-7, 180 mg, 22%) as a yellow solid.

[0862] MS: m / z=252 (M+1, ESI+).

[0863] Step 5: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-(pyridazine-3-carbonyl)hydrazine-1-carbothioamide

[0864] A mixture of 2-(3-isothiocyanatophenyl)-1H-benzo[d]imidazole (2-7, 180 mg, 0.7 mmol) and pyridazine-3-carboxylic acid hydrazide (2-1, 97 mg, 0.7 mmol) in EtOH (30 mL) was stirred at room temperature under N2 atmosphere for 16 hours. The resulting precipitate was collected by filtration, washed with EtOH and dried. The residue was purified by preparative HPLC to obtain the title compound (2-8, 190 mg, 70%) as a yellow solid.

[0865] MS: m / z=390 (M+1, ESI+).

[0866] Step 6: N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4- Synthesis of 2-oxadiazole

[0867] To a solution of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-(pyridazine-3-carbonyl)hydrazine-1-thiocarboamide (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 for 16 h under N2 atmosphere. The reactants were diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (50 mg, 56%) as a white solid.

[0868] Example 124: Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0869]

[0870] Step 1: Synthesis of 2-(3-nitrophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0871] To a solution of 4-(trifluoromethyl)benzene-1,2-diamine (3-2, 821 mg, 4.7 mmol) dissolved in DMF (10 mL) was added 3-nitrobenzaldehyde (3-1, 774 mg, 5.1 mmol) followed by potassium persulfate (2.0 g, 3.3 mmol). The mixture was stirred at room temperature for 2 hours, after which LCMS analysis indicated the reaction was complete. The reactants were quenched by aqueous K2CO3 (1 M, 25 mL) and then H2O (60 mL) was added dropwise to the mixture under vigorous stirring. The resulting precipitate was collected by filtration, washed with H2O and dried to obtain the title compound (3-3, 1.5 g, crude product), which was used in the next step without further purification.

[0872] MS: m / z=308 (M+1, ESI+).

[0873] Step 2: Synthesis of 3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0874] A mixture of 2-(3-nitrophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (3-3, 1.5 g, crude product) and 150 mg of Pd / C in MeOH (30 mL) was stirred at room temperature under H2 atmosphere for 2 hours. The reaction mixture was then filtered through celite and then washed with MeOH. The combined filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=60:1) to obtain the title compound (3-4, 410 mg, 31%) as a brown solid.

[0875] MS: m / z=278 (M+1, ESI+).

[0876] Step 3: Synthesis of 3-chloro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridazine

[0877] PdCl2(dppf) was added to the flame-dried flask. (The mixture was stirred for 2 hours at 40 ℃ for 1 h. After the starting material was completely consumed, the mixture was cooled to room temperature, which was determined by monitoring with TLC. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with (PE:EtOAc=2:1) ​​to obtain the title compound (3-7, 1.2 g, 71%) as an off-white solid.

[0878] MS: m / z=253 (M+1, ESI+).

[0879] Step 4: Synthesis of 3-(1,4-dioxaspiro[4.5]decane-8-yl)pyridazine

[0880] 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 H2 atmosphere for 16 hours. The reaction mixture was then filtered through celite and subsequently washed with MeOH. The combined filtrates were concentrated to give the title compound (3-8, 0.95 g, crude product) as a yellow solid, which was used in the next step without further purification.

[0881] MS: m / z=221 (M+1, ESI+).

[0882] Step 5: Synthesis of 4-(pyridazin-3-yl)cyclohexanone

[0883] To a stirred solution of 3-(1,4-dioxaspiro[4.5]decane-8-yl)pyridazine (3-8, 0.95 g, crude product) in THF (20 mL) was added 1N-HCl (aqueous solution) (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the disappearance of the starting material was confirmed 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 obtain the title compound (3-9, 480 mg, 57%) as a white solid.

[0884] MS: m / z=177 (M+1, ESI+).

[0885] Step 6: Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

[0886] 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 for 16 h under N2 atmosphere. The reaction was quenched by aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (78 mg, mixture of two isomers, 31%) as a white solid.

[0887] 19 F NMR (376MHz, DMSO-d6): δ-58.78.

[0888] Example 125: Synthesis of 1-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidin-4-amine

[0889]

[0890] Step 1: Synthesis of 8-(pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane

[0891] 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 hours 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 obtain the title compound (4-3, 2.5 g, crude product), which was used without further purification.

[0892] MS: m / z=222 (M+1, ESI+).

[0893] Step 2: Synthesis of 1-(pyridazin-3-yl)piperidin-4-one

[0894] To a stirred solution of 8-(pyridazine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4-3, 2.5 g, crude product) in THF (20 mL) was added 1N-HCl (aqueous solution) (10 mL) at room temperature. The resulting mixture was stirred at 70 ° C for 2 hours. After the reaction was completed by TLC, the mixture 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 obtain the title compound (4-4, 490 mg, 27%) as a brown oil.

[0895] MS: m / z=178 (M+1, ESI+).

[0896] Step 3: Synthesis of 1-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidin-4-amine

[0897] 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 N2 atmosphere for 16 h. The reaction was quenched by aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (77 mg, 31%) as a white solid.

[0898] 19 F NMR (376MHz, DMSO-d6): δ-58.81.

[0899] 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

[0900]

[0901] 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 obtain the title compound (17 mg, 13.82%) as a white solid.

[0902] Example 317: Synthesis of 6-(piperidin-4-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine

[0903]

[0904] 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 3M-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.

[0905] Compounds other than the examples described above were prepared using Methods A to F as described above.

[0906] The chemical structural formulas, NMR and LC-MS analysis results of the compounds of Examples 1 to 336 are summarized in Table 2 below.

[0907] [Table 2]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942] Experimental Example 1: Efficacy test of antithrombotic substances (carotid artery thrombosis model induced by ferric chloride)

[0943] 1. Experimental Materials and Equipment

[0944] Isoflurane (HanaPharm, catalog number 9008), iron (III) chloride (Sigma-Aldrich, catalog number 157740), dimethyl sulfoxide (Sigma-Aldrich, catalog number D5879), poly(ethylene glycol), polyethylene glycol 400 with an average Mn of 400 (PEG400, Sigma-Aldrich, catalog number 202398), hydroxypropyl-β-cyclodextrin (HP-β-CD, TCI, catalog number H0979).

[0945] 2. Experimental Animals

[0946] The experimental animals were 8-week-old male SD rats (ORIENTBIO.), acclimated for two weeks, and the number of animals was confirmed when they were obtained, and general symptoms were observed and weighed, and the inspection report provided by the animal supplier was saved as basic test data. The general symptoms of all animals were observed once a day during the isolation and adaptation period. Rats were raised in polycarbonate cages under sterile conditions, with a temperature (22±3°C), a relative humidity of 30-70%, a ventilation frequency of 10 to 15 times / hour, and a 12-hour day and night cycle (illuminance of 150 to 300 lux). The cages were changed once a week and the drinking water was changed at least twice a week. Animal laboratory-grade solid food (Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C, Envigo RMS, Inc., USA) was fed ad libitum with a feeder.

[0947] After the final examination, the animals were divided into groups according to the rated body weight measurements to ensure that the average body weights of the groups were distributed as evenly as possible, and the animals remaining after the division were excluded from the study and euthanized by inhalation of carbon dioxide (CO2) gas.

[0948] 3. Experimental Procedure

[0949] 3-1. Preparation of control substances and test substances

[0950] The required amount of control substance 1 (Rivaroxaban), control substance 2 (Edoxaban) and the test substance were weighed, DMSO in an amount of 5% of the required solution was added, and then sonicated for 2 minutes to confirm that the substance was dissolved. Thereafter, PEG400 in an amount of 50% was added, and the resulting mixture was sonicated for 2 minutes. A 20% HP-β-CD-containing distilled water solution in an amount of 45% was added thereto and completely dissolved by sonication for 2 minutes. The test substance was prepared and used immediately before administration to the test animal.

[0951] 3-2. Preparation of inducing substance (50% FeCl solution)

[0952] Weigh the required amount of inducing substance and add water for injection and vortex. Thereafter add water for injection to prepare the required amount of liquid.

[0953] 3-3. Administration of test substance

[0954] The test substance was orally administered 2 hours before thrombosis induction by setting the dosage to 10 mL / kg and connecting the oral administration probe to a disposable syringe. The control substance was orally administered 25 minutes before thrombosis induction by setting the dosage to 10 mL / kg and connecting the oral administration probe to a disposable syringe. The normal control group and the negative control group orally took the same amount of excipient (5% DMSO, 50% PEG400, 45% (distilled water solution containing 20% ​​HP-β-CD)).

[0955] 3-4. Thrombosis induction and vascular weight measurement

[0956] The test animals were anesthetized with isoflurane and the carotid artery was exposed. A Whatman No. 1 filter paper (4.2 mm 2 ) was placed on the carotid artery for 10 minutes. After 10 minutes, the paper was removed, the FeCl3 remaining in the blood vessel was washed with PBS, and the blood vessel was allowed to stand for 20 minutes and separated. The G1 group was also soaked in PBS with Whatman No.1 filter paper (4.2 mm 2 ) treatment. 20 minutes after removing the Whatman No.1 filter paper, the two ends of the blood vessel were tied together with a 4-0 ligature silk thread, and the blood vessel was separated. At this time, the length of the blood vessel was the same as the length of the ligature. The ligature was removed, and then the two ends of the blood vessel were gently touched with Kimwipes to remove the blood in the blood vessel, and the weight was measured. Subsequently, the image was taken and the length was measured using the ImageJ program.

[0957] 3-5. End of test

[0958] The blood vessel weight and blood vessel length were measured and photographed, and the test was terminated. The test results were expressed by calculating the inhibition rate (%) using the index value (blood vessel weight (mg) / blood vessel length (mm)) as follows.

[0959] Inhibition rate (%) = [(induction control average pointer value - normal control average pointer value) - (test group average pointer value - normal control average pointer value)] / (induction control average pointer value - normal control average pointer value) × 100

[0960] The test results (inhibition rate %) of each example compound treatment group are shown in Figures 1 to 6 , and exemplary compounds administered in each figure are shown in Table 3 below.

[0961] [Table 3]

[0962] picture Compound No. picture Compound No. 1 20，24 4 23，58，45 2 25，1 5 21 3 27，28 6 52，223

[0963] Experimental Example 2: LactC2 analysis (measuring the function of phosphatidylserine externalization promiscuous enzyme)

[0964] 1. Materials and Equipment

[0965] Ionomycin (Alomonelab, catalog number I-700), DAPI (Sigma-Aldrich, catalog number D8417), paraformaldehyde (Biosesang, catalog number P2031), LionheartFX automated fluorescence microscope (BioTek), Gen5 TM software program (BioTek) and ImageJ analysis software program.

[0966] 2. Cell Culture

[0967] Fisher rat thyroid (FRT) cells expressing human ANO6 (variant 5; GenBank accession number NP_001191732.1) were cultured at 37°C, 5% CO2 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.

[0968] 3. Test Methods

[0969] Fisher rat thyroid (FRT) cells expressing human ANO6 (variant 5) were cultured in 96-well microtiter plates (2 × 10 4Cells / well) for 24 hours. After cultivation, cells were treated with compounds dissolved in DMSO to 1v / v%, with each concentration in each well being 50nM, 100nM and 1μM and a reaction time of 10 minutes. Thereafter, each well was treated with ionomycin to a final concentration of 10μM, allowed to react for 10 minutes, and then washed with 200μL PBS. After washing, each well was treated with 50μL of Lactadherin-C2 (Lact-C2)-GFP mixed in DMEM culture medium at a final concentration of 500nM to stain phosphatidylserine, and cultured at 37°C for 10 minutes. After the reaction was complete, the cells were washed with 200μL PBS and fixed with 4% paraformaldehyde at room temperature for 5 minutes. For morphological analysis, DAPI solution was added, and the cells were cultured for 15 minutes, followed by washing with PBS. The fluorescence intensity of Lact-C2-GFP bound to phosphatidylserine on the cell surface was measured using an automated fluorescence microscope. To quantify the fluorescence intensity of Lact-C2-GFP, BioTekGen5 TM Software and ImageJ analysis software program.

[0970] The phosphatidylserine externalization inhibitory activity (%) of the compound was calculated by the following analytical method. Specifically, the background fluorescence value was subtracted from the measured Lact-C2-GFP fluorescence value, and the fluorescence values ​​of the ionomycin non-treated group and the ionomycin treated group in the same row were calculated, wherein each test group was located in a 96-well microplate. In order to calculate the inhibitory activity (%) of the compound, the relative inhibitory activity was calculated by setting the compound and the ionomycin non-treated group to 100% inhibitory activity and setting the ionomycin treated group alone to 0% inhibitory activity. To obtain the results, the test was repeated three times, and the mean values ​​of the results were classified according to the following ranges and are shown in Table 4 below (A:>60% inhibition, B:30 to 60% inhibition, N / A: no test).

[0971] [Table 4]

[0972]

[0973]

[0974]

[0975]

Claims

1. A compound represented by the following chemical formula 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: [Chemical formula 1] In the above chemical formula 1, Ring X is a 5-6 membered heteroaryl, a 5-6 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl, wherein at least one of the H in the 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl ring is -C 1-6 Alkyl, -benzyl, -C 1-6 Haloalkyl, -(CH2)nR e 、-O-(CH2)nR e or -halogen substitution; Y1 to Y4 are each independently CR Y or N; R Y -H, -C 1-6 Alkyl, -C 1-6 Amine alkyl, -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, -halogen or 5-6 membered heteroaryl, at least one of the 5-6 membered heteroaryl groups is -C 1-6 Alkyl substitution; Ring A and Ring B are each independently an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group is monocyclic or polycyclic, and at least one H of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Amine alkyl, -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 , -halogen or 5-6 membered heterocycloalkyl, at least one of the H in the 5-6 membered heterocycloalkyl is -C 1-6 Alkyl substitution; 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 -H or -C 1-6 alkyl; Z is -H, -C 1-6 -C alkyl, -CN, -C alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, at least one H in the -C alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Amine alkyl, -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 , -halogen or 5-6 membered heterocycloalkyl, at least one H in the above 5-6 membered heterocycloalkyl may be substituted by -C 1-6 Alkyl substitution; R a and R b are 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, at least one H in the heterocycloalkyl may be -C 1-6 Alkyl substitution; 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 For -C 1-6 Amine alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), heteroaryl, heterocycloalkyl or heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl or heterocycloalkenyl is monocyclic or polycyclic, and at least one H in the heteroaryl, heterocycloalkyl or heterocycloalkenyl ring is -C 1-6 Alkyl substitution; and n is 0, 1, 2, 3 or 4.

2. The compound represented by Chemical Formula 1 according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 1-1; [Chemical formula 1-1] 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 alkyl; Y1 to Y4 are each independently CR Y or N; R Y -H, -C 1-6 Alkyl, -C 1-6 Amine alkyl, -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, -halogen or 5-6 membered heteroaryl, at least one of the 5-6 membered heteroaryl groups is -C 1-6 Alkyl substitution; Ring A and Ring B are each independently an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group is monocyclic or polycyclic, and at least one 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 , -halogen or 5-6 membered heterocycloalkyl, at least one of the H in the 5-6 membered heterocycloalkyl is -C 1-6 Alkyl substitution; 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 -H or -C 1-6 alkyl; Z is -H, -CN, -C2 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, and at least one H in the -C2 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Amine alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NO2, -NR a R b 、-OR c , -C(=O)-R d 、-O-(CH2)nR e -, -halogen or 5-6 membered heterocycloalkyl, at least one H in the above 5-6 membered heterocycloalkyl ring is -C 1-6 Alkyl substitution; R a and R b are 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, at least one of the H in the heterocycloalkyl is -C 1-6 Alkyl substitution; 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, at least one H of the heteroaryl, heterocycloalkyl or heterocycloalkenyl ring is -C 1-6 Alkyl substitution; and n is 0, 1, 2, 3 or 4.

3. The compound represented by Chemical Formula 1 according to claim 2, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: X1 is NR3 or O; X2 is CR4 or N; R3 and R4 are each independently -H or -C 1-6 alkyl; Y1 and Y4 are each independently CR Y ; Y2 and Y3 are each independently CR Y or N, wherein when ring X1 is S, one of Y2 and Y3 is N, 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, -halogen or 5-6 membered heteroaryl, at least one of the 5- to 6-membered heteroaryl groups is -C 1-6 Alkyl substitution.

4. The compound represented by Chemical Formula 1 according to claim 2, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, 5-6 membered heteroaryl or 5-6 membered cycloalkyl, and at least one of the H in the phenyl, 5-6 membered heteroaryl or 5-6 membered cycloalkyl ring is -C 1-6 Haloalkyl, -NO2, -NR a R b 、-OR c , -halogen or 5-6 membered heterocycloalkyl, at least one of the H in the 5-6 membered heterocycloalkyl is -C 1-6 Alkyl substitution.

5. The compound represented by Chemical Formula 1 according to claim 2, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: L is -NR L -、-C≡C-NR L , -O- or -S(=O)2-; and R L -H or -C 1-6 alkyl.

6. The compound represented by Chemical Formula 1 according to claim 2, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl, and at least one of the H in the phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -NO2, -NR a R b 、-OR c or -halogen substituted.

7. The compound represented by Chemical Formula 1 according to claim 2, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Z is -CN, phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl, and at least one of the H rings of the phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -CN, -OR c , -C(=O)-R d 、-(CH2)nR e , -halogen or 5-6 membered heterocycloalkyl, at least one of the H in the 5-6 membered heterocycloalkyl is -C 1-6 Alkyl substitution, when the above ring B is phenyl, 6-membered heteroaryl or 6-membered heterocycloalkyl, Z is connected to the para position relative to L.

8. The compound represented by Chemical Formula 1 according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound represented by the above Chemical Formula 1 is selected from the group consisting of the following compounds: 9 . A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 , its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

10. A pharmaceutical composition for treating or preventing thrombosis or thrombosis-related diseases, comprising the compound according to any one of claims 1 to 8, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

11. The pharmaceutical composition according to claim 10, wherein The thrombosis or thrombosis-related disease is at least one disease selected from the group consisting of: Acute myocardial infarction; atrial fibrillation; unstable angina; chronic stable angina; transient ischemic attack; stroke; peripheral vascular disease; preeclampsia; eclampsia; deep vein thrombosis; embolism; cancer-related thrombosis; disseminated intravascular coagulation; thrombotic thrombocytopenia; and thrombotic complications or restenotic complications following invasive procedures such as angioplasty, carotid endarterectomy, post-coronary artery bypass graft surgery, vascular graft surgery, stent placement, and insertion of intravascular devices and prostheses.

12. Use of the compound represented by Chemical Formula 1 according to any one of claims 1 to 8, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating the above-mentioned thrombosis or thrombosis-related diseases.

13. A method for preventing or treating such thrombosis or thrombosis-related diseases, comprising administering a therapeutically effective amount of the compound represented by Chemical Formula 1 according to any one of claims 1 to 8, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

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