DOYLE KEVIN (GB)
STOTT ANDREW (GB)
CEREVANCE LTD (GB)
| WO2005097759A1 | 2005-10-20 | |||
| WO2022167819A1 | 2022-08-11 | |||
| WO2020210828A1 | 2020-10-15 | |||
| WO2013078254A1 | 2013-05-30 | |||
| WO2019152419A1 | 2019-08-08 |
| EP3181552A1 | 2017-06-21 | |||
| EP0648752A1 | 1995-04-19 | |||
| US20100298334A1 | 2010-11-25 |
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| Claims 1. A compound of formula (I) or a pharmaceutically N- or prodrug thereof, for use in treating or preventing a disease, disorder or condition associated with KCNK13 activity, wherein: each A1, A2, A3 and A4 is independently selected from CR4 or N, provided that no more than three of A1, A2, A3 and A4 are N; each A5, A6, A7, A8 and A9 is independently selected from CR1 or N, provided that no more than three of A5, A6, A7, A8 and A9 are N; one of V, X and Z is selected from N, NR2, CR2 or CH, and the other two of V, X and Z are independently selected from N, NR2 or CR2; each of W and Y is independently selected from N or C; provided that two or three of V, W, X, Y and Z are N or NR2; and provided that the compound comprises one or two R2; each R1 is independently selected from hydrogen, halo, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), -NH2, -NH-(C1-C2 alkyl), -NH-(C1-C2 haloalkyl), -N-(C1-C2 alkyl)2, -N-(C1-C2 alkyl)(C1-C2 haloalkyl), -N-(C1-C2 haloalkyl)2, -SO2(C1-C2 alkyl), or -SO2(C1-C2 haloalkyl); or two R1, which are attached to two adjacent carbon atoms, together with the said two adjacent carbon atoms can form a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); each R2 is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), or -O-(C3-C6 halocycloalkyl); R3 is cyano, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3- C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), -N-(C1-C3 haloalkyl)2, -N-(C2-C5 alkylene), -N-(C2-C5 haloalkylene), -S-(C1-C3 alkyl), -S-(C1-C3 haloalkyl), -S-(C3-C6 cycloalkyl), or -S-(C3-C6 halocycloalkyl); each R4 is independently selected from hydrogen, halo, cyano, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3-C6 halocycloalkyl), -S-(C1-C3 alkyl), -S-(C1-C3 haloalkyl), -S-(C3-C6 cycloalkyl), -S-(C3-C6 halocycloalkyl), -NH-(C1-C3 alkyl), -NH-(C1- C3 haloalkyl), -NH-(C3-C6 cycloalkyl), -NH-(C3-C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), or -N-(C1-C3 haloalkyl)2; or when A1 is CR4, then the said CR4 and R3 together with the carbon atom to which they are attached can form a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); or when A1 and A2, or A2 and A3, or A3 and A4 are both CR4, then the said two CR4 can together form a 5- or 6-membered heteroaryl group or a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl), and wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), or oxo [=O]; provided that the compound comprises at least one R1 which is not hydrogen; and provided that the compound comprises at least one R4 which is not hydrogen. 2. A compound of formula (I) or a pharmaceutically N- or prodrug thereof, for use in therapy, wherein: each A1, A2, A3 and A4 is independently selected from CR4 or N, provided that no more than three of A1, A2, A3 and A4 are N; each A5 and A9 is independently selected from CR1; each A6, A7 and A8 is independently selected from CR1 or N; V is selected from N, CR2 or CH; W is selected from N or C; X is selected from N, NR2, CR2 or CH; Y is selected from N or C; Z is selected from N, CR2 or CH; provided that two or three of V, W, X, Y and Z are N or NR2; and provided that the compound comprises one or two R2; each R1 is independently selected from hydrogen, halo, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), -NH2, -NH-(C1-C2 alkyl), -NH-(C1-C2 haloalkyl), -N-(C1-C2 alkyl)2, -N-(C1-C2 alkyl)(C1-C2 haloalkyl), -N-(C1-C2 haloalkyl)2, -SO2(C1-C2 alkyl), or -SO2(C1-C2 haloalkyl); or two R1, which are attached to two adjacent carbon atoms, together with the said two adjacent carbon atoms can form a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); each R2 is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), or -O-(C3-C6 halocycloalkyl); R3 is cyano, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3- C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), -N-(C1-C3 haloalkyl)2, -N-(C2-C5 alkylene), -N-(C2-C5 haloalkylene), -S-(C1-C3 alkyl), -S-(C1-C3 haloalkyl), -S-(C3-C6 cycloalkyl), or -S-(C3-C6 halocycloalkyl); each R4 is independently selected from hydrogen, halo, cyano, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3-C6 halocycloalkyl), -S-(C1-C3 alkyl), -S-(C1-C3 haloalkyl), -S-(C3-C6 cycloalkyl), -S-(C3-C6 halocycloalkyl), -NH-(C1-C3 alkyl), -NH-(C1- C3 haloalkyl), -NH-(C3-C6 cycloalkyl), -NH-(C3-C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), or -N-(C1-C3 haloalkyl)2; or when A1 is CR4, then the said CR4 and R3 together with the carbon atom to which they are attached can form a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); provided that the 5-membered heteroaryl group is not a pyrrole or thiophene group; or when A1 and A2, or A2 and A3, or A3 and A4 are both CR4, then the said two CR4 can together form a 5- or 6-membered heteroaryl group or a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl), and wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), or oxo [=O]; provided that the compound comprises at least one R1 which is not hydrogen; provided that the compound comprises at least one R4 which is not hydrogen; and provided that the compound is not: a) 4-methyl-3-(2-(methylthio)-4-(trifluoromethyl)phenyl)-5-(2- (trifluoromethyl)phenyl)-4H-1,2,4-triazole or a stereoisomer thereof. 3. A compound of formula (I) or a pharmaceutically thereof, wherein: 1 2 3 each A , A , A CR4 or N, provided that no more than three of A1, A2, A3 and A4 are N; each A5 and A9 is independently selected from CR1; each A6, A7 and A8 is independently selected from CR1 or N; V is selected from N, CR2 or CH; W is selected from N or C; X is selected from N, NR2, CR2 or CH; Y is selected from N or C; Z is selected from N, CR2 or CH; provided that two or three of V, W, X, Y and Z are N or NR2; and provided that the compound comprises one or two R2; each R1 is independently selected from hydrogen, halo, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), -NH2, -NH-(C1-C2 alkyl), -NH-(C1-C2 haloalkyl), -N-(C1-C2 alkyl)2, -N-(C1-C2 alkyl)(C1-C2 haloalkyl), -N-(C1-C2 haloalkyl)2, -SO2(C1-C2 alkyl), or -SO2(C1-C2 haloalkyl); or two R1, which are attached to two adjacent carbon atoms, together with the said two adjacent carbon atoms can form a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); each R2 is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), or -O-(C3-C6 halocycloalkyl); R3 is cyano, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3- C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), -N-(C1-C3 haloalkyl)2, -N-(C2-C5 alkylene), or -N-(C2-C5 haloalkylene); each R4 is independently selected from hydrogen, halo, cyano, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3-C6 halocycloalkyl), -S-(C1-C3 alkyl), -S-(C1-C3 haloalkyl), -S-(C3-C6 cycloalkyl), -S-(C3-C6 halocycloalkyl), -NH-(C1-C3 alkyl), -NH-(C1- C3 haloalkyl), -NH-(C3-C6 cycloalkyl), -NH-(C3-C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), or -N-(C1-C3 haloalkyl)2; or when A1 is CR4, then the said CR4 and R3 together with the carbon atom to which they are attached can form a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); provided that the 5-membered heteroaryl group is not a pyrrole or thiophene group; or when A1 and A2, or A2 and A3, or A3 and A4 are both CR4, then the said two CR4 can together form a 5- or 6-membered heteroaryl group or a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl), and wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), or oxo [=O]; provided that the compound comprises at least one R1 which is not hydrogen; provided that the compound comprises at least one R4 which is not hydrogen; and provided that the compound is not: b) 1-methyl-2-(2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-5-(4- (trifluoromethyl)phenyl)-1H-imidazole; c) 2-(2-ethoxy-4-(trifluoromethyl)phenyl)-1-methyl-5-(4- (trifluoromethyl)phenyl)-1H-imidazole; d) 2-(1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)-5- (trifluoromethyl)benzonitrile; or e) 2-(2-(2-(ethylsulfonyl)-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-5-yl)- 5-(trifluoromethyl)benzonitrile; or a stereoisomer of any of the above compounds. 4. A compound of formula (IA) or a pharmaceutically N- or thereof, wherein: each A1, A2, A3 and A4 is independently selected from CR4 or N, provided that no more than three of A1, A2, A3 and A4 are N; one of V, X and Z is selected from N, NR2, CR2 or CH, and the other two of V, X and Z are independently selected from N, NR2 or CR2; each of W and Y is independently selected from N or C; provided that two or three of V, W, X, Y and Z are N or NR2; and provided that the compound comprises one or two R2; each R1 is independently selected from halo, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); n is 1, 2 or 3; each R2 is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), or -O-(C3-C6 halocycloalkyl); R3 is -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3-C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), -N-(C1-C3 haloalkyl)2, -N-(C2-C5 alkylene), or -N-(C2-C5 haloalkylene); each R4 is independently selected from hydrogen, halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), or -O-(C3-C6 halocycloalkyl); or when A1 is CR4, then the said CR4 and R3 together with the carbon atom to which they are attached can form a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); or when A1 and A2, or A2 and A3, or A3 and A4 are both CR4, then the said two CR4 can together form a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); provided that the compound comprises at least one R4 which is not hydrogen; and provided that the compound is not: i. 3-(5-chloro-2-methoxyphenyl)-1-methyl-5-(4-(trifluoromethyl)phenyl)-1H- pyrazole; ii. 1-methyl-2-(2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-5-(4- (trifluoromethyl)phenyl)-1H-imidazole; iii. 3,5-bis(2,4-dimethoxyphenyl)-1-methyl-1H-pyrazole; iv. 2-(2-ethoxy-4-(trifluoromethyl)phenyl)-1-methyl-5-(4- (trifluoromethyl)phenyl)-1H-imidazole; v. 3-(2-chloro-6-fluorophenyl)-5-(2-ethoxy-4,5-difluorophenyl)-1-methyl-1H- 1,2,4-triazole; vi. 3-(2-chloro-6-fluorophenyl)-5-(4,5-dichloro-2-ethoxyphenyl)-1-methyl-1H- 1,2,4-triazole; vii. 3-(2-chlorophenyl)-5-(4,5-dichloro-2-ethoxyphenyl)-1-methyl-1H-1,2,4- triazole; viii. 5-(4-chloro-2-methoxyphenyl)-1-cyclobutyl-3-(p-tolyl)-1H-1,2,4-triazole; ix. 4-(5-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-3-chloro-5- methoxypyridine; x. 3-(3-chlorophenyl)-5-(2,6-dimethoxyphenyl)-1-methyl-1H-1,2,4-triazole; xi. 3-(3-ethoxyphenyl)-5-(4-iodo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole; xii. 3-(2-chlorophenyl)-5-(2-ethoxy-4,5-difluorophenyl)-1-methyl-1H-1,2,4-triazole; xiii. 1-methyl-4-[4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl]-1H- indole; xiv. 4-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1H-indole; xv. 4-[5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1H-indole; xvi. 4-[4-(3-fluorophenyl)-3-methyl-1H-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine; xvii. 4-[3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]benzonitrile; xviii. 3-[3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]benzonitrile; xix. 4-[4-(2,6-dimethylphenyl)-3-methyl-1H-pyrazol-1-yl]-1H-pyrrolo[2,3- b]pyridine; xx. 4-[4-(3,5-difluorophenyl)-3-methyl-1H-pyrazol-1-yl]-1H-pyrrolo[2,3- b]pyridine; xxi. 4-[4-[3,5-bis(trifluoromethyl)phenyl]-3-methyl-1H-pyrazol-1-yl]-1H- pyrrolo[2,3-b]pyridine; or xxii. 4-[3-(3-bromophenyl)-5-methyl-1H-pyrazol-1-yl]thieno[2,3-d]pyrimidine; or a stereoisomer of any of the above compounds. 5. A compound of formula (I) or a pharmaceutically or thereof, wherein: each A1, A2 and A4 is independently selected from CR4 or N; A3 is CR5; each A5, A6, A7, A8 and A9 is independently selected from CR1 or N, provided that no more than three of A5, A6, A7, A8 and A9 are N; one of V, X and Z is selected from N, NR2, CR2 or CH, and the other two of V, X and Z are independently selected from N, NR2 or CR2; each of W and Y is independently selected from N or C; provided that two or three of V, W, X, Y and Z are N or NR2; and provided that the compound comprises one or two R2; each R1 is independently selected from hydrogen, halo, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), -NH2, -NH-(C1-C2 alkyl), -NH-(C1-C2 haloalkyl), -N-(C1-C2 alkyl)2, -N-(C1-C2 alkyl)(C1-C2 haloalkyl), -N-(C1-C2 haloalkyl)2, -SO2(C1-C2 alkyl), or -SO2(C1-C2 haloalkyl); or two R1, which are attached to two adjacent carbon atoms, together with the said two adjacent carbon atoms can form a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl); each R2 is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), or -O-(C3-C6 halocycloalkyl); R3 is halo; each R4 is independently selected from hydrogen, halo, cyano, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3-C6 halocycloalkyl), -S-(C1-C3 alkyl), -S-(C1-C3 haloalkyl), -S-(C3-C6 cycloalkyl), -S-(C3-C6 halocycloalkyl), -NH-(C1-C3 alkyl), -NH-(C1- C3 haloalkyl), -NH-(C3-C6 cycloalkyl), -NH-(C3-C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), or -N-(C1-C3 haloalkyl)2; or when A1 and A2 are both CR4, then the said two CR4 can together form a 5- or 6-membered heteroaryl group or a 5- or 6-membered non-aromatic heterocyclic group, wherein the 5- or 6-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl), and wherein the 5- or 6- membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1-C2 haloalkyl), or oxo [=O]; R5 is hydroxyl, -O-(C1-C3 alkyl), -O-(C1-C3 haloalkyl), -O-(C3-C6 cycloalkyl), -O-(C3-C6 halocycloalkyl), -S-(C1-C3 alkyl), -S-(C1-C3 haloalkyl), -S-(C3-C6 cycloalkyl), -S-(C3-C6 halocycloalkyl), -NH-(C1-C3 alkyl), -NH-(C1-C3 haloalkyl), -NH-(C3-C6 cycloalkyl), -NH-(C3-C6 halocycloalkyl), -N-(C1-C3 alkyl)2, -N-(C1-C3 alkyl)(C1-C3 haloalkyl), or -N-(C1-C3 haloalkyl)2; or when A2 or A4 is CR4, then the said CR4 and R5 together with the carbon atom to which they are attached can form a 5- or 6-membered heteroaryl group or a 5- or 6- membered non-aromatic heterocyclic group, wherein the 5- or 6-membered heteroaryl group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), or -O-(C1-C2 haloalkyl), and wherein the 5- or 6-membered non-aromatic heterocyclic group is optionally substituted with C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2 alkyl), -O-(C1- C2 haloalkyl), or oxo [=O]; provided that the compound comprises at least one R1 which is not hydrogen. 6. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 5, wherein one of A1, A2, A3 and A4 is N, and the other three of A1, A2, A3 and A4 are CR4. 7. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 5, wherein each A1, A2, A3 and A4 is CR4. 8. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 7, wherein each R4 is independently selected from hydrogen, fluoro, chloro, bromo, cyano, or methyl, provided that at least one R4 is not hydrogen. 9. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 7, wherein A1 is CR4, and the said CR4 and R3 together with the carbon atom to which they are attached form a 5-membered heteroaryl group which is optionally substituted with methyl, fluoromethyl, methoxy, or fluoromethoxy, and each further R4, if any, is independently selected from hydrogen, fluoro, chloro, bromo, cyano, or methyl. 10. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of the preceding claims, wherein R3 is methoxy, ethoxy, isopropoxy, fluoromethoxy, fluoroethoxy, fluoroisopropoxy, cyclopropoxy, or fluorocyclopropoxy. 11. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of the preceding claims, wherein V, W, X, Y and Z are selected such that ring B is a pyrazole, imidazole, 1,2,3-triazole, or 1,2,4-triazole group, which is substituted with one R2 group. 12. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of the preceding claims, wherein each R2 is independently selected from methyl, ethyl, methoxy, or ethoxy. 13. The compound, salt, N-oxide, solvate or prodrug as claimed in claim 1 or 5, wherein one of A5, A6, A7, A8 and A9 is N, and the other four of A5, A6, A7, A8 and A9 are CR1. 14. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1, 2, 3 or 5, wherein each A5, A6, A7, A8 and A9 is CR1. 15. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of the preceding claims, wherein each R1 is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, fluoromethyl, methoxy, or fluoromethoxy, provided that at least one R1 is not hydrogen. 16. The compound, salt, N-oxide, solvate or prodrug as claimed in claim 4, wherein n is 1 or 2. 17. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of the preceding claims, wherein the compound is selected from: 5-chloro-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-3-(5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine; 5-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(2,2,2- trifluoroethoxy)pyridine; 5-chloro-2-cyclopropoxy-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol- 3-yl)pyridine; 5-chloro-3-(5-(3-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluorophenyl)-4-methyl-4H-1,2,4-triazol- 3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(3,5-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluorophenyl)-4-methyl-4H-1,2,4-triazol- 3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(o-tolyl)-4H-1,2,4-triazol-3- yl)pyridine; 2-(difluoromethoxy)-3-(5-(2,4-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)- 5-fluoropyridine; 5-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- isopropoxypyridine; 2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)- 5-methylpyridine; 5-chloro-2-(difluoromethoxy)-3-(4-ethyl-5-(3-fluorophenyl)-4H-1,2,4-triazol-3- yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(3-(difluoromethoxy)phenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine; 5-bromo-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3- yl)nicotinonitrile; 5-chloro-2-(difluoromethoxy)-3-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3- triazol-4-yl)pyridine; 3-(5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazole; 3-(5-(2-bromophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-chloro-2- (difluoromethoxy)pyridine; 2-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3- yl)benzonitrile; 5-chloro-2-(difluoromethoxy)-3-(2-(2,6-difluorophenyl)-1-methyl-1H-imidazol- 5-yl)pyridine; 3-chloro-6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)-2-methylpyridine; 6-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3- yl)benzo[c][1,2,5]thiadiazole; 3-(5-chloro-2-methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazole; 5-chloro-2-(difluoromethoxy)-3-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2,3- triazol-1-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(3-(2,6-difluorophenyl)-5-methoxy-1H- pyrazol-1-yl)pyridine; 3-(5-chloro-2-(trifluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazole; 3-(4-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazole; 3-(3-bromo-5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazole; 3-(5-chloro-2-(difluoromethoxy)-3-methylphenyl)-5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazole; 3-(5-chloro-2-(difluoromethoxy)-3-fluorophenyl)-5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazole; 3-(5-chloro-2-(difluoromethoxy)-4-fluorophenyl)-5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazole; 3-(4,5-dichloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl- 4H-1,2,4-triazole; 4-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)- 6-methoxypyrimidine; 2-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5- methoxypyridine; 2-chloro-5-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6- isopropoxypyridine; 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6- (methylthio)pyridine; 6-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-3- (methylthio)pyridine; 3-chloro-2-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)-6- methoxypyridine; 3-chloro-6-(difluoromethoxy)-2-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2,3- triazol-1-yl)pyridine; 3-(2-chloro-5-methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazole; 3-(2-chloro-5-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazole; 3-chloro-2-(2-(2,6-difluorophenyl)-1-methyl-1H-imidazol-5-yl)-6- methoxypyridine; 3-chloro-6-(difluoromethoxy)-2-(2-(2,6-difluorophenyl)-1-methyl-1H-imidazol- 5-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluoro-6-methylphenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(methylsulfonyl)phenyl)-4H- 1,2,4-triazol-3-yl)pyridine; 3-chloro-6-(difluoromethoxy)-2-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3- triazol-4-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2,3,6-trifluorophenyl)-4H-1,2,4- triazol-3-yl)pyridine; 2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6- methoxynicotinonitrile; 5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-N- methylpyridin-2-amine; 4-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenol; 3-chloro-2-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-6- methoxypyridine; 3-chloro-6-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 6-chloro-3-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(2-methoxyphenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(trifluoromethyl)phenyl)-4H- 1,2,4-triazol-3-yl)pyridine; 5-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- methoxypyridine; 5-chloro-2-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 6-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)- 3-fluoropyridine; 2-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3- yl)aniline; 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2,4,6-trifluorophenyl)-4H-1,2,4- triazol-3-yl)pyridine; 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6- (methoxy-d3)pyridine; 3,5-bis(4-chloro-2-(difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazole; 5-chloro-2-(difluoromethoxy)-3-(5-(3,5-difluoropyridin-4-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine; 5-chloro-3-(5-(2-chloropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine; 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)- 4H-1,2,4-triazol-3-yl)pyridine; 5-chloro-3-(5-(3-chloropyridin-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine; 5-chloro-3-(5-(3-chloropyridin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-dihydrobenzofuran-7-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine; 5-chloro-3-(5-(4-chloropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl)-2- (difluoromethoxy)pyridine; 3-(5-(benzo[d][1,3]dioxol-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-chloro-2- (difluoromethoxy)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-dihydrobenzofuran-4-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-4-yl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(5-fluorobenzo[d][1,3]dioxol-4-yl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(6-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5- yl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-2-yl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine; 5-chloro-2-(difluoromethoxy)-3-(5-(3-(difluoromethoxy)pyridin-2-yl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine; 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)chroman-4- one; 3-(6-chlorochroman-5-yl)-5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazole; 5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2,3- dihydrofuro[2,3-b]pyridine; 4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)thieno[2,3- b]pyridine-5-carbonitrile; 5-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3- yl)thieno[2,3-c]pyridine; 5-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3- yl)thieno[2,3-b]pyridine; 3-(5-chloro-2,3-dihydrobenzofuran-4-yl)-5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazole; 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)quinoline; 3-chloro-6-methoxy-2-(4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3- yl)pyridine; 3-chloro-2-(5-(3-chloropyridin-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl)-6- (difluoromethoxy)pyridine; 3-chloro-2-[5-(3-chloro-6-methoxy-2-pyridyl)-4-methyl-1,2,4-triazol-3-yl]-6- methoxy-pyridine; 5-chloro-3-[5-[5-chloro-2-(difluoromethoxy)-3-pyridyl]-4-methyl-1,2,4-triazol- 3-yl]-2-(difluoromethoxy)pyridine; or an enantiomer of any of the foregoing; or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug of any of the foregoing. 18. A process for the preparation of a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, as claimed in any one of claims 1 to 17, wherein the process comprises: (a) reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof: wherein Q1 and one of B1 and B2 NH2, one B1 B2 R2; R2, R3, A1, A2, A3, A4, A5, A6, A7, A8 and A9 are as defined in any one of claims 1 to 17; or (b) reacting a compound of formula (IV) or a salt thereof with a compound of formula (V) or a salt thereof: wherein R6 is H V, W, X, Y, Z, R3, are as in any one of claims 1 to 17; and LG1 and LG2 are leaving groups such as halo (such as fluoro, chloro, bromo, or iodo), a sulfate group (such as methyl sulfate), or a sulfonate group (such as mesylate, triflate, or tosylate); or (c) (i) reacting a compound of formula (VI) or a salt thereof with a compound of formula (VII) or a salt thereof, to provide a compound of formula (VIII) or a salt thereof: R3 O NH R3 N A8 A7 1 to a group as as or , a sulfate group (such as methyl sulfate), or a sulfonate group (such as mesylate, triflate, or tosylate); and thereafter (ii) reacting the compound of formula (VIII) or the salt thereof with a compound of formula R2-LG or a salt thereof, wherein R2 is as defined in any one of claims 1 to 17 and LG is a leaving group such as halo (such as fluoro, chloro, bromo, or iodo), a sulfate group (such as methyl sulfate), or a sulfonate group (such as mesylate, triflate, or tosylate); or (d) reacting a compound of formula (XI) or a salt thereof with a compound of formula (XII) or a salt thereof: wherein: one of G1 and G2 is NH2, and the other one of G1 and G2 ; PG is a protecting group, such as toluenesulfonyl (tosyl), (mesyl) or tert-butyloxycarbonyl (Boc); and R2, R3, A1, A2, A3, A4, A5, A6, A7, A8 and A9 are as defined in any one of claims 1 to 17; or (e) (i) reacting a compound of formula (XIII) or a salt thereof with a compound of formula (XIV) or a salt thereof to provide a compound of formula (XV) or a salt thereof: or - ; R3, are as any one of claims 1 to 17; and thereafter (ii) reacting the compound of formula (XV) or the salt thereof with a compound of formula R7-LG or a salt thereof, wherein R7 is C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl, and LG is a leaving group such as halo (such as fluoro, chloro, bromo, or iodo), a sulfate group (such as methyl sulfate), or a sulfonate group (such as mesylate, triflate, or tosylate); and optionally thereafter carrying out one or more of the following procedures: - converting a compound of formula (I) or formula (IA) into another compound of formula (I) or formula (IA); - removing any protecting groups; - forming a pharmaceutically acceptable salt or N-oxide. 19. A pharmaceutical composition comprising a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, as claimed in any one of claims 1 to 17, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents. 20. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 17, for use in therapy. 21. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 17, for use in treating or preventing a disease, disorder or condition associated with KCNK13 activity. 22. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 17, for use in treating or preventing a neurodegenerative disease, a psychiatric disease, a genetic disease, hearing loss, an ocular or retinal disease, a cardiovascular disease, an inflammatory disease, an autoimmune disease, or a metabolic disease. 23. The compound, salt, N-oxide, solvate or prodrug as claimed in any one of claims 1 to 17, for use in treating or preventing Alzheimer’s disease, Parkinson’s disease, frontal temporal dementia, progressive supranuclear palsy (PSP) and related tauopathies, amyotrophic lateral sclerosis (ALS) / motor neuron disease (MND), traumatic brain injury, multiple sclerosis, stroke, ischemic insult, depression, stress, anxiety related disorder (including social and generalised anxiety), post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, cryopyrin-associated periodic syndrome (CAPS) (including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal onset multisystem inflammatory disease (NOMID)), age related hearing loss, genetic related hearing loss (including NLRP3 mutation related hearing loss), autoimmune related hearing loss, macular degeneration, age related macular degeneration, diabetic retinopathy, atherosclerosis, myocardial infarction, ischemia, rheumatoid arthritis, gout, Lupus, asthma, respiratory inflammation, inflammatory or autoimmune skin disease, psoriasis, inflammatory bowel disease, colitis, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, or diabetes. |
For example, G 1 is NH 2 and the compound of formula (XI) is a primary amine, and G 2 is the compound of formula (XII) comprises a protected hydrazone. For the compound of formula (XII) may be N'-(1-(2,6- difluorophenyl)propylidene)-4-methylbenzenesulfonohydrazide. Step (e) part (i) may be carried out by combining a compound of formula (XIII) or a salt thereof with a compound of formula (XIV) or a salt thereof in the presence of an acid such as acetic acid. The reaction is typically carried out at a temperature of 100 °C to 130 °C, preferably 110 °C, for about 0.5 to 2 hours, typically 1 hour. Part (ii) of step (e) may be carried out by combining a compound of formula (XV) or a salt thereof with a compound of formula R 7 -LG or a salt thereof in the presence of a base such as sodium hydride. The compound of formula R 7 -LG may be, for example, methyl iodide. The reaction is typically carried out in a solvent such as THF, typically under a nitrogen atmosphere. Typically, the reaction is carried out a temperature of 20 °C to 30 °C, preferably about 25 °C, for about 1 hour. In one embodiment of the third aspect, the present invention provides a process for the preparation of a compound of formula (IA) or a pharmaceutically acceptable salt, N- oxide, solvate or prodrug thereof, according to the first aspect of the present invention, wherein the process comprises: (a) reacting a compound of formula (IIA) or a salt thereof with an amide of formula (IIIA) or a salt thereof: wherein R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , A 4 and n are as defined in the first aspect of the present invention; or (b) reacting a compound of formula (IVA) or a salt thereof with a compound of formula (VA) or a salt thereof: wherein V, W, first aspect of the present are groups as (such as fluoro, chloro, bromo, or iodo), a sulfate group (such as methyl sulfate), or a sulfonate group (such as mesylate, triflate, or tosylate); or (c) (i) reacting a compound of formula (VIA) or a salt thereof with a compound of formula (VIIA) or a salt thereof, to provide a compound of formula (VIIIA) or a salt thereof: a group as as or iodo), a sulfate group (such as methyl sulfate), or a sulfonate group (such as mesylate, triflate, or tosylate); and thereafter (ii) reacting the compound of formula (VIIIA) or the salt thereof with a compound of formula R 2 -LG or a salt thereof, wherein R 2 is as defined in the first aspect of the present invention and LG is a leaving group such as halo (such as fluoro, chloro, bromo, or iodo), a sulfate group (such as methyl sulfate), or a sulfonate group (such as mesylate, triflate, or tosylate); and optionally thereafter carrying out one or more of the following procedures: - converting a compound of formula (IA) into another compound of formula (IA); - removing any protecting groups; - forming a pharmaceutically acceptable salt or N-oxide. An example of converting a compound of formula (IA) into another compound of formula (IA) can be found in Example 17 and Example 21. Step (a) may be carried out by combining a compound of formula (IIA) or a salt thereof with an amide of formula (IIIA) or a salt thereof in the presence of an activating agent such as trifluoromethanesulfonic anhydride and a base such as 2-fluoropyridine. The reaction is typically carried out in a solvent such as 1,2-dichloroethane (DCE), preferably under an atmosphere of nitrogen. Typically, the reaction is carried out at a temperature of 100 °C to 150 °C, typically under microwave irradiation. The reaction may take 1 to 4 hours, typically about 2 hours. The compound of formula (IIA) or a salt thereof may be synthesised in a two-step process as shown in Scheme 1, wherein R 3 , A 1 , A 2 A 3 and A 4 are as defined in the first aspect of the present invention. In the compound of formula (IXA) or a salt thereof, the group LG is a leaving group such as fluoro, chloro, bromo, iodo, mesylate, or triflate. Step (iii) may conventionally be carried out by a carbonylation reaction. In step (iii), a compound of formula (IXA) or a salt thereof may be combined with a palladium catalyst, such as palladium acetate, in the presence of a ligand, such as 1,3-bis(diphenylphosphino)propane (dppp), under an atmosphere of carbon monoxide. The reaction is typically carried out in a solvent such as methanol and in the presence of a base such as triethylamine. Typically, the reaction is carried out for 6 to 12 hours at a temperature of 70 °C to 100 °C, preferably around 80 °C. In step (iv), the compound of formula (XA) or a salt thereof can be combined with hydrazine (such as hydrazine hydrate) to provide a compound of formula (IIA) or a salt thereof. The reaction is typically carried out in a solvent such as ethanol at a temperature of 70 °C to 100 °C, preferably around 80 °C. Typically, the reaction takes 1 to 10 hours. In step (b), LG 1 and LG 2 may be the same or different. Step (b) may be carried out by combining a compound of formula (IVA) or a salt thereof with a compound of formula (VA) or a salt thereof and a diboron compound such as 4,4,4′,4′,5,5,5′,5′-octamethyl- 2,2′-bi-1,3,2-dioxaborolane (bis(pinacolato) diboron) in the presence of a palladium catalyst such as palladium (II) acetate. The reaction is typically carried out in the presence of a base such as caesium fluoride and in the presence of a ligand such as di(1- adamantyl)-n-butylphosphine. Typically, the reaction is carried out under an atmosphere of nitrogen in a solvent such as toluene, or in a mixture of toluene and water. The reaction is typically carried out at a temperature of 80 °C to 100 °C, preferably about 90 °C, for about 5 hours. Step (c) part (i) may be carried out by combining a compound of formula (VIA) or a salt thereof with a compound of formula (VIIA) in the presence of a base such as sodium hydrogen carbonate. The reaction is typically carried out in a solvent such as THF or water, or a mixture thereof. Typically, the reaction is carried out a temperature of 40 °C to 60 °C, preferably about 50 °C, for about 1 hour. Part (ii) of step (c) may be carried out by combining a compound of formula (VIIIA) or a salt thereof with a compound of formula R 2 -LG or a salt thereof. The reaction may conveniently be an alkylation reaction. Typically, the reaction is carried out in the presence of a base such as sodium hydride in a solvent such as THF. The reaction is typically carried out under an atmosphere of nitrogen at a temperature of about 0 °C for about 0.5 hours. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as phenol, hydroxy or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds, salts, N-oxides, solvates and prodrugs of the present invention may involve, at an appropriate stage, the introduction and/or removal of one or more protecting groups. The protection and deprotection of functional groups are described, for example, in ‘Protective Groups in Organic Chemistry’, edited by J.W.F. McOmie, Plenum Press (1973); ‘Greene’s Protective Groups in Organic Synthesis’, 4th edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (2007); and ‘Protecting Groups’, 3rd edition, P.J. Kocienski, Thieme (2005). The compounds of formula (I) and (IA) may be converted into a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi- formate, hydrochloride, hydrobromide, benzenesulfonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulfate, nitrate, phosphate, acetate, fumarate, semi- fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1-hydroxy-2-naphthoate (xinafoate), methanesulfonate or p-toluenesulfonate salt. In one embodiment of the invention, the compounds of formula (I) and (IA) are in the form of a hydrochloride, formate or fumarate salt. Compounds of formula (I) and (IA) and their salts and N-oxides may be in the form of hydrates or solvates which form another embodiment of the present invention. Such solvates may be formed with common organic solvents including, but not limited to alcoholic solvents e.g. methanol, ethanol or isopropanol. In one embodiment of the present invention, therapeutically inactive prodrugs are provided. Prodrugs are compounds which, when administered to a subject such as a human, are converted in whole or in part to a compound of formula (I) or (IA). Generally, the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds of formula (I) and (IA) can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound of formula (I) or (IA) or to otherwise alter the properties of the compound of formula (I) or (IA). Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include, but are not limited to compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound. The present invention also encompasses salts, N-oxides and solvates of such prodrugs as described above. Where the compounds, salts, N-oxides, solvates and prodrugs of the present invention are capable of existing in stereoisomeric forms, it will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) and mixtures thereof. The use of tautomers and mixtures thereof also forms an embodiment of the present invention. The compounds, salts, N-oxides, solvates and prodrugs of the present invention may contain at least one chiral centre. The compounds, salts, N- oxides, solvates and prodrugs may therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, salts, N-oxides, solvates and prodrugs of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this invention, a “substantially enantiomerically pure” isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2%, more typically less than 1%, and most typically less than 0.5% by weight. Enantiomerically pure isomers are particularly desired. The compounds, salts, N-oxides, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to 12 C, 13 C, 1 H, 2 H (D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127 I, and any radioisotope including, but not limited to 11 C, 14 C, 3 H (T), 13 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 I. Therefore, the term “hydrogen”, for example, encompasses 1 H, 2 H (D) and 3 H (T). Similarly, carbon atoms are to be understood to include 11 C, 12 C, 13 C and 14 C, nitrogen atoms are to be understood to include 13 N, 14 N and 15 N, oxygen atoms are to be understood to include 15 O, 16 O, 17 O and 18 O, fluorine atoms are to be understood to include 18 F and 19 F, and iodine atoms are to be understood to include 123 I, 124 I, 125 I, 127 I and 131 I. In one embodiment, the compounds, salts, N-oxides, solvates and prodrugs of the present invention may be isotopically labelled. As used herein, an “isotopically labelled” compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature. Any of the compounds, salts, N-oxides, solvates and prodrugs of the present invention can be isotopically labelled, for example, any of examples 1 to 31. In one embodiment, the compounds, salts, N-oxides, solvates and prodrugs of the present invention may bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds, salts, N-oxides, solvates or prodrugs, or may be introduced by coupling the compounds, salts, N-oxides, solvates or prodrugs to chelating moieties capable of binding to a radioactive metal atom. Such radiolabelled versions of compounds, salts, N-oxides, solvates and prodrugs may be used, for example, in diagnostic imaging studies. In one embodiment, the compounds, salts, N-oxides, solvates and prodrugs of the present invention may be tritiated, i.e. they contain one or more 3 H (T) atoms. Any of the compounds, salts, N-oxides, solvates and prodrugs of the present invention can be tritiated, for example, any of examples 1 to 31. The compounds, salts, N-oxides, solvates and prodrugs of the present invention may be amorphous or in a polymorphic form or a mixture of any of these, each of which is an embodiment of the present invention. The compounds, salts, N-oxides, solvates and prodrugs of the present invention have activity as pharmaceuticals and may be used in treating or preventing a disease, disorder or condition associated with KCNK13 activity. Therefore, a fourth aspect of the present invention provides a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, for use in therapy, in particular for use in treating or preventing a neurodegenerative disease, a psychiatric disease, a genetic disease, hearing loss, an ocular or retinal disease, a cardiovascular disease, an inflammatory disease, an autoimmune disease, or a metabolic disease. The fourth aspect of the present invention also provides a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, for use in treating or preventing Alzheimer’s disease, Parkinson’s disease, frontal temporal dementia, progressive supranuclear palsy (PSP) and related tauopathies, amyotrophic lateral sclerosis (ALS) / motor neuron disease (MND), traumatic brain injury, multiple sclerosis, stroke, ischemic insult, depression, stress, anxiety related disorder (including social and generalised anxiety), post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, cryopyrin-associated periodic syndrome (CAPS) (including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal onset multisystem inflammatory disease (NOMID)), age related hearing loss, genetic related hearing loss (including NLRP3 mutation related hearing loss), autoimmune related hearing loss, macular degeneration, age related macular degeneration, diabetic retinopathy, atherosclerosis, myocardial infarction, ischemia, rheumatoid arthritis, gout, Lupus, asthma, respiratory inflammation, inflammatory or autoimmune skin disease, psoriasis, inflammatory bowel disease, colitis, metabolic syndrome, non- alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, or diabetes. A fifth aspect of the present invention provides a use of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, for the manufacture of a medicament for treating or preventing a neurodegenerative disease, a psychiatric disease, a genetic disease, hearing loss, an ocular or retinal disease, a cardiovascular disease, an inflammatory disease, an autoimmune disease, or a metabolic disease. The fifth aspect of the present invention also provides a use of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, for the manufacture of a medicament for treating or preventing Alzheimer’s disease, Parkinson’s disease, frontal temporal dementia, progressive supranuclear palsy (PSP) and related tauopathies, amyotrophic lateral sclerosis (ALS) / motor neuron disease (MND), traumatic brain injury, multiple sclerosis, stroke, ischemic insult, depression, stress, anxiety related disorder (including social and generalised anxiety), post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, cryopyrin-associated periodic syndrome (CAPS) (including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal onset multisystem inflammatory disease (NOMID)), age related hearing loss, genetic related hearing loss (including NLRP3 mutation related hearing loss), autoimmune related hearing loss, macular degeneration, age related macular degeneration, diabetic retinopathy, atherosclerosis, myocardial infarction, ischemia, rheumatoid arthritis, gout, Lupus, asthma, respiratory inflammation, inflammatory or autoimmune skin disease, psoriasis, inflammatory bowel disease, colitis, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, or diabetes. A sixth aspect of the present invention provides a method of treating or preventing a neurodegenerative disease, a psychiatric disease, a genetic disease, hearing loss, an ocular or retinal disease, a cardiovascular disease, an inflammatory disease, an autoimmune disease, or a metabolic disease; the method comprising administering a therapeutically or prophylactically effective amount of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, to a patient in need thereof. The sixth aspect of the present invention also provides a method of treating or preventing Alzheimer’s disease, Parkinson’s disease, frontal temporal dementia, progressive supranuclear palsy (PSP) and related tauopathies, amyotrophic lateral sclerosis (ALS) / motor neuron disease (MND), traumatic brain injury, multiple sclerosis, stroke, ischemic insult, depression, stress, anxiety related disorder (including social and generalised anxiety), post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, cryopyrin-associated periodic syndrome (CAPS) (including Muckle- Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal onset multisystem inflammatory disease (NOMID)), age related hearing loss, genetic related hearing loss (including NLRP3 mutation related hearing loss), autoimmune related hearing loss, macular degeneration, age related macular degeneration, diabetic retinopathy, atherosclerosis, myocardial infarction, ischemia, rheumatoid arthritis, gout, Lupus, asthma, respiratory inflammation, inflammatory or autoimmune skin disease, psoriasis, inflammatory bowel disease, colitis, metabolic syndrome, non- alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, or diabetes; the method comprising administering a therapeutically or prophylactically effective amount of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, to a patient in need thereof. Unless stated otherwise, in any of the fourth, fifth or sixth aspects of the invention, the subject or patient may be any human or other animal. Typically, the subject or patient is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse etc. Most typically, the subject is a human. In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question. Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder. The terms “treat”, “treatment” and “treating” include improvement of the conditions described herein. The terms “treat”, “treatment” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition. The terms “treat”, “treatment” and “treating” are intended to include therapeutic as well as prophylactic treatment of such conditions. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of a compound of the invention (that is, a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N- oxide, solvate or prodrug thereof), if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 1 milligram per kilogram body weight (mg/kg). Alternatively, if the compound is administered orally or parenterally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 500 milligrams per kilogram body weight (mg/kg). The desired dosage may be presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day. The compounds of formula (I) and (IA) and pharmaceutically acceptable salts, N- oxides, solvates and prodrugs thereof may be used on their own, but will generally be administered in the form of a pharmaceutical composition in which the active ingredient is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, a seventh aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents. The invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, according to the first aspect of the present invention, with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceutics - The Science of Dosage Form Design”, M.E. Aulton, Churchill Livingstone, 1988. Pharmaceutically acceptable adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally, ocularly, topically or via an implanted reservoir. Oral administration is preferred. The pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers. The term parenteral as used herein includes subcutaneous, intracutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratracheal, intraperitoneal, intraarticular, and epidural injection or infusion techniques. The term topical as used herein includes transdermal, mucosal, sublingual and topical ocular administration. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the acceptable diluents and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant. The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to capsules, tablets, caplets, troches, lozenges, powders, granules, and aqueous suspensions, solutions and dispersions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose, sodium and calcium carbonate, sodium and calcium phosphate, and corn starch. Lubricating agents, such as magnesium stearate, stearic acid or talc, are also typically added. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/or dissolving tablets. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient may be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents and/or preservatives may be added to any oral dosage form. The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient. Such materials include, but are not limited to cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art. For ocular administration, the compounds, salts, N-oxides, solvates or prodrugs of the invention will generally be provided in a form suitable for topical administration, e.g. as eye drops. Suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels, and ocular inserts. Alternatively, the compounds, salts, N-oxides, solvates or prodrugs of the invention may be provided in a form suitable for other types of ocular administration, for example as intraocular preparations (including as irrigating solutions, as intraocular, intravitreal or juxtascleral injection formulations, or as intravitreal implants), as packs or corneal shields, as intracameral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations. For transdermal and other topical administration, the compounds, salts, N-oxides, solvates or prodrugs of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.05 to 80% by weight, still more preferably from 0.1 to 70% by weight, and even more preferably from 0.1 to 50% by weight of active ingredient, all percentages by weight being based on total composition. The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions. The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents for the treatment of one or more of the conditions previously indicated. The compound of the invention or the pharmaceutical composition or formulation comprising the compound of the invention may be administered simultaneously with, separately from or sequentially to the one or more other therapeutic agents. The compound of the invention and the one or more other therapeutic agents may be comprised in the same pharmaceutical composition or formulation, or in separate pharmaceutical compositions or formulations, i.e. in the form of a kit. The one or more other therapeutic agents may, for example, be an antibody designed to clear forms of tau, alpha synuclein, or fragments of amyloid. Typically, the mode of administration selected is that most appropriate to the disorder, disease or condition to be treated or prevented. Where one or more further active agents are administered, the mode of administration may be the same as or different to the mode of administration of the compound or pharmaceutical composition of the invention. Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent(s) within approved dosage ranges. Definitions An “alkyl” group may be linear (i.e. straight-chained) or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl ( i Pr), n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, and 2,2- dimethyl-1-propyl groups. Unless stated otherwise, the term “alkyl” does not include “cycloalkyl”. Typically an alkyl group is a C 1 -C 12 alkyl group. More typically an alkyl group is a C 1 -C 6 alkyl group. An “alkylene” group is similarly defined as a divalent alkyl group. An “alkenyl” group is an unsaturated alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, 1-butenyl, 2- butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups. Unless stated otherwise, the term “alkenyl” does not include “cycloalkenyl”. Typically an alkenyl group is a C 2 -C 12 alkenyl group. More typically an alkenyl group is a C 2 -C 6 alkenyl group. An “alkenylene” group is similarly defined as a divalent alkenyl group. An “alkynyl” group is an unsaturated alkyl group having one or more carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups. Typically an alkynyl group is a C 2 -C 12 alkynyl group. More typically an alkynyl group is a C 2 -C 6 alkynyl group. An “alkynylene” group is similarly defined as a divalent alkynyl group. A “cycloalkyl” group is a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl ( c Pr), cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic. A “cycloalkenyl” group is a non-aromatic unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex- 1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic. An “aryl” group is an aromatic hydrocarbyl ring. The term “aryl” includes monocyclic aromatic hydrocarbons (such as phenyl) and polycyclic fused-ring aromatic hydrocarbons (such as naphthyl, anthracenyl and phenanthrenyl). Unless stated otherwise, the term “aryl” does not include “heteroaryl”. A “heterocyclic” group is a non-aromatic cyclic group which includes one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, O or S, in the ring structure. A heterocyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic. Typically, a heterocyclic group is a 4- to 14- membered heterocyclic group, which means it contains from 4 to 14 ring atoms. More typically, a heterocyclic group is a 4- to 10-membered heterocyclic group, which means it contains from 4 to 10 ring atoms. Heterocyclic groups include unsaturated heterocyclic groups (such as azetinyl, tetrahydropyridinyl, and 2-oxo-1H-pyridinyl) and saturated heterocyclic groups. Examples of saturated monocyclic heterocyclic groups are azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl and thiomorpholinyl groups. Examples of saturated bicyclic heterocyclic groups are quinuclidinyl, 8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 6- azaspiro[2.5]octanyl and hexahydro-1H-pyrrolizinyl groups. A “heteroaryl” group is an aromatic cyclic group which includes one or more carbon atoms and one or more (such as one, two, three or four) heteroatoms, e.g. N, O or S, in the ring structure. Typically, a heteroaryl group is a 5- to 14-membered heteroaryl group, which means it contains from 5 to 14 ring atoms. More typically, a heteroaryl group is a 5- to 10-membered heteroaryl group, which means it contains from 5 to 10 ring atoms. The term “heteroaryl” includes monocyclic aromatic heterocycles (such as pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl) and polycyclic fused-ring aromatic heterocycles (such as indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzimidazolyl, 1H- imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl and cinnolinyl). Examples of heteroaryl groups include the following: N N N N N N N N N N For the purposes of the present specification, where a combination of moieties is referred to as one group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl. The term “halo” includes fluoro, chloro, bromo and iodo. Unless stated otherwise, where a group is prefixed by the term “halo”, such as a “haloalkyl” or “halomethyl” group, it is to be understood that the group in question is substituted with one or more (such as one, two, three, four or five) halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix. For example, a “halomethyl” group may contain one, two or three halo substituents. A “haloethyl” or “halophenyl” group may contain one, two, three, four or five halo substituents. Similarly, unless stated otherwise, where a group is prefixed by a specific halo group, it is to be understood that the group in question is substituted with one or more (such as one, two, three, four or five) of the specific halo groups. For example, the term “fluoromethyl” refers to a methyl group substituted with one, two or three fluoro groups, and the term “fluoroethyl” refers to an ethyl group substituted with one, two, three, four or five fluoro groups. A “hydroxyalkyl” group is an alkyl group substituted with one or more (such as one, two or three) hydroxyl (-OH) groups. Typically a hydroxyalkyl group has one or two hydroxyl substituents, more typically a hydroxyalkyl group has one hydroxyl substituent. Unless stated otherwise, any reference to an element is to be considered a reference to all isotopes of that element. Thus, for example, unless stated otherwise, any reference to hydrogen is considered to encompass all isotopes of hydrogen including 1 H, 2 H (D) and 3 H (T). Therefore, for the avoidance of doubt, it is noted that, for example, the terms “alkyl” and “methyl” include, for example, trideuteriomethyl. Unless stated otherwise, any reference to a compound or group is to be considered a reference to all tautomers of that compound or group. When any chemical group or moiety is described as substituted, it will be appreciated that the number and nature of substituents will be selected so as to avoid sterically undesirable combinations. Examples The present invention will now be further explained by reference to the following illustrative examples, in which the starting materials and reagents used are available from commercial suppliers or prepared via literature procedures or procedures similar to the ones described in this application. ‘Room temperature’, as used in the present specification, means a temperature in the range from about 18°C to about 25°C. For the purposes of the present invention, for all of the experimental details described below, where there are reaction conditions described, such as reagents, solvents and temperatures, above and/or below an arrow in a graphical representation, it is to be understood that these reaction conditions, in particular solvents and temperatures, are not essential to the reaction being carried out and may be varied. Abbreviations ACN acetonitrile DCE 1,2-dichloroethane DIEA N,N-diisopropylethylamine DMSO dimethyl sulfoxide dppp 1,3-bis(diphenylphosphino)propane EtOAc ethyl acetate EtOH ethanol h hour HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3- oxide hexafluorophosphate HPLC high-performance liquid chromatography MeOH methanol min minutes MW microwave NMP N-Methyl-2-pyrrolidone RT room temperature TEA triethylamine THF tetrahydrofuran General procedures Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz and at 298.2K or 294.1K unless otherwise stated; the chemical shifts ( ^) are reported in parts per million. Spectra were recorded using a Bruker TM 400 AVANCE instrument fitted with a 5mm iprobe or smart probe with instrument controlled by Bruker TopSpin 4.0.9 or Bruker TopSpin 4.1.1 software. Reactions were monitored using Agilent 1290 infinity II UPLC coupled with 6130 quadrupole LCMS; Chromatographic Conditions: Mobile Phase A: 0.037% TFA in water; Mobile Phase B: 0.018% TFA in acetonitrile; Column: Xtimate® C182.1*30mm, 3μm; Column Temp.: 50°C; Sample Temp.: RT; Detection (nm): 220nm and 254nm; Flow Rate: 1.0 mL/min; Analysis Time: 4.0 min; Measured Mass Range: 100 to 1500. Purity was assessed using Ultra Performance Liquid Chromatography (UPLC) with UV (photodiode array) detection over a wide range of wavelengths, normally 220-254 nm, using Shimadzu TM Nexera X2 UPLC controlled by Lab Solution software equipped with Acquity UPLC BEH, HSS or HSS T3 C18 columns (2.1mm id x 50mm long) operated at 50°C. Mobile phases typically consisted of acetonitrile mixed with water containing 0.037% TFA. Mass spectra were recorded with a Shimadzu single quadrupole mass spectrometer using DUIS ionisation. Compounds were purified using Biotage or ISCO® instrument using normal phase chromatography on silica or by preparative high performance liquid chromatography (HPLC). Preparative HPLC was performed using Gilson GX-281 system using Phenomenex C18 75*30mm*3μm; Xtimate C18 100*30mm*10μm; Xtimate C18 150*40mm*10μm; Xtimate C18 150*40mm*10μm; Phenomenex C18 75*30mm*3μm or Gemini NX C18 10*150mm*5μm columns at room temperature. Mobile phases typically consisted of acetonitrile mixed with water containing either 0.225% formic acid or 0.05% ammonia+10 nM NH 4 HCO 3 , unless otherwise stated. 1. Synthetic Intermediates Intermediate 1: 5-chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide bromo-5-chloro-pyridin-2-ol (5 g, 23.99 mmol) in THF (15 mL) in one portion at 0°C under N 2 , and then 2,2-difluoro-2-fluorosulfonyl-acetic acid (5.13 g, 28.79 mmol) was added in one portion at 0°C under N 2 . The mixture was stirred at 25 °C for 1 hour. The mixture was poured into saturated NH 4 Cl (250 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were concentrated to afford the crude product, which was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient @ 55mL/min)., Petroleum ether/Ethyl acetate=3:1, Rf=0.6) to give 3-bromo-5-chloro-2- (difluoromethoxy)pyridine (3.6 g, 13.93 mmol, 58.07% yield) as a colourless liquid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.50 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 7.68 (t, J = 71.7 Hz, 1H) Step 2: To a solution of 3-bromo-5-chloro-2-(difluoromethoxy)pyridine (2 g, 7.74 mmol), 1,3-bis(diphenylphosphino)propane (2.23 g, 5.42 mmol) and triethylamine (2.35 g, 23.22 mmol) in MeOH (20 mL) was added Pd(OAc) 2 (868.7 mg, 3.87 mmol) under N 2 . The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 10 hours. The mixture was filtered and concentrated to afford the crude product, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~8% Ethyl acetate/Petroleum ether gradient @ 55mL/min); Petroleum ether/ Ethyl acetate=3:1, Rf= 0.6) to give methyl 5-chloro-2-(difluoromethoxy)pyridine-3- carboxylate (1.6 g, 6.73 mmol, 87.02% yield) as a brown solid. MS ES + : 238.0 Step 3: To a mixture of methyl 5-chloro-2-(difluoromethoxy)pyridine-3-carboxylate (1.6 g, 6.73 mmol) in EtOH (16 mL) was added hydrazine hydrate (2.11 g, 33.67 mmol, 80% purity) in one portion at 25°C. The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated to afford the crude, which was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/ Petroleum ether gradient @ 55 mL/min); Petroleum ether/Ethyl acetate=2:1, Rf=0.4) to afford the product 5-chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide (1.26 g, 5.30 mmol, 78.75% yield) as a white solid, which was used without further purification. MS ES + : 237.9 Intermediate 2: 2,6-difluoro-N-methylbenzamide To a mixture and methanamine hydrochloride mg, g, mmol, 3.31 mL) in dichloromethane (10 mL) was added HATU (3.61 g, 9.49 mmol) in one portion at 25°C. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into H 2 O (20 mL) and extracted with ethyl acetate ( 3 x 20 mL). The combined organic layers were concentrated to afford the crude product, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50 % Ethyl acetate/Petroleum ether gradient 25mL/min). TLC: petroleum ether: ethyl acetate = 2:1, Rf = 0.5) to give 2,6-difluoro-N-methylbenzamide as a white solid (590 mg, 2.80 mmol, 81% yield). 1 H NMR (400 MHz, DMSO-d 6 ): 8.64 (br s, 1H), 7.50 (tt, J = 6.7, 8.4 Hz, 1H), 7.25 - 7.09 (m, 2H), 2.76 (d, J = 4.6 Hz, 3H). MS ES + :172.1 Intermediate 3: 2-chloro-N-methylbenzamide Following the procedure used in of Intermediate 2, using 2- chlorobenzoic acid (1 g, 6.39 mmol) gave N-methylbenzamide as a white solid (1.0g, 5.90 mmol, 92% yield), which was used without further purification. MS ES + : 170.1 Intermediate 4: 5-chloro-2-(2,2,2-trifluoroethoxy)pyridine-3- carbohydrazide was g, g, 59.40 mmol). The mixture was stirred at 90 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=5/1, Rf=0.50) to give 3-bromo-5-chloro- 2-(2,2,2-trifluoroethoxy)pyridine (6.2 g, 21.35 mmol, 89.83% yield) as yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.35 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 5.09 - 4.97 (m, 2H). MS ES + : 289.9 Step 2: To a solution of 3-bromo-5-chloro-2-(2,2,2-trifluoroethoxy)pyridine (3 g, 10.33 mmol), 1,3-bis(diphenylphosphino)propane (2.98 g, 7.23 mmol) in triethylamine /MeOH=1/10 (10 mL) was added Pd(OAc) 2 (1.16 g, 5.16 mmol) under N 2 . The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 10 hours. The mixture was filtered and the filtrate was concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3/1, Rf=0.30) gave methyl 5-chloro-2-(2,2,2- trifluoroethoxy)pyridine-3-carboxylate (2.5 g, 9.27 mmol, 89.78% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.50 (d, J = 2.6 Hz, 1H), 8.28 (d, J = 2.6 Hz, 1H), 5.11 - 5.02 (m, 2H), 3.84 (s, 3H). Step 3: To a solution of methyl 5-chloro-2-(2,2,2-trifluoroethoxy)pyridine-3- carboxylate (2.5 g, 9.27 mmol) in EtOH (10 mL) was added hydrazine hydrate (2.73 g, 46.36 mmol, 85% purity). The mixture was stirred at 80 °C for 1 hour. The mixture was concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Ethyl acetate: Petroleum ether=1/1, Rf=0.35) gave 5-chloro-2-(2,2,2-trifluoroethoxy)pyridine-3- carbohydrazide (1.8 g, 6.68 mmol, 72.00% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.44 (br s, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 2.6 Hz, 1H), 5.11 - 4.96 (m, 2H), 4.60 (s, 2H). Intermediate 5: 5-chloro-2-(cyclopropoxy)pyridine-3-carbohydrazide in was g, g, 59.40 mmol). The mixture was stirred at 90 °C for 1 hour. The mixture was filtered and then concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Ethyl acetate: Petroleum ether=0/1, Rf=0.50) gave 3-bromo-5-chloro-2- (cyclopropoxy)pyridine (4.8 g, 19.32 mmol, 81.29% yield) as colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.25 - 8.21 (m, 1H), 8.20 - 8.15 (m, 1H), 4.26 (tt, J = 3.0, 6.2 Hz, 1H), 0.83 - 0.65 (m, 4H). MS ES + : 249.7 Step 2: To a solution of 3-bromo-5-chloro-2-(cyclopropoxy)pyridine (1 g, 4.02 mmol), 1,3-bis(diphenylphosphino)propane (1.16 g, 2.82 mmol), in triethylamine/MeOH=1/10 (5 mL) was added Pd(OAc) 2 (451.7 mg, 2.01 mmol) under N 2 . The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50psi) at 80 °C for 10 hours. The mixture was filtered and then concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3/1, Rf=0.3) gave methyl 5-chloro-2-(cyclopropoxy)pyridine-3-carboxylate (680 mg, 2.99 mmol, 74.23% yield) as a colourless oil. 1 NMR (400 MHz, DMSO-d 6 ): 8.46 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 4.30 (td, J = 3.2, 6.2 Hz, 1H), 3.79 (s, 3H), 0.83 - 0.63 (m, 4H). Step 3: To a mixture of methyl 5-chloro-2-(cyclopropoxy)pyridine-3-carboxylate (680 mg, 2.99 mmol) in EtOH (1 mL) was added hydrazine hydrate (879.6 mg, 14.94 mmol, 85% purity) in EtOH (1 mL) in one portion at 25°C. The mixture was stirred at 80 °C for 1 hours. The mixture was concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Ethyl acetate: Petroleum ether=1/1, Rf=0.40) gave 5-chloro-2- (cyclopropoxy)pyridine-3-carbohydrazide (510 mg, 2.24 mmol, 75.00% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.24 (br s, 1H), 8.37 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 2.6 Hz, 1H), 4.57 (d, J = 4.4 Hz, 2H), 4.32 - 4.25 (m, 1H), 0.78 - 0.74 (m, 4H). Intermediate 6: 3-chloro-N-methyl-benzamide Following the procedure used in of Intermediate 2, using 3- chlorobenzoic acid (556.5 mg, gave 3-chloro-N-methyl-benzamide (500 mg, 2.95 mmol, 99.52% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.55 (br d, J = 2.6 Hz, 1H), 7.86 (t, J = 1.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.52 - 7.45 (m, 1H), 2.78 (d, J = 4.5 Hz, 3H). Intermediate 7: 3-fluoro-N-methyl-benzamide Following the procedure used in of Intermediate 2, using 3- fluorobenzoic acid (500 mg, 3.57 , gave fluoro-N-methyl-benzamide (350 mg, 2.19 mmol, 61.38% yield, 95.85% purity) as a colourless liquid. MS ES + : 154.4 Intermediate 8: 2,3-difluoro-N-methyl-benzamide Following the procedure used in of Intermediate 2, using 2,3- difluorobenzoic acid (561.6 mg, gave 2,3-difluoro-N-methyl-benzamide (500 mg, 2.92 mmol, 98.7% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-d6): 8.40 (br s, 1H), 7.59 - 7.49 (m, 1H), 7.43 - 7.36 (m, 1H), 7.32 - 7.23 (m, 1H), 2.82 - 2.75 (m, 3H). MS ES + : 171.0 Intermediate 9: 3,5-difluoro-N-methyl-benzamide Following the procedure used in of Intermediate 2, using 3,5- difluorobenzoic acid (1.12 g, 7.11 gave 3,5-difluoro-N-methyl-benzamide (830 mg, 4.85 mmol, 81.86% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 - 8.55 (m, 1H), 7.55 - 7.49 (m, 2H), 7.48 - 7.40 (m, 1H), 2.81 - 2.75 (m, 3H). MS ES + : 171.0 Intermediate 10: 2-fluoro-N-methyl-benzamide Following the procedure used in of Intermediate 2, using 2- fluorobenzoic acid (996.1 mg, 7.11 gave fluoro-N-methyl-benzamide (420 mg, 2.74 mmol, 46.29% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.23 (br s, 1H), 7.66 - 7.57 (m, 1H), 7.55 - 7.47 (m, 1H), 7.32 - 7.23 (m, 2H), 2.77 (d, J = 4.6 Hz, 3H). MS ES + : 153.1 Intermediate 11: N,2-dimethylbenzamide Following the procedure used in of Intermediate 2, using 2- methylbenzoic acid (1.09 g, 8.00 gave dimethylbenzamide (900 mg, 6.03 mmol, 90.51% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.20 - 8.09 (m, 1H), 7.29 - 7.29 (m, 1H), 7.33 - 7.27 (m, 1H), 7.25 - 7.18 (m, 2H), 2.74 (d, J = 4.6 Hz, 3H), 2.34 - 2.30 (m, 3H). MS ES+: 149. Intermediate 12: 2,4-difluoro-N-methyl-benzamide Following the procedure used in of Intermediate 2, using 2,4- difluorobenzoic acid (1 g, 6.33 , gave N-methyl-benzamide (888 mg, 5.14 mmol, 81.19% yield, 98.97% purity) as a white solid. MS ES + : 172.0 Intermediate 13: 2-(difluoromethoxy)-5-fluoro-pyridine-3-carbohydrazide in conc. was at was to dryness to afford 5-fluoro-2-hydroxy-pyridine-3-carboxylic acid (3.5 g, 22.3 mmol, 97.8% yield) as an off-white solid which was used in the next step directly. Step 2: To a mixture of 5-fluoro-2-hydroxy-pyridine-3-carboxylic acid (500 mg, 3.18 mmol) in MeOH (3 mL) was added conc. H 2 SO 4 (3.2 mL). The mixture was stirred at 90 °C for 1 hour under microwave irradiation. After cooling to room temperature, the solvent was removed by evaporation under reduced pressure. The obtained mixture was treated with a solution of sat. NaHCO 3 (aq.) until pH to 7-8. The mixture was extracted with dichloromethane (3 x 15mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and evaporated to dryness to give methyl 5-fluoro-2-hydroxy- pyridine-3-carboxylate (340 mg, 1.99 mmol, 62.4% yield, crude purity) as a yellow solid which was used in the next step directly. MS ES + : 172.1 Step 3: NaH (145 mg, 3.62 mmol, 60% purity) was added into a mixture of methyl 5- fluoro-2-hydroxy-pyridine-3-carboxylate (310 mg, 1.81 mmol) in THF (1 mL) in portions at 0°C under N 2 , and then 2,2-difluoro-2-fluorosulfonyl-acetic acid (323 mg, 1.81 mmol) in THF (1 mL) was dropwise added at 0°C under N 2 . The mixture was stirred at 25 °C for 1 hour. The mixture was poured into sat. NH 4 Cl (aq.) (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to afford the crude product which was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give methyl 2-(difluoromethoxy)-5- fluoro-pyridine-3-carboxylate (155 mg, 0.676 mmol, 37.3% yield) as a yellow liquid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.66 - 8.19 (m, 2H), 7.71 (t, J = 72.0 Hz, 1H), 3.88 (s, 3H) Step 4: To a solution of methyl 2-(difluoromethoxy)-5-fluoro-pyridine-3-carboxylate (155 mg, 0.701 mmol) in EtOH (2 mL) was added hydrazine hydrate (219.3 mg, 3.50 mmol). The mixture was stirred at 80 ℃ for 10 hours. The mixture was concentrated, then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried with anhydrous Na 2 SO 4 and concentrated to afford 2-(difluoromethoxy)-5-fluoro- pyridine-3-carbohydrazide (108 mg, crude) as a white solid. MS ES + : 222.0 Intermediate 14: 2-(difluoromethoxy)-5-methyl-pyridine-3-carbohydrazide g, was NaH (638.2 mg, 15.96 mmol, 60% purity) in one portion at 0°C under N 2 . The mixture was stirred at 25 °C for 4 hours. The mixture was poured into water (5 mL) and extracted with dichloromethane (3 x 5 mL) and the combined organic layers were concentrated to afford the crude product. Purification by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~ 5% Ethyl acetate/Petroleum ether gradient @ 40 mL/min), Petroleum ether/Ethyl acetate= 5:1, Rf=0.4) gave 3-bromo-2-(difluoromethoxy)-5-methyl-pyridine (1.8 g, 7.56 mmol, 71.09% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.12 - 8.03 (m, 2H), 7.88 - 7.46 (m, 1H), 2.27 (s, 3H). MS ES+: 237.0 Step 2: To a solution of 3-bromo-2-(difluoromethoxy)-5-methyl-pyridine (1.8 g, 7.56 mmol), 1,3-bis(diphenylphosphino)propane (2.18 g, 5.29 mmol) and triethylamine (2.30 g, 22.69 mmol) in MeOH (18 mL) was added Pd(OAc) 2 (848.9 mg, 3.78 mmol) under N 2 . The suspension was degassed under vacuum and purged with CO (7.56 mmol) several times. The mixture was stirred under CO (50psi) at 80 °C for 10 hours. The mixture was concentrated to afford the crude product. Purification by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~ 10% Ethyl acetate/Petroleum ether gradient @ 45 mL/min)., Petroleum ether/Ethyl acetate=3:1, Rf=0.4) gave methyl 2-(difluoromethoxy)-5-methyl-pyridine-3- carboxylate (1.55 g, 7.14 mmol, 94.38% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.32 - 8.26 (m, 1H), 8.21 - 8.10 (m, 1H), 7.73 (t, J = 72.5 Hz, 1H), 3.90 - 3.79 (m, 3H), 2.39 - 2.25 (m, 3H). MS ES+: 217.1 Step 3: To a mixture of methyl 2-(difluoromethoxy)-5-methyl-pyridine-3-carboxylate (1.55 g, 7.14 mmol) in EtOH (15 mL) was added hydrazine hydrate (2.23 g, 35.69 mmol 80% purity) in one portion at 25°C. The mixture was stirred at 80 °C for 1 hour. The mixture was concentrated to afford the crude product. Purification by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~55% Ethyl acetate/Petroleum ether gradient @ 45mL/min), Petroleum ether/Ethyl acetate=2:1, Rf=0.4) gave 2-(difluoromethoxy)-5-methyl-pyridine-3-carbohydrazide (1.5 g, 6.91 mmol, 96.77% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 9.46 (br s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.85 - 7.45 (m, 2H), 4.55 (br d, J = 3.0 Hz, 2H), 2.29 (s, 3H). MS ES+: 217.1 Intermediate 15: N-ethyl-3-fluoro-benzamide To a (291.0 mg, 3.57 mmol) was g, DIEA (1.38 g, 10.71 mmol) in one portion at 25°C. The mixture was stirred at 25 °C for 1 hour. The mixture was poured into aq. NaCl (10 mL) and extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were concentrated to afford the crude product. Purification by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~18% Ethyl acetate/Petroleum ether gradient @ 45 mL/min), Petroleum ether/Ethyl acetate=2:1, Rf=0.5) gave N-ethyl-3-fluoro-benzamide (450 mg, 2.69 mmol, 75.43% yield) as a yellow liquid. 1 H NMR (400MHz, DMSO-d6): 8.56 (br s, 1H), 7.72 - 7.67 (m, 1H), 7.63 (td, J = 1.9, 10.1 Hz, 1H), 7.51 (dt, J = 6.0, 7.9 Hz, 1H), 7.39 - 7.32 (m, 1H), 2.88 (s, 1H), 2.75 - 2.71 (m, 1H), 1.12 (t, J = 7.3 Hz, 3H). MS ES+: 167.9 Intermediate 16: 3-(difluoromethoxy)-N-methyl-benzamide Following the procedure used of Intermediate 2, using 3- (difluoromethoxy)benzoic acid gave -N-methyl-benzamide (680 mg, 3.38 mmol, 63.59% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.53 (br d, J = 3.6 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.48 - 7.08 (m, 2H), 2.79 (d, J = 4.5 Hz, 3H). MS ES + : 202.1 Intermediate 17: N'-(1-(2,6-difluorophenyl)propylidene)-4- methylbenzenesulfonohydrazide Step1: To a 2.94 mmol) in MeOH (5 mL) was mg, 2.94 mmol). The mixture was stirred at 60°C for 4 hours. The mixture was cooled down to room temperature and evaporated to dryness. The residue was poured into water (100 mL) and stirred for 10 minutes. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with brine (100 mL x 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO® 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30mL/min). N'-(1-(2,6- difluorophenyl)propylidene)-4-methylbenzenesulfonohydrazide (642 mg, 1.90 mmol, 91.7% yield) was obtained as a white solid. ESI + : 339.0 1 H NMR (400 MHz, DMSO-d 6 ) 10.59 - 10.48 (m, 1H), 7.71 (br d, J = 8.0 Hz, 2H), 7.61 - 7.51 (m, 1H), 7.40 (br d, J = 7.6 Hz, 2H), 7.24 - 7.10 (m, 2H), 2.42 - 2.35 (m, 5H), 0.97 - 0.80 (m, 3H). Intermediate 18: N'-(1-(3-chloro-6-methoxypyridin-2-yl)propylidene)-4- methylbenzenesulfonohydrazide g, , (63.8 g, 354 mmol, 30% purity in MeOH) in MeOH (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 100 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 3-chloro-6-methoxypicolinic acid (5.5 g, crude) as a white solid, which was used in next step without further purification. ESI + : 187.8 1 H NMR (400 MHz, DMSO-d 6 ): 14.04 - 13.45 (m, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.86 (s, 3H). Step 2: To a solution of 3-chloro-6-methoxypicolinic acid (5.5 g, 29.32 mmol) and N,O- dimethylhydroxylamine hydrochloride (4.29 g, 43.98 mmol) in dichloromethane (5 mL) was added HATU (16.72 g, 43.98 mmol) and N-ethyl-N-isopropylpropan-2-amine (11.37 g, 87.96 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give the product 3- chloro-N,6-dimethoxy-N-methylpicolinamide (6.5 g, 28.18 mmol, 96.11% yield) as a white solid. ESI + : 230.9 1 H NMR (400 MHz, DMSO-d 6 ): 7.88 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 3.57 (s, 3H), 3.35 - 3.25 (m, 3H). Step 3: A mixture of 3-chloro-N,6-dimethoxy-N-methylpicolinamide (4 g, 17.34 mmol) in THF (40 mL) was degassed and purged with N 2 3 times, then EtMgBr (17.3 mL, 3 M in 2-MeTHF) was dropwise added into the mixture at 0°C. The mixture was stirred at 25 °C for 1 hour under N 2 atmosphere. The reaction mixture was quenched by the addition of saturated NH 4 Cl (aq., 400 mL) at 25°C, and then diluted with H 2 O (40 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 70 mL/min) to give the product 1-(3- chloro-6-methoxypyridin-2-yl)propan-1-one (1.32 g, 6.61 mmol, 38.13% yield) as yellow oil. ESI + : 200.2 1 H NMR (400 MHz, DMSO-d 6 ): 7.91 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.07 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H). Step 4: To a solution of 1-(3-chloro-6-methoxypyridin-2-yl)propan-1-one (1.32 g, 6.61 mmol) in EtOH (14 mL) was added 4-methylbenzenesulfonohydrazide (3.69 g, 19.84 mmol). The mixture was stirred at 90 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove most of the solvent. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 70 mL/min) to give the product N'-(1-(3-chloro-6-methoxypyridin-2-yl)propylidene)-4- methylbenzenesulfonohydrazide (1.7 g, 4.62 mmol, 69.89% yield) as a yellow solid. ESI + : 368.2 Intermediate 19: 5-chloro-2-methoxyisonicotinohydrazide Step 1: To a solution 4-carboxylate (1 g, 4.96 mmol) in EtOH (10 mL) was added NH 2 NH 2 •H 2 O (2.34 g, 39.68 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled down to room temperature and quenched by water (15 mL) at 25 °C before being extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give 5-chloro-2-methoxyisonicotinohydrazide (1.1 g, crude) as white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.73 (br s, 1H), 8.28 (s, 1H), 6.85 (s, 1H), 4.55 (br s, 2H), 3.87 (s, 3H). Intermediate 20: 5-chloro-2-(difluoromethoxy)-N-methylnicotinamide Step a g, mmol) (Prepared as described for Intermediate 1) in MeOH (10 mL) was added 1 M LiOH (aq. 4.21 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by the addition of 1N HCl (aq.20 mL) to pH =6 at 0°C, then was diluted with ethyl acetate (20 mL) and washed with H 2 O (20 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. 5-Chloro-2-(difluoromethoxy)nicotinic acid (1.1 g, crude) was obtained as a yellow solid. Step 2: To a solution of methanamine hydrochloride hydrochloride (471 mg, 6.98 mmol), 5-chloro-2-(difluoromethoxy)nicotinic acid (1.3 g, crude) in dichloromethane (13 mL) was added HATU (3.32 g, 8.72 mmol) and triethylamine (1.77 g, 17.44 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/ Petroleum ether gradient @ 60mL/min) to give a product. 5-Chloro-2- (difluoromethoxy)-N-methylnicotinamide (370 mg, 1.56 mmol, 26.89% yield) was obtained as a white solid. ESI + : 237.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.44 - 8.36 (m, 2H), 8.14 (d, J = 2.6 Hz, 1H), 7.67 (t, J = 71.9 Hz, 1H), 2.78 (d, J = 4.6 Hz, 3H). Intermediate 21: 5-chloro-2-(difluoromethoxy)-N-methylpyridine-3- carbothioamide Step 1: To a -N-methylnicotinamide (Intermediate 20) (500 mg, 2.11 mmol) in THF (5 mL) was added Lawesson’s Reagent (1.28 g, 3.17 mmol). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give 5-chloro-2-(difluoromethoxy)-N-methylpyridine-3-carbothioami de (509 mg, 2.01 mmol, 95.33% yield) as a red brown solid. ESI + : 252.9. 1 H NMR (400 MHz, DMSO-d 6 ): 10.63 (br d, J = 3.5 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.64 (t, J = 71.9 Hz, 1H), 3.30 (s, 3H). Intermediate 22: Methyl 6-fluoro-2,3-dihydroxybenzoate Step 1: To g, 320.24 mmol, 47% purity in acetic acid) was added 6-fluoro-2,3-dimethoxy-benzoic acid (2.5 g, 12.49 mmol) at 25 °C. The mixture was stirred at 130 °C for 1 hour. The residue was diluted with ice water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 6-fluoro-2,3-dihydroxybenzoic acid (2.03 g, crude) as a white solid. Step 2: To a solution of 6-fluoro-2,3-dihydroxybenzoic acid (2 g, crude) in MeOH (20 mL) was dropwise added SOCl 2 (2.07 g, 17.43 mmol) at 0 ºC. The mixture was stirred at 65 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give methyl 6-fluoro-2,3-dihydroxybenzoate (1.38 g, crude) as a white powder. 1 H NMR (400 MHz, DMSO-d 6 ): 10.11 - 9.28 (m, 2H), 6.86 (dd, J = 6.1, 8.3 Hz, 1H), 6.55 (t, J = 9.4 Hz, 1H), 3.83 (s, 3H). 2. Synthetic Examples Example 1: 5-chloro-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine To a mg, N- benzamide (Intermediate 2) (100 mg, 0.584 mmol) in DCE (0.8 mL) was added 2-fluoropyridine (62.4 mg, 0.643 mmol) and trifluoromethanesulfonic anhydride (181.3 mg, 0.643 mmol) in one portion at -78°C under N 2 . The mixture was stirred at 140 °C for 2 hours under microwave irradiation. The mixture was concentrated to afford the crude product which was purification by preparative HPLC (Column: Xtimate C18100*30mm*10μm, Mobile Phase A: water (FA)-ACN, Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 45% B to 65%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-met hyl-4H-1,2,4-triazol-3- yl)pyridine (32.48 mg, 0.085 mmol, 14.62% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d 6 ): 8.62 (d, J = 2.6 Hz, 1H), 8.44 (d, J = 2.5 Hz, 1H), 7.97 - 7.59 (m, 2H), 7.41 (t, J = 8.3 Hz, 2H), 3.46 (s, 3H). MS ES + : 373.2 Example 2: 5-chloro-3-(5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-y l)- 2-(difluoromethoxy)pyridine Following the procedure used in the preparation of Example 1, using 5-chloro-2- (difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (154.1 mg, 0.649 mmol) and 2-chloro-N-methyl-benzamide (Intermediate 3) gave 5-chloro-3-(5-(2- chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(difluoromet hoxy)pyridine (49.02 mg, 0.131 mmol, 22.2% yield) as an off-white powder. 1 H NMR (400 MHz, DMSO-d6): 8.63 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 2.6 Hz, 1H), 7.97- 7.73 (m, 2H), 7.69 - 7.59 (m, 3H), 3.34 (s, 3H). MS ES + : 371.2 Example 3: 5-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)-2-(2,2,2-trifluoroethoxy)pyridine Following the procedure Example 1, using 5-chloro-2- (2,2,2-trifluoroethoxy) 4) (236.3 mg, 0.876 mmol) and 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (150 mg, 0.876 mmol) gave 5-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3-yl)-2- (2,2,2-trifluoroethoxy)pyridine (50 mg, 0.123 mmol, 14.04% yield, 99.6% purity) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.55 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.77 (quin, J = 7.6 Hz, 1H), 7.41 (t, J = 8.3 Hz, 2H), 5.09 (q, J = 9.0 Hz, 2H), 3.41 (s, 3H). MS ES + : 405.0 Example 4: 5-chloro-2-cyclopropoxy-3-(5-(2,6-difluorophenyl)-4-methyl- 4H-1,2,4-triazol-3-yl)pyridine Following the procedure Example 1, using 5-chloro-2- (cyclopropoxy)pyridine-3- 5) (70 mg, 0.307 mmol) and 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (78.9 mg, 0.461 mmol) gave 5- chloro-2-(cyclopropoxy)-3-[5-(2,6-difluorophenyl)-4-methyl-1 ,2,4-triazol-3-yl]pyridine (3.7 mg, 0.010 mmol, 3.30% yield, 99.4% purity) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.54 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.77 (quin, J = 7.5 Hz, 1H), 7.40 (t, J = 8.2 Hz, 2H), 4.35 (td, J = 3.0, 6.0 Hz, 1H), 3.36 - 3.34 (m, 3H), 0.85 - 0.76 (m, 2H), 0.70 - 0.59 (m, 2H). MS ES + : 363.1 Example 5: 5-chloro-3-(5-(3-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-y l)- 2-(difluoromethoxy)pyridine Following the procedure Example 1, using 3-chloro-N- methyl-benzamide mg, mmol) and 5-chloro-2- (difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) gave 5-chloro-3-(5-(3- chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(difluoromet hoxy)pyridine (21.04 mg, 0.057 mmol, 13.43% yield) as an off white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 8.62 (br s, 1H), 8.34 (br s, 1H), 8.01 - 7.53 (m, 5H), 3.63 (br s, 3H). MS ES + : 371.0 Example 6: 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluorophenyl)-4-methyl- 4H-1,2,4-triazol-3-yl)pyridine Following the procedure Example 1, using 3-fluoro-N- methyl-benzamide 2-(difluoromethoxy)pyridine-3- carbohydrazide (Intermediate 1) gave 5-chloro-2-(difluoromethoxy)-3-[5-(3- fluorophenyl)-4-methyl-1,2,4-triazol-3-yl]pyridine (2.07 mg, 0.0058 mmol, 2.77% yield) as a white powder. 1 H NMR (400 MHz, MeOH-d 4 ) δ = 8.50 (d, J = 2.4 Hz, 1H), 8.22 (d, J =2.4 Hz, 1H), 7.94 - 7.49 (m, 4H), 7.44 - 7.30 (m, 1H), 3.67 (s, 3H). MS ES+: 354.9 Example 7: 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine Following the procedure used 1, using 2,3-difluoro-N- methyl-benzamide mg, 0.292 mmol) and 5-chloro-2- (difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) gave 5-chloro-2- (difluoromethoxy)-3-[5-(2,3-difluorophenyl)-4-methyl-1,2,4-t riazol-3-yl]pyridine (5.49 mg, 0.014. mmol, 4.93% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.62 (d, J = 2.5 Hz, 1H), 8.39 (d, J = 2.6 Hz, 1H), 7.98 - 7.60 (m, 2H), 7.56 - 7.50 (m, 1H), 7.50 - 7.43 (m, 1H), 3.54 - 3.48 (m, 3H). MS ES + : 372.0 Example 8: 5-chloro-2-(difluoromethoxy)-3-(5-(3,5-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine Following the procedure 1, using 3,5-difluoro-N- methyl-benzamide mg, 0.292 mmol) and 5-chloro-2- (difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (76.4 mg, 0.321 mmol) gave 5-chloro-2-(difluoromethoxy)-3-[5-(3,5-difluorophenyl)-4-met hyl-1,2,4- triazol-3-yl]pyridine (7.26 mg, 0.018 mmol, 6.39% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.62 (d, J = 2.6 Hz, 1H), 8.32 (d, J = 2.6 Hz, 1H), 7.98 - 7.61 (m, 1H), 7.61 - 7.48 (m, 3H), 3.65 (s, 3H). MS ES + : 372.0 Example 9: 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluorophenyl)-4-methyl- 4H-1,2,4-triazol-3-yl)pyridine Following the procedure Example 1, using 2-fluoro-N- methyl-benzamide mg, 0.326 mmol) and 5-chloro-2- (difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (85.3 mg, 0.359 mmol) gave 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluorophenyl)-4-methyl- 4H-1,2,4- triazol-3-yl)pyridine (11.38 mg, 0.031 mmol, 9.50% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.63 - 8.59 (m, 1H), 8.40 - 8.36 (m, 1H), 7.98 - 7.59 (m, 3H), 7.54 - 7.42 (m, 2H), 3.46 (d, J = 1.8 Hz, 3H). MS ES + : 354.0 Example 10: 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(o-tolyl)-4H- 1,2,4-triazol-3-yl)pyridine Following the procedure of Example 1, using N,2- dimethylbenzamide mg, 0.335 mmol) and 5-chloro-2- (difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (87.6 mg, 0.368 mmol) gave 5-chloro-2-(difluoromethoxy)-3-[4-methyl-5-(o-tolyl)-1,2,4-t riazol-3- yl]pyridine (7.4 mg, 0.020 mmol, 6.04% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.63 - 8.59 (m, 1H), 8.41 - 8.38 (m, 1H), 7.98 - 7.59 (m, 1H), 7.54 - 7.49 (m, 1H), 7.47 - 7.43 (m, 1H), 7.42 - 7.39 (m, 2H), 3.34 (s, 3H), 2.23 - 2.20 (m, 3H). MS ES+: 350.1 Example 11: 2-(difluoromethoxy)-3-(5-(2,4-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)-5-fluoropyridine Following the procedure used in the preparation of Example 1, using 2,4-difluoro-N- methyl-benzamide (Intermediate 12) (38.7 mg, 0.226 mmol) and 2- (difluoromethoxy)-5-fluoro-pyridine-3-carbohydrazide (Intermediate 13) (50 mg, 0.226 mmol) gave 2-(difluoromethoxy)-3-(5-(2,4-difluorophenyl)-4-methyl-4H-1, 2,4- triazol-3-yl)-5-fluoropyridine (2.08 mg, 0.00580 mmol, 2.56% yield) as a white powder. 1 H NMR (400 MHz, DMSO- d 6 ): 8.58 (d, J = 2.8 Hz, 1H), 8.27 (dd, J = 2.8, 8.0 Hz, 1H), 8.01 - 7.67 (m, 2H), 7.59 (s, 1H), 7.42 - 7.24 (m, 1H), 3.47 (s, 3H). MS ES + : 357.3 Example 12: 5-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-2-isopropoxypyridine and propan- mg, NMP was t- M, mL) in one portion at 0°C under N 2 . The mixture was stirred at 25 °C for 1 hour. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL) and the combined organic layers were concentrated to afford the crude product. Purification by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10 % Ethyl acetate/Petroleum ether gradient 35/min, TLC: petroleum ether: ethyl acetate = 5:1, Rf = 0.6) gave 3-bromo-5-chloro-2-isopropoxypyridine (760 mg, 3.03 mmol, 63.84% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.26 - 8.17 (m, 2H), 5.21 (td, J = 6.2, 12.3 Hz, 1H), 1.30 (d, J = 6.1 Hz, 6H). MS ES+: 249.0 Step 2: To a solution of 3-bromo-5-chloro-2-isopropoxy-pyridine (760 mg, 3.03 mmol,), 1,3-bis(diphenylphosphino)propane (875.9 mg, 2.12 mmol)and Pd(OAc) 2 (340.5 mg, 1.52 mmol) in MeOH (7 mL) was added triethylamine (920.9 mg, 9.10 mmol). The suspension was degassed under vacuum and purged with argon several times. The mixture was stirred under CO (50psi) at 80 °C for 12 hours. The mixture was concentrated to afford the crude product. Purification by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient 25mL/min) gave methyl 5-chloro-2- isopropoxynicotinate (478 mg, 1.77 mmol, 58.32% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.40 (d, J = 2.6 Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 5.29 (td, J = 6.1, 12.4 Hz, 1H), 3.81 (s, 3H), 1.30 (d, J = 6.1 Hz, 6H). MS ES+: 229.1 Step 3: To a mixture of methyl 5-chloro-2-isopropoxy-pyridine-3-carboxylate (470 mg, 2.05 mmol) in EtOH (5 mL) was added hydrazine hydrate (640.3 mg, 10.23 mmol, 80% purity) in EtOH (5 mL) in one portion at 25°C. The mixture was stirred at 80 °C for 1 hour. The mixture was concentrated to afford the crude product. Purification by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100 % Ethyl acetate/Petroleum ether gradient 25 mL/min, TLC: petroleum ether: ethyl acetate =0:1, Rf= 0.5) gave 5-chloro-2-isopropoxynicotinohydrazide (400 mg, 1.48 mmol, 72.34% yield, 85% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.23 (br s, 1H), 8.33 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 2.6 Hz, 1H), 5.33 (q, J = 6.2 Hz, 1H), 4.63 (br d, J = 3.5 Hz, 2H), 1.35 (d, J = 6.1 Hz, 6H). MS ES+: 229.1 Step 4: To a solution of 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (37.3 mg, 0.217 mmol) in 1,2-dichloroethane (0.5 mL) was added 2-fluoropyridine (23.3 mg, 0.239 mmol) and trifluoromethanesulfonic anhydride (67.6 mg, 0.239 mmol) at 0°C. The mixture was stirred at 0°C for 0.5 hour under N 2 , then 5-chloro-2-isopropoxy- pyridine-3-carbohydrazide (50 mg, 0.217 mmol) was added dropwise into the mixture at 0°C. The mixture was stirred at 140 °C for 2 hours under microwave irradiation. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The product was further purified by prep. HPLC (Column: Phenomenex C18 75*30mm*3μm, Mobile Phase A: water (NH 3 H 2 O+NH 4 HCO 3 ), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 32% B to 72%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-3-[5-(2,6-difluorophenyl)-4-methyl-1,2,4- triazol-3-yl]-1H-pyridin-2-one (10 mg, 0.00372 mmol, 1.71% yield, 12% chemical purity) as a yellow solid. MS ES+: 322.0 Step 5: To a mixture of 5-chloro-3-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol-3- yl]- 1H-pyridin-2-one (4 mg, 0.012 mmol) and 2-iodopropane (2.1 mg, 0.012 mmol) in CHCl 3 (0.1 mL) was added Ag 2 O (8.2 mg, 0.037 mmol) in one portion at 25°C. The mixture was stirred at 65 °C for 1 hour. The mixture was poured into water (10 mL) and extracted with dichloromethane (3 x 10 mL) and the combined organic layers were concentrated to afford the crude product. The product was further purified by prep. HPLC (column: Xtimate C18 100*30mm*10μm; mobile phase:[water(FA)- ACN];Mobile Phase B: 60mL/min, gradient condition from 50%-80%.10 min). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-3-[5-(2,6-difluorophenyl)-4-methyl-1,2,4- triazol-3-yl]-2-isopropoxy-pyridine (1.1 mg, 0.002 mmol, 23.11% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): 8.55 - 8.40 (m, 1H), 8.20 - 8.06 (m, 1H), 7.85 - 7.71 (m, 1H), 7.51 - 7.33 (m, 2H), 5.42 - 5.23 (m, 1H), 3.40 (br s, 3H), 1.28 (d, J = 6.1 Hz, 6H). MS ES+: 364.1 Example 13: 2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)-5-methylpyridine Following the procedure used Example 1, using 2,6-difluoro-N- methyl-benzamide mg, mmol) and 2-(difluoromethoxy)- 5-methyl-pyridine-3-carbohydrazide (Intermediate 14) (63.5 mg, 0.292 mmol) gave 2-(difluoromethoxy)-3-[5-(2,6-difluorophenyl)-4-methyl-1,2,4 -triazol-3-yl]-5-methyl- pyridine (3.51 mg, 0.098 mmol, 3.36% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.37 - 8.31 (m, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.99 - 7.60 (m, 2H), 7.41 (t, J = 8.2 Hz, 2H), 3.45 - 3.40 (m, 3H), 2.38 (s, 3H). MS ES+: 352.1 Example 14: 5-chloro-2-(difluoromethoxy)-3-(4-ethyl-5-(3-fluorophenyl)- 4H-1,2,4-triazol-3-yl)pyridine Following the procedure Example 1, using 5-chloro-2- (difluoromethoxy)pyridine-3- 1) (62.5 mg, 0.263 mmol) and N-ethyl-3-fluorobenzamide (Intermediate 15) (40 mg, 0.239 mmol) gave 5-chloro-2-(difluoromethoxy)-3-[4-ethyl-5-(3-fluorophenyl)-1 ,2,4-triazol-3-yl]pyridine (1.05 mg, 0.00274 mmol, 96.3% yield, 96.3% purity) as a white solid. 1 H NMR (400 MHz, MeOD-d 4 ): 8.51 (d, J = 2.8 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.89 - 7.60 (m, 2H), 7.58 (s, 2H), 7.44 - 7.36 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). MS ES+: 369.3 Example 15: 5-chloro-2-(difluoromethoxy)-3-(5-(3- (difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyri dine Following the of Example 1, using 3- (difluoromethoxy)-N- 16) (84.7 mg, 0.421 mmol) and 5-chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (100 mg, 0.421 mmol) gave 5-chloro-2-(difluoromethoxy)-3-(5-(3- (difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyri dine (15.38 mg, 0.037 mmol, 8.83% yield) as black brown oil. 1 H NMR (MeOD-d 4 , 400 MHz): 8.49 (d, 1H, J = 2.5 Hz), 8.21 (d, 1H, J = 2.5 Hz), 7.6- 7.7 (m, 3H), 7.57 (s, 1H), 7.41 (br d, 1H, J = 7.5 Hz), 6.97 (t, 1H, J= 73.6 Hz), 3.67 (s, 3H). MS ES + : 403.0 Example 16: 5-bromo-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine g, mL) was added NaH (1.03 g, 25.86 mmol, 60% purity) in one portion at 0°C under N 2 . The mixture was stirred at 25 °C for 1 hour. The mixture was poured into saturated NH 4 Cl (100 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Ethyl acetate : Petroleum ether=3/1, Rf=0.50) gave methyl 5-bromo-2- (difluoromethoxy)pyridine-3-carboxylate (2.2 g, 7.80 mmol, 90.49% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.64 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.72 (t, J = 71.8 Hz, 1H), 3.86 (s, 3H). Step 2: To a solution of methyl 5-bromo-2-(difluoromethoxy)pyridine-3-carboxylate (1 g, 3.55 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.04 g, 17.73 mmol, 85% purity). The mixture was stirred at 80 °C for 1 hour. The mixture was concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Ethyl acetate: Petroleum ether=1/1, Rf=0.30) gave 5-bromo-2-(difluoromethoxy)pyridine-3-carbohydrazide (700 mg, 2.48 mmol, 70.00% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.61 (br s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 2.5 Hz, 1H), 7.67 (t, J = 71.9 Hz, 1H), 4.58 (d, J = 3.5 Hz, 2H). Step 3: To a mixture of 5-bromo-2-(difluoromethoxy)pyridine-3-carbohydrazide (200 mg, 0.709 mmol) and 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (121.4 mg, 0.709 mmol) in DCE (1 mL) was added 2-fluoropyridine (75.7 mg, 0.780 mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate (220.1 mg, 0.780 mmol) in one portion at 0 °C under N 2 . The mixture was stirred at 140 °C for 2 hours under microwave irradiation. The mixture was concentrated to afford the crude product. Purification by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1/1, Rf=0.25) followed by purification using prep. TLC (petroleum ether/ ethyl acetate =1/1, Rf=0.25) gave 5- bromo-2-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4-methyl -4H-1,2,4-triazol-3- yl)pyridine (43 mg, 0.110 mmol, 14.54% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.69 (d, J = 2.1 Hz, 1H), 8.55 - 8.48 (m, 1H), 7.97 - 7.58 (m, 2H), 7.41 (t, J = 8.3 Hz, 2H), 3.46 (s, 3H). MS ES + : 419.0 Example 17: 6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)nicotinonitrile A mixture -4-methyl-4H- 1,2,4-triazol- mg, copper(I) cyanide (55.4 mg, 0.618 mmol), in NMP (1 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 150 °C for 1.5 hours under N 2 atmosphere. The mixture was concentrated to afford the crude product. The crude product was purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 30%-60%, 58min B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% B to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1, 2,4-triazol-3- yl)nicotinonitrile (3.04 mg, 0.008 mmol, 8.06% yield, 99.3% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) 9.06 (s, 1H), 8.82 (s, 1H), 8.08 - 7.67 (m, 2H), 7.42 (t, J = 8.3 Hz, 2H), 3.47 (s, 3H). MS ES + : 364.0 Example 18: 5-chloro-2-(difluoromethoxy)-3-(1-(2,6-difluorophenyl)-5- methyl-1H-1,2,3-triazol-4-yl)pyridine (6.69 g, 58.1 mmol) in acetonitrile (50 mL) was dropwise added isopentyl nitrite (6.81 g, 58.1 mmol) at 0°C. The mixture was stirred at 25 °C for 1 hour. The mixture was poured into H 2 O (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were concentrated to dryness to afford 2-azido-1,3-difluoro-benzene (4.7 g, crude) as brown oil which was used in the next step directly. Step 2: To a mixture of 2-azido-1,3-difluoro-benzene (1 g, crude) and methyl 3- oxobutanoate (749 mg, 6.45 mmol) in DMSO (10 mL) was added K2CO3 (1.78 g, 12.9 mmol) in one portion at 25°C. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into H 2 O (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were concentrated to afford the crude product, which was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient 100 mL/min) to give methyl 1-(2,6-difluorophenyl)-5-methyl-triazole-4-carboxylate (990 mg, 3.82 mmol, 59.2% yield, 97.6% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ): 7.90 - 7.79 (m, 1H), 7.54 (t, J = 8.5 Hz, 2H), 3.89 (s, 3H), 2.44 (s, 3H). MS ES + : 254.2 Step 3: A mixture of methyl 1-(2,6-difluorophenyl)-5-methyl-triazole-4-carboxylate (300 mg, 1.18 mmol) in MeOH (3 mL) and 1 M LiOH (aq.) (1 M, 2.37 mL) was stirred at 25 °C for 30 minutes. The mixture was adjusted to pH=5 with 1M HCl (aq.). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated to afford 1-(2,6-difluorophenyl)-5-methyl-triazole-4-carboxylic acid (280 mg, crude) as a yellow solid. MS ES + : 240.1 Step 4: To a mixture of 1-(2,6-difluorophenyl)-5-methyl-triazole-4-carboxylic acid (280 mg, 1.17 mmol) and KOH (79 mg, 1.40 mmol) was added Br 2 (225 mg, 1.40 mmol) in H 2 O (3 mL) in one portion at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was poured into brine (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated to afford the crude product, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient 100mL/min) to give 4-bromo-1-(2,6-difluorophenyl)-5-methyl-triazole (180 mg, 0.631 mmol, 53.9% yield, 96.1% purity) as a yellow oil. 1H NMR (400 MHz, DMSO-d 6 ): 7.89 - 7.78 (m, 1H), 7.54 (t, J = 8.5 Hz, 2H), 2.21 (s, 3H). MS ES + : 273.8 Step 5: To a mixture of 4-bromo-1-(2,6-difluorophenyl)-5-methyl-triazole (50 mg, 0.182 mmol) and 3-bromo-5-chloro-2- (difluoromethoxy)pyridine (Intermediate 1, Step 1) (47 mg, 0.182 mmol) in toluene (0.5 mL) and H 2 O (0.5 mL) was added 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (93 mg, 0.365 mmol), caesium fluoride (55 mg, 0.365 mmol), diacetoxypalladium (4 mg, 0.018 mmol) and di(1-adamantyl)-n-butylphosphine (6.5 mg, 0.018 mmol) in one portion at 25°C under N 2 . The mixture was stirred at 90 °C for 5 hours. The mixture was poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to afford the crude product which was purified by prep. HPLC (Column: Xtimate C18 100*30mm*10μm, Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 55% B to 85%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3- (1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)pyrid ine (2.45 mg, 0.006 mmol, 3.6% yield, 99.2% purity) as a yellow solid. 1H NMR (400 MHz, MeOD-d 4 ): 8.33 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.85 - 7.72 (m, 1H), 7.67 - 7.47 (m, 1H), 7.39 (t, J = 8.2 Hz, 2H), 2.29 (s, 3H). MS ES + : 373.1 Example 19: 3-(5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole Step 1: To a solution of 2-bromo-4-chloro-1-(difluoromethoxy)benzene (2 g, 7.77 mmol) in triethylamine/ methanol=1/10 (10 mL) was added dppp (2.24 g, 5.44 mmol) and Pd(OAc) 2 (872 mg, 3.88 mmol). The mixture was stirred under CO (50 psi) at 80 °C for 10 hours. The mixture was cooled down to room temperature and filtered by Celite. The filtrate was concentrated to afford the crude product, which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3/1) to give methyl 5-chloro-2- (difluoromethoxy)benzoate (1.48 g, 6.26 mmol, 80.5% yield) as a colourless liquid. 1 H NMR (400 MHz, DMSO-d6): 7.83 (d, J = 2.6 Hz, 1H), 7.71 (ddd, J = 8.8, 2.7, 1.2 Hz, 1H), 6.98-7.40 (m, 2H), 3.85 (s, 3H). Step 2: To a solution of methyl 5-chloro-2-(difluoromethoxy)benzoate (1.48 g, 6.26 mmol) in EtOH (15 mL) was added hydrazine hydrate (1.84 g, 31.28 mmol, 85% purity). The mixture was stirred at 80 °C for 1 hour. The mixture was filtered and the filtrate was concentrated to afford the crude product, which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/ Ethyl acetate=1/1) to give 5-chloro-2- (difluoromethoxy)benzohydrazide (927 mg, 3.92 mmol, 62.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.55 (br s, 1H), 7.49-7.61 (m, 2H), 7.17-7.36 (m, 2H), 4.51 (br d, J = 4.1 Hz, 2H). Step 3: To a solution of 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (109 mg, 0.634 mmol), trifluoromethanesulfonic anhydride (197 mg, 0.697 mmol) and 2- fluoropyridine (68 mg, 0.697 mmol) in 1,2-dichloroethane (1 mL) was added 5-chloro- 2-(difluoromethoxy)benzohydrazide (150 mg, 0.634 mmol) at 20°C for 2 hours. The mixture was stirred at 140 °C for 2 hours under microwave irradiation. The mixture was filtered and the filtrate was concentrated to afford the crude product, which was purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm*10μm, Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 36% B to 66%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl )-4-methyl-4H-1,2,4- triazole (10.95 mg, 0.029 mmol, 4.6% yield, 98.0% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.73-7.85 (m, 3H), 7.13-7.52 (m, 4H), 3.39 (s, 3H). MS ES + : 372.0 Example 20: 3-(5-(2-bromophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5- chloro-2-(difluoromethoxy)pyridine Following the procedure Example 1, using 2-bromo-N- methyl-benzamide (200 mg, 0.934 mmol) and 5-chloro-2-(difluoromethoxy)pyridine- 3-carbohydrazide (Intermediate 1) (222 mg, 0.934 mmol) gave 3-[5-(2- bromophenyl)-4-methyl-1,2,4-triazol-3-yl]-5-chloro-2-(difluo romethoxy)pyridine (2.71 mg, 0.007 mmol, 0.7 % yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.62 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.70 - 7.51 (m, 4H), 3.38 (s, 3H). MS ES + : 414.9 Example 21: 2-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)benzonitrile A 2- (difluoromethoxy)pyridine (50 mg, 0.12 mmol) (Example 20) and CuCN (108 mg, 1.20 mmol) was added into N,N-dimethylformamide (1 mL) and was degassed and purged with N 2 three times, and then the mixture was stirred at 150 °C for 2 hours under microwave irradiation. The reaction mixture was quenched by saturated NH 3 •H 2 O (aq.) (10 mL), and then diluted with H 2 O (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue which was further purified by prep. HPLC (Column: Welch Ultimate C18 150*25mm*5μm, Mobile Phase A: water (NH 4 HCO 3 ), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 22% B to 52%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 2-[5-[5-chloro-2- (difluoromethoxy)-3-pyridyl]-4-methyl-1,2,4-triazol-3-yl]ben zonitrile (15.01 mg, 0.042 mmol, 34.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.66 - 8.57 (m, 1H), 8.42 - 8.34 (m, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.99 - 7.91 (m, 1.2H), 7.87 - 7.77 (m, 2.6H), 7.61 (s, 0.2H), 3.56 - 3.52 (m, 3H). MS ES + : 362.0 Example 22: 5-chloro-2-(difluoromethoxy)-3-(2-(2,6-difluorophenyl)-1- methyl-1H-imidazol-5-yl)pyridine a g, and 2,2-difluoro-2-fluorosulfonyl-acetic acid (1.42 g, 8.00 mmol) in acetonitrile (20 mL) at 0°C under N 2 . The mixture was stirred at 25 °C for 1 hour, at which point the mixture was poured into saturated NH 4 Cl (aq.) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were concentrated to afford the crude product, which was purified by flash silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 3 / 1) to afford methyl 5-chloro-2-(difluoromethoxy)pyridine-3-carboxylate (885 mg, 3.72 mmol, 69.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6 ): 8.58 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.73 (t, J = 71.8 Hz, 1H), 3.87 (s, 3H). Step 2: To a solution of methyl 5-chloro-2-(difluoromethoxy)pyridine-3-carboxylate (300 mg, 1.26 mmol) in THF (1 mL) was added 1 M LiOH (aq.) (1 M, 1.26 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude 5-chloro-2-(difluoromethoxy)nicotinate lithium (280 mg, crude) as a white solid, which was used into the next step without further purification. Step 3: To a solution of 5-chloro-2-(difluoromethoxy)nicotinate lithium (280 mg, crude) and N,O-dimethylhydroxylamine hydrochloride (183 mg, 1.88 mmol) in dichloromethane (3 mL) was added HATU (1.43 g, 3.76 mmol) and N,N- diisopropylethylamine (485.6 mg, 3.76 mmol). The mixture was stirred at 25 °C for 1 hour, at which point the reaction mixture was diluted with H 2 O (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with H 2 O (3 x 20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 5-chloro-2-(difluoromethoxy)-N-methoxy-N-methyl- pyridine-3-carboxamide (100 mg, 0.38 mmol, 29.9% yield) as a white solid, which was used without further purification. Step 4: A mixture of 5-chloro-2-(difluoromethoxy)-N-methoxy-N-methyl-pyridine-3- carboxamide (100 mg, 0.38 mmol) in THF (1 mL) was degassed and purged with N 2 for 3 times, and then MeMgBr (3 M in THF, 0.38 mL) was added dropwise and the resulting mixture was stirred at 25 °C for 1 hour under N 2 atmosphere. After this time, the reaction mixture was quenched by addition saturated NH 4 Cl (aq.) at 25°C, and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with H 2 O (3 x 10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep. TLC (SiO 2 , Petroleum ether: ethyl acetate = 3:1) to give 1-[5-chloro-2-(difluoromethoxy)-3-pyridyl]ethanone (60 mg, 0.27 mmol, 72.20% yield) as a white solid. Step 5: To a solution of 1-[5-chloro-2-(difluoromethoxy)-3-pyridyl]ethanone (60 mg, 0.271 mmol) in dichloromethane (0.5 mL) was added tetrabutylammonium tribromide (144 mg, 0.30 mmol). The reaction was stirred at 40 °C for 2 hours at which point the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep. TLC (SiO 2 , Petroleum ether: ethyl acetate = 10:1) to afford 2-bromo-1- [5-chloro-2-(difluoromethoxy)-3-pyridyl]ethanone (70 mg, 0.23 mmol, 86.03% yield) as a white solid. Step 6: To a solution of 2-bromo-1-[5-chloro-2-(difluoromethoxy)-3-pyridyl]ethanone (70 mg, 0.23 mmol) and 2,6-difluorobenzamidine hydrochloride (53.8 mg, 0.23 mmol) in THF/H 2 O = 4/1 (0.5 mL) was added NaHCO 3 (78.3 mg, 0.93 mmol). The mixture was stirred at 50 °C for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep. TLC (SiO 2 , petroleum ether: ethyl acetate = 3:1) to afford 5-chloro-2-(difluoromethoxy)-3-(2-(2,6- difluorophenyl)-1H-imidazol-5-yl)pyridine (20 mg, 0.56 mmol, 24.0% yield) as a white solid. MS ES + : 357.8 Step 7: A mixture of NaH (6.7 mg, 0.17 mmol, 60% purity) in THF (0.5 mL) was degassed and purged with N 2 for 3 times, and then 5-chloro-2-(difluoromethoxy)-3-[2- (2,6-difluorophenyl)-1H-imidazol-5-yl]pyridine (20 mg, 0.56 mmol) and MeI (79.4 mg, 0.26 mmol) were added and the mixture was stirred at 0 °C for 0.5 hour under N 2 atmosphere. After this time, the reaction mixture was quenched by saturated NH 4 Cl (aq.) at 25°C, and then diluted with H2O (2 mL) and extracted with ethyl acetate (3 x 2 mL), The combined organic layers was separated and concentrated under reduced pressure to give a residue. Then the residue was further purified by prep. HPLC (Column: Phenomenex luna 150*25mm* 10μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 53% B to 83%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-[2-(2,6- difluorophenyl)-3-methyl-imidazol-4-yl]pyridine (1.06 mg, 0.03 mmol, 4.90% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.46 - 8.36 (m, 1H), 8.23 (d, J = 2.5 Hz, 1H), 7.93 (s, 0.3H), 7.75 (s, 0.4H), 7.72 - 7.63 (m, 1H), 7.57 (s, 0.3H), 7.38 - 7.26 (m, 3H), 3.41 (br s, 3H). MS ES + : 371.8 Example 23: 3-chloro-6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)-2-methylpyridine Step 1: To a solution of 5-chloro-2-hydroxy-6-methylnicotinic acid (700 mg, 3.73 mmol) in MeOH (0.5 mL) and dichloromethane (5 mL) was dropwise added diazomethyl(trimethyl)silane (2 M in hexane, 3.73 mL) at 0 ºC. The mixture was stirred at 0 °C for 1 hour, at which point the reaction mixture was diluted with H 2 O (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 15 mL/min) to afford methyl 5-chloro-2-hydroxy-6-methylnicotinate (660 mg, 3.27 mmol, 87.7% yield) as a white solid. Step 2: Sodium hydride (214 mg, 5.36 mmol, 60% purity) was added into a mixture of methyl 5-chloro-2-hydroxy-6-methyl-pyridine-3-carboxylate (360 mg, 1.79 mmol) in THF (3 mL), then 2,2-difluoro-2-fluorosulfonyl-acetic acid (1.91 g, 10.71 mmol) was added into the mixture under N 2 , and then the mixture was stirred at 25 °C for 8 hours under N 2 atmosphere. The reaction mixture was quenched by the addition of saturated NH 4 Cl (aq.) at 25°C, and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude methyl 5-chloro-2-(difluoromethoxy)-6-methyl-pyridine-3- carboxylate (380 mg, 1.51 mmol, 84.6% yield) as a white solid, which was used without further purification. MS ES + :251.9 Step 3: To a solution of methyl 5-chloro-2-(difluoromethoxy)-6-methyl-pyridine-3- carboxylate (300 mg, 1.19 mmol) in ethanol (3 mL) was added hydrazine hydrate (702.2 mg, 11.92 mmol, 85% purity in H 2 O). The mixture was stirred at 85 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep. TLC (SiO 2 , Petroleum ether: ethyl acetate = 1:1) to give 5-chloro-2-(difluoromethoxy)-6-methyl-pyridine-3-carbohydraz ide (280 mg, 1.11 mmol, 93.3% yield) as a white solid. Step 4: To a solution of 5-chloro-2-(difluoromethoxy)-6-methyl-pyridine-3- carbohydrazide (50 mg, 0.199 mmol) and 2,6- difluoro-N-methylbenzamide (Intermediate 2) (37.4 mg, 0.219 mmol) in 1,2-dichloroethane (1 mL) was added trifluoromethanesulfonic anhydride (61.7 mg, 0.219 mmol) and 2-fluoropyridine (21.2 mg, 0.219 mmol). The mixture was stirred at 120 °C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure to give a residue which was further purified by prep. HPLC (Column: Phenomenex luna C18150*25mm* 10μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the compound 3-chloro-6-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)-2-methylpyridine (1.35 mg, 0.031 mmol, 1.56% yield, 0.3 eq. formate salt) as a white solid. 1H NMR (400 MHz, MeOD-d4): 8.52 (br s, 0.3H), 8.17 (s, 1H), 7.90 - 7.50 (m, 2H), 7.29 (t, J = 8.2 Hz, 2H), 3.54 (s, 3H), 2.67 (s, 3H). MS ES + : 386.7. Example 24: 6-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)benzo[c][1,2,5]thiadiazole was g, . was at 90°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give methyl 2,3-diamino-5-chloro-benzoate (400 mg, crude) as a yellow solid which was used for next step directly. MS ES + : 200.8. Step 2: To a solution of methyl 2,3-diamino-5-chloro-benzoate (400 mg, crude) in dichloromethane (4 mL) was added sulfuryl dichloride (759 mg, 6.38 mmol) and triethylamine (868 mg, 8.57 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford methyl 6-chlorobenzo[c][1,2,5]thiadiazole-4-carboxylate (350 mg, 1.53 mmol, 76.8% yield) as a yellow solid. Step 3: To a solution of hydrazine hydrate (245 mg, 4.16 mmol, 85% purity in H 2 O) was added methyl 6-chlorobenzo[c][1,2,5]thiadiazole-4-carboxylate (350 mg, 1.53 mmol) in ethanol (1 mL). The mixture was stirred at 85 °C for 1 hour. The reaction mixture was diluted with H 2 O (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with H 2 O (3 x 10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford 6-chloro- 2,1,3-benzothiadiazole-4-carbohydrazide (250 mg, 1.09 mmol, 71.2% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.92 (br s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 4.83 (s, 2H). Step 4: A mixture of 6-chloro-2,1,3-benzothiadiazole-4-carbohydrazide (100 mg, 0.44 mmol), 2,6-difluoro-N-methylbenzamide (Intermediate 2) (74.9 mg, 0.44 mmol), trifluoromethanesulfonic anhydride (136 mg, 0.48 mmol), 2-fluoropyridine (46.7 mg, 0.48 mmol) in 1,2-dichloroethane (1 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 140 °C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure to give a residue which was further purified by prep. HPLC (Column: Phenomenex luna 150*25mm*10μm, Mobile Phase A: water (NH 4 HCO 3 ), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 25% B to 55%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 6-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)benzo[c][1,2,5]thiadiazole (2.02 mg, 0.006 mmol, 1.3% yield) as a white solid. 1 H NMR (400 MHz, MeOD-d 4 ): 8.40 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.83 - 7.71 (m, 1H), 7.31 (t, J = 8.2 Hz, 2H), 3.60 (s, 3H). MS ES + : 363.9. Example 25: 3-(5-chloro-2-methoxyphenyl)-5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazole a mg, in EtOH (5 mL) was added NH 2 NH 2 •H2O (1.47 g, 24.92 mmol, 85% purity in H2O). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched by addition of H 2 O (50 mL) at 25 °C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give 5-chloro-2- methoxybenzohydrazide (500 mg, 2.49 mmol, 100.00% yield) as a white solid. ESI+: 201.0 1 H NMR (400 MHz, DMSO-d 6 ): 9.31 (br s, 1H), 7.60 (d, J = 2.6 Hz, 1H), 7.49 (dd, J = 2.6, 8.9 Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H), 4.55 (br d, J = 4.0 Hz, 2H), 3.85 (s, 3H). Step 2: To a solution of 2,6-difluoro-N-methylbenzamide (Intermediate 2) (282 mg, 1.64 mmol) and 5-chloro-2-methoxybenzohydrazide (300 mg, 1.50 mmol) in 1,2- dichloroethane (1 mL) was added trifluoromethanesulfonic anhydride (464 mg, 1.64 mmol) and 2-fluoropyridine (160 mg, 1.64 mmol). The mixture was stirred at 120 °C for 2 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 3-(5-chloro-2- methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-tria zole (30.77 mg, 0.917 mmol, 6.13% yield, 100% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.82 - 7.71 (m, 1H), 7.66 (dd, J = 2.8, 8.9 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 3.85 (s, 3H), 3.34 (s, 3H). ESI+: 336.0 Example 26: 5-chloro-2-(difluoromethoxy)-3-(4-(2,6-difluorophenyl)-5- methyl-1H-1,2,3-triazol-1-yl)pyridine , tert-butyl carbamate (499 mg, 4.26 mmol), Cs 2 CO 3 (3.78 g, 11.61 mmol), XantPhos (448 mg, 0.774 mmol) and Pd 2 (dba) 3 (354 mg, 0.387 mmol) in dioxane (7 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 100 °C for 1 hour under N 2 atmosphere. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford tert-butyl (5-chloro-2-(difluoromethoxy)pyridin-3- yl)carbamate (1.1 g, 3.73 mmol, 96.47% yield) as a yellow solid. ESI + : 294.7 Step 2: To tert-butyl (5-chloro-2-(difluoromethoxy)pyridin-3-yl)carbamate (1.10 g, 3.73 mmol) was added HCl (10 mL, 4M in dioxane). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and the filtrate was evaporated to dryness to give 5-chloro-2-(difluoromethoxy)pyridin-3-amine hydrochloride (705 mg, crude) as white solid which was used in the next step directly without further purification. ESI + : 194.9 Step 3: To a solution of 5-chloro-2-(difluoromethoxy)pyridin-3-amine (100 mg, crude, HCl) and N-[1-(2,6-difluorophenyl)propylideneamino]-4-methyl-benzenes ulfonamide (Intermediate 17) (191 mg, 0.565 mmol) in toluene (2 mL) was added diacetoxycopper (93.4 mg, 0.514 mmol) and 2,2-dimethylpropanoic acid (105 mg, 1.03 mmol). The mixture was stirred at 110 °C for 1 hour. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). The reaction mixture was filtered and the filtrated was evaporated to dryness to give 5-chloro-2- (difluoromethoxy)-3-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2, 3-triazol-1-yl)pyridine (63.8 mg, 0.165 mmol, 32.0% yield, 96.2% purity) as a yellow solid. ESI + : 373.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.68 (br d, J = 2.0 Hz, 2H), 7.58-7.97 (m, 2H), 7.31 (t, J = 8.0 Hz, 2H), 2.19 ppm (s, 3H). Example 27: 5-chloro-2-(difluoromethoxy)-3-(3-(2,6-difluorophenyl)-5- methoxy-1H-pyrazol-1-yl)pyridine H F Boc N F F N Boc as described for WO2020/210828) (600 mg, 2.32 mmol), tert-butyl N-(tert- butoxycarbonylamino)carbamate (593 mg, 2.55 mmol), CuI (88.4 mg, 0.464 mmol) and K 3 PO 4 (1.48 g, 6.96 mmol) in dioxane (3 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 100 °C for 1 hour under N 2 atmosphere. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to afford di-tert-butyl 1-(5-chloro-2-(difluoromethoxy)pyridin-3- yl)hydrazine-1,2-dicarboxylate (288 mg, 0.703 mmol, 30.27% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.84 (br s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.91 (br dd, J = 7.1, 3.4 Hz, 0.2H), 7.84 (br s, 1H), 7.69-7.76 (m, 0.5H), 7.49-7.59 (m, 0.3H), 1.39 (d, J = 2.9 Hz, 18H. ESI + : 410.2 Step 2: A mixture of di-tert-butyl 1-(5-chloro-2-(difluoromethoxy)pyridin-3- yl)hydrazine-1,2-dicarboxylate (288 mg, 0.703 mmol) in 4M HCl in dioxane (3 mL) was stirred at 25 °C for 1 hour. The reaction mixture was filtered and the filtrated was evaporated to dryness to give 5-chloro-2-(difluoromethoxy)-3-hydrazineylpyridine hydrochloride (238 mg, crude) as yellow solid, which was used in the next step directly without further purification. ESI + : 209.8 Step 3: To a solution of 5-chloro-2-(difluoromethoxy)-3-hydrazineylpyridine hydrochloride (238 mg, crude) in AcOH (2 mL) was added ethyl 3-(2,6- difluorophenyl)-3-oxo-propanoate (285 mg, 1.25 mmol). The mixture was stirred at 110 °C for 1 hour. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford 2-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-5-(2,6- difluorophenyl)-1,2-dihydro-3H-pyrazol-3-one (112 mg, 0.30 mmol, 26.39% yield) as a white solid. ESI + :373.9 1 H NMR (400 MHz, DMSO-d 6 ): 11.89 (s, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.74 (t, J = 71.8 Hz, 1H), 7.42-7.51 (m, 1H), 7.19 (t, J = 8.4 Hz, 2H), 5.81 (s, 1H). Step 4: To a solution of NaH (19.3 mg, 0.482 mmol, 60% purity in mineral oil) in THF (1 mL) was added 2-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-5-(2,6- difluorophenyl)-1,2-dihydro-3H-pyrazol-3-one (60 mg, 0.161 mmol). The mixture was stirred for 10 min, then CH 3 I (114 mg, 0.903 mmol) was added in portions at 0 °C under N 2 . The mixture was stirred at 25 °C for 1 hour. The residue was purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)]; B acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% B to 60%). The solution was lyophilized to dryness to give the product 5-chloro-2- (difluoromethoxy)-3-(3-(2,6-difluorophenyl)-5-methoxy-1H-pyr azol-1-yl)pyridine (2.51 mg, 0.00634 mmol, 3.97% yield, 98.4% purity) as white solid. ESI + : 387.9. 1 H NMR (400 MHz, DMSO-d 6 ): 8.46-8.53 (m, 1H), 8.34-8.41 (m, 1H), 7.56-7.94 (m, 1H), 7.46- 7.54 (m, 1H), 7.22 (t, J = 8.4 Hz, 2H), 6.22 (s, 1H), 3.95 (s, 3H). Example 28: 3-(5-chloro-2-(trifluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole c , diazomethyl(trimethyl)silane (2 M in Hexane, 1.66 mL) in MeOH (0.5 mL) and dichloromethane (5 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 0 °C for 1 hour under N 2 atmosphere. The reaction mixture was diluted with H 2 O (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organics were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @30mL/min). Compound methyl 5-chloro-2- (trifluoromethoxy)benzoate (390mg, 1.50 mmol, 90.29% yield, 98% purity) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.96 - 7.91 (m, 1H), 7.81 (dd, J = 2.8, 8.9 Hz, 1H), 7.56 (dd, J = 1.1, 8.8 Hz, 1H), 3.91 - 3.81 (m, 3H). Step 2: To a solution of methyl 5-chloro-2-(trifluoromethoxy)benzoate (380 mg, 1.49 mmol) in EtOH (5 mL) was added NH 2 NH 2 •H 2 O (879 mg, 14.93 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched by the addition of H 2 O (10 mL) at 25°C, and then diluted with H 2 O (10mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give 5-chloro-2-(trifluoromethoxy)benzohydrazide (280 mg, 1.03 mmol, 69.1 % yield, 94% purity) as a white solid. ESI + : 255.1 1 H NMR (400 MHz, DMSO-d 6 ): 9.72 - 9.65 (m, 1H), 7.66 (dd, J = 2.7, 8.8 Hz, 1H), 7.58 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 1.0, 8.8 Hz, 1H), 4.53 (s, 2H). Step 3: A mixture of 5-chloro-2-(trifluoromethoxy)benzohydrazide (150 mg, 0.589 mmol), 2,6-difluoro-N-methylbenzamide (Intermediate 2) (111 mg, 0.648 mmol), trifluoromethanesulfonic anhydride (183 mg, 0.648 mmol) and 2-fluoropyridine (62.9 mg, 0.648 mmol) in 1,2-dichloroethane (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 140 °C for 2 hours under microwave atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @15 mL/min) to give 3-(5-chloro-2-(trifluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole (27.59 mg, 0.07 mmol, 11.90% yield, 99.05% purity) as a white solid. ESI + : 390.0. 1 H NMR (400 MHz, DMSO-d 6 ): 7.98 (d, J = 2.6 Hz, 1H), 7.86 (dd, J = 2.8, 8.9 Hz, 1H), 7.77 (tt, J = 6.6, 8.5 Hz, 1H), 7.70 (dd, J = 1.3, 8.9 Hz, 1H), 7.45 - 7.35 (m, 2H), 3.40 (s, 3H). Example 29: 3-(4-chloro-2-(difluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole To a solution of difluoromethyl trifluoromethanesulfonate (1.44 g, 7.20 mmol) and methyl 4-chloro-2-hydroxybenzoate (500 mg, 2.68 mmol) in acetonitrile (5 mL) was added 6 M KOH (aq. 5.00 mL). The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to remove acetonitrile. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). Then combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @15 mL/min) to give the product methyl 4- chloro-2-(difluoromethoxy)benzoate (146 mg, 0.617 mmol, 12.86% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 7.86 (d, J = 8.4 Hz, 1H), 7.50 - 7.43 (m, 2.2H), 7.26 (s, 0.6H), 7.08 (s, 0.2H), 3.84 (s, 3H). Step 2: To a solution of methyl 4-chloro-2-(difluoromethoxy)benzoate (140 mg, 0.592 mmol) in EtOH (5 mL) was added NH 2 NH 2 •H 2 O (348 mg, 5.92 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched by the addition of H 2 O (10 mL) at 25°C, and then diluted with H 2 O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give 4-chloro-2-(difluoromethoxy)benzohydrazide (83 mg, 0.351 mmol, 59.28% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.48 (br s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.43 (s, 0.2H), 7.42 - 7.34 (m, 2H), 7.25 (s, 0.6H), 7.08 - 7.05 (m, 0.2H), 4.51 (br s, 2H). Step 3: To a solution of 2,6-difluoro-N-methylbenzamide (Intermediate 2) (63.7 mg, 0.372 mmol) and 4-chloro-2-(difluoromethoxy)benzohydrazide (80 mg, 0.338 mmol) in 1,2-dichloroethane (1 mL) was added trifluoromethanesulfonic anhydride (105 mg, 0.372 mmol) and 2-fluoropyridine (36.1 mg, 0.372 mmol). The mixture was stirred at 120 °C for 2 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give the crude product. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm*10μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 32% B to 62%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(4-chloro-2-(difluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole (2.88 mg, 0.0077 mmol, 2.28% yield, 99.5% purity) as a white solid. ESI + : 372.0 1 H NMR (400 MHz, DMSO-d 6 ): 7.82 - 7.71 (m, 2H), 7.60 (s, 1H), 7.55 (dd, J = 2.0, 8.3 Hz, 1H), 7.45 - 7.21 (m, 3H), 3.37 (s, 3H). Example 30: 3-(3-bromo-5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole methyl 3-bromo-5-chloro-2-hydroxy-benzoate (550 mg, 2.07 mmol) in acetonitrile (3 mL) was added 6 M KOH (aq.) (6 M, 3 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by the addition of 2M HCl (aq, 5mL) to pH=3, and then diluted with H 2 O (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 3-bromo-5-chloro-2-(difluoromethoxy)benzoic acid (400 mg, crude) as a white solid, which was used in the next step without further purification. Step 2: To a solution of 3-bromo-5-chloro-2-(difluoromethoxy)benzoic acid (400 mg, crude) in MeOH (0.4 mL) and dichloromethane (4 mL) was added diazomethyl(trimethyl)silane (2 M in Hexane, 1.33 mL) at 0 ºC. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched by the addition of H 2 O (10 mL) at 25°C, and then diluted with H 2 O (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). Compound methyl 3-bromo-5-chloro-2-(difluoromethoxy)benzoate (200 mg, 0.634 mmol, 47.78% yield) was obtained as a white solid. Step 3: To a solution of methyl 3-bromo-5-chloro-2-(difluoromethoxy)benzoate (200 mg, 0.634 mmol) in EtOH (2 mL) was added NH 2 NH 2 •H 2 O (317 mg, 6.34 mmol). The mixture was stirred at 90 °C for 0.5 hour. The reaction mixture was quenched by the addition of H 2 O (20 mL) at 25°C, and then diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. Compound 3- bromo-5-chloro-2-(difluoromethoxy)benzohydrazide (200 mg, crude) was obtained as a white solid, which was used in next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ): 9.70 (br s, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.37 - 6.79 (m, 1H), 4.51 (br s, 2H). Step 4: A mixture of 2,6-difluoro-N-methylbenzamide (Intermediate 2) (119 mg, 0.697 mmol), 3-bromo-5-chloro-2-(difluoromethoxy)benzohydrazide (200 mg, crude), trifluoromethanesulfonic anhydride (198 mg, 0.697 mmol), 2-fluoropyridine (67.70 mg, 0.697 mmol) in 1,2-dichloroethane (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 140 °C for 2 hours under microwave atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @15 mL/min) to afford the crude product. The crude product was further purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm, Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(3-bromo-5-chloro-2-(difluoromethoxy)phenyl)-5-(2,6-difluo rophenyl)-4-methyl- 4H-1,2,4-triazole (39.65 mg, 0.087 mmol, 13.67% yield, 98.47% purity) as a white solid. ESI + : 450.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.24 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.83 - 7.71 (m, 1H), 7.40 (t, J = 8.1 Hz, 2H), 6.95 (t, J = 72.0 Hz, 1H), 3.40 (s, 3H). Example 31: 3-(5-chloro-2-(difluoromethoxy)-3-methylphenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole Step -5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole (Example 30) (100 mg, 0.222 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 0.076 mL), Cs 2 CO 3 (217 mg, 0.666 mmol) in dioxane (3 mL) and H2O (0.6 mL) was degassed and purged with N 2 3 times, and then Pd(dppf)Cl 2 (32.5 mg, 0.044 mmol) was added. The mixture was stirred at 100 °C for 12 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: ethyl acetate=1:1) to give 3-(5-chloro-2-(difluoromethoxy)- 3-methylphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-tri azole (13.15 mg, 0.033 mmol, 15.04% yield, 97.9% purity) as a white solid. ESI + : 385.9. 1 H NMR (400 MHz, DMSO-d 6 ): 7.81 - 7.72 (m, 2H), 7.67 (d, J = 2.6 Hz, 1H), 7.39 (t, J = 8.1 Hz, 2H), 6.85 (t, J = 72.9 Hz, 1H), 3.38 (s, 3H), 2.36 (s, 3H). Example 32: 3-(5-chloro-2-(difluoromethoxy)-3-fluorophenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole
Step and g, (10 mL) was added 6 M KOH (aq.) (10 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent, before being diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~3% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford 1-bromo-5-chloro-2- (difluoromethoxy)-3-fluorobenzene (950 mg, 3.45 mmol, 77.75% yield) as colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 7.83 - 7.75 (m, 2H), 7.39 - 7.00 (m, 1H). Step 2: A mixture of 1-bromo-5-chloro-2-(difluoromethoxy)-3-fluorobenzene (500 mg, 1.82 mmol), DPPP (524 mg, 1.27 mmol) and Pd(OAc) 2 (204 mg, 0.908 mmol) in MeOH/ triethylamine =10:1 (5 mL) was degassed and purged with CO three times, and then the mixture was stirred at 80 °C for 12 hours under CO (15 psi) atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to afford methyl 5-chloro-2-(difluoromethoxy)-3-fluorobenzoate (160 mg, 0.628 mmol, 34.62% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-d 6 ): 7.99 (dd, J = 2.6, 10.0 Hz, 1H), 7.80 - 7.68 (m, 1H), 7.34 - 6.95 (m, 1H), 3.86 (s, 3H). Step 3: To a solution of methyl 5-chloro-2-(difluoromethoxy)-3-fluorobenzoate (160 mg, 0.629 mmol) in EtOH (2 mL) was added NH 2 NH 2 •H 2 O (555 mg, 9.43 mmol, 85% purity in H2O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled down to room temperature and quenched by water (5 mL) at 25 °C before being extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 45 mL/min) to give the compound 5-chloro-2-(difluoromethoxy)-3-fluorobenzohydrazide (140 mg, 0.55 mmol, 87.50% yield) as a white solid. ESI+: 255.1 Step 4: To a solution of 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (210 mg, 0.943 mmol) in 1,2-dichloroethane (3 mL) was added dropwise 2-fluoropyridine (83.9 mg, 0.864 mmol) and trifluoromethanesulfonic anhydride (244 mg, 0.864 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-(difluoromethoxy)-3-fluorobenzohydrazide (100 mg, 0.393 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction was stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The separated organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to afford the compound 3-(5-chloro-2-(difluoromethoxy)-3-fluorophenyl)-5-(2,6-diflu orophenyl)-4- methyl-4H-1,2,4-triazole (72.73 mg, 0.183 mmol, 46.52% yield, 97.9% purity) as a white solid. ESI+: 389.8. 1 H NMR (400 MHz, MeOD-d 4 ): 7.79 - 7.70 (m, 2H), 7.64 (t, J = 2.1 Hz, 1H), 7.29 (t, J = 8.2 Hz, 2H), 7.02 - 6.63 (m, 1H), 3.52 (s, 3H). Example 33: 3-(5-chloro-2-(difluoromethoxy)-4-fluorophenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole Step mg, in dichloromethane/MeOH=10:1 (5 mL) was degassed and purged with N 2 3 times, and then trimethylsilyldiazomethane (2 M in Hexane, 2.62 mL) was added slowly at 0 °C. The mixture was stirred at 0 °C for 1 hour under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude compound methyl 5-chloro- 4-fluoro-2-hydroxybenzoate (462 mg, 2.26 mmol, 86.06% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 11.02 - 10.52 (m, 1H), 7.95 - 7.86 (m, 1H), 7.08 (d, J = 10.9 Hz, 1H), 3.87 (s, 3H). Step 2: To a solution of methyl 5-chloro-4-fluoro-2-hydroxybenzoate (240 mg, 1.17 mmol), difluoromethyl trifluoromethanesulfonate (469 mg, 2.35 mmol) in acetonitrile (3 mL) was added 6 M KOH (aq., 3.60 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (10 mL) and adjusted to pH=3~5 with 1 M HCl (aq.), and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude compound 5-chloro-2-(difluoromethoxy)-4- fluorobenzoic acid (300 mg, crude) as a white solid, which was used in next step without further purification. Step 3: To a solution of 5-chloro-2-(difluoromethoxy)-4-fluorobenzoic acid (350 mg, 1.45 mmol), methanamine hydrochloride (118 mg, 1.75 mmol), N-ethyl-N- isopropylpropan-2-amine (564 mg, 4.36 mmol) and HOBt (295 mg, 2.18 mmol) in dichloromethane (2 mL) was added EDCI (418 mg, 2.18 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to afford the compound 5-chloro-2- (difluoromethoxy)-4-fluoro-N-methylbenzamide (185 mg, 0.729 mmol, 50.14% yield) as a white solid. ESI+: 254.1 1 H NMR (400 MHz, DMSO-d 6 ): 8.31 (br d, J = 4.1 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.41 - 7.03 (m, 1H), 2.75 (d, J = 4.6 Hz, 3H). Step 4: To a solution of 5-chloro-2-(difluoromethoxy)-4-fluoro-N-methyl-benzamide (100 mg, 0.394 mmol) in 1,2-dichloroethane (1 mL) was added dropwise 2- fluoropyridine (42 mg, 0.434 mmol) and trifluoromethanesulfonic anhydride (122 mg, 0.434 mmol) at 0 °C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 2, 6-difluorobenzohydrazide (75 mg, 0.434 mmol) in 1,2-dichloroethane (1 mL) was added and the reaction mixture stirred for 10 min. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The mixture was concentrated under reduced pressure to give a residue. The residue was further purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 7μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 32% to 62%). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give the compound 3-(5-chloro-2-(difluoromethoxy)-4-fluorophenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole (71.57 mg, 0.183 mmol, 46.48% yield, 99.8% purity) as a white solid. ESI+: 389.9 1 H NMR (400 MHz, DMSO-d 6 ): 8.04 (d, J = 8.3 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.72 - 7.68 (m, 1H), 7.44 - 7.36 (m, 3H), 3.38 (s, 3H). Example 34: 3-(4,5-dichloro-2-(difluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole mL) was added 1-chloropyrrolidine-2,5-dione (3.02 g, 22.60 mmol). The mixture was stirred at 25 °C for 1 hour. The formed precipitate was filtered and washed with cold water (100 mL x 3), the filter cake was dried under reduced pressure to give 4,5- dichloro-2-hydroxybenzoic acid (3 g, crude) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): 7.91 - 7.86 (m, 1H), 7.30 (s, 1H). Step 2: To a solution of 4,5-dichloro-2-hydroxybenzoic acid (3 g, 14.49 mmol) in H 2 SO 4 (3 mL) was added MeOH (30 mL). The mixture was stirred at 75 °C for 1 hour. The reaction mixture was quenched by the addition of saturated NaHCO 3 (aq.20 mL) at 25 °C, and then diluted with H 2 O (50 mL) and extracted with ethyl acetate (30 mL x 3), filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 18 mL/min) to give methyl 4,5-dichloro-2-hydroxybenzoate (1.5 g, 6.79 mmol, 46.83% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 10.68 (br s, 1H), 7.88 (s, 1H), 7.29 (s, 1H), 3.87 (s, 3H). Step 3: To a solution of methyl 4,5-dichloro-2-hydroxybenzoate (1 g, 4.52 mmol) and 6 M KOH (aq, 10 mL) in acetonitrile (10 mL) was added difluoromethyl trifluoromethanesulfonate (1.81 g, 9.05 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 4,5-dichloro-2-(difluoromethoxy)benzoic acid (1.22 g, crude) was obtained as a white solid, which was used in the next step without further purification. Step 4: To a solution of 4,5-dichloro-2-(difluoromethoxy)benzoic acid (500 mg, crude), methanamine hydrochloride (158 mg, 2.33 mmol), N-ethyl-N-isopropylpropan-2- amine (754 mg, 5.84 mmol) and HOBt (394 mg, 2.92 mmol) in dichloromethane (5 mL) was added EDCI (559 mg, 2.92 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 25 mL/min) to give 4,5-dichloro-2-(difluoromethoxy)-N-methylbenzamide (200 mg, 0.741 mmol, 38.07% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.36 (br d, J = 4.4 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.60 (s, 1H), 7.45 - 7.04 (m, 1H), 2.75 (d, J = 4.6 Hz, 3H). Step 5: To a solution of 4,5-dichloro-2-(difluoromethoxy)-N-methylbenzamide (130 mg, 0.481 mmol) in 1,2-dichloroethane (1.5 mL) was added trifluoromethanesulfonic anhydride (136 mg, 0.482 mmol) and 2-fluoropyridine (46.7 mg, 0.482 mmol). The mixture was stirred at 0°C for 1 hour, and then 2,6-difluorobenzohydrazide (Intermediate 23) (63.7 mg, 0.37 mmol) was added. The mixture was stirred at 140 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: water (HCOOH); Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(4,5-dichloro-2-(difluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole (2.5 mg, 0.006 mmol, 1.65% yield, 99.5% purity) as a white solid. ESI + : 406.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.05 (s, 1H), 7.83 (s, 1H), 7.77 (br t, J = 7.4 Hz, 1H), 7.58 - 7.20 (m, 3H), 3.40 (br s, 3H). Example 35: 4-(difluoromethoxy)-5-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)-6-methoxypyrimidine Step 1: A mixture of 6-chloropyrimidin-4-ol (5 g, 38.30 mmol) and NaOMe (27.59 g, 153.22 mmol, 30% purity in MeOH) in MeOH (20 mL) was heated to 90°C in a sealed tube, and then the mixture was stirred at 90 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to dryness which was then purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~8% Methanol /Dichloromethane gradient @ 60 mL/min) to afford 6-methoxypyrimidin-4- ol (4.6 g, 25.39 mmol, 66.28% yield, 69.6% purity) as white solid. ESI + : 127.0 1 H NMR (400 MHz, DMSO-d 6 ): 12.40 (br s, 1H), 8.07 (s, 1H), 5.53 (s, 1H), 3.77 (s, 3H). Step 2: A solution of 6-methoxypyrimidin-4-ol (2 g, 15.86 mmol, 69.6% purity) in acetonitrile (20 mL) was added KOH (17.8 g, 317 mmol) in H 2 O (20 mL) dropwise at 0 °C, and then the mixture was stirred at 25 °C for 0.5 h. The mixture was cooled down to 0 °C and 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (16.94 g, 63.44 mmol) was added and the mixture was stirred at 25 °C for 10 h. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% Dichloromethane/ Petroleum ether gradient @ 50 mL/min) to give 4-(difluoromethoxy)-6-methoxypyrimidine (1.3 g, 7.08 mmol, 44.64% yield, 95.9% purity) as white solid. ESI + : 177.0 1 H NMR (400 MHz, DMSO-d 6 ): 8.61 (s, 1H), 7.94 - 7.57 (m, 1H), 6.61 (d, J = 0.6 Hz, 1H), 3.94 (s, 3H). Step 3: To a solution of 4-(difluoromethoxy)-6-methoxypyrimidine (1.3 g, 7.38 mmol) in acetonitrile (6 mL) was added Br 2 (5.90 g, 36.91 mmol) dropwise at 0 °C, and then the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% Dichloromethane/Petroleum ether gradient @ 60 mL/min) to give 5-bromo-4-(difluoromethoxy)-6-methoxy-pyrimidine (1.3 g, 5.10 mmol, 69.06% yield, 100% purity) as white solid. ESI + : 254.9 1 H NMR (400 MHz, DMSO-d 6 ): 8.56 (s, 1H), 7.96 - 7.59 (m, 1H), 4.04 (s, 3H). Step 4: A mixture of 5-bromo-4-(difluoromethoxy)-6-methoxy-pyrimidine (1.64 g, 6.43 mmol) in THF (30 mL) was degassed and purged with N 2 3 times, and n-BuLi (2.5 M in n-Hexane, 3.86 mL) was dropwise added. The reaction was stirred at -78 °C for 0.5 hour, then dry ice (5 g, 6.43 mmol) was added and the reaction stirred at -78 °C for 2 hours under N 2 atmosphere. The reaction mixture was quenched by the addition of saturated NH 4 Cl (aq.) (80 mL) dropwise at 0 °C under N 2 flow and then extracted with ethyl acetate (60 mL x 2). The aqueous layers were adjusted to pH=3-6 with 1 M HCl (aq., 10 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 4- (difluoromethoxy)-6-methoxy-pyrimidine-5-carboxylic acid (460 mg, crude) as a light yellow solid, which was used in next step without further purification. ESI + : 221.0 Step 5: To a solution of 4-(difluoromethoxy)-6-methoxy-pyrimidine-5-carboxylic acid (420 mg, 1.91 mmol), methanamine hydrochloride (322 mg, 4.77 mmol) and N-ethyl- N-isopropylpropan-2-amine (740 mg, 5.72 mmol) in dichloromethane (5 mL) was added butylphosphonic anhydride (2.06 g, 2.86 mmol, 50% purity in ethyl acetate). The mixture was stirred at 25 °C for 10 hours. The mixture was concentrated to afford the crude. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford 4-(difluoromethoxy)-6-methoxy-N- methylpyrimidine-5-carboxamide (250 mg, 1.07 mmol, 56.03% yield, 99.7% purity) was obtained as a white solid. ESI + : 234.1 1 H NMR (400 MHz, DMSO-d 6 ): 8.63 (s, 1H), 8.40 (br d, J = 4.5 Hz, 1H), 7.77 (t, J = 71.5 Hz, 1H), 3.97 (s, 3H), 2.73 (d, J = 4.6 Hz, 3H). Step 6: To a solution of 4-(difluoromethoxy)-6-methoxy-N-methylpyrimidine-5- carboxamide (230 mg, 0.986 mmol) in toluene (5 mL) was added Lawesson’s Reagent (798 mg, 1.97 mmol) in one portion. The mixture was stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to dryness which was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give 4-(difluoromethoxy)-6-methoxy-N-methylpyrimidine-5-carbothio amide (200 mg, 0.649 mmol, 65.81% yield, 80.9% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 10.55 (br d, J = 3.9 Hz, 1H), 8.59 (s, 1H), 7.78 (t, J = 71.5 Hz, 1H), 3.96 (s, 3H), 3.09 (d, J = 4.8 Hz, 3H). Step 7: A mixture of 4-(difluoromethoxy)-6-methoxy-N-methyl-pyrimidine-5- carbothioamide (20 mg, 0.08 mmol, 80.9% purity), 2,6-difluorobenzohydrazide (Intermediate 23) (16.58 mg, 0.096 mmol), benzoyloxysilver (36.8 mg, 0.16 mmol) and AcOH (14.5 mg, 0.241 mmol) in 1,2-dichloroethane (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 12 hours under N 2 atmosphere. The mixture was concentrated to dryness which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). The crude product was further purified by prep. HPLC (Column: Waters xbridge 150*25mm 10μm, Mobile Phase A: water (NH 4 HCO 3 ), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 26% B to 56%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 4-(difluoromethoxy)-5-(5- (2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6-metho xypyrimidine (5.48 mg, 0.015 mmol, 18.49% yield, 100% purity) was obtained as white powder. ESI + : 370.0. 1 H NMR (400 MHz, MeOD-d 4 ): 8.72 (s, 1H), 7.90 - 7.53 (m, 2H), 7.33 - 7.25 (m, 2H), 4.11 (s, 3H), 3.48 (s, 3H). Example 36: 2-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-5-methoxypyridine and mg, was added DIEA (413 mg, 3.20 mmol) and HATU (1.22 g, 3.20 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 2-chloro-5-methoxy-N- methylnicotinamide (210 mg, 1.05 mmol, 98.2% yield) as a white solid. ESI + : 201.0 1 H NMR: (400 MHz, DMSO-d 6 ): 8.61 - 8.41 (m, 1H), 8.17 (d, J = 3.1 Hz, 1H), 7.52 (d, J = 3.1 Hz, 1H), 3.86 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H). Step 2: A mixture of 2-chloro-5-methoxy-N-methylnicotinamide (210 mg, 1.05 mmol), 2,6-difluorobenzohydrazide (Intermediate 23) (120 mg, 0.697 mmol), 2- fluoropyridine (135 mg, 1.39 mmol), trifluoromethanesulfonic anhydride (393 mg, 1.39 mmol) in 1,2-dichloroethane (2 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 140 °C for 2 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 100*40mm*3 μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 2-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)-5-methoxypyridine (3.1 mg, 0.009 mmol, 1.3% yield, 99.6% purity) as a white solid. ESI + : 337.0. 1 H NMR: (400 MHz, DMSO-d 6 ): 8.39 (d, J = 3.1 Hz, 1H), 7.88 (d, J = 3.1 Hz, 1H), 7.83 - 7.73 (m, 1H), 7.41 (t, J = 8.3Hz, 2H), 3.92 (s, 3H), 3.41 (s, 3H). Example 37: 2-chloro-5-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine 3-yl]- 5- mg, (1 mL) was added BBr 3 (335 mg, 1.34 mmol) under N 2 , and then the mixture was stirred at 80 °C for 2 hours under N 2 atmosphere. The reaction mixture was quenched by the addition of saturated NaHCO 3 (10 mL) at 25 °C, and then diluted with H 2 O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)pyridin-3-ol (90 mg, 0.279 mmol, 62.6% yield) as a white solid. ESI + : 323.1 Step 2: To a solution of 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)pyridin-3-ol (60 mg, 0.186 mmol) in acetonitrile (0.03 mL) was added KOH (0.03 mL, 6 M in H 2 O) and difluoromethyl trifluoromethanesulfonate (74.4 mg, 0.372 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 24% B to 54%). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product, compound 2-chloro-5-(difluoromethoxy)-3-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine (2.39 mg, 0.006 mmol, 3.4% yield, 99.1% purity) as a white solid. ESI + : 373.1. 1 H NMR: (400 MHz, DMSO-d 6 ): 8.63 (d, J = 3.0 Hz, 1H), 8.22 (d, J = 3.0 Hz, 1H), 7.84 - 7.71 (m, 1H), 7.64 - 7.24 (m, 3H), 3.44 (s, 3H). Example 38: 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-6-isopropoxypyridine Step propan- 2- mg, i- was and purged with N 2 3 times, and then the mixture was stirred at 100 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure and then adjusted to pH 5-6 with 3M HCl (aq. 1 mL). The residue was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 3-chloro-6-isopropoxypicolinic acid (90 mg, crude) as a white solid which was used in the next step without further purification. ESI + : 216.2 Step 2: To a solution of 3-chloro-6-isopropoxypicolinic acid (90 mg, crude) and methanamine hydrochloride (31 mg, 0.459 mmol) in dichloromethane (1 mL) was added HATU (238 mg, 0.626 mmol) and DIEA (162 mg, 1.25 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 10 mL/min) to give 3-chloro-6-isopropoxy-N- methylpicolinamide (50 mg, 0.219 mmol, 52.4% yield) as a white solid. ESI + : 229.2 1 H NMR: (400 MHz, DMSO-d 6 ): 8.49 - 8.34 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.29 (spt, J = 6.1 Hz, 1H), 2.77 (d, J = 4.8 Hz, 3H), 1.28 (d, J = 6.1 Hz, 6H) Step 3: To a solution of 3-chloro-6-isopropoxy-N-methylpicolinamide (50 mg, 0.219 mmol) in THF (0.5 mL) was added Lawesson’s Reagent (133 mg, 0.328 mmol). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 10 mL/min) to give 3-chloro-6-isopropoxy-N- methylpyridine-2-carbothioamide (50 mg, 0.204 mmol, 93.4% yield) as a white solid. ESI + : 245.0 Step 4: A mixture of 3-chloro-6-isopropoxy-N-methylpyridine-2-carbothioamide (50.0 mg, 0.204 mmol), 2,6-difluorobenzohydrazide (Intermediate 23) (38.7 mg, 0.225 mmol), benzoyloxysilver (93.6 mg, 0.409 mmol), AcOH (36.8 mg, 0.613 mmol) in 1,2- dichloroethane (0.5 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the crude product. Then the crude product was further purified by prep. HPLC (Column: Waters Xbridge C18 150*50mm* 10μm, Mobile Phase A: water (NH 3 H 2 O), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 40% B to 70%). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-chloro-2-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)-6-isopropoxypyridine (11.78 mg, 0.032 mmol, 15.63% yield, 98.9% purity) as a white solid. ESI + : 365.0. 1 H NMR: (400 MHz, DMSO-d 6 ): 8.04 (d, J = 8.9 Hz, 1H), 7.78 (quin, J = 7.5 Hz, 1H), 7.47 - 7.34 (m, 2H), 7.02 (d, J = 8.9 Hz, 1H), 5.30 - 5.09 (m, 1H), 3.55 (s, 3H), 1.30 (br d, J = 6.0 Hz, 6H). Example 39: 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-6-(methylthio)pyridine Example 40: 6-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-3-(methylthio)pyridine 1 was g, . The mixture was stirred at 65 °C for 1 hour. The reaction mixture was quenched by the addition of H 2 O (50 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give 3,6- dichloropicolinohydrazide (1.05 g, 5.10 mmol, 95.5% yield) as a white solid. ESI + : 206.0 Step 2: A mixture of 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (1.27 g, 7.44 mmol), 3,6-dichloropicolinohydrazide (1.02 g, 4.96 mmol), 2-fluoropyridine (963 mg, 9.92 mmol) and trifluoromethanesulfonic anhydride (2.8 g, 9.92 mmol,) in 1,2- dichloroethane (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 140 °C for 2 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 15 mL/min) to give 3,6-dichloro- 2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyr idine (650 mg, 1.91 mmol, 38.4% yield) was obtained as a white solid. ESI + : 341.8 Step 3: To a solution of 3,6-dichloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine (650 mg, 1.91 mmol) in THF (0.5 mL) was added NaSMe (160 mg, 2.29 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by the addition of NaOCl (10 mL, 6% in H 2 O) at 25 °C and the addition of saturated Na 2 SO 3 (20 mL, aq.). The mixture was then diluted with H 2 O (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The product was purified by SFC separation (separation condition: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); Mobile phase: A: Supercritical CO 2 , B: 0.1%NH 3 H 2 O MeOH, A:B =65:35 at 80 mL/min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Wavelength: 220 nm). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The mixture was lyophilized to dryness to give 3-chloro-2-[5-(2,6-difluorophenyl)-4- methyl-1,2,4-triazol-3-yl]-6-methylsulfanyl-pyridine (2.91 mg, 0.008 mmol, 0.4% yield, 100% purity) as a white solid, and 6-chloro-2-[5-(2,6-difluorophenyl)-4-methyl-1,2,4- triazol-3-yl]-3-methylsulfanyl-pyridine (4.82 mg, 0.013 mmol, 0.7% yield, 98.1% purity) as a white solid. Example 39: 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3-yl)-6- (methylthio)pyridine. ESI + : 352.8. 1 H NMR: (400 MHz, DMSO-d 6 ): 8.07 - 8.00 (m, 1H), 7.84 - 7.74 (m, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.46 - 7.37 (m, 2H), 3.55 (s, 3H), 2.55 (s, 3H). Example 40: 6-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3-yl)-3- (methylthio)pyridine. ESI + : 352.8. 1 H NMR: (400 MHz, MeOD-d 6 ): 7.99 (d, J = 8.5 Hz, 1H), 7.75 (tt, J = 6.5, 8.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.29 (t, J = 8.1 Hz, 2H), 3.65 (s, 3H), 2.54 (s, 3H). Example 41: 3-chloro-2-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol - 1-yl)-6-methoxypyridine Step : 1 To a mg, 1.17 mmol), N'- (1-(2,6- - (Intermediate 17) (395 mg, 1.17 mmol), diacetoxycopper (212 mg, 1.17 mmol) was added 2,2-dimethylpropanoic acid (238 mg, 2.33 mmol) in toluene (2 mL) at 25°C. The mixture was stirred at 110 °C for 1 hour under open flask. The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 3 / 1) to afford 3-chloro-2- (4-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)-6-me thoxypyridine (6.92 mg, 0.020 mmol, 1.7% yield) as a black brown solid. ESI + : 337.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.24 (d, J = 8.8 Hz, 1H), 7.68 - 7.57 (m, 1H), 7.36 - 7.21 (m, 3H), 3.90 (s, 3H), 2.22 (s, 3H). Example 42: 3-chloro-6-(difluoromethoxy)-2-(4-(2,6-difluorophenyl)-5- methyl-1H-1,2,3-triazol-1-yl)pyridine To a - 1- yl)-6-methoxypyridine (Example 44) (130 mg, 0.386 mmol) in 1,2-dichloroethane (2 mL) was added BBr 3 (484 mg, 1.93 mmol) in one portion at 0 ºC under N 2 . The mixture was stirred at 80 °C for 1 hour. The mixture was cooled down and water (1 mL) was added to quench the reaction. The pH was adjusted to 7-8 with saturated NaHCO3 (aq., 10 mL), then extracted with ethyl acetate (20 mL x 3). The combined organics were dried over anhydrous Na 2 SO 4 , filtered, and the volatiles removed under reduced pressure. 5-chloro-6-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol -1-yl)pyridin-2- ol (150 mg, crude) was obtained as a black brown solid, which was used into the next step without further purification. Step 2： To a solution of 5-chloro-6-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol - 1-yl)pyridin-2-ol (150 mg, 0.465 mmol) in acetonitrile (1 mL) was added 6M KOH (aq. 0.243 mL) and difluoromethyl trifluoromethanesulfonate (93 mg, 0.465 mmol). The mixture was stirred at 25 °C for 0.5 hour. The aqueous phase was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with brine (10 mL x 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18150*25mm* 10μm; mobile phase A: [water (HCOOH)]; B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 39% B to 69%). The pure fractions were collected, and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-Chloro-6- (difluoromethoxy)-2-(4-(2,6-difluorophenyl)-5-methyl-1H-1,2, 3-triazol-1-yl)pyridine (8.41 mg, 0.0225 mmol, 4.8% yield, 99.6% purity) as an off-white solid. ESI + : 373. 1 H NMR (400 MHz, DMSO-d 6 ) 8.50 (d, J = 8.8 Hz, 1H), 7.90 - 7.51 (m, 3H), 7.33 (br t, J = 8.1 Hz, 2H), 2.24 (s, 3H). Example 43: 3-(2-chloro-5-methoxyphenyl)-5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazole Step To a g, in EtOH (10 mL) was added NH 2 NH 2 •H 2 O (1.47 g, 24.92 mmol, 85% purity in H 2 O). The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 0 / 1) to afford 2-chloro-5-methoxybenzohydrazide (940 mg, 4.69 mmol, 94.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.54 (br s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.01 (dd, J = 3.1, 8.8 Hz, 1H), 6.93 (d, J = 3.0 Hz, 1H), 4.47 (d, J = 4.1 Hz, 2H), 3.77 (s, 3H). Step 2: To a solution of 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (128 mg, 0.748 mmol) in 1,2-dichloroethane (2 mL) was added dropwise 2-fluoropyridine (96.8 mg, 0.997 mmol) and trifluoromethanesulfonic anhydride (281 mg, 0.997 mmol) at 0°C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 2-chloro-5-methoxybenzohydrazide (100 mg, 0.498 mmol) in 1,2- dichloroethane (2 mL) was added and the reaction stirred for 10 min. The resulting mixture was stirred at 140°C for 2 hours under microwave. The mixture was filtered, and the filtrate was concentrated to afford the crude. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 0 / 1) to afford the crude product which was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)]; B: MeOH, Flow rate: 25 mL/min, gradient condition from 35% B to 65%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(2-Chloro-5- methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-tria zole (37.66 mg, 0.112 mmol, 22.50% yield, 100% purity) as a light yellow solid. ESI + : 336. 1 H NMR (400 MHz, MeOD-d 4 ): 7.78 - 7.68 (m, 1H), 7.58 - 7.53 (m, 1H), 7.29 (t, J = 8.2 Hz, 2H), 7.24 - 7.18 (m, 2H), 3.87 (s, 3H), 3.48 (s, 3H). Example 44: 3-(2-chloro-5-(difluoromethoxy)phenyl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole 4H-1,2,4- mg, was up a tube in conc. HCl/H 2 O (v/v=1.5/1) (1 mL). The sealed tube was heated at 140°C for 1 hour under microwave. The mixture was filtered and the filtrate was concentrated to afford the crude. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.30) to afford 4-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)phenol (88 mg, 0.213 mmol, 35.8% yield, 78% purity) as a yellow oil. ESI + : 321.9 Step 2: To a solution of 4-chloro-3-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol-3- yl]phenol (88 mg, 0.213 mmol, 78% purity) in DMF/H 2 O=4/1 (1 mL) was added Cs 2 CO 3 (139 mg, 0.427 mmol) and sodium 2-chloro-2,2-difluoro-acetate (65.1 mg, 0.427 mmol). The mixture was stirred at 120°C for 1 hour. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. Then the product was further purified by prep. HPLC (column: Waters Xbridge C18 150*50mm* 10μm; mobile phase A: [water (NH 3 H 2 O)]; B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 31% B to 61%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(2-Chloro-5-(difluoromethoxy)phenyl)-5-(2,6-difluorophenyl )-4-methyl-4H-1,2,4- triazole (7.98 mg, 0.0213 mmol, 9.99% yield, 99.3% purity) as a light yellow solid. ESI + : 372.0. 1 H NMR (400 MHz, MeOD-d 4 ) 7.79 - 7.68 (m, 2H), 7.53 - 7.43 (m, 2H), 7.29 (t, J = 8.3 Hz, 2H), 6.98 (t, J = 73.2 Hz, 1H), 3.49 (s, 3H). Example 45: 3-chloro-2-(2-(2,6-difluorophenyl)-1-methyl-1H-imidazol-5- yl)-6-methoxypyridine g, 28.04 mmol) and 2,2-dimethoxy-N-methyl-ethanamine (3.34 g, 28.04 mmol). The mixture was stirred at 85 °C for 6 hours. The mixture was concentrated to afford the crude product. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1/1) to afford N-(2,2-dimethoxyethyl)-2,6-difluoro-N-methylbenzimidamide (2.5 g, 9.68 mmol, 44.88% yield) as yellow oil. ESI + : 259.0 1H NMR (400 MHz, DMSO-d 6 ) 7.54 - 7.42 (m, 1H), 7.22 - 7.10 (m, 2H), 7.03 (br s, 1H), 4.88 - 4.09 (m, 1H), 3.68 - 2.58 (m, 11H). Step 2: To N-(2,2-dimethoxyethyl)-2,6-difluoro-N-methylbenzimidamide (2.5 g, 9.68 mmol) was added conc. HCl / MeOH=4/1 (20 mL). The mixture was stirred at 65°C for 6 hours. The mixture was concentrated to afford the crude product. 2-(2,6- Difluorophenyl)-1-methyl-1H-imidazole (2 g, crude) as a light yellow solid, which was used into the next step without further purification. 1H NMR (400 MHz, DMSO-d 6 ) 8.01 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.89 (s, 1H), 7.49 (t, J = 8.4 Hz, 2H), 3.78 (s, 3H). Step : 3 A mixture of 2-(2,6-difluorophenyl)-1-methyl-1H-imidazole (131 mg, crude) , 2- bromo-3-chloro-6-methoxypyridine (Prepared as described for WO2013/78254) (100 mg, 0.450 mmol), XantPhos Pd G3 (42.6 mg, 0.045 mmol) and Cs 2 CO 3 (439 mg, 1.35 mmol) in 2-methylbutan-2-ol (1 mL) and H 2 O (0.01 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 100ºC for 16 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 1) to afford product P13-chloro-2-(2-(2,6-difluorophenyl)-1-methyl-1H-imidazol-5- yl)- 6-methoxypyridine (4.45 mg, 0.0132 mmol, 2.96% yield, 99.7% purity) as a yellow solid. ESI + : 336.0. 1 H NMR (400 MHz, DMSO-d 6 ) 7.96 (d, J = 8.8 Hz, 1H), 7.75 - 7.65 (m, 2H), 7.39 - 7.29 (m, 2H), 6.88 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H), 3.64 (s, 3H). Example 46: 3-chloro-6-(difluoromethoxy)-2-(2-(2,6-difluorophenyl)-1- methyl-1H-imidazol-5-yl)pyridine methoxypyridine (Example 48) (280 mg, 0.834 mmol) was taken up into a microwave tube in conc. HCl (2 mL) and H 2 O (0.2 mL). The sealed tube was heated at 140 °C for 2 hours under microwave. The mixture was concentrated to afford the crude. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 0 / 1) to afford 5-chloro-6-(2-(2,6-difluorophenyl)-1-methyl-1H-imidazol-5-yl )pyridin-2-ol (240 mg, 0.746 mmol, 89.45% yield) as a light yellow solid. ESI + : 322.0 1H NMR (400 MHz, DMSO-d 6 ) 8.29 (s, 1H), 7.99 - 7.85 (m, 2H), 7.50 (t, J = 8.4 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 3.74 (s, 3H). Step 2: To a solution of 5-chloro-6-(2-(2,6-difluorophenyl)-1-methyl-1H-imidazol-5- yl)pyridin-2-ol (100 mg, 0.311 mmol) in DMF/H 2 O=4/1 (0.5 mL) was added Cs 2 CO 3 (203 mg, 0.622 mmol) and sodium 2-chloro-2,2-difluoro-acetate (94.8 mg, 0.622 mmol). The mixture was stirred at 120 °C for 0.5 hour. The aqueous phase was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. Then the product was purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)]; B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product. 3-Chloro-6-(difluoromethoxy)-2-(2-(2,6-difluorophenyl)-1-met hyl-1H- imidazol-5-yl)pyridine (11.84 mg, 0.0306 mmol, 9.83% yield, 95.9% purity) was obtained as a white powder. ESI + : 372.0. 1 H NMR (400 MHz, DMSO-d 6 ) 8.20 (d, J = 8.8 Hz, 1H), 7.92 - 7.50 (m, 3H), 7.39 - 7.30 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 3.60 (s, 3H). Example 47: 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluoro-6-methylphenyl)- 4-methyl-4H-1,2,4-triazol-3-yl)pyridine Step 1: To a solution of 2-fluoro-6-methyl-benzoic acid (1 g, 6.49 mmol), methanamine hydrochloride (876 mg, 12.98 mmol) and triethylamine (1.97 g, 19.46 mmol) in 1,1- dichloroethane (10 mL) was added HATU (3.7 g, 9.73 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 35 mL/min) to give 2-fluoro-N,6-dimethylbenzamide (1.2 g, 6.17 mmol, 95.2% yield, 86% purity) as white solid. ESI + : 168.2 1 H NMR (400 MHz, DMSO-d 6 ): 8.38 (br s, 1H), 7.34 - 7.27 (m, 1H), 7.10 - 7.01 (m, 2H), 2.76 (d, J = 4.6 Hz, 3H), 2.24 (s, 3H). Step 2: To a solution of 2-fluoro-N,6-dimethyl-benzamide (98.2 mg, 0.505 mmol) in 1,2-dichloroethane (0.5 mL) was added dropwise 2-fluoropyridine (49 mg, 0.505 mmol) and trifluoromethanesulfonic anhydride (143 mg, 0.505 mmol) at 0 °C under N2 atmosphere. After addition, the mixture was stirred at 0 °C for 1 hour, and then 5- chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (60 mg, 0.253 mmol) in 1,2-dichloroethane (0.5 mL) was added and stirred for 10 min. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The mixture was concentrated to afford a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.35) to afford crude product. The crude product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)], Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 36% B to 66%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (4 mL) and water (20 mL). The solution was lyophilized to dryness to give the product 5-chloro-2-(difluoromethoxy)-3-(5-(2-fluoro-6-methylphenyl)- 4-methyl- 4H-1,2,4-triazol-3-yl)pyridine (7.32 mg, 0.0196 mmol, 7.8% yield, 98.9% purity) as a white solid. ESI + : 369.0. 1 H NMR (400 MHz, DMSO-d 6 ) 8.62 (d, J = 2.6 Hz, 1H), 8.44 (d, J = 2.6 Hz, 1H), 7.97 - 7.53 (m, 2H), 7.36 - 7.24 (m, 2H), 3.35 (s, 3H), 2.20 (s, 3H). Example 48: 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2- (methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)pyridine Step 1: To a solution of 2-methylsulfonylbenzoic acid (1 g, 4.99 mmol) and methanamine hydrochloride (337 mg, 4.99 mmol) in dichloromethane (10 mL) was added HATU (2.85 g, 7.49 mmol and triethylamine (1.52 g, 14.98 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give the compound N-methyl-2- (methylsulfonyl)benzamide (1 g, 4.69 mmol, 93.88% yield) as a white solid. ESI + : 214.2 1 H NMR (400 MHz, DMSO-d 6 ): 8.51 (br d, J = 4.1 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.72 - 7.66 (m, 1H), 7.53 (d, J = 7.4 Hz, 1H), 3.37 (s, 3H), 2.75 (d, J = 4.6 Hz, 3H). Step 2: To a solution of N-methyl-2-(methylsulfonyl)benzamide (89.8 mg, 0.421 mmol) in 1,2-dichloroethane (0.5 mL) was added dropwise 2-fluoropyridine (40.9 mg, 0.421 mmol) and trifluoromethanesulfonic anhydride (119 mg, 0.421 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-(difluoromethoxy) pyridine-3-carbohydrazide (Intermediate 1) (50 mg, 0.21 mmol) in 1,2-dichloroethane (0.5 mL) was added and stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep. TLC (SiO 2 , Petroleum ether: ethyl acetate = 0:1), then the product was further purified by prep. HPLC (column: Welch Xtimate C18150*25mm*5μm; mobile phase A: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 21% B to 51%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(methylsulfony l)phenyl)- 4H-1,2,4-triazol-3-yl)pyridine (2.85 mg, 0.007 mmol, 3.21% yield, 98.4% purity) as a white solid. ESI + : 415.0. 1 H NMR (400 MHz, MeOD-d 4 ): 8.52 (d, J = 2.6 Hz, 1H), 8.30 (dd, J = 1.6, 7.5 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H), 7.97 (dt, J = 1.5, 6.8 Hz, 2H), 7.88 - 7.51 (m, 2H), 3.42 (s, 3H), 3.26 (s, 3H). Example 49: 3-chloro-6-(difluoromethoxy)-2-(1-(2,6-difluorophenyl)-5- methyl-1H-1,2,3-triazol-4-yl)pyridine Step 1: To a solution of N'-(1-(3-chloro-6-methoxypyridin-2-yl)propylidene)-4- methylbenzenesulfonohydrazide (Intermediate 18) (1 g, 2.72 mmol) in toluene (10 mL) was added 2,6-difluoroaniline (351 mg, 2.72 mmol), Cu(OAc) 2 (494 mg, 2.72 mmol) and 2,2-dimethylpropanoic acid (555 mg, 5.44 mmol). The mixture was stirred at 110 °C for 12 hours under open flask. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @80 mL/min) to give the product 3-chloro-2- (1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-6-me thoxypyridine (55 mg, 0.14 mmol, 5.17% yield, 86% purity) as yellow oil. ESI + : 337.1 Step 2: A mixture of 3-chloro-2-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol -4- yl)-6-methoxypyridine (50 mg, 0.14 mmol, 86% purity) in conc. HCl (0.012 mL) was stirred at 140 °C for 1 hour under microwave. The reaction mixture was concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography by prep. TLC (SiO 2 , dichloromethane : MeOH = 20:1) to give the product 5-chloro-6-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol -4-yl)pyridin-2-ol (20 mg, 0.062 mmol, 41.74% yield) as a yellow solid. ESI + : 323.0 Step 3: To a solution of 5-chloro-6-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol -4- yl)pyridin-2-ol (20 mg, 0.062 mmol) in acetonitrile (0.5 mL) was added 6 M KOH (aq.) (0.031 mL), and difluoromethyl trifluoromethanesulfonate (12.4 mg, 0.062 mmol). The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 46% B to 76%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 3-chloro-6- (difluoromethoxy)-2-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2, 3-triazol-4-yl)pyridine (3.04 mg, 0.008 mmol, 13.09% yield, 99.5% purity) as a white solid. ESI + : 373.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.22 (d, J = 8.8 Hz, 1H), 7.93 - 7.70 (m, 2H), 7.57 (t, J = 8.2 Hz, 2H), 7.23 (d, J = 8.6 Hz, 1H), 2.37 (s, 3H). Example 50: 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2,3,6- trifluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine Step 1: To a solution of 2,3,6-trifluorobenzoic acid (500 mg, 2.84 mmol) in dichloromethane (5 mL) was added methanamine hydrochloride (192 mg, 1.84 mmol) HATU (1.62 g, 4.26 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.10 g, 8.52 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give the product 2,3,6-trifluoro-N-methylbenzamide (470 mg, 2.49 mmol, 87.52% yield) as a white solid. ESI + : 190.0 1H NMR (400 MHz, DMSO-d 6 ): 8.75 (br s, 1H), 7.60 (dd, J = 5.1, 10.1 Hz, 1H), 7.32 - 7.00 (m, 1H), 2.79 (d, J = 4.8 Hz, 3H). Step 2: To a solution of 2,3,6-trifluoro-N-methylbenzamide (470 mg, 2.49 mmol) in THF (26 mL) was added Lawesson’s Reagent (1.51 g, 3.73 mmol) and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~14% Ethyl acetate/Petroleum ether gradient @ 25 mL/min) to give the product 2,3,6-trifluoro-N-methylbenzothioamide (120 mg, 0.585 mmol, 23.53% yield) as a red solid. ESI + : 206.1 1H NMR (400 MHz, DMSO-d 6 ): 10.86 (br s, 1H), 7.54 (dd, J = 5.1, 9.7 Hz, 1H), 7.28 - 7.14 (m, 1H), 3.13 (d, J = 4.6 Hz, 3H). Step 3: A mixture of 2,3,6-trifluoro-N-methylbenzothioamide (80 mg, 0.39 mmol) in dichloromethane (0.5 mL) was added 5-chloro-2-(difluoromethoxy)pyridine-3- carbohydrazide (Intermediate 1) (92.6 mg, 0.39 mmol), benzoyloxysilver (179 mg, 0.78 mmol), acetic acid (70.2 mg, 1.17 mmol) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient @ 20 mL/min). Then the product was further purified by prep. HPLC (column: Waters Xbridge C18 150*50mm* 10μm; mobile phase: [water (NH 3 H 2 O)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 40% B to 60%)). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5- (2,3,6-trifluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine (4.59 mg, 0.0117 mmol, 3.00% yield, 99.5% purity) as a white powder. ESI + : 390.9. 1 H NMR (400 MHz, DMSO-d 6 ): 8.63 (d, J = 2.5 Hz, 1H), 8.45 (d, J = 2.5 Hz, 1H), 7.97 - 7.59 (m, 2H), 7.52 - 7.40 (m, 1H), 3.50 (s, 3H). Example 51: 2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6- methoxynicotinonitrile g, was with N 2 for 3 times, and then the mixture was stirred at 100 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure and then adjusted pH=4~5 with 3M HCl (aq., 30mL). The residue was diluted with H 2 O (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. 3-chloro-6-methoxy-pyridine-2-carboxylic acid (9.4 g, crude) as an off-white solid, which was used in next step without further purification. ESI + : 188.0 1 H NMR (400 MHz, DMSO-d 6 ): 13.76 (br s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 3.86 (s, 3H). Step 2: To a solution of 3-chloro-6-methoxy-pyridine-2-carboxylic acid (2.2 g, crude) in DCM (7 mL) was added methanamine hydrochloride (1.22 g, 11.73 mmol), HATU (6.69 g, 17.59 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.55 g, 35.18 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give the product. 3-Chloro-6- methoxy-N-methyl-pyridine-2-carboxamide (2.1 g, 10.47 mmol, 89.25% yield) was obtained as a white solid. ESI + : 201.0 1 H NMR (400 MHz, DMSO-d 6 ): 8.47 (br d, J = 3.6 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H). Step 3: To a solution of 3-chloro-6-methoxy-N-methylpicolinamide (2 g, 9.97 mmol) in THF (20 mL) was added Lawesson’s Reagent (6.05 g, 14.95 mmol). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give the product. Compound 3- chloro-6-methoxy-N-methylpyridine-2-carbothioamide (2.5 g, 9.92 mmol, 99.53% yield, 86% purity) was obtained as a white solid. ESI+: 217.1 1 H NMR (400 MHz, DMSO-d 6 ): 10.65 (br s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.11 (d, J = 4.8 Hz, 3H). Step 4: To a mixture of 3-chloro-6-methoxy-N-methyl-pyridine-2-carbothioamide (600 mg, 2.77 mmol, 86% purity) in 1,2-dichloroethane (6 mL) was added 2,6- difluorobenzohydrazide (Intermediate 23) (524 mg, 3.05 mmol), benzoyloxysilver (1.27 g, 5.54 mmol), acetic acid (499 mg, 8.31 mmol) and the mixture was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 60 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~50%Ethylacetate/Petroleum ether gradient @ 30 mL/min) to give the product 3- chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3 -yl)-6-methoxypyridine (270 mg, 0.802 mmol, 28.96% yield) as a white solid. Step 5: To a solution of 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-6-methoxypyridine (135 mg, 0.401 mmol) in NMP (1.5 mL) was added CuCN (359 mg, 4.01 mmol). The mixture was stirred at 150 °C for 2 hours. The reaction mixture was quenched by the addition of NH 3 •H 2 O (20mL, 37% purity), and then diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 24% B to 54%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to give the product 2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6- methoxynicotinonitrile (46.59 mg, 0.14 mmol, 34.87% yield, 98.2% purity) as a white powder. ESI + : 328.0 1 H NMR (400 MHz, DMSO-d 6 ): 8.38 (d, J = 8.8 Hz, 1H), 7.87 - 7.76 (m, 1H), 7.44 (s, 2H), 7.19 (d, J = 8.8 Hz, 1H), 4.02 (s, 3H), 3.81 (s, 3H). Example 52: 5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-N-methylpyridin-2-amine Step in was g, 26.04 mmol), HATU (14.85 g, 39.06 mmol) and N-ethyl-N-isopropylpropan-2-amine (10.1 g, 78.13 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 70 mL/min) to give the product 3,6-dichloro-N-methylpicolinamide (3.7 g, 18.05 mmol, 69.29% yield) as a white solid. ESI + : 205.0 1 H NMR (400 MHz, DMSO-d 6 ): 8.62 (br d, J = 3.3 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H). Step 2: To a solution of 3,6-dichloro-N-methylpicolinamide (2.5 g, 12.19 mmol) in THF (26 mL) was added Lawesson’s Reagent (7.40 g, 18.29 mmol). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give dryness which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~16% Ethyl acetate/Petroleum ether gradient @70 mL/min) to give the product 3,6-dichloro-N-methylpyridine-2- carbothioamide (2.1 g, 9.50 mmol, 77.90% yield) as a white solid. ESI + : 221.1 1 H NMR (400 MHz, DMSO-d6): 10.83 (br s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 3.13 (d, J = 4.6 Hz, 3H). Step 3: To a mixture of 3,6-dichloro-N-methylpyridine-2-carbothioamide (1 g, 4.52 mmol) in 1,2-dichloroethane (10 mL) was added 2,6-difluorobenzohydrazide (Intermediate 23) (779 mg, 4.52 mmol), benzoyloxysilver (2.07 g, 9.05 mmol) and acetic acid (815 mg, 13.57 mmol). The mixture was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrousNa 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~38% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give the product 3,6-dichloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine (550 mg, 1.61 mmol, 35.65% yield) as a white solid. ESI + : 341.1 1 H NMR (400 MHz, DMSO-d 6 ): 8.31 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.43 (s, 2H), 3.56 (s, 3H). Step 4: To a solution of 3,6-dichloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine (100 mg, 0.293 mmol) in NMP (0.5 mL) was added K 2 CO 3 (122 mg, 0.879 mmol), methanamine hydrochloride (33.5 mg, 0.322 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (38.7 mg, 0.147 mmol). The mixture was stirred at 120 °C for 2 hours. The reaction mixture concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO 2 , Petroleum ether: ethyl acetate = 1:1). Then the crude product was further purified by prep. HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase A: [water (NH 4 HCO 3 )]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 25% B to 55%)). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 5-chloro-6-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)-N-methylpyridin-2-amine (3.87 mg, 0.011 mmol, 3.76% yield, 95.5% purity) as a white powder. ESI + : 336.1. 1 H NMR (400 MHz, DMSO-d 6 ): 7.84 - 7.72 (m, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.40 (t, J = 8.2 Hz, 2H), 7.09 (br d, J = 5.0 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 3.52 (s, 3H), 2.78 (d, J = 4.8 Hz, 3H). Example 53: 4-chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)phenol Step 1: To , K 2 CO 3 (2.96 g, DMF was MeI g, mmol). The mixture was stirred at 40 °C for 2 hours. The reaction mixture was poured into saturated LiCl (aq., 50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0~8% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give the product methyl 2-chloro-5-methoxybenzoate (1 g, 4.98 mmol, 93.01% yield) was obtained as colourless oil. ESI + : 201.1 1 H NMR (400 MHz, DMSO-d 6 ): 7.46 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H), 7.14 (dd, J = 3.1, 8.9 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H). Step 2: To a solution of methyl 2-chloro-5-methoxybenzoate (4.5 g, 22.43 mmol) in EtOH (10 mL) was added a solution of NH 2 NH 2 •H 2 O (13.21 g, 224.31 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature and quenched by water (50 mL) before being extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried by anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 100mL/min). The product was further purified by prep. HPLC (column: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 0% B to 30%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 2-chloro-5-methoxybenzohydrazide (3.6 g, 17.94 mmol, 80.00% yield) as a white solid. ESI + : 200.9 1 H NMR (400 MHz, DMSO-d 6 ): 9.54 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.01 (dd, J = 3.1, 8.8 Hz, 1H), 6.93 (d, J = 3.1 Hz, 1H), 4.47 (br s, 2H), 3.77 (s, 3H). Step 3: A mixture of 2-chloro-5-methoxybenzohydrazide (1.6 g, 7.98 mmol) in 1,2- dichloroethane (10 mL) was added 2,6-difluoro-N-methyl-benzenecarbothioamide (1.49 g, 7.98 mmol), benzoyloxysilver (3.65 g, 15.95 mmol) and acetic acid (1.44 g, 23.93 mmol) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 12 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® Silica Flash Column, Eluent of 0~65 % Ethyl acetate/Petroleum ether gradient @ 70 mL/min) to give the product 3- (2-chloro-5-methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl-4 H-1,2,4-triazole (450 mg, 0.563 mmol, 7.06% yield, 42% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.82 - 7.73 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.40 (t, J = 8.2 Hz, 2H), 7.28 - 7.19 (m, 2H), 3.83 (s, 3H), 3.36 (s, 3H). Step 3: 3-(2-chloro-5-methoxyphenyl)-5-(2,6-difluorophenyl)-4-methyl -4H-1,2,4- triazole (450 mg, 1.34 mmol, 42% purity) was added conc. HCl (4 mL) and H 2 O (0.8 mL). The mixture was stirred at 140 °C for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The product was further purified by prep. HPLC (column: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [water (HCl)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 20% B to 50%)). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 4- chloro-3-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3 -yl)phenol (15.29 mg, 0.046 mmol, 36.89% yield, 96.5%purity) as a white powder. ESI + : 322.0. 1 H NMR (400 MHz, DMSO-d 6 ): 10.18 (s, 1H), 7.85 - 7.64 (m, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.07 - 6.97 (m, 2H), 3.35 (s, 3H). Example 54: 3-chloro-2-(1-(2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazol - 4-yl)-6-methoxypyridine Step 1: To a 2-yl)propylidene)-4- methylbenzenesulfonohydrazide (Intermediate 18) (300 mg, 0.816 mmol) in toluene (3 mL) was added 2,6-difluoroaniline (105 mg, 0.816 mmol), Cu(OAc) 2 (148 mg, 0.816 mmol) and 2,2-dimethylpropanoic acid (167 mg, 1.63 mmol). The mixture was stirred at 110 °C for 12 hours under air atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @30 mL/min). Then the product was further purified by prep. HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase: [water (NH 4 HCO 3 )]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%)). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 3-chloro-2-(1-(2,6- difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-6-methoxypyr idine (7.12 mg, 0.021 mmol, 2.6% yield, 99.1% purity) as a white solid. ESI + : 337.1. 1 H NMR (400 MHz, MeOD-d 4 ): 7.92 - 7.70 (m, 2H), 7.48 - 7.31 (m, 2H), 6.95 - 6.83 (m, 1H), 4.02 - 3.94 (m, 3H), 2.46 - 2.36 (m, 3H). Example 55: 3-chloro-6-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine methoxypyridine (Example 54) (100 mg, 0.297 mmol) in HCl (aq.) (866 mg, 5.94 mmol, 25% purity in H 2 O) was stirred at 140 °C for 1 hour under microwave. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3) and the combined organic layers were then concentrated under reduced pressure to give the compound 5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)pyridin-2-ol (110 mg, crude) as a white solid, which was used in next step without further purification. ESI + : 323.1 Step 2：To a solution of 5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)pyridin-2-ol (110 mg, 0.341 mmol) and difluoromethyl trifluoromethanesulfonate (136 mg, 0.682 mmol) in acetonitrile (1 mL) was added 6 M KOH (aq.) 1 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to remove the acetonitrile and diluted with water (10 mL), and then extracted with ethyl acetate (10 mL x 3). The organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to give a residue which was purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 33% to 63%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give compound 3-chloro-6-(difluoromethoxy)-2-(5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridine (24.45 mg, 0.065 mmol, 19.05% yield, 99% purity) as a white solid. ESI + : 373.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.32 (d, J = 8.8 Hz, 1H), 7.94 - 7.55 (m, 2H), 7.47 - 7.35 (m, 3H), 3.58 (s, 3H). Example 56: 6-chloro-3-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine was g, in MeOH). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was acidified to pH=5 with acetic acid (5 mL) and the solvent was removed by evaporation. The residue obtained was extracted with dichloromethane (20 mL) and washed sequentially with water (20 mL). The organic solvent was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 18 mL/min). Compound methyl 6-chloro-3-methoxypicolinate (828 mg, 4.11 mmol, 86.51% yield) was obtained as white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.79 - 7.75 (m, 1H), 7.71 - 7.66 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H). Step 2: To a solution of methyl 6-chloro-3-methoxypicolinate (700 mg, 3.47 mmol) in EtOH (10 mL) was added NH 2 NH 2 •H 2 O (3.07 g, 52.08 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled to room temperature and quenched by water (20 mL) at 25 °C, extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrousNa 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 18 mL/min) to give 6-chloro-3- methoxypicolinohydrazide (1.09 g, crude) as white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.51 (br s, 1H), 7.68 - 7.63 (m, 1H), 7.58 - 7.52 (m, 1H), 4.48 (br d, J = 3.6 Hz, 2H), 3.82 (s, 3H). Step 3: To a solution of 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (990 mg, 5.21 mmol) in 1,2-dichloroethane (7 mL) was added 2-fluoropyridine (506 mg, 5.21 mmol) and trifluoromethanesulfonic anhydride (1.47 g, 5.21 mmol) under N 2 atmosphere. After stirring at 0°C for 2 hours, to the mixture was added 6-chloro-3- methoxypicolinohydrazide (700 mg, crude) in 1,2-dichloroethane. The mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was extracted with H 2 O (100 mL) and ethyl acetate (50 mL x 3). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10μm; mobile phase: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 25% B to 55%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product. Compound 6-chloro- 2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-3- methoxypyridine (0.7 eq. formate) (200 mg, 0.542 mmol, 15.61% yield, 100% purity, 0.7 HCOOH) was obtained as a yellow solid. ESI + : 337.0 1 H NMR (400 MHz, DMSO-d 6 ): 8.13 (s, 0.7H), 7.86 (d, J = 9.0 Hz, 1H), 7.83 - 7.77 (m, 1H), 7.41 (dt, J = 2.4, 8.2 Hz, 3H), 3.91 (s, 3H), 3.45 (s, 3H). Step 4: A mixture of 6-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)-3-methoxypyridine (0.7 eq. formate) (100 mg, 0.211 mmol, 0.7 HCOOH) in dichloromethane (1 mL) was degassed and purged with N 2 3 times, and then BBr 3 (264 mg, 1.05 mmol) was dropwise added at 0 °C. The mixture was stirred at 25 °C for 4 hours under N 2 atmosphere. The reaction mixture was quenched by warm water (5 mL) slowly, then extracted with ethyl acetate (5 mL x 3) and then concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 6-chloro-2-(5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-ol (40 mg, 0.124 mmol, 58.79% yield) as white solid. ESI + : 323.1 Step 5: To a solution of 6-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)pyridin-3-ol (40 mg, 0.124 mmol), difluoromethyl trifluoromethanesulfonate (49.6 mg, 0.248 mmol) in acetonitrile (0.5 mL) was added 6 M KOH (aq, 0.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 33% to 63%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 6- chloro-3-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methy l-4H-1,2,4-triazol-3- yl)pyridine (1.06 mg, 0.0028 mmol, 2.22% yield, 96.6% purity) was obtained as yellow solid. ESI + : 372.8. 1 H NMR (400 MHz, MeOD-d 4 ): 7.97 (d, J = 8.8 Hz, 1H), 7.80 - 7.70 (m, 2H), 7.29 (t, J = 8.2 Hz, 2H), 7.03 (t, J = 72.8 Hz, 1H), 3.68 (s, 3H). Example 57: 5-chloro-2-(difluoromethoxy)-3-(5-(2-methoxyphenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine Step a g, , hydrochloride (888 mg, 13.15 mmol) and triethylamine (2.00 g, 19.72 mmol) in dichloromethane (10 mL) was added HATU (3.75 g, 9.86 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give 2-methoxy-N- methylbenzamide (1.08 g, 5.75 mmol, 87.54% yield, 88% purity) as colourless oil. ESI + : 166.2 1 H NMR (400 MHz, DMSO-d 6 ): 8.20 - 8.02 (m, 1H), 7.77 - 7.71 (m, 1H), 7.49 - 7.40 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 3.88 - 3.85 (m, 3H), 2.79 (d, J = 4.8 Hz, 3H). Step 2: To a solution of 2-methoxy-N-methylbenzamide (94.8 mg, 0.505 mmol) in 1,2- dichloroethane (1 mL) was added dropwise 2-fluoropyridine (49 mg, 0.505 mmol) and trifluoromethanesulfonic anhydride (143 mg, 0.505 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (60 mg, 0.253 mmol) in 1,2-dichloroethane (1 mL) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm; Mobile Phase A: water(HCOOH), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 32% to 62%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 5-chloro-2- (difluoromethoxy)-3-(5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-t riazol-3-yl)pyridine (30.38 mg, 0.083 mmol, 32.67% yield, 99.6% purity) as white solid. ESI + : 366.9. 1 H NMR (400 MHz, DMSO-d 6 ): 8.60 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 7.99 - 7.62 (m, 1H), 7.62 -7.58 (m, 1H), 7.48 (dd, J = 1.6, 7.5 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 3.84 (s, 3H), 3.35 (s, 3H). Example 58: 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2- (trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)pyridine Step 1: To a solution of 2-(trifluoromethyl)benzoic acid (1 g, 5.26 mmol), methanamine hydrochloride (710 mg, 10.52 mmol) and triethylamine (1.60 g, 15.78 mmol) in dichloromethane (10 mL) was added HATU (3.00 g, 7.89 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give N-methyl-2- (trifluoromethyl)benzamide (1.15 g, 4.87 mmol, 92.55% yield, 86% purity) as a white solid. ESI + : 204.1 1 H NMR (400 MHz, DMSO-d 6 ): 8.38 (br s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.66 - 7.60 (m, 1H), 7.50 (d, J = 7.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H). Step 2: To a solution of N-methyl-2-(trifluoromethyl)benzamide (199 mg, 0.842 mmol, 86% purity) in 1,2-dichloroethane (1 mL) was added dropwise 2-fluoropyridine (81.7 mg, 0.842 mmol) and trifluoromethanesulfonic anhydride (238 mg, 0.842 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (100 mg, 0.421 mmol) in 1,2-dichloroethane (1 mL) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Column: Phenomenex luna C18150*25mm* 7μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 34% to 64%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 5- chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-(trifluoromethyl )phenyl)-4H-1,2,4- triazol-3-yl)pyridine (34.46 mg, 0.084 mmol, 19.93% yield, 98.5% purity) as white solid. ESI + : 404.9. 1 H NMR (400 MHz, DMSO-d 6 ): 8.62 (d, J = 2.6 Hz, 1H), 8.36 (d, J = - - - 4.96 mmol) in 1,2-dichloroethane (6 mL) was added dropwise 2-fluoropyridine (482 mg, 4.96 mmol) and trifluoromethanesulfonic anhydride (1.40 g, 4.96 mmol) at 0 °C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-methoxyisonicotinohydrazide (Intermediate 19) (500.00 mg, crude) in 1,2-dichloroethane (6 mL) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~10% Dichloromethane/Methanol gradient @ 30 mL/min). Compound 5-chloro-4- (5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyrid in-2-ol (360 mg, 0.558 mmol, 22.49% yield, 50% purity) was obtained as yellow solid. Step 2: The mixture of 5-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)pyridin-2-ol (260 mg, 0.403 mmol, 50% purity) in POCl 3 (1.65 g, 10.73 mmol) was stirred at 110 °C for 1 hour. The reaction mixture was quenched by the addition of warm water (1 mL), and then diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). Compound 2,5- dichloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3-yl)pyridine (60 mg, 0.176 mmol, 43.66% yield) was obtained as off white solid. ESI + : 341.2 1 H NMR (400 MHz, DMSO-d6): 8.81 (s, 1H), 8.06 (s, 1H), 7.83 - 7.74 (m, 1H), 7.42 (t, J = 8.3 Hz, 2H), 3.46 (s, 3H). Step 3: To a solution of 2,5-dichloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)pyridine (60 mg, 0.176 mmol) in MeOH (0.5 mL) was added NaOMe (63.3 mg, 0.352 mmol, 30% purity in MeOH). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give 5-chloro-4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3-yl)-2- methoxypyridine (29.76 mg, 0.085 mmol, 48.34% yield, 96.2% purity) as white solid. ESI + : 337.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.51 (s, 1H), 7.82 - 7.74 (m, 1H), 7.41 (t, J = 8.3 Hz, 2H), 7.28 (s, 1H), 3.94 (s, 3H), 3.42 (s, 3H). Example 60: 5-chloro-2-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine Step 1: 2) (1.02 g, 5.95 was (578 mg, 5.95 mmol) and trifluoromethanesulfonic anhydride (1.68 g, 5.95 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-methoxyisonicotinohydrazide (Intermediate 19) (600 mg, crude) in 1,2-dichloroethane (6 mL) was added and the reaction stirred for 10 min. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 3 mL/min, gradient condition from 10% to 40%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 5-chloro-4-(5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridin-2-ol (60 mg, 0.186 mmol, 6.25% yield) as yellow solid. ESI + : 323.1 Step 2: To a solution of 5-chloro-4-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol-3- yl]pyridin-2-ol (60 mg, 0.186 mmol), difluoromethyl trifluoromethanesulfonate (74.4 mg, 0.372 mmol) in acetonitrile (0.5 mL) was added 6 M KOH (aq., 0.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to remove the acetonitrile and diluted with water (5 mL), and then extracted with ethyl acetate (5 mL x 3). The organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to dryness which was purified by prep. TLC (Petroleum ether: ethyl acetate =1:1) to give 5-chloro-2-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-met hyl- 4H-1,2,4-triazol-3-yl)pyridine (2.07 mg, 0.0055 mmol, 2.95% yield, 98.6% purity) as a white solid. ESI + : 373.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.65 (s, 1H), 7.95 - 7.57 (m, 3H), 7.42 (br t, J = 8.3 Hz, 2H), 3.46 (s, 3H). Example 61: 6-(difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)-3-fluoropyridine
Step g, 7.39 was g, in H 2 O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled down to room temperature and quenched by water (15 mL) at 25 °C before being extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to dryness which was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give 6-chloro-3-fluoropicolinohydrazide (650 mg, 3.43 mmol, 46.43% yield) as white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.84 (br s, 1H), 7.96 (t, J = 9.0 Hz, 1H), 7.74 (dd, J = 3.3, 8.8 Hz, 1H), 4.60 (d, J = 4.3 Hz, 2H). Step 2: To a solution of 2,6-difluoro-N-methyl-benzamide (Intermediate 2) (1.17 g, 6.86 mmol) in 1,2-dichloroethane (7 mL) was added dropwise 2-fluoropyridine (666 mg, 6.86 mmol) and trifluoromethanesulfonic anhydride (1.93 g, 6.86 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 6-chloro-3-fluoropyridine- 2-carbohydrazide (650 mg, 3.43 mmol) in 1,2-dichloroethane (7 mL) was added and the reaction stirred for 10 min. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). Compound 6-chloro-2-(5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-3-fluoropyri dine (840 mg, 2.59 mmol, 75.45% yield) was obtained as a light yellow solid. ESI + : 325.2 1 H NMR (400 MHz, DMSO-d 6 ): 8.15 (t, J = 9.0 Hz, 1H), 7.86 - 7.75 (m, 2H), 7.43 (t, J = 8.2 Hz, 2H), 3.67 (s, 3H). Step 3: A mixture of 6-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3- yl)-3-fluoropyridine (400 mg, 1.23 mmol), Pd 2 (dba) 3 (113 mg, 0.123 mmol), di-tert- butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (52.3 mg, 0.123 mmol) and KOH (138 mg, 2.46 mmol) in dioxane/H 2 O=5:1 (10 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 100 °C for 1 hour under N 2 atmosphere. The reaction mixture was concentrated and diluted with water (5 mL), and then extracted with ethyl acetate (5 mL x 3). The organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give 6-(5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-fluoropyri din-2-ol (176 mg, 0.575 mmol, 46.65% yield) as a yellow solid. ESI + : 307.2 Step 4: To a solution of 6-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5- fluoropyridin-2-ol (100 mg, 0.327 mmol), difluoromethyl trifluoromethanesulfonate (131 mg, 0.653 mmol) in acetonitrile (1 mL) was added 6 M KOH (aq., 1 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and diluted with water (5 mL), and then extracted with ethyl acetate (5 mL x 3). The organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to dryness which was then purified by prep. HPLC (Phenomenex luna C18 150*25mm* 10μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 30% to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 6- (difluoromethoxy)-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2, 4-triazol-3-yl)-3- fluoropyridine (13.77 mg, 0.039 mmol, 11.84% yield, 100% purity) as white solid. ESI + : 357.2. 1 H NMR (400 MHz, DMSO-d6): 8.18 (t, J = 9.1 Hz, 1H), 7.93 - 7.55 (m, 2H), 7.46 - 7.37 (m, 3H), 3.69 (s, 3H). Example 62: 2-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)aniline dichloroethane (2 mL) was added dropwise 2-fluoropyridine (163 mg, 1.68 mmol,) and trifluoromethanesulfonic anhydride (475 mg, 1.68 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5- chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (200 mg, 0.842 mmol) in 1,2-dichloroethane (2 mL) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Welch Xtimate C18150*25mm*5μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 3-(5-(2-bromophenyl)-4-methyl-4H-1,2,4- triazol-3-yl)-5-chloro-2-(difluoromethoxy)pyridine (120 mg, 0.289 mmol, 34.30% yield) as light yellow solid. Step 2: A mixture of 3-(5-(2-bromophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-chlor o-2- (difluoromethoxy)pyridine (120 mg, 0.289 mmol), acetamide (20.5 mg, 0.346 mmol), CuI (11 mg, 0.058 mmol), K 3 PO 4 (184 mg, 0.866 mmol), N,N'-dimethylethane-1,2- diamine (10.2 mg, 0.115 mmol) in dioxane (1.5 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 100 °C for 8 hours under N 2 atmosphere. The reaction mixture was diluted with water (5 mL), and then extracted with ethyl acetate (5 mL x 3). The organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to dryness which was then purified by prep-TLC (SiO 2 , Petroleum ether: ethyl acetate =0:1) to give N-(2-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl- 4H- 1,2,4-triazol-3-yl)phenyl)acetamide (35 mg, 0.089 mmol, 30.78% yield) as light yellow solid. Step 3: To N-[2-[5-[5-chloro-2-(difluoromethoxy)-3-pyridyl]-4-methyl-1, 2,4-triazol-3- yl]phenyl]acetamide (35 mg, 0.089 mmol) was added HCl (aq.) (178 mg, 0.979 mmol, 20% purity in H 2 O). The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Waters xbridge 150*25mm 10μm; Mobile Phase A: water (NH 4 HCO 3 ), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 2-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H- 1,2,4-triazol-3- yl)aniline (10.36 mg, 0.029 mmol, 33.10% yield, 99.9% purity) as white solid. ESI + : 352.1. 1 H NMR (400 MHz, DMSO-d6): 8.60 (d, J = 2.5 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.78 (t, J = 71.7 Hz, 1H), 7.28 (dd, J = 1.2, 7.7 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 5.71 (s, 2H), 3.47 (s, 3H). Example 63: 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2,4,6- trifluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine , hydrochloride (230.05 mg, 3.41 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.10 g, 8.52 mmol) in dichloromethane (5 mL) was added HATU (1.08 g, 2.84 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to dryness which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give 2,4,6-trifluoro-N-methylbenzamide (410 mg, 1.68 mmol, 59.17% yield, 77.5% purity) as white solid. 1H NMR (400 MHz, DMSO-d 6 ): 8.63 (br d, J = 3.4 Hz, 1H), 7.28 (dd, J = 7.9, 9.3 Hz, 2H), 2.76 (d, J = 4.6 Hz, 3H). Step 2: To a solution of 2,4,6-trifluoro-N-methyl-benzamide (410 mg, 2.17 mmol, 77.5% purity) in THF (5 mL) was added Lawesson’s Reagent (1.32 g, 3.25 mmol) in one portion. The mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~17% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give 2,4,6-trifluoro-N- methylbenzothioamide (240 mg, 1.16 mmol, 53.68% yield, 99.5% purity) as a white solid. ESI + : 206.0 1 H NMR (400 MHz, DMSO-d 6 ): 10.76 (br s, 1H), 7.32 - 7.23 (m, 2H), 3.11 (d, J = 4.8 Hz, 3H). Step 3: A mixture of 2,4,6-trifluoro-N-methylbenzothioamide (120 mg, 0.549 mmol), 5- chloro-2-(difluoromethoxy)pyridine-3-carbohydrazide (Intermediate 1) (167 mg, 0.702 mmol), benzoyloxysilver (268 mg, 1.17mmol) and AcOH (105 mg, 1.75 mmol) in dichloromethane (3 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 25 °C for 12 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to dryness which was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~34% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). The crude product was further purified by prep. HPLC (Column: Welch Xtimate C18 250*50mm*10μm, Mobile Phase A: water (NH 3 H 2 O), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 35% B to 65%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 5- chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2,4,6-trifluorophe nyl)-4H-1,2,4-triazol-3- yl)pyridine (17.89 mg, 0.046 mmol, 7.82% yield, 99.9% purity) as white powder. ESI + : 391.0. 1 H NMR (400 MHz, MeOD-d 4 ): 8.50 (d, J = 2.5 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 7.87 - 7.50 (m, 1H), 7.23 (dd, J = 8.0, 8.8 Hz, 2H), 3.56 (s, 3H). Example 64: 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-6-(methoxy-d 3 )pyridine a g, mmol, 1 eq) in CHCl 3 (20 mL) was added Ag 2 CO 3 (2.132 g, 21.324 mmol, 2 eq.) followed by CD 3 I (3.091 g, 21.324 mmol, 2 eq.) and the reaction mixture was stirred at RT for 16 h. After completion of the reaction, the suspension was poured into a mixture of DCM and H 2 O. The organic layer was separated, washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl 3- chloro-6-(methoxy-d3)picolinate as a yellow gummy compound (1.5 g, 70%). 1 HNMR (400 MHz, DMSO-d 6 ): δ 7.95 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H). ESI + : 204.98. Step 2: To a well stirred solution of methyl 3-chloro-6-(methoxy-d3)picolinate (2 g, 9.774 mmol, 1 eq.) in a mixture of H 2 O (20 mL) and THF (20 mL) was added lithium hydroxide monohydrate (820 mg, 19.548 mmol, 2 eq.) and the reaction mixture was stirred at RT for 1h. After completion, the reaction mixture was acidified with 1N hydrochloric acid up to pH = 4 and extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-chloro-6-(methoxy-d3)picolinic acid as a white solid. (1.8 g, 80 %). 1 HNMR (400 MHz, DMSO-d 6 ): δ 10.63 (bs, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H). ESI + : 191.16. Step 3: To a well stirred solution of 3-chloro-6-(methoxy-d3)picolinic acid (1 g, 5.247 mmol, 1 eq.) in THF (10 mL) at 0 °C, was added ethylchloroformate (0.99 mL, 10.493 mmol, 2 eq.) and the reaction stirred for 30 min at the same temperature. After 30 min, 2M methylamine solution in THF (2 mL) was added and the reaction mixture was stirred at RT for 16 h. After completion of reaction, suspension was diluted with water and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain crude product, which was purified by flash column chromatography (DAVISIL® silica), eluted with 50-60 % ethyl acetate in pet ether. Collected fraction was concentrated under reduced pressure to afford 3-chloro-6-(methoxy-d3)-N-methylpicolinamide as an off-white solid (900 mg, 82 %). 1 HNMR (400 MHz, DMSO-d 6 ): δ 8.47 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.77 (d, J = 4.8 Hz, 3H). ESI + : 204.18. Step 4: To the well stirred solution of 3-chloro-6-(methoxy-d3)-N-methylpicolinamide (500 mg, 2.455 mmol, 1 eq.) in THF (5 mL) was added Lawesson’s Reagent (993 mg, 2.455 mmol, 1 eq.) and the reaction mixture stirred for 16h at RT. The reaction mixture was poured into saturated aq. NaHCO 3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to get crude product, which was purified by flash column chromatography (DAVISIL® silica), eluted with 30 % ethyl acetate in pet ether. Collected fraction was concentrated under reduced pressure to afford 3-chloro-6- (methoxy-d3)-N-methylpyridine-2-carbothioamide as off-white solid (200 mg, 38 %). 1 HNMR (400 MHz, DMSO-d 6 ): δ 8.10 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 3.36 (d, J = 4.8 Hz, 3H). ESI+: 220.17. Step 5: To a well stirred solution of 3-chloro-6-(methoxy-d3)-N-methylpyridine-2- carbothioamide (76 mg, 0.346 mmol, 1 eq.) and 2,6-difluorobenzohydrazide (Intermediate 23) (59.546 mg, 0.346 mmol, 1 eq.) in DCE (0.25 ml) at RT, was added silver benzoate (158.420 mg, 0.692 mmol, 2 eq.) followed by acetic acid (0.021 mL, 0.346 mmol, 1 eq.) and the reaction mixture was stirred at RT for 12h. After completion of reaction, volatiles were evaporated under reduced pressure to obtain crude product, which was purified by flash column chromatography (DAVISIL® silica), eluted with 30 % ethyl acetate in pet ether. The collected fraction was concentrated under reduced pressure to afford 3-chloro-2-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol -3-yl)- 6-(methoxy-d3)pyridine (40 mg) as a pale yellow gum. ESI + : 340.21. 1 HNMR (400 MHz, DMSO-d 6 ): δ 8.07 (d, J = 8.8 Hz, 1H), 7.83-7.75 (m, 1H), 7.44-7.39 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H), 3.58 (s, 3H). Example 65: 3,5-bis(4-chloro-2-(difluoromethoxy)phenyl)-4-methyl-4H- 1,2,4-triazole Step 1: To a well stirred solution of methyl 4-chloro-2-(difluoromethoxy)benzoate (0.1 g, 0.421 mmol, 1.0 eq) in MeOH:THF:water (1:1:1, 1.5 mL) was added lithium hydroxide monohydrate (0.053 g, 1.263 mmol, 3.0 eq) and the reaction mixture was stirred at rt for 1h. After completion, the reaction mixture was acidified with 1N hydrochloric acid up to pH = 4 and extracted with DCM (20 mL). Organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4- chloro-2-(difluoromethoxy)benzoic acid (0.099 g, 95%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 ): δ 13.31 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (t, J = 74.0 Hz, 1H). ESI-: 220.87. Step 2: To a well stirred solution of 4-chloro-2-(difluoromethoxy)benzoic acid (0.200 g, 1.013mmol, 1.0 eq) in N,N-dimethylformamide (2 mL) at rt, was added DIPEA (0.4 ml, 4.054 mmol, 4.0 eq), followed by HATU (0.770 g, 2.026 mmol, 2.0 eq) and the reaction mixture stirred for 10 min. To the reaction mixture, methylamine hydrochloride (0.101 g, 1.520 mmol, 1.5 eq) was added and the reaction mixture was stirred at rt for 2h. After completion of reaction, suspension was diluted with water and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate (3×50 ml) and the combined organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain crude product, which was purified by flash column chromatography (DAVISIL® silica), eluted with 50-60 % Ethyl acetate in petroleum ether. Collected fraction was concentrated under reduced pressure to afford 4-chloro-2- (difluoromethoxy)-N-methylbenzamide (0.170 g, 90%) as an off-white solid. 1 HNMR (400 MHz, DMSO-d 6 ): δ 8.24 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.43-7.36 (m, 2H), 7.24 (t, J = 73.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H). ESI + : 236.17. Step 3: To a well stirred solution of methyl 4-chloro-2-(difluoromethoxy)benzoate (0.2 g, 0.842 mmol, 1.0 eq) in ethanol (2.0 mL) was added hydrazine monohydrate (0.195 ml, 4.209 mmol, 5.0 eq) and the reaction mixture stirred at 80 °C for 1h. After completion of reaction, the suspension was concentrated under reduced pressure to obtain crude product which was purified by flash column chromatography (DAVISIL® silica), eluted with 5 % methanol in DCM solution. Collected fraction was concentrated under reduced pressure to afford 4-chloro-2-(difluoromethoxy)benzohydrazide (0.19 g) as an off-white solid. 1 HNMR (400 MHz, DMSO-d 6 ): δ 9.48 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44-7.36 (m, 2H), 7.25 (t, J = 73 Hz, 1H), 4.51 (s, 2H). ESI + : 236.94. Step 4: To a well stirred solution of 4-chloro-2-(difluoromethoxy)benzohydrazide (0.15 g, 0.635 mmol, 1.0 eq) and 4-chloro-2-(difluoromethoxy)-N-methylbenzamide (0.164 g, 0.699 mmol, 1.1 eq) in DCE (1.5 mL) was added 2-fluropyridine (0.15 mL, 1.271 mmol, 2.0eq) at rt and the reaction mixture stirred for 10 min, before the addition of triflic anhydride (0.15 ml, 0.953 mmol, 1.1 eq) at 0 °C. The reaction mixture was allowed to stir at 140 °C for 3h. After completion of reaction, suspension was concentrated under reduced pressure to obtain crude product, which was purified by flash column chromatography (DAVISIL® silica), eluted with 5 % Methanol in DCM solution. Collected fraction was concentrated under reduced pressure and the product was repurified by preparative achiral SFC to afford 3,5-bis(4-chloro-2- (difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazole (0.024 g, 27%) as an off-white solid. 1 HNMR (400 MHz, DMSO-d 6 ): δ 7.67 (d, J = 8.0 Hz, 2H), 7.59-7.53 (m, 4H), 7.40 (t, J = 72.8 Hz, 2H), 3.33 (s, 3H). ESI + : 436.23. Example 66: 5-chloro-2-(difluoromethoxy)-3-(5-(3,5-difluoropyridin-4-yl) - 4-methyl-4H-1,2,4-triazol-3-yl)pyridine
Step 1: mmol) and methanamine hydrochloride (255 mg, 3.77 mmol) in dichloromethane (5 mL) was added HATU (1.79 g, 4.71 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.22 g, 9.43 mmol). The mixture was stirred at 25 °C for 1 hour. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate/Petroleum ether gradient @ 25 mL/min) to give the compound 3,5-difluoro-N-methylisonicotinamide (250 mg, 1.45 mmol, 46.21% yield) as a white solid. ESI + : 173.2. 1 H NMR (400 MHz, DMSO-d 6 ): 8.87 (br s, 1H), 8.63 (s, 2H), 2.80 (d, J = 4.6 Hz, 3H). Step 2: To a mixture of 3-bromo-5-chloro-pyridin-2-ol (15 g, 71.96 mmol) in acetonitrile (300 mL) was added NaH (7.20 g, 179.91 mmol, 60% purity) in portions at 0 °C under N 2 , then 2,2-difluoro-2-fluorosulfonyl-acetic acid (19.22 g, 107.94 mmol) was dropwise added into the mixture at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was poured into saturated NH 4 Cl (aq. 500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were concentrated to afford the crude. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 3 / 1) to afford 3-bromo-5-chloro-2-(difluoromethoxy)pyridine (12 g, 46.43 mmol, 64.52% yield) as light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ): 8.47 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 7.66 (t, J = 71.7 Hz, 1H). Step 3: To a solution of 3-bromo-5-chloro-2-(difluoromethoxy)pyridine (3 g, 11.61 mmol), DPPP (3.35 g, 8.13 mmol) in triethylamine/MeOH=1/10 (15 mL) was added Pd(OAc) 2 (1.30 g, 5.80 mmol) under Ar. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 12 hours. The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 5 / 1) to afford methyl 5-chloro-2- (difluoromethoxy)nicotinate (1.2 g, 5.05 mmol, 43.51% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.57 (d, J = 2.5 Hz, 1H), 8.45 - 8.34 (m, 1H), 7.73 (br t, J = 71.8 Hz, 1H), 3.87 (s, 3H). Step 4: To a solution of methyl 5-chloro-2-(difluoromethoxy)nicotinate (500 mg, 2.10 mmol) in EtOH (3 mL) was added NH 2 NH 2 •H 2 O (124 mg, 2.1 mmol, 85% purity in H 2 O). The mixture was stirred at 90 °C for 1 hour. The reaction mixture was quenched by the addition of H 2 O (20 mL) at 25 °C, and then diluted with H 2 O (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give the product. Compound 5-chloro-2-(difluoromethoxy)nicotinohydrazide (250 mg, 1.05 mmol, 50.00% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.73 - 9.41 (m, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.87 - 7.48 (m, 1H), 4.79 - 4.33 (m, 2H). Step 5: A mixture of 3,5-difluoro-N-methyl-pyridine-4-carboxamide (86.9 mg, 0.505 mmol), 5-chloro-2-(difluoromethoxy)nicotinohydrazide (60 mg, 0.253 mmol), 2- fluoropyridine (49 mg, 0.505 mmol), trifluoromethanesulfonic anhydride (143 mg, 0.505 mmol) in 1,2-dichloroethane (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 140 °C for 2 hours under microwave. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 100*40mm*3 μm, Mobile Phase A: water (0.225%HCOOH)), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(3,5-difluoropyridin- 4-yl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridine (18.72 mg, 0.049 mmol, 19.22% yield, 96.9% purity) as a white solid. ESI + : 374.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.86 (s, 2H), 8.64 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.78 (t, J = 71.6 Hz, 1H), 3.54 (s, 3H). Example 67: 5-chloro-3-(5-(2-chloropyridin-3-yl)-4-methyl-4H-1,2,4- triazol-3-yl)-2-(difluoromethoxy)pyridine F F O O N To a solution 0.293 mmol) in 1,2-dichloroethane (1 mL) was added 2-fluoropyridine (31.3 mg, 0.322 mmol) and trifluoromethanesulfonic anhydride (91 mg, 0.322 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes under N 2 , then 5-chloro-2- (difluoromethoxy)nicotinohydrazide (Intermediate 1) (76.6 mg, 0.322 mmol) was dropwise added into the mixture at 25 °C. The mixture was stirred at 120 °C for 2 hours under microwave. The mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL x 3) and the combined organic layers were concentrated to afford the crude. Then the product was further purified by prep. HPLC (Column: Welch Xtimate C18 150*30mm*5μm, mobile phase A: water (HCOOH); Mobile Phase B: 60mL/min, gradient condition from 12%B to 52%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-3-(5-(2-chloropyridin-3-yl)-4-methyl-4H-1,2,4-triaz ol-3-yl)-2- (difluoromethoxy)pyridine (16.42 mg, 0.044 mmol, 14.96% yield, 99.4% purity) as a yellow solid. ESI + : 372.2. 1 H NMR (400 MHz, DMSO-d 6 ): 8.79 - 8.57 (m, 2H), 8.39 (d, J = 2.5 Hz, 1H), 8.17 (dd, J = 1.9, 7.6 Hz, 1H), 7.98 - 7.59 (m, 2H), 3.46 (s, 3H). Example 68: 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2- (trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin e mmol) in dichloromethane (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.03 g, 15.70 mmol), methanamine hydrochloride (530 mg, 7.85 mmol) and HATU (3.98 g, 10.47 mmol). The mixture was stirred at 25 °C for 1 hour. The residue was diluted with H 2 O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude was purified by flash silica gel chromatography (ISCO®;12g SepaFlash® Silica Flash Column, Eluent of 0~50%, dichloromethane: MeOH @ 50 mL/min) to afford the product N-methyl-2-(trifluoromethyl)nicotinamide (912 mg, 4.47 mmol, 85.37% yield) as a yellow solid. ESI + : 205.0. 1 H NMR (400 MHz, DMSO- d6): 8.82 - 8.70 (m, 1H), 8.63 - 8.47 (m, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.77 (dd, J = 4.8, 7.9 Hz, 1H), 2.77 (d, J = 4.6 Hz, 3H). Step 2: To a solution of N-methyl-2-(trifluoromethyl)nicotinamide (50 mg, 0.245 mmol) in 1,2-dichloroethane (1 mL) was added 2-fluoropyridine (26.2 mg, 0.269 mmol) and trifluoromethanesulfonic anhydride (76 mg, 0.269 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes under N 2 , then 5-chloro-2- (difluoromethoxy)nicotinohydrazide (Intermediate 1) (64 mg, 0.269 mmol) was dropwise added into the mixture at 25 °C. The mixture was stirred at 120 °C for 2 hours under microwave. The mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL x 3), the combined organic layers were concentrated to afford the crude. Then the product was further purified by prep. HPLC (column: Xtimate C18 150*40mm*10μm, Mobile phase A: [water (NH 3 H 2 O+NH 4 HCO 3 )]; Mobile Phase B: acetonitrile, 60mL/min, gradient condition from 18% B to 58%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2- (trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin e (4.18 mg, 0.0098 mmol, 4.00% yield, 95.2% purity) as a brown solid. ESI + : 406.0. 1 H NMR (400 MHz, DMSO- d 6 ): 9.01 (d, J = 4.6 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.36 (d, J = 2.6 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.02 - 7.57 (m, 2H), 3.37 (s, 3H). Example 69: 5-chloro-3-(5-(3-chloropyridin-2-yl)-4-methyl-4H-1,2,4- triazol-3-yl)-2-(difluoromethoxy)pyridine Step 1: To in MeOH (10 mL) was dropwise added SOCl 2 (1.13 g, 9.52 mmol) at 0 °C. The mixture was stirred at 65 °C for 2 hours. The mixture was cooled down to RT and concentrated to afford the crude. Methyl 3-chloropyridine-2-carboxylate (1.28 g, crude) was obtained as white solid, which was used in next step without further purification. ESI + : 172.1. 1 H NMR (400 MHz, DMSO-d6): 8.61 (dd, J = 1.0, 4.6 Hz, 1H), 8.13 (dd, J = 1.0, 8.3 Hz, 1H), 7.64 (dd, J = 4.6, 8.3 Hz, 1H), 3.92 (s, 3H). Step 2: To a solution of methyl 3-chloropyridine-2-carboxylate (1.28 g, 7.46 mmol) in EtOH (15 mL) was added NH 2 NH 2 •H 2 O (3.08 g, 52.22 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled to RT and quenched by water (15 mL) at 25 °C and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 45 mL/min) to give the product. Compound 3-chloropicolinohydrazide (830 mg, 4.84 mmol, 64.84% yield) was obtained as off- white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.71 (br s, 1H), 8.55 - 8.50 (m, 1H), 8.01 (dd, J = 0.9, 8.1 Hz, 1H), 7.52 (dd, J = 4.7, 8.2 Hz, 1H), 4.56 (br s, 2H). Step 3: To a solution of 5-chloro-2-(difluoromethoxy)-N-methylnicotinamide (Intermediate 20) (165 mg, 0.699 mmol) in 1,2-dichloroethane (2 mL) was added dropwise 2-fluoropyridine (67.9 mg, 0.699 mmol) and trifluoromethanesulfonic anhydride (197 mg, 0.699 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at 0 °C for 1 hour, and then 3-chloropicolinohydrazide (60 mg, 0.35 mmol) in 1,2-dichloroethane (1 mL) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with H 2 O (20 mL x 3), then extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4gSepaFlash®Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient @ 20mL/min) to give a product. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 29% B to 59%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (10 mL) and water (20 mL). The solution was lyophilized to dryness to give 5-chloro-3-(5-(3-chloropyridin-2-yl)-4-methyl-4H-1,2,4-triaz ol-3-yl)-2- (difluoromethoxy)pyridine (26.87 mg, 0.071 mmol, 10.11% yield, 98% purity). ESI + : 372.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.77 (br d, J = 4.3 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.24 (br d, J = 8.3 Hz, 1H), 7.98 - 7.58 (m, 2H), 3.54 (s, 3H). Example 70: 5-chloro-3-(5-(3-chloropyridin-4-yl)-4-methyl-4H-1,2,4- triazol-3-yl)-2-(difluoromethoxy)pyridine Step 1: mmol) and methanamine hydrochloride (257 mg, 3.81 mmol) in dichloromethane (5 mL) was added HATU (1.81 g, 4.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.23 g, 9.52 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). Compound 3- chloro-N-methylisonicotinamide (400 mg, 2.34 mmol, 73.88% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 8.70 (s, 1H), 8.58 (br d, J = 4.8 Hz, 2H), 7.46 (d, J Hz, 1H), 2.78 (d, J = 4.6 Hz, 3H). Step 2: A mixture of 3-chloro-N-methylisonicotinamide (86.2mg, 0.505 mmol), 5- chloro-2-(difluoromethoxy)nicotinohydrazide (Intermediate 1) (60 mg, 0.253 mmol), 2-fluoropyridine (49 mg, 0.505 mmol), trifluoromethanesulfonic anhydride (143 mg, 0.505 mmol) in 1,2-dichloroethane (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 100*40mm*3 μm, Mobile Phase A: water(0.225% HCOOH)), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-3-(5-(3-chloropyridin-4-yl)-4-methyl-4H-1,2,4- triazol-3-yl)-2-(difluoromethoxy)pyridine (4.72 mg, 0.012 mmol, 4.88% yield, 99.6% purity) as a white solid. ESI + : 372.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.94 (s, 1H), 8.78 (d, J = 4.8 Hz, 1H), 8.63 (d, J = 2.6 Hz, 1H), 8.47 (br s, 0.2H), 8.39 (d, J = 2.6 Hz, 1H), 7.98 - 7.58 (m, 2H), 3.46 (s, 3H). Example 71: 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-dihydrobenzofuran-7- yl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridine Step 1: mmol) in dichloromethane (10 mL) was added methanamine hydrochloride (494 mg, 7.31 mmol), HATU (3.47 g, 9.14 mmol) and triethylamine (1.85 g, 18.28 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~55% Ethyl acetate/Petroleum ether gradient @80 mL/min) to afford N-methyl-2,3- dihydrobenzofuran-7-carboxamide (1.4 g, crude) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.75 (br s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.1 Hz, 1H), 6.96 - 6.89 (m, 1H), 4.73 - 4.64 (m, 2H), 3.23 (t, J = 8.7 Hz, 2H), 2.81 (dd, J = 0.8, 4.7 Hz, 3H). ESI + : 178.3 Step 2: To a solution of N-methyl-2,3-dihydrobenzofuran-7-carboxamide (74.6 mg, 0.421 mmol) in 1,2-dichloroethane (1 mL) was added dropwise 2-fluoropyridine (40.9 mg, 0.421 mmol) and trifluoromethanesulfonic anhydride (119 mg, 0.421 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at 0 °C for 1 hour, and then 5-chloro-2-(difluoromethoxy)nicotinohydrazide (Intermediate 1) (50 mg, 0.21 mmol) in 1,2-dichloroethane (1 mL) was added and stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with H 2 O (10 mL x 3) and then extracted with ethyl acetate (10 mL). The organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~65% Ethyl acetate/Petroleum ether gradient @ 18mL/min) to give a product. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; Mobile phase A: [water(HCOOH))]; Mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 33% B to 63%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-dihydrobenzofuran-7-y l)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine (2.97 mg, 0.0076 mmol, 3.63% yield, 97.4% purity) as a white solid. ESI + : 379.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.60 (d, J = 2.5 Hz, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.98 - 7.59 (m, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 4.65 (t, J = 8.7 Hz, 2H), 3.45 (s, 3H), 3.31 - 3.27 (m, 2H). Example 72: 5-chloro-3-(5-(4-chloropyridin-3-yl)-4-methyl-4H-1,2,4- triazol-3-yl)-2-(difluoromethoxy)pyridine
Step mmol) in EtOH (5 mL) was added NH2NH2•H2O (1.76 g, 29.91 mmol, 85% purity in H2O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled to RT and quenched by water (15 mL) at 25 °C and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~6% dichloromethane/ MeOH @ 40 mL/min) to give the product 4- methoxynicotinohydrazide (410 mg, 2.45 mmol, 82.00% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.31 (br s, 1H), 8.58 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 7.15 (d, J = 5.9 Hz, 1H), 4.54 (d, J = 4.1 Hz, 2H), 3.90 (s, 3H). Step 2: To a solution of 5-chloro-2-(difluoromethoxy)-N-methylnicotinamide (Intermediate 20) (170 mg, 0.718 mmol) in 1,2-dichloroethane (1 mL) was added dropwise trifluoromethanesulfonic anhydride (203 mg, 0.718 mmol) and 2- fluoropyridine (69.7 mg, 0.718 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 4- methoxynicotinohydrazide (60 mg, 0.359 mmol) in 1,2-dichloroethane (1 mL) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30mL/min). Then the residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~6% dichloromethane/ MeOH@ 30 mL/min) to give the product 3-(5-(5-chloro-2- (difluoromethoxy)pyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-y l)pyridin-4-ol (80 mg, 0.226 mmol, 63.01% yield) as a yellow solid. ESI + : 354.2 Step 3: To a solution of 3-(5-(5-chloro-2-(difluoromethoxy)pyridin-3-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridin-4-ol (80 mg, 0.226 mmol) was added POCl 3 (1.65 g, 10.73 mmol) at 25 °C. The mixture was stirred at 110 °C for 1 hour. The reaction mixture was quenched by addition H 2 O (10 mL) at 25 °C, and then diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO 2 , Petroleum ether: ethyl acetate= 0:1). Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase: water(HCOOH)) Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 21% B to 51%)). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-3-(5-(4-chloropyridin-3-yl)-4- methyl-4H-1,2,4-triazol-3-yl)-2-(difluoromethoxy)pyridine (9.05 mg, 0.024 mmol, 10.75% yield, 100% purity) as a white solid. ESI+: 371.9. 1 H NMR (400 MHz, MeOD- d 4 ): 8.82 - 8.77 (m, 2H), 8.52 (d, J = 2.5 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H), 7.87 - 7.50 (m, 2H), 3.55 (s, 3H). Example 73: 3-(5-(benzo[d][1,3]dioxol-4-yl)-4-methyl-4H-1,2,4-triazol-3- yl)-5-chloro-2-(difluoromethoxy)pyridine in dichloromethane (10 mL) was added methanamine hydrochloride (406 mg, 6.02 mmol) HATU (3.43 g, 9.03 mmol) and triethylamine (1.83 g, 18.06 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give the product N- methylbenzo[d][1,3]dioxole-4-carboxamide (1 g, 5.58 mmol, 92.72% yield) as a white solid. ESI + : 180.2. 1 H NMR (400 MHz, DMSO-d 6 ): 7.72 (br d, J = 2.3 Hz, 1H), 7.23 (dd, J = 1.1, 8.1 Hz, 1H), 7.05 (dd, J = 1.1, 7.8 Hz, 1H), 6.94 - 6.87 (m, 1H), 6.12 (s, 2H), 2.80 (d, J = 4.6 Hz, 3H). Step 2: To a solution of N-methylbenzo[d][1,3]dioxole-4-carboxamide (75.4 mg, 0.421 mmol) in 1,2-dichloroethane (0.5 mL) was added dropwise 2-fluoropyridine (40.9 mg, 0.421 mmol) and trifluoromethanesulfonic anhydride (119 mg, 0.421 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-(difluoromethoxy)nicotinohydrazide (Intermediate 20) (50 mg, 0.21 mmol) in 1,2-dichloroethane (0.5 mL) was added and stirred for 10 min. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO 2 , Petroleum ether: ethyl acetate= 0:1). Then the product was further purified by prep. HPLC (column: Welch Xtimate C18150*25mm*5μm; Mobile phase A: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 26% B to 56%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(5-(benzo[d][1,3]dioxol-4-yl)-4-methyl-4H-1,2,4-triazol-3- yl)-5-chloro-2- (difluoromethoxy)pyridine (10.59 mg, 0.028 mmol, 13.19% yield, 99.8% purity) as a white solid. ESI + : 381.0. 1 H NMR (400 MHz, MeOD-d 4 ): 8.49 (d, J = 2.5 Hz, 1H), 8.22 (d, J = 2.5 Hz, 1H), 7.69 (t, J = 71.7 Hz, 1H), 7.16 - 7.12 (m, 1H), 7.11 - 7.05 (m, 2H), 6.13 (s, 2H), 3.62 (s, 3H). Example 74: 5-chloro-2-(difluoromethoxy)-3-(5-(2,3-dihydrobenzofuran-4- yl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridine
Step 1: A Pd/C (201 mg, 10% purity in activated carbon) in EtOH (4 mL) was degassed and purged with H 2 three times, and then the mixture was stirred at 30 °C for 12 hours under H 2 (30 psi) atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product 2,3-dihydrobenzofuran-4-carboxylic acid (170 mg, crude) as an off-white solid, which was used in next step without further purification. ESI + : 165.2. 1 H NMR (400 MHz, DMSO-d6): 13.19 - 12.35 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.54 (t, J = 8.8 Hz, 2H), 3.48 - 3.42 (m, 2H). Step 2: To a solution of 2,3-dihydrobenzofuran-4-carboxylic acid (170 mg, 1.04 mmol), methanamine hydrochloride (83.9 mg, 1.24 mmol) and triethylamine (314 mg, 3.11 mmol) in dichloromethane (2 mL) was added HATU (591 mg, 1.55 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give N-methyl-2,3- dihydrobenzofuran-4-carboxamide (120 mg, 0.677 mmol, 65.39% yield) as white solid. Step 3: To a solution of N-methyl-2,3-dihydrobenzofuran-4-carboxamide (74.6 mg, 0.421 mmol) in 1,2-dichloroethane (1 mL) was added dropwise 2-fluoropyridine (40.9 mg, 0.421 mmol) and trifluoromethanesulfonic anhydride (119 mg, 0.421 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-2-(difluoromethoxy)nicotinohydrazide (Intermediate 1) (50 mg, 0.21 mmol) in 1,2-dichloroethane (1 mL) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with H 2 O (10 mL x 3) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Welch Xtimate C18 150*25mm*5μm; Mobile Phase A: water (HCOOH)), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3- (5-(2,3-dihydrobenzofuran-4-yl)-4-methyl-4H-1,2,4-triazol-3- yl)pyridine (5.03 mg, 0.013 mmol, 6.31% yield, 100% purity) was obtained as a white solid. ESI + : 379.0. 1 H NMR (400 MHz, CDCl 3 -d): 8.34 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.56 (t, J = 72.0 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.66 (t, J = 8.8 Hz, 2H), 3.63 (s, 3H), 3.46 (t, J = 8.8 Hz, 2H). Example 75: 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-4-yl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine To a solution of (Intermediate 20) (114 mg, 0.483 mmol) in 1,2-dichloroethane (1.5 mL) was added dropwise 2- fluoropyridine (62.6 mg, 0.645 mmol) and trifluoromethanesulfonic anhydride (182 mg, 0.645 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 3-fluoroisonicotinohydrazide (50 mg, 0.322 mmol) in 1,2-dichloroethane (1.5 mL) was added and the reaction stirred for 10 min. The resulting mixture was stirred at 140 °C for 2 hours under microwave. The reaction mixture was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25mL/min, gradient condition from 22% B to 52%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-4-yl)-4-m ethyl-4H-1,2,4- triazol-3-yl)pyridine (15.17 mg, 0.042 mmol, 13.05% yield, 98.6% purity) as a white solid. ESI + : 356.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.88 (d, J = 1.5 Hz, 1H), 8.68 (dd, J = 0.8, 4.9 Hz, 1H), 8.63 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 2.6 Hz, 1H), 7.97 - 7.59 (m, 2H), 3.54 (d, J = 1.8 Hz, 3H). Example 76: 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2- methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridine Step 1: To a -N-methylpyridine-3- carbothioamide (Intermediate 21) (70 mg, 0.277 mmol) in 1,2-dichloroethane (1 mL) was added2-methylnicotinohydrazide (50.3 mg, 0.332 mmol), benzoyloxysilver (127 mg, 0.554 mmol) and AcOH (49.9 mg, 0.831 mmol)) at 25 °C, and then the mixture was stirred at 60 °C for 6 hours under N 2 atmosphere. The mixture was concentrated to afford the crude. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel) to afford the product. Then the product was further purified by prep. HPLC (column: Waters Xbridge 150*25mm* 5μm; Mobile phase A: water(NH 4 HCO 3 ); Mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 18% B to 48%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(4-methyl-5-(2-methylpyridin- 3-yl)-4H-1,2,4-triazol- 3-yl)pyridine (14.59 mg, 0.041 mmol, 14.97% yield, 100% purity) as a white powder. ESI + : 352.1. 1 H NMR (400 MHz, DMSO-d 6 ): 8.68 (dd, J = 1.5, 4.8 Hz, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.39 (d, J = 2.6 Hz, 1H), 7.98 - 7.58 (m, 2H), 7.45 (dd, J = 4.9, 7.6 Hz, 1H), 3.38 (s, 3H), 2.42 (s, 3H). Example 77: 5-chloro-2-(difluoromethoxy)-3-(5-(5- fluorobenzo[d][1,3]dioxol-4-yl)-4-methyl-4H-1,2,4-triazol-3- yl)pyridine Step 1: A 22) (400 mg, 2.15 mmol) in N,N-dimethylformamide (4 mL) was added bromo(chloro)methane (417 mg, 3.22 mmol) and Cs 2 CO 3 (2.10 g, 6.45 mmol) at 25 °C, and then the mixture was stirred at 110 °C for 1.5 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give methyl 5- fluorobenzo[d][1,3]dioxole-4-carboxylate (135 mg, 0.681 mmol, 31.70% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.10 (dd, J = 4.1, 8.6 Hz, 1H), 6.76 (dd, J = 8.5, 11.5 1H), 6.17 (s, 2H), 3.83 (s, 3H). Step 2: To a solution of methyl 5-fluorobenzo[d][1,3]dioxole-4-carboxylate (135 mg, 0.681 mmol) in EtOH (1.5 mL) was added NH 2 NH 2 •H 2 O (401 mg, 6.81 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled to RT and quenched by water (15 mL) at 25 °C before being extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~2%Methanol / Dichloromethane @ 25 mL/min) to afford 5- fluorobenzo[d][1,3]dioxole-4-carbohydrazide (130 mg, 0.656 mmol, 96.29% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d 6 ): 9.58 (br s, 1H), 6.96 (dd, J = 4.3, 8.6 Hz, 1H), 6.69 (dd, J = 8.6, 10.4 Hz, 1H), 6.09 (s, 2H), 4.62 - 4.41 (m, 2H). Step 3: A mixture of 5-fluorobenzo[d][1,3]dioxole-4-carbohydrazide (80 mg, 0.404 mmol) in dichloromethane (0.5 mL) was added 5-chloro-2-(difluoromethoxy)-N- methylpyridine-3-carbothioamide (Intermediate 21) (102 mg, 0.404 mmol), benzoyloxysilver (185 mg, 0.807 mmol) and acetic acid (72.7 mg, 1.21 mmol) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 20 mL/min). Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 33% B to 63%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(5-fluorobenzo[d][1,3]diox ol-4-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine (36.24 mg, 0.091 mmol, 22.47% yield, 99.8% purity) as a white powder . ESI + : 399.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.62 (d, J = 2.6 Hz, 1H), 8.41 (d, J = 2.6 Hz, 1H), 7.78 (t, J = 71.7 Hz, 1H), 7.16 (dd, J = 4.4, 8.6 Hz, 1H), 6.92 (dd, J = 8.7, 10.6 Hz, 1H), 6.20 (s, 2H), 3.49 (s, 3H). Example 78: 5-chloro-2-(difluoromethoxy)-3-(5-(6-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)-4-methyl-4H-1,2,4-triazol-3 -yl)pyridine Step 1: A 22) (350 mg, 1.88 mmol) in N,N-dimethylformamide (3.5 mL) was added 1,2- dibromoethane (530 mg, 2.82 mmol) and Cs 2 CO 3 (1.84 g, 5.64 mmol) at 25°C, and then the mixture was stirred at 110 °C for 1.5 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford methyl 6- fluoro-2,3-dihydro-1,4-benzodioxine-5-carboxylate (220mg, 1.04 mmol, 55.14% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 7.01 (dd, J = 5.6, 9.1 Hz, 1H), 6.78 (t, J = 9.1 Hz, 1H), 4.32 - 4.28 (m, 2H), 4.26 - 4.23 (m, 2H), 3.83 (s, 3H). Step 2: To a solution of NH 2 NH 2 •H 2 O (305.33 mg, 5.18 mmol) in EtOH (1.1 mL) was added methyl 6-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate (110 mg, 0.518 mmol). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled to RT and quenched by water (15 mL) at 25 °C, extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of Methanol/Dichloromethane 0~7% @ 24mL/min) to afford 6-fluoro-2,3- dihydrobenzo[b][1,4]dioxine-5-carbohydrazide (80 mg, 0.377 mmol, 72.73% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.61 - 9.36 (m, 1H), 6.90 (dd, J = 5.5, 9.0 Hz, 1H), 6.70 (t, J = 8.9 Hz, 1H), 4.46 (d, J = 4.3 Hz, 2H), 4.29 - 4.16 (m, 4H). Step 3: A mixture of 6-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-5-carbohydrazide (80 mg, 0.377 mmol) in dichloromethane (0.8 mL) was added 5-chloro-2- (difluoromethoxy)-N-methylpyridine-3-carbothioamide (Intermediate 21) (95.3 mg, 0.377 mmol), benzoyloxysilver (173 mg, 0.754 mmol) and acetic acid (67.9 mg, 1.13 mmol) at 25 °C, and then the mixture was stirred at 60 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 20 mL/min). Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water (HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 33% B to 63%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(6-fluoro-2,3-dihydrobenzo [b][1,4]dioxin-5-yl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine (8.63 mg, 0.021 mmol, 5.53% yield, 99.8% purity) as a white powder. ESI + : 413.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.61 (d, J = 2.5 Hz, 1H), 8.41 (d, J = 2.6 Hz, 1H), 7.78 (t, J = 71.8 Hz, 1H), 7.16 (dd, J = 5.5, 9.1 Hz, 1H), 6.94 (t, J = 9.1 Hz, 1H), 4.30 (s, 4H), 3.41 (s, 3H). Example 79: 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-2-yl)-4- methyl-4H-1,2,4-triazol-3-yl)pyridine Step 1: mmol) in EtOH (5 mL) was added NH 2 NH 2 (25.79 mmol, 1M in THF). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled to RT and quenched by water (30 mL) at 25 °C and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~3% Methanol/Dichloromethane @ 30 mL/min) to afford 3-fluoropicolinohydrazide (270 mg, 1.74 mmol, 54.00% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 9.77 (br s, 1H), 8.45 (td, J = 1.4, 4.6 Hz, 1H), 7.84 (ddd, J = 1.2, 8.6, 10.5 Hz, 1H), 7.62 (td, J = 4.3, 8.5 Hz, 1H), 4.56 (s, 2H). Step 2: To a mixture of 3-fluoropicolinohydrazide (70 mg, 0.451 mmol) in dichloromethane (0.5 mL) was added 5-chloro-2-(difluoromethoxy)-N-methylpyridine- 3-carbothioamide (Intermediate 21) (114 mg, 0.451 mmol), benzoyloxysilver (207 mg, 0.902 mmol) and acetic acid (81.3 mg, 1.35 mmol) at 25 °C, and then the mixture was stirred at 60 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 20 mL/min). Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: [water(HCOOH)]; Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 28% B to 58%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(3-fluoropyridin-2- yl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridine (5.47 mg, 0.015 mmol, 3.36% yield, 98.7% purity) as a white powder. 1 H NMR (400 MHz, DMSO-d 6 ): 8.69 - 8.65 (m, 1H), 8.63 (d, J = 2.6 Hz, 1H), 8.41 (d, J = 2.6 Hz, 1H), 8.04 (ddd, J = 1.1, 8.8, 10.1 Hz, 1H), 7.98 - 7.61 (m, 2H), 3.67 (s, 3H). Example 80: 5-chloro-2-(difluoromethoxy)-3-(5-(3- (difluoromethoxy)pyridin-2-yl)-4-methyl-4H-1,2,4-triazol-3-y l)pyridine Step 1: 3.27 mmol) in N,N-dimethylformamide (11 mL) was added K 2 CO 3 (812 mg, 5.88 mmol) and sodium 2-chloro-2,2-difluoro-acetate (796 mg, 5.22 mmol). The mixture was stirred at 70 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 10 mL/min) to afford methyl 3-(difluoromethoxy)picolinate (230 mg, 1.13 mmol, 34.68% yield) as a white solid. ESI + : 204.0. 1 H NMR (400 MHz, CDCl 3 -d): 8.61 (d, J = 4.5 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 4.6, 8.3 Hz, 1H), 6.85 - 6.45 (m, 1H), 4.01 (s, 3H). Step 2: To a solution of methyl 3-(difluoromethoxy)pyridine-2-carboxylate (100 mg, 0.492 mmol) in EtOH (0.2 mL) was added NH 2 NH 2 (3.94 mmol, 1M in THF). The mixture was stirred at 90 °C for 1 hour. The reaction mixture was quenched by the addition of H 2 O (10 mL) at 25 °C, and then diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 10 mL/min) to give 3-(difluoromethoxy)picolinohydrazide (80 mg, 0.394 mmol, 80.00% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 -d): 8.84 - 8.62 (m, 1H), 8.48 (dd, J = 1.1, 4.5 Hz, 1H), 7.70 J = 8.3 Hz, 1H), 7.52 (dd, J = 4.6, 8.4 Hz, 1H), 6.81 (t, J = 75.0 Hz, 1H). Step 3: A mixture of 3-(difluoromethoxy)picolinohydrazide (80 mg, 0.394 mmol), 5- chloro-2-(difluoromethoxy)-N-methylpyridine-3-carbothioamide (Intermediate 21) (99.5 mg, 0.394 mmol), benzoyloxysilver (180 mg, 0.788 mmol) and acetic acid (71 mg, 1.18 mmol) was added to 1,2-dichloroethane (1 mL) at 25 °C, and then the mixture was stirred at 60 °C for 1 hour under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 150*25mm* 10μm, Mobile Phase A: water (0.225%HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% B to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-chloro-2-(difluoromethoxy)-3-(5-(3-(difluoromethoxy)pyridi n-2-yl)-4-methyl-4H- 1,2,4-triazol-3-yl)pyridine (16.37 mg, 0.040 mmol, 10.23% yield, 99.4% purity) as a white solid. ESI + : 404.0. 1 H NMR (400 MHz, DMSO-d 6 ): 8.69 (dd, J = 1.1, 4.6 Hz, 1H), 8.62 (d, J = 2.6 Hz, 1H), 8.42 (d, J = 2.6 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.81 - 7.60 (m, 2H), 7.57 - 7.15 (m, 1H), 3.57 (s, 3H). Example 81: 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)chroman-4-one Step triazol-3- yl]phenol (Example 44, Step 1) (620 mg, 1.33 mmol) in THF (8 mL) at 0°C was added t-BuOK (224 mg, 1.99 mmol), followed by oxetan-2-one (144 mg, 1.99 mmol). The mixture was stirred at 25 °C for 6 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 2). The aqueous phase was acidified to pH 5 with 1 M HCl (aq.) and extracted with EtOAc (50 mL x 3). Then the combined organic layers were concentrated under reduced pressure to give a residue which was triturated with ethyl acetate / Petroleum ether =1 / 1 (10mL) at 25 o C for 5 minutes to give 3-[4-chloro-3-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol -3- yl]phenoxy]propanoic acid (500 mg, crude) as a white solid. ESI + : 394.1. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.59 - 7.52 (m, 1H), 7.43 (d, J = 9.1 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.24 (d, J = 3.0 Hz, 1H), 7.11 (s, 1H), 7.07 (dd, J = 2.9, 8.9 Hz, 1H), 4.32 (t, J = 6.3 Hz, 2H), 3.48 (s, 3H), 2.86 (t, J = 6.3 Hz, 2H). Step 2: A mixture of 3-[4-chloro-3-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol -3- yl]phenoxy]propanoic acid (500 mg, crude) in Eaton’s Reagent (Phosphorus pentoxide, 7.7 wt. % in methanesulfonic acid) (5 mL) was stirred at 70 °C for 0.5 hour. The reaction mixture was diluted with water (100 mL). The aqueous phase was acidified to pH>7 with saturated NaHCO 3 (aq.) then extracted with EtOAc (50 mL x 3). Then the combined organic layers were concentrated under reduced pressure to dryness, which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=0 / 1) to afford the crude product. Then the crude product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: water (HCOOH); mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 23% B to 53%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)chroman-4-one (8.95 mg, 0.023 mmol, 1.8% yield, 98.1% purity) as a white solid. ESI + : 376.1. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.61 (d, J = 9.0 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.20 (d, J = 9.0 Hz, 1H), 7.12 (t, J = 7.9 Hz, 2H), 4.69 - 4.48 (m, 2H), 3.34 (s, 3H), 2.92 - 2.71 (m, 2H). Example 82: 3-(6-chlorochroman-5-yl)-5-(2,6-difluorophenyl)-4-methyl- 4H-1,2,4-triazole Step 1: To a solution of 6-chloro-5-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol-3- yl]chroman-4-one (Example 81) (27 mg, 0.072 mmol) in TFA (0.2 mL) was added triethylsilane (39.3 mg, 0.338 mmol). The mixture was stirred at 60 °C for 12 hours. After pouring into crushed ice, the mixture was basified with the careful addition of saturated NaHCO 3 (aq., pH = 7), then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 before being concentrated to dryness. The residue was purified by prep. TLC (Petroleum ether / ethyl acetate = 0 / 1) to give the crude product, which was further purified by prep. HPLC (column: Phenomenex luna C18150*25mm* 10μm; mobile phase A: water (HCOOH); phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 36% B to 56%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18150*25mm* 10μm; mobile phase A: water (HCOOH); phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 34% B to 64%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-(6-chlorochroman-5-yl)-5-(2,6-difluorophenyl)-4- methyl-4H-1,2,4-triazole (1.31 mg, 0.003 mmol, 4.8% yield, 95.7% purity) as a light- yellow gum. ESI + : 362.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.77 (quin, J = 7.6 Hz, 1H), 7.43 - 7.37 (m, 3H), 7.07 - 7.01 (m, 1H), 4.24 - 4.08 (m, 2H), 3.29 (s, 3H), 2.49 - 2.48 (m, 2H), 1.94 - 1.78 (m, 2H). Example 83: 5-chloro-6-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)-2,3-dihydrofuro[2,3-b]pyridine Step 1: To a solution of methyl 5-bromo-3-chloro-pyridine-2-carboxylate (25 g, 99.8 mmol) in CHCl 3 (45 mL) was added urea hydrogen peroxide adduct (18.8 g, 200 mmol) at 0 °C, and then (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (41.9 g, 200 mmol) in CHCl 3 (45 mL) was added dropwise. The mixture was stirred at 25 °C for 8 hours. The reaction was quenched with aqueous saturated Na 2 SO 3 (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL x3), dried over anhydrous Na 2 SO 4 and concentrated to give the residue which was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give methyl (24.9 g, 93.44 mmol, 93.62% yield) as a white solid. Step 2: To a solution of methyl 5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate (24.9 g, 93.44 mmol) in N,N-dimethylformamide (250 mL) was added trifluoroacetic anhydride (177 g, 841 mmol) dropwise under 0 °C. The mixture was stirred at 25 °C for 8 hours. The reaction mixture was added to ice water (1 L) and extracted with EtOAc (0.5 L x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Phenomenex luna C18 250*70mm, 10μm); Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 140 mL/min, gradient condition from 10% to 40%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give methyl 5-bromo-3-chloro-6- hydroxy-pyridine-2-carboxylate (10 g, 37.5 mmol, 40.2% yield) as an off-white solid. ESI + : 265.8 Step 3: To a solution of methyl 5-bromo-3-chloro-6-hydroxy-pyridine-2-carboxylate (4.98 g, 18.7 mmol) in dichloromethane/MeOH=10:1 (50 mL) was dropwise added TMSCHN 2 (2 M in hexane, 28 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 25 mL/min) to give methyl 5-bromo-3-chloro-6-methoxy-pyridine-2-carboxylate (1.8 g, 6.42 mmol, 34.34% yield) as white solid. ESI + : 279.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H). Step 4: A mixture of methyl 5-bromo-3-chloro-6-methoxy-pyridine-2-carboxylate (1.6 g, 5.70 mmol), ethynyl(trimethyl)silane (728 mg, 7.42 mmol), Pd(PPh 3 ) 2 Cl 2 (400 mg, 0.570 mmol), CuI (163 mg, 0.856 mmol) and triethylamine (1.73 g, 17.1 mmol) in THF (16 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 1 hour under N 2 atmosphere. The reaction mixture was diluted with water 10 mL and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give methyl 3-chloro-6-methoxy-5-(2-trimethylsilylethynyl)pyridine-2- carboxylate (1.16 g, 3.90 mmol, 68.29% yield) as an off-white solid. ESI + : 298.0 Step 5: To a solution of methyl 3-chloro-6-methoxy-5-(2- trimethylsilylethynyl)pyridine-2-carboxylate (800 mg, 2.69 mmol) in acetonitrile (8 mL) was added NaI (1.21 g, 8.06 mmol) and TMSCl (876 mg, 8.06 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to dryness, which was purified by prep. HPLC (Phenomenex luna C18250*50mm*10μm); Mobile Phase A: water (CF 3 COOH), Mobile Phase B: acetonitrile, Flow rate: 75 mL/min, gradient condition from 35% to 65%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10mL). The solution was lyophilized to dryness to give the crude product. The crude product was further purified by prep. HPLC (Welch Xtimate C18250*50mm*5μm); Mobile Phase A: water (CF 3 COOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 36% to 66%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10mL). The solution was lyophilized to dryness to give methyl 3-chloro-6-hydroxy-5- (2-trimethylsilylethynyl)pyridine-2-carboxylate (160 mg, 0.564 mmol, 20.99% yield) as a light yellow solid. ESI + : 284.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.51 - 12.43 (m, 1H), 7.98 (s, 1H), 3.87 (s, 3H), 0.23 (s, 9H). Step 6: To a solution of methyl 3-chloro-6-hydroxy-5-(2-trimethylsilylethynyl)pyridine- 2-carboxylate (140 mg, 0.493 mmol) in EtOH (1.5 mL) was added CuI (4.70 mg, 0.025 mmol) and triethylamine (99.8 mg, 0.987 mmol). The mixture was stirred at 70 °C for 1 hour under N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to dryness which was purified by prep-TLC (SiO 2 , Petroleum ether : ethyl acetate = 3 : 1) to give methyl 5-chlorofuro[2,3-b]pyridine-6-carboxylate (40 mg, 0.189 mmol, 38.3% yield) as white solid. ESI + : 211.9 Step 7: A mixture of methyl 5-chlorofuro[2,3-b]pyridine-6-carboxylate (40 mg, 0.189 mmol), Rh/Al 2 O 3 (19.5 mg, 0.009 mmol, 5% purity) in EtOH (0.5 mL) was degassed and purged with H 2 3 times, and then the mixture was stirred at 25 °C for 2 hours under H 2 (15 psi) atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 5-chloro-2,3-dihydrofuro[2,3- b]pyridine-6-carboxylate (40 mg, crude) as off white solid which was used for next step without further purification. ESI + : 213.8 Step 8: To a solution of methyl 5-chloro-2,3-dihydrofuro[2,3-b]pyridine-6-carboxylate (40 mg, 0.187 mmol) in EtOH (0.5 mL) was added NH 2 NH 2 •H 2 O (110 mg, 1.87 mmol, 85% purity in H 2 O). The mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was cooled down to RT and quenched by water (3 mL) at 25 °C, extracted with EtOAc (5 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to dryness which was then purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 5-chloro-2,3- dihydrofuro[2,3-b]pyridine-6-carbohydrazide (20 mg, 0.094 mmol, 50% yield) as a white solid. Step 9: A mixture of 5-chloro-2,3-dihydrofuro[2,3-b]pyridine-6-carbohydrazide (10 mg, 0.047 mmol), 2,6-difluoro-N-methyl-benzenecarbothioamide (9.64 mg, 0.051 mmol), benzoyloxysilver (21.4 mg, 0.094 mmol), acetic acid (8.43 mg, 0.140 mmol) in 1,2-dichloroethane (0.5 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 2 hours under N 2 atmosphere. The reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep. HPLC (Phenomenex luna C18 150*25mm* 10μm); Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 18% to 48%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the title product (0.94 mg, 0.003 mmol, 5% yield, 96.4% purity) as a light yellow gum. ESI + : 349.1. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 7.92 - 7.85 (m, 1H), 7.78 - 7.69 (m, 1H), 7.33 - 7.24 (m, 2H), 4.77 (t, J = 8.6 Hz, 2H), 3.56 (s, 3H), 3.43 (t, J = 8.6 Hz, 2H). Example 84: 4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3- yl)thieno[2,3-b]pyridine-5-carbonitrile NH F O NH F F Step 1: To (4.17 g, 24.2 mmol) in dichloromethane (41 mL) was added triethylamine (7.35 g, 72.7 mmol) and N-methylcarbamoyl chloride (6.80 g, 72.7 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to dryness which was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 70 mL/min) to give [(2,6- difluorobenzoyl)amino]-3-methyl-urea (3.8 g, 16.58 mmol, 68.44% yield) as a white solid. ESI + : 229.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.20 (s, 1H), 7.59 - 7.50 (m, 1H), 7.18 (t, J = 8.1 Hz, 2H), 6.07 (d, J = 4.5 Hz, 1H), 2.61 (d, J = 4.5 Hz, 3H). Step 2: A mixture of 1-[(2,6-difluorobenzoyl)amino]-3-methyl-urea (3.7 g, 16.14 mmol) in 2 M NaOH (aq.) (37.00 mL) was stirred at 100 °C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-(2,6- difluorophenyl)-4-methyl-1,2,4-triazol-3-ol (2.4 g, crude) as off-white solid which was used in the next step directly without further purification. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.22 (s, 1H), 7.79 - 7.68 (m, 1H), 7.35 (t, J = 8.3 Hz, 2H), 3.02 (s, 3H). Step 3: A mixture of 5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol-3-ol (500 mg, crude) in POBr 3 (5 mL) was stirred at 110 °C for 1 hour. After pouring onto crushed ice, the mixture was basified with the careful addition of sat. NaHCO 3 (aq., pH > 7), then extracted with dichloromethane (200 mL x 3). The combined organic layers were dried over Na 2 SO 4 and concentrated to dryness which was then purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 1 / 1, Rf = 0.30 ) to afford 3-bromo-5-(2,6- difluorophenyl)-4-methyl-1,2,4-triazole (160 mg, 0.584 mmol, 24.66% yield) as a white solid. ESI + : 273.8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.76 (tt, J = 6.7, 8.5 Hz, 1H), 7.43 - 7.34 (m, 2H), 3.49 (s, 3H). Step 4: To a mixture of 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (85.2 mg, 0.438 mmol) and 3-bromo-5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazole (100 mg, 0.365 mmol) in dioxane (2 mL) and H 2 O (0.2 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (185 mg, 0.730 mmol), cataCXium A-Pd-G2 (48.8 mg, 0.073 mmol) and Cs 2 CO 3 (357 mg, 1.09 mmol) in one portion at 25 °C. The resulting mixture was degassed and purged with N 2 3 times, and then the mixture was stirred at 90 °C for 12 hours under N 2 atmosphere. The mixture was filtered and the filtrate was concentrated to dryness which was purified by prep. TLC (Petroleum ether / ethyl acetate = 0 / 1, Rf =0.45) to give the crude product. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: water (HCOOH); mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 22% B to 52%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 4-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)thi eno[2,3-b]pyridine- 5-carbonitrile (0.76 mg, 0.002 mmol, 0.31% yield, 99.3% purity) as an off white solid. ESI + : 354.0. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.98 (s, 1H), 7.90 - 7.81 (m, 1H), 7.67 - 7.57 (m, 1H), 7.55 (d, J = 6.1 Hz, 1H), 7.17 (t, J = 8.3 Hz, 2H), 3.65 (s, 3H). Example 85: 5-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)thieno[2,3-c]pyridine Step 1: A mixture of 5-chlorothieno[2,3-c]pyridine-4-carbonitrile (Prepared as described for US2010/298334) (4.3 g, 22.1 mmol) in conc. H 2 SO 4 (43.00 mL) was stirred at 100 °C for 0.5 hour. The reaction mixture was quenched by the addition of H 2 O (100 mL) at 25 °C and then diluted with NaOH (20% aq.） (100 mL) before being extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 5- chlorothieno[2,3-c]pyridine-4-carboxamide (3.3 g, 15.5 mmol, 70.24% yield) as a white solid. ESI + : 212.8. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.97 (s, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.62 J = 5.4 Hz, 1H), 6.20 (s, 2H). Step 2: To a solution of 5-chlorothieno[2,3-c]pyridine-4-carboxamide (3.3 g, 15.5 mmol) in conc. H 2 SO 4 (20 mL) was added NaNO 2 (1.93 g, 27.9 mmol). The mixture was stirred at 70 °C for 6 hours. The reaction mixture was quenched by the addition of H 2 O (200 mL) at 25 °C then extracted with dichloromethane (300 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 5-chlorothieno[2,3-c]pyridine-4-carboxylic acid (3 g, 14.0 mmol, 90.5% yield) as a white solid which was used in the next step without further purification. ESI + : 214.0 Step 3: To a mixture of 5-chlorothieno[2,3-c]pyridine-4-carboxylic acid (800 mg, 3.74 mmol) in MeOH (5 mL) was added sodium methanolate (4.59 g, 25.46 mmol, 30% purity in MeOH). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was quenched by the addition of conc. HCl (10 mL), and then diluted with H 2 O (20 mL) before being extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 5- methoxythieno[2,3-c]pyridine-4-carboxylic acid (700 mg, 3.35 mmol, 89.35% yield) as a white solid which was used into the next step without further purification. ESI + : 210.2 Step 4: A mixture of 5-methoxythieno[2,3-c]pyridine-4-carboxylic acid (700 mg, 3.35 mmol), methanamine hydrochloride (339 mg, 5.02 mmol), HATU (1.91 g, 5.02 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.30 g, 10.0 mmol) in dichloromethane (7 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness which was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 10 mL/min) to give 5-methoxy-N-methyl- thieno[2,3-c]pyridine-4-carboxamide (600 mg, 2.70 mmol, 80.7% yield) as a white solid. ESI + : 223.0 Step 5: A mixture of 5-methoxy-N-methyl-thieno[2,3-c]pyridine-4-carboxamide (200 mg, 0.900 mmol), 2,6-difluorobenzohydrazide (Intermediate 23) (201 mg, 1.17 mmol), 2-fluoropyridine (96.1 mg, 0.990 mmol), trifluoromethanesulfonic anhydride (279 mg, 0.990 mmol) in 1,2-dichloroethane (2 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 140 °C for 2 hours under microwave irradiation. The reaction mixture was evaporated to dryness which was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 10 mL/min) to give 4-[5-(2,6- difluorophenyl)-4-methyl-1,2,4-triazol-3-yl]thieno[2,3-c]pyr idin-5-ol (10 mg, 0.029 mmol, 3.2% yield) as a white solid. Step 6: To a solution of 4-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol-3- yl]thieno[2,3-c]pyridin-5-ol (10 mg, 0.029 mmol) in N,N-dimethylformamide:H 2 O=4:1 (1 mL) was added Cs 2 CO 3 (28.4 mg, 0.087 mmol) and sodium 2-chloro-2,2- difluoroacetate (8.86 mg, 0.058 mmol). The mixture was stirred at 120 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. Then the product was further purified by prep. HPLC (Column: Phenomenex luna C18 100*40mm*3 μm, Mobile Phase A: water (0.225% HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 38% B to 68%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the title compound (2.26 mg, 0.006 mmol, 19.4% yield, 98.5% purity) as a white solid. ESI + : 394.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.12 - 7.66 (m, 2H), 7.43 (t, J = 8.4 Hz, 2H), 7.36 (d, J = 5.5 Hz, 1H), 3.43 (s, 3H). Example 86: 5-(difluoromethoxy)-4-(5-(2,6-difluorophenyl)-4-methyl-4H- 1,2,4-triazol-3-yl)thieno[2,3-b]pyridine
H 2 SO 4 (6 M aq., 5.05 mL) at 0-5ºC was added dropwise NaNO 2 (253 mg, 3.66 mmol) and H 2 O (0.5 mL). The mixture was stirred at 100 °C for 10 minutes. The aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried with anhydrous Na 2 SO 4 , then filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane/MeOH = 10 / 1) to afford thieno[2,3-b]pyridin-5-ol (490 mg, 2.65 mmol, 79.74% yield, 81.9% purity) as a black brown solid. ESI + : 150.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (br s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 5.9 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 5.9 Hz, 1H). Step 2: To a solution of thieno[2,3-b]pyridin-5-ol (490 mg, 2.65 mmol) in N,N- dimethylformamide /H 2 O=4/1 (5 mL) was added Cs 2 CO 3 (2.59 g, 7.96 mmol and sodium 2-chloro-2,2-difluoro-acetate (1.21 g, 7.96 mmol). The mixture was stirred at 120 °C for 1 hour. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 3 / 1) to afford 5-(difluoromethoxy)thieno[2,3-b]pyridine (130 mg, 0.646 mmol, 24.34% yield) as a light yellow oil. ESI + : 201.9 Step 3: To a solution of 5-(difluoromethoxy)thieno[2,3-b]pyridine (240 mg, 1.19 mmol) in dichloromethane (0.2 mL) was added m-CPBA (363 mg, 1.79 mmol). The mixture was stirred at 25 °C for 6 hours. The mixture was filtered and the filtrate was concentrated to afford the crude product which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 1 / 1) to afford 5-(difluoromethoxy)-7-oxido- thieno[2,3-b]pyridin-7-ium (61 mg, 0.281 mmol, 23.54% yield) as a yellow solid. Step 4: Trifluoromethanesulfonic anhydride (392 mg, 1.39 mmol) was added dropwise to a stirred suspension of 5-(difluoromethoxy)-7-oxido-thieno[2,3-b]pyridin-7-ium (151 mg, 0.695 mmol) and TBAB (336 mg, 1.04 mmol) in dichloromethane (0.1 mL) at 0 °C over a period of 10 minutes under N 2 . Then the mixture was stirred at 25 °C for 6 hours under N 2 atmosphere. The mixture was filtered and the filtrate was concentrated to afford the crude product which was purified by prep. TLC (Petroleum ether / ethyl acetate = 4 / 1) to give 4-bromo-5-(difluoromethoxy)thieno[2,3-b]pyridine (80 mg, 0.286 mmol, 41.08% yield) as off white solid. ESI + : 279.7 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.56 (s, 1H), 8.17 (d, J = 6.0 Hz, 1H), 7.58 - 7.14 (m, . Step 5: To a solution of 4-bromo-5-(difluoromethoxy)thieno[2,3-b]pyridine (80 mg, 0.286 mmol) and Pd(OAc) 2 (32.1 mg, 0.143 mmol) in triethylamine/MeOH = 1/10 (1 mL) was added DPPP (82.46 mg, 0.200 mmol) under N 2 . The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 12 hours. The mixture was filtered and the filtrate was concentrated to afford the crude product which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 4 / 1) to afford methyl 5- (difluoromethoxy)thieno[2,3-b]pyridine-4-carboxylate (50 mg, 0.193 mmol, 67.53% yield) as a white solid. ESI + : 259.9 Step 6: To a solution of methyl 5-(difluoromethoxy)thieno[2,3-b]pyridine-4- carboxylate (50 mg, 0.193 mmol) in EtOH (0.1 mL) was added NH 2 NH 2 •H 2 O (114 mg, 1.93 mmol, 85% purity in water). The mixture was stirred at 80 °C for 1 hour. The mixture was filtered and the filtrate was concentrated to afford the crude product. The residue was purified by prep. TLC (Petroleum ether / ethyl acetate = 0 / 1, Rf = 0.35) to give 5-(difluoromethoxy)thieno[2,3-b]pyridine-4-carbohydrazide (30 mg, 0.116 mmol, 60.0% yield) as a white solid. ESI + : 259.9 Step 7: To a solution of 5-(difluoromethoxy)thieno[2,3-b]pyridine-4-carbohydrazide (20 mg, 0.077 mmol), 2,6-difluoro-N-methyl-benzenecarbothioamide (21.7 mg, 0.116 mmol) in 1,2-dichloroethane (0.05 mL) was added benzoyloxy silver (35.3 mg, 0.154 mmol) and acetic acid (13.9 mg, 0.231 mmol). The mixture was stirred at 60 °C for 1 hour under N 2 . The mixture was filtered and the filtrate was concentrated to dryness which was further purified by prep. HPLC (column: Phenomenex luna C18150*25mm* 10μm; mobile phase A: water (HCOOH); mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 28% B to 58%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product. Then the product was further purified by prep. HPLC (column: Daisogel SP ODS RPS 150*25mm*5μm; mobile phase A: water (NH4HCO3); mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 29% B to 59%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 5-(difluoromethoxy)-4-[5-(2,6-difluorophenyl)-4-methyl- 1,2,4-triazol-3-yl]thieno[2,3-b]pyridine (1.31 mg, 0.003 mmol, 4.1% yield, 96.0% purity) as a white solid. ESI + : 395.0. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.70 (s, 1H), 7.78 (d, J = 6.1 Hz, 1H), 7.64 - 7.54 (m, 1H), 7.42 (d, J = 6.1 Hz, 1H), 7.16 (t, J = 8.0 Hz, 2H), 6.49 (t, J = 72.9 Hz, 1H), 3.51 (s, 3H). Example 87: 3-(5-chloro-2,3-dihydrobenzofuran-4-yl)-5-(2,6- difluorophenyl)-4-methyl-4H-1,2,4-triazole Step as described for WO2019/152419) (250 mg, 1.26 mmol), methanamine hydrochloride (102 mg, 1.51 mmol), HOBt (255 mg, 1.89 mmol) and N-ethyl-N-isopropylpropan-2-amine (488 mg, 3.78 mmol) in dichloromethane (3 mL) was added EDCI (362 mg, 1.89 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give 5-chloro-N- methyl-2,3-dihydrobenzofuran-4-carboxamide (200 mg, 0.945 mmol, 75.1% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (br d, J = 4.0 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 4.57 (t, J = 8.8 Hz, 2H), 3.12 (t, J = 8.8 Hz, 2H), 2.75 (d, J = 4.6 Hz, 3H). Step 2: To a solution of 2,6-difluorobenzohydrazide (Intermediate 23) (50 mg, 0.290 mmol) in 1,2-dichloroethane (1 mL) was added dropwise 2-fluoropyridine (42.3 mg, 0.436 mmol) and trifluoromethanesulfonic anhydride (123 mg, 0.436 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 5-chloro-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (73.8 mg, 0.349 mmol) in 1,2-dichloroethane (1 mL) was added and stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave irradiation. The reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (5 mL x 3). The organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to dryness which was purified by prep. HPLC (Phenomenex luna C18 150*25mm* 10μm; Mobile Phase A: water (HCOOH), Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to dryness to give 3-(5-chloro-2,3-dihydrobenzofuran-4-yl)-5-(2,6-difluoropheny l)-4-methyl- 1,2,4-triazole (41.82 mg, 0.120 mmol, 41.4% yield, 100% purity) as a white powder. ESI + : 348.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (tt, J = 6.7, 8.5 Hz, 1H), 7.45 - 7.36 (m, 3H), 7.03 (d, J = 8.5 Hz, 1H), 4.70 - 4.57 (m, 2H), 3.37 (s, 3H), 3.25 - 3.15 (m, 1H), 3.06 - 2.96 (m, 1H). Example 88: 6-chloro-5-(5-(2,6-difluorophenyl)-4-methyl-4H-1,2,4-triazol - 3-yl)quinoline Step 1: To a solution of 5-bromo-6-chloro-quinoline (250 mg, 1.03 mmol)and DPPP (298 mg, 0.722 mmol) in triethylamine/MeOH = 1 / 10 (5 mL) was added Pd(OAc) 2 (116 mg, 0.515 mmol) under N 2 . The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 12 hours. The mixture was filtered and the filtrate was concentrated to afford the crude product. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / ethyl acetate = 3 / 1) to afford methyl 6-chloroquinoline-5-carboxylate (180 mg, 0.812 mmol, 78.78% yield) as a light yellow solid. ESI + : 221.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.02 (dd, J = 1.6, 4.2 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 4.1, 8.6 Hz, 1H), 4.04 (s, 3H). Step 2: To a solution of methyl 6-chloroquinoline-5-carboxylate (10 mg, 0.045 mmol) in MeOH (0.1 mL) was added NaOH (3 M (aq.), 0.045 mL). The mixture was stirred at 60 °C for 0.5 hour. The mixture was filtered and the filtrate was concentrated to afford the crude 6-chloroquinoline-5-carboxylic acid (15 mg, crude) as a white solid which was used in the next step directly without further purification. Step 3: To a solution of 6-chloroquinoline-5-carboxylic acid (15 mg, crude) and methanamine hydrochloride (4.88 mg, 0.072 mmol) in N,N-dimethylformamide (0.1 mL) was added EDCI (20.8 mg, 0.108 mmol), N-ethyl-N-isopropylpropan-2-amine (28.0 mg, 0.217 mol) and HOBt (14.6 mg, 0.108 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was filtered and the filtrate was concentrated to afford the crude product. The residue was purified by prep. TLC (dichloromethane / MeOH = 10 / 1) to give 6-chloro-N-methyl-quinoline-5-carboxamide (25 mg, crude) as a light-yellow solid which was used in the next step directly without further purification. ESI + : 221.0 Step 4: To a solution of 6-chloro-N-methyl-quinoline-5-carboxamide (59.0 mg, 0.267 mmol) in 1,2-dichloroethane (1 mL) was added dropwise 2-fluoropyridine (26.0 mg, 0.267 mmol) and trifluoromethanesulfonic anhydride (75.4 mg, 0.267 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour and then 2,6-difluorobenzohydrazide (Intermediate 23) (23 mg, 0.134 mmol) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave irradiation. The mixture was filtered and the filtrate was concentrated to afford the crude product. The residue was purified by prep. TLC (Petroleum ether / ethyl acetate = 1 / 1 ) to give the compound as a yellow oil. Then the product was further purified by prep. HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase A: water (NH 4 HCO 3 ); mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 21% B to 51%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 6-chloro-5-[5-(2,6-difluorophenyl)-4-methyl-1,2,4-triazol-3- yl]quinoline (1.02 mg, 0.003 mmol, 2.1% yield, 98.1% purity) as a light yellow powder. ESI + : 357.1. 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.01 (d, J = 4.1 Hz, 1H), 8.39 - 8.26 (m, 1H), 8.05 - 7.92 (m, 1H), 7.88 (br d, J = 9.4 Hz, 1H), 7.64 - 7.48 (m, 2H), 7.16 (t, J = 7.9 Hz, 2H), 3.41 (s, 3H). Example 89: 3-chloro-6-methoxy-2-(4-methyl-5-(2-methylpyridin-3-yl)-4H- 1,2,4-triazol-3-yl)pyridine Step 1: A 0.331 mmol), 3- chloro-6-methoxy-N-methyl-pyridine-2-carbothioamide (Example 51, Step 3) (71.7 mg, 0.331 mmol), benzoyloxysilver (151 mg, 0.662 mmol) and acetic acid (60.0 mg, 0.992 mmol) in 1,2-dichloroethane (1 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 60 °C for 6 hours under N 2 atmosphere. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @30 mL/min) to give the crude product which was further purified by prep. HPLC (Column: Waters xbridge 150*25mm 10μm, Mobile Phase A: water (NH 4 HCO 3 ), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 16% B to 46%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product. Then the product was further purified by prep-TLC (SiO 2 , Petroleum ether: ethyl acetate = 0:1) to give the title compound (11.41 mg, 0.035 mmol, 10.6% yield, 97.6% purity) as a white solid. ESI + : 316.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (dd, J = 1.6, 4.9 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.97 (dd, J = 1.6, 7.8 Hz, 1H), 7.44 (dd, J = 4.9, 7.6 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 3.91 (s, 3H), 3.52 (s, 3H), 2.44 (s, 3H). Example 90: 3-chloro-2-(5-(3-chloropyridin-2-yl)-4-methyl-4H-1,2,4- triazol-3-yl)-6-(difluoromethoxy)pyridine Step 1: To a solution of 3-chloro-6-methoxy-N-methyl-pyridine-2-carboxamide (Example 51, Step 2) (1.17 g, 5.83 mmol) in 1,2-dichloroethane (10 mL) was added dropwise 2-fluoropyridine (566 mg, 5.83 mmol) and trifluoromethanesulfonic anhydride (1.64 g, 5.83 mmol) at 0 °C under N 2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hour, and then 3-chloropyridine-2-carbohydrazide (500 mg, 2.91 mmol) was added and the reaction stirred for 10 minutes. The resulting mixture was stirred at 140 °C for 2 hours under microwave irradiation. The mixture was concentrated to afford the crude product. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18150*25mm* 10μm; mobile phase A: water (HCOOH); Mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 25% B to 55%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give 3-chloro-2-[5-(3-chloro-2-pyridyl)- 4-methyl-1,2,4-triazol-3-yl]-6-methoxy-pyridine (16 mg, 0.048 mmol, 1.63% yield) as a white solid. ESI + : 335.9 Step 2: A mixture of 3-chloro-2-[5-(3-chloro-2-pyridyl)-4-methyl-1,2,4-triazol-3- yl]-6- methoxy-pyridine (16 mg, 0.048 mmol) in conc. HCl (0.1 mL) was stirred at 140 °C for 2 hours under microwave irradiation. The mixture was evaporated to dryness which was purified by prep. TLC (Petroleum ether / ethyl acetate = 0 / 1) to give 5- chloro-6-[5-(3-chloro-2-pyridyl)-4-methyl-1,2,4-triazol-3-yl ]pyridin-2-ol (12 mg, 0.037 mmol, 78.27% yield) as a light yellow solid. ESI + : 321.9 Step 3: To a solution of 5-chloro-6-[5-(3-chloro-2-pyridyl)-4-methyl-1,2,4-triazol-3- yl]pyridin-2-ol (12 mg, 0.037 mmol) in acetonitrile (0.1 mL) was added KOH (6 M (aq.), 0.019 mL) and difluoromethyl trifluoromethanesulfonate (14.91 mg, 0.075 mmol). The mixture was stirred at 25 °C for 0.5 hour. The mixture was concentrated to dryness which was purified by prep. TLC (Petroleum ether / ethyl acetate = 0/ 1) to give the product. Then the product was further purified by prep. HPLC (column: Phenomenex luna C18 150*25mm* 10μm; mobile phase A: water (HCOOH); mobile phase B: acetonitrile, Flow rate: 25 mL/min, gradient condition from 30% B to 60%). The pure fractions were collected and the volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give the product 3-chloro-2-[5-(3-chloro-2-pyridyl)-4- methyl-1,2,4-triazol-3-yl]-6-(difluoromethoxy)pyridine (1.01 mg, 0.003 mmol, 7.23% yield, 99.2% purity) as a white solid. ESI + : 372.0. 1 H NMR (400 MHz, METHANOL-d 4 ) δ 8.75 (dd, J = 1.2, 4.7 Hz, 1H), 8.24 - 8.13 (m, 2H), 7.77 - 7.34 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 3.70 (s, 3H). Example 91: 3-chloro-2-[5-(3-chloro-6-methoxy-2-pyridyl)-4-methyl-1,2,4- triazol-3-yl]-6-methoxy-pyridine Step g, 0.496 mmol, 1.0 eq) and hydrazine monohydrate (0.126 ml, 2.480 mmol, 5.0 eq) in ethanol (1 mL) was heated at 80 °C for 1 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (DAVISIL® silica), eluted with 5 % Methanol in DCM solution. Collected fraction was concentrated under reduced pressure to afford 3-chloro-6-methoxypicolinohydrazide (0.080 g, 80%) as an off-white solid. 1 HNMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.54 (d, J = 4.4 Hz, 2H), 3.87 (s, 3H). MS ESI + : 201.97 Step 2: To a well stirred solution of methyl 3-chloro-6-methoxypicolinate (0.1 g, 0.496 mmol) in methanol:THF:water (1:1:1, 2.0 mL), was added lithium hydroxide monohydrate (0.062 g, 1.488 mmol, 3.0 eq) and the reaction mixture was stirred at RT for 1 h. After completion, the reaction mass was acidified with 1M hydrochloric acid up to pH = 4 then extracted with DCM (20 mL x 2). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3- chloro-6-methoxypicolinic acid (0.099 g, 80%) as a white solid. ESI + : 187.93 Step 3: To a well stirred solution of 3-chloro-6-methoxypicolinic acid (0.08 g, 0.426 mmol) and methylamine hydrochloride (0.043 g, 0.640 mmol, 1.5 eq) in N,N- dimethylformamide (0.8 mL) was added N, N-diisopropylethylamine (0.315 ml, 1.706 mmol, 4.0 eq) followed by HATU (0.324 g, 0.853 mmol, 2.0 eq) and the reaction was stirred at RT for 2 h. After completion of the reaction, chilled water was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulphate then concentrated under reduced pressure to obtain the crude which was purified by flash chromatography (DAVISIL® silica), eluted with 50-60 % Ethyl acetate in Petroleum ether solution. Collected fractions were concentrated under reduced pressure to afford 3-chloro-6-methoxy-N- methylpicolinamide (0.07 g, 81.8%) as an off-white solid. 1 H NMR (400 MHz, DMSO- d6): δ 8.48 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H). ESI + : 200.95 Step 4: To a well stirred solution of 3-chloro-6-methoxypicolinohydrazide (0.04 g, 0.198 mmol) and 3-chloro-6-methoxy-N-methylpicolinamide (0.040 g, 0.198 mmol, 1.0 eq) in DCE (0.4 mL) was added 2-fluoropyridine (0.027 ml, 0.298 mmol, 1.5 eq) and the reaction stirred at rt for 10 min. To the reaction mixture, was added triflic anhydride (0.038 ml, 0.218 mmol, 1.1 eq) at 0 °C and the reaction mixture was subjected to microwave irradiation at 140 °C for 3h. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude which was purified by flash chromatography (DAVISIL® silica), eluted with 5 % methanol in DCM solution. Collected fraction was concentrated under reduced pressure and the obtained material was re-purified by achiral Prep-SFC to afford 6,6'-(4-methyl-4H- 1,2,4-triazole-3,5-diyl)bis(5-chloro-2-methoxypyridine) (0.009 g, 11% yield, 99.1% purity) as an off-white solid. 1 H NMR 400 MHz, DMSO-d6: δ 8.08 (d, J = 8.80 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 3.91 (s, 6H), 3.70 (s, 3H). ESI + : 366.24 Example 92: 5-chloro-3-[5-[5-chloro-2-(difluoromethoxy)-3-pyridyl]-4- methyl-1,2,4-triazol-3-yl]-2-(difluoromethoxy)pyridine Step 1: To a well stirred solution of 5-chloro-2-(difluoromethoxy)nicotinohydrazide (Intermediate 1) (0.06 g, 0.253 mmol) and 5-chloro-2-(difluoromethoxy)-N- methylnicotinamide (Intermediate 20) (0.06 g, 0.253 mmol, 1.0 eq) in DCE (0.6 mL) was added 2-flouropyridine (0.07 mL, 0.506 mmol, 2.0 eq) at RT and the reaction stirred for 10 min. To the reaction mixture was added triflic anhydride (0.049 ml, 0.278 mmol, 1.1 eq) at 0 °C and the reaction mixture was subjected to microwave irradiation at 140°C for 3 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain crude product, which was purified by flash column chromatography (DAVISIL® silica), eluted with 5 % methanol in DCM solution. Collected fractions were concentrated under reduced pressure to afford 5-chloro-3-[5- [5-chloro-2-(difluoromethoxy)-3-pyridyl]-4-methyl-1,2,4-tria zol-3-yl]-2- (difluoromethoxy)pyridine (0.03 g, 27.1% yield, 97.6 % purity) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.63 (d, J = 2.8 Hz, 2H), 8.35 (d, J = 2.4 Hz, 2H), 7.78 (t, J = 71.6 Hz, 2H), 3.51 (s, 3H). ESI + : 438.25 3. Biological efficacy of compounds of the invention KCNK13 antagonist activity was determined by measuring changes in intracellular Thallium (Tl + ) concentrations using a Tl + sensitive fluorescent dye. The changes in fluorescent signal were monitored by Fluorescent Imaging Plate Reader (FLIPR TM ) technology available from Molecular Devices, LLC, US. KCNK13 mediated increases in intracellular Tl + concentration were readily detected by addition of a thallium sulfate stimulus. 24 hours prior to the assay, human embryonic kidney 293 cells (HEK 293 cells) stably expressing human KCNK13 were seeded in cell culture medium in PDL coated black, clear-bottom 384-well plates (commercially available from Corning Inc., 356663) and grown overnight at 37°C, 5% CO 2 . On the day of the assay, cell culture media was removed and cells were loaded with potassium dye (commercially sold by Molecular Devices, LLC, US, R8222) for 1 hour at room temperature in the dark. Test compounds (at 10 point half log concentration response curves from 10 µM) were added to cells for 15 minutes prior to the addition of thallium sulfate to all wells. The IC 50 values were determined from ten point concentration response curves. Curves were generated using the average of two wells for each data point. The results are summarised in table 2. hKCNK13 hKCNK13 hKCNK13 Example Example Example IC ( M) IC ( M) IC ( M) hKCNK13 hKCNK13 hKCNK13 Example Example Example IC ( M) IC ( M) IC ( M) It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.