POISSONNET GUILLAUME (FR)
FAUCHER NICOLAS (FR)
TYRBERG BJÖRN (SE)
LANGMEAD CHRISTOPHER (AU)
SEXTON PATRICK (AU)
WOOTTEN DENISE (AU)
HUANG YU (CN)
YIN YIN (CN)
WO2020207474A1 | 2020-10-15 | |||
WO2022040600A1 | 2022-02-24 | |||
WO2018109607A1 | 2018-06-21 | |||
WO2019239319A1 | 2019-12-19 | |||
WO2019239371A1 | 2019-12-19 | |||
WO2020103815A1 | 2020-05-28 | |||
WO2020207474A1 | 2020-10-15 | |||
WO2020263695A1 | 2020-12-30 |
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FAERCH ET AL., DIABETES, vol. 64, 2015, pages 2513 - 2525
ARMSTRONG ET AL., LANCET, vol. 387, 2016, pages 679 - 690
KALWAT ET AL., ACS SENS, 2016
CLAIMS 1. Compound of formula (I): wherein: R1 represents a group chosen among: C represents a five-membered heterocycle chosen among: it being understood that both points of attachment of each heterocycle can be linked either to E or X, D represents a carbon or a nitrogen atom, E represents a group chosen among * indicating the point of attachment, R2 representing a hydrogen atom or a methyl group, X represents either an oxygen or a sulfur atom, Z1 represents either a carbon or a nitrogen atom, and: - If Z1 represents a nitrogen atom, R3 is absent and R4 represents a chlorine atom Z2 represents either a carbon or a nitrogen atom, and: - if Z2 represents a carbon atom: · R3 represents either a hydrogen, a chlorine atom, a fluorine atom or a cyano group, · R4 represents either a cyano group, a fluorine atom or a chlorine atom, - if Z2 represents a nitrogen atom, R3 represents a hydrogen atom and R4 is absent, provided that Z1 and Z2 do not simultaneously represent a nitrogen atom, or a pharmaceutically acceptable salt thereof. 2. Compound of formula (I) according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt. 3. Compound of formula (I) according to claim 2, wherein the compound is in the form of an ammonium salt. 4. Compound of formula (I) according to anyone of claims 1 to 3, wherein R1 represents the following group: 5. Compound of formula (I) according to anyone of claims 1 to 4, wherein C represents 6. Compound of formula (I) according to anyone of claims 1 to 5, wherein Z1 and Z2 represent both a carbon atom. 7. Compound of formula (I) according to anyone of claims 1 to 3, wherein - E represents - R2 represents a hydrogen atom, - C represents - D represents a carbon atom, and - Z1 and Z2 both represent a carbon atom. 8. Compound of formula (I) according to anyone of claims 1 to 3, wherein the compound is of the formula: wherein C, D, E, R2, R3, R4, X, Z1 and Z2 are defined as in claim 1 9. Compound of formula (I) according to anyone of claims 1 to 3, wherein the compound is of the formula: wherein C, D, E, R2, R3, R4, X, Z1 and Z2 are defined as in claim 1 10. Compound of formula (I) according to anyone of claims 1 to 3, wherein the compound is of the formula: wherein D, E, R2, R3, R4, Z1 and Z2 are defined as in claim 1 11. Compound of formula (I) according to anyone of claims 1 to 3, wherein the compound is of the formula: wherein C, E, R2, R3, R4 and X are defined as in claim 1 12. Compound of formula (I) according to claim 1, wherein the compound is: - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol-1-yl}piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol-1-yl}piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{3-[(4-cyanophenyl)methoxy]-1H-pyrazol-1-yl}piperidin-1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{3-[(pyridin-4-yl)methoxy]-1H- pyrazol-1-yl}piperidin-1-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{3-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-1-yl}piperidin-1-yl)methyl]-1- [(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{1-[(4-fluorophenyl)methoxy]-1H- pyrazol-3-yl}piperidin-1-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-cyanophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}-2-methylpiperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1- yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl]-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt or a pharmaceutically acceptable salt thereof, or - 2-{[4-(3-{[(4-cyano-2-fluorophenyl)methyl]sulfanyl}-1H-pyrazol-1-yl)piperidin-1- yl]methyl}-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl]-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl]-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl]-1- [(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1- yl)methyl]-1-[(1,3-oxazol-2-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}piperidin-1- yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(5-((4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1-((1-ethyl- 1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (R or S)-2-((4-(5-(1-(4-chloro-2-fluorophenyl)ethoxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-[[4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3- [[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((2-chloro-4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (R)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-methyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-methyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((5-chloropyridin-2-yl)methoxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)- 1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3- ((1-ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3- ((1-ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2,5-difluorobenzyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- ((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2-fluoro-5- methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or - (S)-2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2-fluoro-5- methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof. 13. Compound according to anyone of claims 1 to 12 for use in the prophylaxis and/or treatment of diabetes and obesity and its comorbidities including NAFLD, NASH and DKD. 14. Pharmaceutical composition comprising as active ingredient a compound of formula (I) according to anyone of claims 1 to 12, in combination with one or more inert, non- toxic, pharmaceutically acceptable excipients or carriers. 15. Pharmaceutical composition according to claim 14, for use in the prophylaxis and/or treatment of diabetes and obesity and its comorbidities including NAFLD, NASH and DKD. |
wherein: R 1 represents a group chosen among: C represents a five-membered heterocycle chosen among: it being understood that both points of attachment of each heterocycle can be linked either to E or X, D represents a carbon or a nitrogen atom, E represents a group chosen among
* indicating the point of attachment, R 2 representing a hydrogen atom or a methyl group, X represents either an oxygen or a sulfur atom, Z 1 and Z 2 represent both a carbon or a nitrogen atom, provided that Z 1 and Z 2 do not simultaneously represent a nitrogen atom, and: - If Z 1 represents a nitrogen atom, Z 2 represents a carbon atom, R 3 is absent and R 4 represents a chlorine atom - if Z 1 and Z 2 both represent a carbon atom: · R 3 represents either a hydrogen, a chlorine atom, a fluorine atom or a cyano group, · R 4 represents either a cyano group, a fluorine atom or a chlorine atom, - if Z 1 represents a carbon atom and Z 2 represents a nitrogen atom, R 3 represents a hydrogen atom and R 4 is absent, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, compound of formula (I) is in the form of a pharmaceutically acceptable salt. In a particularly preferred embodiment, compound of formula (I) is in the form of an ammonium salt. Formula (I) includes all individual enantiomers, and mixtures thereof, as well as racemates, and pharmaceutically acceptable salts thereof. In one embodiment, R 1 represents the following group: In another embodiment, R 1 represents the following group: In one embodiment: - E represents - R 2 represents a hydrogen atom, - C represents - Z 1 and Z 2 both represent a carbon atom, - R 3 represents either a hydrogen, a fluorine atom, a chlorine atom or a cyano group, - R 4 represents either a cyano group, a fluorine atom or a chlorine atom. In another embodiment, a compound of formula (Ia) is provided:
In another embodiment, a compound of formula (Ib) is provided: In one embodiment, in formula (I), (Ia) or (Ib), E represents: In one embodiment, in formula (I), (Ia) or (Ib), R 2 represents a hydrogen atom. In another embodiment, in formula (I), (Ia) or (Ib), R 2 represents a methyl group. In one embodiment, in formula (I), (Ia) or (Ib), E represents a group chosen among In one embodiment, in formula (I), (Ia) or (Ib), C represents the following heterocycle: In another embodiment, in formula (I), (Ia) or (Ib), C represents the following heterocycle: In another embodiment, in formula (I), (Ia) or (Ib), C represents the following heterocycle: In another embodiment, in formula (I), (Ia) or (Ib), C represents the following heterocycle: In one embodiment, in formula (I), (Ia) or (Ib), C represents: , In one embodiment, in formula (I), (Ia) or (Ib), D represents a carbon atom. In one embodiment, in formula (I), (Ia) or (Ib), D represents a nitrogen atom. In one embodiment, in formula (I), (Ia) or (Ib), X represents an oxygen atom. In one embodiment, in formula (I), (Ia) or (Ib), X represents a sulfur atom. In one embodiment, in formula (I), (Ia) or (Ib), Z 1 represents a carbon atom, Z 2 represents a nitrogen atom, R 3 represents a hydrogen atom and R 4 is absent. In one embodiment, in formula (I), (Ia) or (Ib), Z 1 represents a nitrogen atom, Z 2 represents a carbon atom, R 3 is absent and R 4 represents a chlorine atom. In one embodiment, in formula (I), (Ia) or (Ib), Z 1 and Z 2 both represent a carbon atom, R 3 represents either a hydrogen, a fluorine atom, a chlorine atom or a cyano group and R 4 represents either a cyano group, a fluorine atom or a chlorine atom. In another embodiment, a compound of formula (Ic) is provided: In one embodiment, in the compound of formula (Ic), E represents a group chosen among
In one embodiment, in the compound of formula (Ic), R 3 represents a fluorine atom and R 4 represents either a chlorine atom or a cyano group. In another embodiment, a compound of formula (Id) is provided: In one embodiment, R 1 represents the following group in formula (Id): In another embodiment, R 1 represents the following group in formula (Id): In one embodiment, in formula (Id), E represents: In one embodiment, in formula (Id), R 2 represents a hydrogen atom. In one embodiment, in formula (Id), E represents a group chosen among In one embodiment, in formula (Id), C represents the following heterocycle: In another embodiment, in formula (Id), C represents the following heterocycle: In one embodiment, the compound of formula (I) is chosen among: - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1- ((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-ca rboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol -1-yl}piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol -1-yl}piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}p iperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{3-[(4-cyanophenyl)methoxy]-1H-pyrazol-1-yl}piperidin- 1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{3-[(pyridin-4-yl )methoxy]-1H- pyrazol-1-yl}piperidin-1-yl)methyl]-1H-benzimidazole-6-carbo xylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{3-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-1-yl}piper idin-1-yl)methyl]-1- [(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carbox ylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{1-[(4-fluorophen yl)methoxy]-1H- pyrazol-3-yl}piperidin-1-yl)methyl]-1H-benzimidazole-6-carbo xylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-cyanophenyl)methoxy]-1H-pyrazol-3-yl}piperidin- 1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}-2-me thylpiperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1- yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-benzimidazole-6-ca rboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1-yl)methyl]-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid, ammonium salt or a pharmaceutically acceptable salt thereof, - 2-{[4-(3-{[(4-cyano-2-fluorophenyl)methyl]sulfanyl}-1H-pyraz ol-1-yl)piperidin-1- yl]methyl}-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1-yl)methyl]-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piper idin-1-yl)methyl]-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piper idin-1-yl)methyl]-1- [(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carbox ylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl} piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1- yl)methyl]-1-[(1,3-oxazol-2-yl)methyl]-1H-benzimidazole-6-ca rboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1- yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-benzimidazole-6-ca rboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(5-((4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl )methyl)-1-((1-ethyl- 1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - (R or S)-2-((4-(5-(1-(4-chloro-2-fluorophenyl)ethoxy)-1H-pyrazol-1 -yl)piperidin-1- yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]i midazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1- ((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-ca rboxylic acid or a pharmaceutically acceptable salt thereof, - 2-[[4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]-1-p iperidyl]methyl]-3- [[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl) piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1- yl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin -1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(3-((2-chloro-4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid or a pharmaceutically acceptable salt thereof, - (R)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1- yl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imida zole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl )piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl )piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl) piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl) piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1- yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5 -carboxylic acid or a pharmaceutically acceptable salt thereof - (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl) piperidin-1- yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5 -carboxylic acid or a pharmaceutically acceptable salt thereof - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1- ((1-methyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-c arboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1- ((1-methyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-c arboxylic acid or a pharmaceutically acceptable salt thereof - 2-((4-(3-((5-chloropyridin-2-yl)methoxy)-1H-pyrazol-1-yl)pip eridin-1-yl)methyl)- 1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-3- ((1-ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo[4,5-b]pyridine -6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-3- ((1-ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo[4,5-b]pyridine -5-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1- ((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imi dazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1- ((1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)-1H-benzo [d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1- ((1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)-1H-benzo [d]imidazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1- ((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole- 6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1- ((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole- 6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1- ((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imi dazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2 ,5-difluorobenzyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1- ((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6 -carboxylic acid or a pharmaceutically acceptable salt thereof, - 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1- ((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imi dazole-6- carboxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2 -fluoro-5- methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-c arboxylic acid or a pharmaceutically acceptable salt thereof, - (S)-2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)- 2-fluoro-5- methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-c arboxylic acid or a pharmaceutically acceptable salt thereof. In a further embodiment, a compound of the invention is provided having a Formula (II): wherein: R 5 represents a group chosen among: R 6 represents a hydrogen atom or a methyl group, A-B represents either -CH-CH 2 - or -C=CH-, F represents a five-membered heterocycle chosen among: it being understood that both points of attachment of each heterocycle can be linked either to A or G, G represents either an oxygen or a sulfur atom and J represents a -CH 2 - group, or G represents a -CH 2 - group and J represents either an oxygen or a sulfur atom, Z represents either a carbon or a nitrogen atom, and: - if Z represents a carbon atom: · R 7 represents either a hydrogen or a fluorine atom · R 8 represents either a cyano group, a fluorine atom or a chlorine atom - if Z represents a nitrogen atom, R 7 represents a hydrogen atom and R8 is absent, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, compound of formula (II) is in the form of a pharmaceutically acceptable salt. In a particularly preferred embodiment, compound of formula (II) is in the form of an ammonium salt. Formula (II) includes all individual enantiomers, and mixtures thereof, as well as racemates, and pharmaceutically acceptable salts thereof. In one embodiment, R 5 represents the following group: In another embodiment, R 5 represents the following group: In another embodiment, a compound of formula (IIa) is provided: In one embodiment, R 6 represents a hydrogen atom. In another embodiment, R6 represents a methyl group. In one embodiment A-B represents -CH-CH 2 -. In another embodiment, A-B represents -C=CH-. In one embodiment, F represents the following heterocycle: In another embodiment, F represents the following heterocycle: In another embodiment, F represents the following heterocycle: In another embodiment, F represents the following heterocycle: In one embodiment, G represents an oxygen atom or a sulfur atom and J represents a -CH 2 - group. In another embodiment G represents a -CH 2 - group and J represents an oxygen atom or a sulfur atom. In one embodiment, Z represents a carbon atom, R 7 represents either a hydrogen or a fluorine atom and R8 represents either a cyano group, a fluorine atom or a chlorine atom. In another embodiment, Z represents a carbon atom, R 7 represents either a hydrogen or a fluorine atom and R8 represents either a chlorine atom or a cyano group. In another embodiment, Z represents a nitrogen atom, R 7 represents a hydrogen atom and R 8 is absent. In one embodiment, - F represents - G represents an oxygen atom or a sulfur atom and J represents a -CH 2 - group. In one embodiment, - R 5 represents , - R6 represents a hydrogen atom, - F represents , - G represents an oxygen atom or a sulfur atom and J represents a -CH 2 - group, - Z represents a carbon atom, R 7 represents a fluorine atom or a hydrogen atom and R 8 represents a chlorine atom or a cyano group. In one embodiment, the compounds according to the invention are intended for use in the prophylaxis and/or treatment of diabetes and obesity and its comorbidities including, but not limited to, NAFLD, NASH and DKD. In one embodiment, the compound of formula (I) according to the present invention is administered in association with one or more additional active ingredients. The administration in association may be in the form of a simultaneous or successive co- administration of two or more separate pharmaceutical compositions each containing one of the active ingredients (free association), or in the form of the administration of a fixed association of the two or more active ingredients in the same pharmaceutical composition. More specifically, the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used in combination with one or more other active ingredients useful in the prevention or treatment of diabetes or NASH, including biguanides, sulfonylureas, SGLT2 inhibitors, Nrf2 activators, FXR agonists, PPAR modulators, Thyroid hormone receptor agonists, FGF21 agonists, FGF19 agonists, DGAT2 inhibitors, ACC inhibitors or FAS inhibitors. A further aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) as active ingredient, alone or in combination with one or more other active ingredients chosen among the ones listed above. In one embodiment, the pharmaceutical composition of the invention is intended for use in the prophylaxis and/or treatment of diabetes and obesity and its comorbidities including, but not limited to, NAFLD, NASH and DKD. In the pharmaceutical composition according to the invention, the proportion of active ingredients by weight (weight of active ingredients over the total weight of the composition) is from 5 to 50 %. Among the pharmaceutical compositions according to the invention there will be more especially used those which are suitable for administration by the oral, parenteral and especially intravenous, per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory route, more specifically tablets, dragées, sublingual tablets, hard gelatin capsules, glossettes, capsules, lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams, ointments, dermal gels etc. The pharmaceutical composition according to the invention comprise one or more excipients or carriers selected from diluents, lubricants, binders, disintegration agents, stabilizers, preservatives, absorbents, colorants, sweeteners, flavorings etc. By way of non-limiting example there may be mentioned: - as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol, - as lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, - as binders: magnesium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, - as disintegrants: agar, alginic acid and its sodium salt, effervescent mixtures. The administration route is preferably oral. In one embodiment of the invention, the compound of formula (I) is the sole active ingredient comprised in the pharmaceutical composition of the invention. In the pharmaceutical composition comprising the compound of formula (I) as the sole active ingredient, the useful dosage regimen varies according to the sex, age and weight of the patient, the administration route, the nature of any associated treatments and ranges from 1 to 350 mg of the compound of formula (I). In one embodiment, the pharmaceutical composition according to the invention and comprising a compound of formula (I) as the sole active ingredient is intended for use in the prophylaxis and/or treatment of diabetes and obesity and its comorbidities including, but not limited to, NAFLD, NASH and DKD. EXAMPLES List of abbreviations ACN : acetonitrile AIBN azobisisobutyronitrile Boc 2 O di-tert-butyl dicarbonate BnBr : benzyl bromide DAST diethylaminosulfur trifluoride DCM dichloromethane DIEA : diisopropylethylamine DMF : N,N-dimethylformamide DMSO : dimethylsulfoxyde EA : ethyl acetate EDTA : ethylene diamine tetraacetic acid ESI : electrospray ionization EtOAc ethyl acetate eq : equivalent(s) HEPES : 4-(2-hydroxyethyl-1-piperazin ethanesulfonic acid HPLC high performance liquid chromatography LCMS : liquid chromatography-mass spectrometry LDA : lithium diidopropylamide MS : mass spectrometry N/A not available NMR : nuclear magnetic resonance PE : petroleum ether TBD 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine TEA : triethylamine TFA : trifluoroacetic acid THF : tetrahydrofurane TLC : thin layer chromatography TsOH : paratoluenesulfonic acid Xantphos : 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Chemical synthetic processes Synthesis of intermediate compounds Intermediate 1 Step 1.3-ethylimidazole-4-carbonitrile To a mixture of methyl 1H-imidazole-5-carboxylate (50 g, 396.47 mmol, 1.0 eq) and bromoethane (64.80 g, 594.70 mmol, 44.38 mL, 1.5 eq) in acetonitrile (600 mL) was added K 2 CO 3 (109.59 g, 792.94 mmol, 2.0 eq) in one portion. The mixture was stirred at 80 °C for 5 h. The mixture was cooled to 20 °C and filtered. The cake was washed with acetonitrile (15 mL x 2) and the filtrate was concentrated in reduced pressure. The residue was purified by flash chromatography (SiO 2 , Petroleum ether/Ethyl acetate = 2/1, 0/1). The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250x80mmx10µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 10%-15%,16min).3-ethylimidazole-4- carbonitrile (9.2 g, 75.95 mmol, 23 % yield) was obtained as yellow oil. 1 H NMR: (400 MHz, CD 3 OD) δ 7.98 (s, 1H), 7.72 (d, J = 0.8 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H). Step 2. (3-ethylimidazol-4-yl)methanamine To a solution of 3-ethylimidazole-4-carbonitrile (9.5 g, 78.42 mmol, 1 eq) in MeOH (150 mL) was added NH 3 .H 2 O (45.50 g, 389.49 mmol, 50 mL, 30% purity, 4.97 eq) and Raney- Ni (1.34 g, 15.68 mmol, 0.2 eq) under N2. The reaction mixture was stirred at 50 °C under H 2 (50 Psi) for 6 h. The mixture was filtered, and the filtrate was concentrated in vacuum. (3-ethylimidazol-4-yl)methanamine (9.8 g, crude) was obtained as a gray oil. LCMS: MS (ESI) m/z: 126.1 [M+1] + . Step 3. methyl 3-[(3-ethylimidazol-4-yl)methylamino]-4-nitro-benzoate To a solution of (3-ethylimidazol-4-yl)methanamine (8 g, 63.91 mmol, 1 eq) in DMAC (80 mL) was added TEA (12.93 g, 127.82 mmol, 17.79 mL, 2 eq) and methyl 3-fluoro-4-nitro- benzoate (12.73 g, 63.91 mmol, 1 eq). The reaction was stirred at 50 °C for 12 h. EtOAc (200 mL) and water (300 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (200 mL x 2), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The mixture was triturated with EtOAc and PE (EA/PE = 1/1, V/V). methyl 3-[(3-ethylimidazol-4-yl)methylamino]-4- nitro-benzoate (11 g, 33.98 mmol, 53% yield, 94% purity) was obtained as a brown solid. LCMS: MS (ESI) m/z: 305.0 [M+1] + . 1 H NMR: (400 MHz, CDCl 3 ) δ 8.25 (d, J = 8.9 Hz, 1H), 7.95 (br s, 1H), 7.69 (s, 1H), 7.57 (br d, J = 3.6 Hz, 1H), 7.34 (dd, J = 1.1, 8.9 Hz, 1H), 7.12 (br d, J = 4.1 Hz, 1H), 4.55 (br s, 2H), 4.03 - 3.94 (m, 5H), 1.49 (br s, 3H). Step 4. methyl 4-amino-3-[(3-ethylimidazol-4-yl)methylamino]benzoate To a solution of methyl 3-[(3-ethylimidazol-4-yl)methylamino]-4-nitro-benzoate (11 g, 36.15 mmol, 1 eq) in MeOH (120 mL) was added Pd/C (300 mg, 10% purity) under N2. The reaction mixture was stirred at 20 °C under H 2 (15 Psi) for 12 h. TLC (dichloromethane:methanol = 10:1) showed new spot was detected. The mixture was filtered and the filtrate was concentrated in vacuum. Methyl 4-amino-3-[(3-ethylimidazol-4- yl)methylamino]benzoate (9.5 g, 34.63 mmol, 95% yield) was obtained as a light yellow solid. LCMS: MS (ESI) m/z: 275.1 [M+1] + . 1 H NMR: (400 MHz, DMSO-d6) □ = 7.63 (d, J = 0.9 Hz, 1H), 7.18 (dd, J = 1.8, 8.1 Hz, 1H), 7.12 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 0.4 Hz, 1H), 6.54 (d, J = 8.1 Hz, 1H), 5.48 (s, 2H), 4.90 (t, J = 5.1 Hz, 1H), 4.24 (d, J = 5.0 Hz, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H) Step 5. methyl 3-[(3-ethylimidazol-4-yl)methyl]-2-(hydroxymethyl)benzimidaz ole-5- carboxylate A solution of methyl 4-amino-3-[(3-ethylimidazol-4-yl)methylamino]benzoate (1 g, 3.65 mmol, 1 eq) , 2-hydroxyacetic acid (416 mg, 5.47 mmol, 1.5 eq) in 1,2,3-trimethylbenzene (5 mL) was stirred at 140 °C for 12 h. The clear yellow solution was decanted off to give a brown residue that was dissolved in methanol (20 mL) and concentrated in vacuum. The residue was purified on silica gel chromatography (dichloromethane:methanol = 1:0 to 10:1). methyl 3-[(3-ethylimidazol-4-yl)methyl]-2-(hydroxymethyl)benzimidaz ole-5-carboxylate (500 mg, 1.50 mmol, 41% yield, 94% purity) was obtained as a light yellow gum. LCMS: (ESI) m/z: 315.1 [M+1] + . 1 H NMR: (400 MHz, CDCl 3 ) δ 8.11 (d, J = 1.0 Hz, 1H), 7.83 (dd, J = 1.6, 8.4 Hz, 1H), 7.74 - 7.66 (m, 2H), 6.55 (s, 1H), 5.70 (s, 2H), 4.74 (s, 2H), 3.96 (q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 1.12 (t, J = 7.3 Hz, 3H). Step 6. methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]benzimidazo le-5- carboxylate To a solution of methyl 3-[(3-ethylimidazol-4-yl)methyl]-2- (hydroxymethyl)benzimidazole-5- carboxylate (500 mg, 1.59 mmol, 1 eq), DMF (116 mg, 1.59 mmol, 0.1 mL, 1 eq) in DCM (5 mL) was added dropwise SOCl 2 (946 mg, 7.95 mmol, 0.58 mL, 5 eq). The reaction mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuum. Methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl] benzimidazole-5-carboxylate (500 mg, crude, HCl) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 333.1 [M+1] + . Intermediate 3a To a stirred solution of 1,2-dihydropyrazol-3-one (2 g, 23.79 mmol, 1 eq) in DCM (20 mL) was added TEA (2.89 g, 28.55 mmol, 3.97 mL, 1.2 eq) and Boc 2 O (6.23 g, 28.55 mmol, 6.56 mL, 1.2 eq).The resulting mixture was stirred at 20°C for 12 h. Water (200 mL) was added to the mixture and the aqueous was extracted with DCM (150 mL x 3). The combined organic layer was dried over Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (DCM:MeOH=100:1-10:1) to obtain tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (3.5 g, 19.00 mmol, 80% yield) as a yellow oil. LCMS: (ESI) m/z: 129.1 [M+1-56] + . Step 2. tert-butyl 3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazole-1-carboxylate
To a stirred solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (1.5 g, 8.14 mmol, 1 eq) and 4-(bromomethyl)-3-fluoro-benzonitrile (1.74 g, 8.14 mmol, 1 eq) in CH 3 CN (15 mL) was added K 2 CO 3 (2.25 g, 16.29 mmol, 2 eq). The resulting mixture was stirred at 50°C for 2 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EA (150 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 100:1-3:1) to give tert-butyl 3-[(4-cyano-2-fluoro- phenyl)methoxy]pyrazole-1-carboxylate (900 mg, 2.84 mmol, 35% yield) as a white solid. LCMS: (ESI) m/z: 217.8 [M+1-100] + . 1 H NMR: (400 MHz, DMSO-d6) δ:8.12 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 10.0 Hz, 1H), 7.76 (d, J = 3.2 Hz, 2H), 6.18 (d, J = 2.8 Hz, 1H), 5.37 (s, 2H), 1.55 (s, 9H). Step 3.4-(((1H-pyrazol-3-yl)oxy)methyl)-3-fluorobenzonitrile To a stirred solution of tert-butyl 3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazole-1- carboxylate (900 mg, 2.84 mmol, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 9.52 eq). The resulting mixture was stirred at 20°C for 1 h. The reaction mixture was poured into saturated NaHCO 3 aqueous (100 mL) at 0 °C and the mixture was stirred at 20°C for 10 min. Then the aqueous was extracted with DCM (60 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum to give 3-fluoro-4-(1H-pyrazol-3-yloxymethyl)benzonitrile (600 mg, 2.76 mmol, 97% yield) as a white solid. LCMS: MS (ESI) m/z: 218.1 [M+1] + . Step 4. tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin e-1- carboxylate To a stirred solution of 3-fluoro-4-(1H-pyrazol-3-yloxymethyl)benzonitrile (400 mg, 1.84 mmol, 1 eq) in DMF (10 mL) was added tert-butyl 4-methylsulfonyloxypiperidine-1- carboxylate (1.29 g, 4.60 mmol, 2.5 eq) and Cs 2 CO 3 (1.80 g, 5.52 mmol, 3 eq). The resulting mixture was stirred at 100°C for 6 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EA (150 mL x 2). The combined organic layer was washed with brine (150 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA=50:1-3:1) to give tert-butyl 4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperidi ne-1- carboxylate (260 mg, 0.65 mmol, 35.26% yield) as a light yellow oil. LCMS: MS (ESI) m/z: 345.1 [M+1-56] + . 1 H NMR: (400 MHz, CDCl 3 ) δ 7.70 (t, J = 7.6 Hz, 1H), 7.47 (dd, J = 8.0, 1.2 Hz, 1H), 7.37 (dd, J = 9.2, 1.5 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 5.70 (d, J = 2.4 Hz, 1H), 5.31 (s, 2H), 4.14 - 4.33 (m, 2H), 3.98 - 4.12 (m, 1H), 2.77 - 2.94 (m, 2H), 2.02 - 2.14 (m, 2H), 1.77 - 1.92 (m, 2H), 1.48 (s, 9H). Step 5.3-fluoro-4-(((1-(piperidin-4-yl)-1H-pyrazol-3-yl)oxy)methy l)benzonitrile
To a stirred solution of tert-butyl 4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (370.00 mg, 0.92 mmol, 1 eq) in EtOAc (10 mL) was added TsOH (954.66 mg, 5.54 mmol, 5 eq). The reaction mixture was stirred at 60 °C for 12 h. The mixture was concentrated under vacuum to give 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3- yl]oxymethyl]benzonitrile (1.2 g, 0.76 mmol, 82% yield, 30% purity, as p-toluenesulfonic acid salt) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 301.1 [M+1] + . Intermediate 3b Step 1: tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylate To a stirred solution of 1,2-dihydropyrazol-3-one (2 g, 23.79 mmol, 1 eq) in DCM (20 mL) was added TEA (2.89 g, 28.55 mmol, 3.97 mL, 1.2 eq) and Boc 2 O (6.23 g, 28.55 mmol, 6.56 mL, 1.2 eq).The resulting mixture was stirred at 20°C for 12 h. Water (200 mL) was added to the mixture and the aqueous was extracted with DCM (150 mL x 3). The combined organic layer was dried over Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (DCM:MeOH=100:1-10:1) to obtain tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (3.5 g, 19.00 mmol, 80% yield) as a yellow oil. LCMS: EW22514-149-P1B; (ESI) m/z: 129.1 [M+1-56] + . Step 2. tert-butyl 3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazole-1-carboxylate To a stirred solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (1.5 g, 8.14 mmol, 1 eq) and 1-(bromomethyl)-4-chloro-2-fluoro-benzene (1.82 g, 8.14 mmol, 1 eq) in CH 3 CN (15 mL) was added K 2 CO 3 (2.25 g, 16.29 mmol, 2 eq). The resulting mixture was stirred at 50°C for 4 h. Water (300 mL) was added to the mixture and the aqueous was extracted with EA (150 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 100:1-3:1) to give tert-butyl 3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazole-1-carboxylate (900 mg, 2.75 mmol, 34% yield) as a light yellow oil. LCMS: (ESI) m/z: 270.8 [M+1-56] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J = 2.8 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.09 - 7.21 (m, 2H), 5.91 (d, J = 2.9 Hz, 1H), 5.37 (s, 2H), 1.64 (s, 9H). Step 3.3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazole
To a stirred solution of tert-butyl 3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazole-1- carboxylate (900 mg, 2.75 mmol, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 9.81 eq). The resulting mixture was stirred at 20°C for 1 h. Saturated NaHCO 3 aqueous (200 mL) was added to the mixture and the mixture was stirred at 20°C for 10 min. Then the mixture was extracted with DCM (100 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum to give 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H-pyrazole (580 mg, 2.56 mmol, 93% yield) as a light yellow solid. LCMS: (ESI) m/z: 227.1 [M+1-100] + . Step 4. tert-butyl 4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidi ne-1- carboxylate To a stirred solution of 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H-pyrazole (500 mg, 2.21 mmol, 1 eq) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1.54 g, 5.53 mmol, 2.5 eq) in DMF (15 mL) was added Cs 2 CO 3 (1.44 g, 4.42 mmol, 2 eq). The resulting mixture was stirred at 100°C for 12 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EA (100 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated. The mixture was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25mmx 10um;mobile phase: [water(0.1%TFA)-ACN];B%: 60%-90%,10min) to afford tert-butyl 4-[3-[(4-chloro-2- fluoro-phenyl)methoxy]pyrazol-1-yl]piperidine-1-carboxylate (630 mg, 1.54 mmol, 69.55% yield) and tert-butyl 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine-1- carboxylate (130 mg, 0.32 mmol, 14% yield) as a colorless oil. LCMS: MS (ESI) m/z: 354.3 [M+1-56] + . 1 H NMR: (400 MHz, CDCl 3 ) δ 7.48 (t, J = 8.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.07 - 7.18 (m, 2H), 5.68 (d, J = 2.4 Hz, 1H), 5.21 (s, 2H), 4.22 (br dd, J = 5.4, 2.4 Hz, 2H), 3.96 - 4.11 (m, 1H), 2.76 - 2.96 (m, 2H), 2.04 - 2.14 (m, 2H), 1.75 - 1.95 (m, 2H), 1.48 (s, 9H). Step 5. 4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidi ne To a stirred solution of tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (130 mg, 0.32 mmol, 1 eq) in DCM (2 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 8.52 eq). The resulting mixture was stirred at 20°C for 1 h. The mixture was concentrated under vacuum to give 4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]piperidine (130 mg, 0.31 mmol, 97% yield, TFA) as a yellow oil. LCMS: MS (ESI) m/z: 309.8 [M+1] + . Intermediate 3d 4-(5-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidi ne To a stirred solution of tert-butyl 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (130 mg, 0.32 mmol, 1 eq) in DCM (2 mL) was added TFA (616.00 mg, 5.40 mmol, 0.4 mL, 17.03 eq). The reaction mixture was stirred at 20°C for 1 h. The mixture was concentrated under vacuum to give 4-[5-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]piperidine (130 mg, 0.31 mmol, 97% yield, TFA) as a yellow oil. LCMS: (ESI) m/z: 310.1 [M+1] + . Intermediate 3h Step 1.1-[(4-methoxyphenyl)methyl]-2-oxido-pyrazol-2-ium To a mixture of 1-hydroxypyrazole (3 g, 35.68 mmol, 1 eq) and 4-Methoxybenzylalcohol (8.84 g, 64.01 mmol, 7.97 mL, 1.79 eq) in CHCl 3 (85 mL) was added TFA (12.68 g, 111.25 mmol, 8.24 mL, 3.12 eq) dropwise, the mixture was heated to 50 °C for 12 h. The mixture was poured into saturated sodium bicarbonate solution (100 mL) to adjust pH to 8-9, the mixture was extracted with dichloromethane (50 mL x 2), washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Dichloromethane:Methanol = 1:0 to 20:1). Compound 1-[(4-methoxyphenyl)methyl]-2-oxido-pyrazol-2-ium (5.1 g, 24.97 mmol, 70% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 204.9 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.21 (d, J = 8.4 Hz, 2H), 7.17 - 7.13 (m, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.72 - 6.65 (m, 1H), 6.03 (dd, J = 2.4, 3.6 Hz, 1H), 5.18 (s, 2H), 3.75 (s, 3H) Step 2.3-bromo-2-[(4-methoxyphenyl)methyl]-1-oxido-pyrazol-1-ium 1-[(4-methoxyphenyl)methyl]-2-oxido-pyrazol-2-ium (4.5 g, 22.03 mmol, 1 eq) was dissolved in CHCl 3 (60 mL) and freshly mortared anhydrous K 2 CO 3 (8.73 g, 63.20 mmol, 2.87 eq) was added. The suspension was cooled to -55 °C in the dark before addition of Br 2 (3.52 g, 22.03 mmol, 1.14 mL, 1 eq) over 10 min at between -55 and -50 °C. Stirring was continued for 30 min before the cooling bath was removed. The mixture was subsequently stirred at 25 °C for 20 min. TLC (Dichloromethane: Methanol=10:1) shows most of the starting material was consumed. 1 M sodium sulfite solution (100 mL) was added, the mixture was extracted with dichloromethane (80 mL x 2). The combined organic phase was washed with brine (70 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min). Compound 3-bromo-2-[(4-methoxyphenyl)methyl]-1-oxido-pyrazol-1-ium (3 g, 10.60 mmol, 48.09% yield) was obtained as a yellow solid. 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.32 - 7.28 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 6.81 - 6.76 (m, 2H), 6.13 (d, J = 2.4 Hz, 1H), 5.30 (s, 2H), 3.72 (s, 3H) Step 3. 3-bromo-1-hydroxy-pyrazole To a mixture of 3-bromo-2-[(4-methoxyphenyl)methyl]-1-oxido-pyrazol-1-ium (3 g, 10.60 mmol, 1 eq) in DCM (15 mL) was added TFA (21.66 g, 189.93 mmol, 14 mL, 17.92 eq) and triisopropylsilane (4.19 g, 26.49 mmol, 5 mL, 2.5 eq), then the reaction mixture was stirred at 50 °C for 12 h. The reaction was concentrated under vacuum. The residue was added ethyl acetate (20 mL), then the mixture was poured into saturated sodium bicarbonate (50 mL) to adjust pH to 8-9, then the mixture was extracted with ethyl acetate (40mLx2), the combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Dichloromethane: Methanol=50:1 to 20:1). Compound 3-bromo-1-hydroxy-pyrazole (800 mg, 4.91 mmol, 46% yield) was obtained as a yellow solid. 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.34 (d, J = 2.4 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H) Step 4.1-benzyloxy-3-bromo-pyrazole To a mixture of 3-bromo-1-hydroxy-pyrazole (400 mg, 2.45 mmol, 1 eq) in DCM (10 mL) was added DIEA (349 mg, 2.70 mmol, 0.5 mL, 1.1 eq) and BnBr (462 mg, 2.70 mmol, 0.3 mL, 1.1 eq), then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate=10:1 to 5:1). Compound 1-benzyloxy-3-bromo-pyrazole (500 mg, 1.98 mmol, 80% yield) was obtained as yellow oil. 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.45 - 7.29 (m, 5H), 6.87 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.29 (s, 2H) Step 5. tert-butyl 4-(1-benzyloxypyrazol-3-yl)-3,6-dihydro-2H-pyridine-1-carbox ylate , , A mixture of 1-benzyloxy-3-bromo-pyrazole (440 mg, 1.74 mmol, 1 eq), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H -pyridine-1-carboxylate (600 mg, 1.94 mmol, 1.12 eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (142 mg, 0.17 mmol, 0.1 eq), Na 2 CO 3 (553 mg, 5.22 mmol, 3 eq) in H 2 O (1.8 mL) and dioxane (9 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 100 °C for 3 hours under N 2 atmosphere. The residue was poured into ice-water (30 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (15 mLx3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. 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 @ 60 mL/min). Compound tert-butyl 4-(1-benzyloxypyrazol-3-yl)-3,6-dihydro-2H-pyridine-1-carbox ylate (430 mg, 1.21 mmol, 70% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 356.2 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.41 - 7.29 (m, 5H), 6.91 (d, J = 2.4 Hz, 1H), 6.17 (br s, 1H), 6.09 (d, J = 2.4 Hz, 1H), 5.27 (s, 2H), 4.07 (br d, J = 2.8 Hz, 2H), 3.62 (br t, J = 5.6 Hz, 2H), 2.57 (br d, J = 2.0 Hz, 2H), 1.49 (s, 9H). Step 6: tert-butyl 4-(1-hydroxypyrazol-3-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(1-benzyloxypyrazol-3-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (200 mg, 0.56 mmol, 1 eq) in MeOH (8 mL) was added Pd/C (20 mg, 10% purity) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15psi) at 25°C for 12 hours. The residue was poured into water (10 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (10mLx2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep- TLC (Petroleum ether: Ethyl acetate=1:1). Compound tert-butyl 4-(1-hydroxypyrazol-3- yl)piperidine-1-carboxylate (110 mg, 0.41 mmol, 73% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 268.2 [M+1] + Step 7. tert-butyl 4-[1-[(4-cyanophenyl)methoxy]pyrazol-3-yl]piperidine-1-carbo xylate To a mixture of tert-butyl 4-(1-hydroxypyrazol-3-yl)piperidine-1-carboxylate (150 mg, 0.56 mmol, 1 eq) in DCM (1 mL) was added 4-(bromomethyl)benzonitrile (121 mg, 0.62 mmol, 1.1 eq) and DIEA (80 mg, 0.62 mmol, 0.1 mL, 1.1 eq), then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ether gradient @ 60 mL/min). Compound tert- butyl 4-[1-[(4-cyanophenyl)methoxy]pyrazol-3-yl]piperidine-1-carbo xylate (180 mg, 0.47 mmol, 84% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 327.0 [M-55] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.67 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 2.4 Hz, 1H), 5.88 (d, J = 2.0 Hz, 1H), 5.32 (s, 2H), 4.23 - 4.10 (m, 2H), 2.85 (br t, J = 12.0 Hz, 2H), 2.80 - 2.70 (m, 1H), 1.98 - 1.86 (m, 2H), 1.61 - 1.54 (m, 2H), 1.48 (s, 9H) Step 8.4-[[3-(4-piperidyl)pyrazol-1-yl]oxymethyl]benzonitrile To a solution of tert-butyl 4-[1-[(4-cyanophenyl)methoxy]pyrazol-3-yl]piperidine-1- carboxylate (120 mg, 0.31 mmol, 1 eq) in DCM (3 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 21.52 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under vacuum. Compound 4-[[3-(4-piperidyl)pyrazol-1- yl]oxymethyl]benzonitrile (124 mg, 0.31 mmol, 100% yield, TFA) was obtained as a yellow oil and used without further purification. Intermediate 3c Step 1. tert-butyl 3-iodo-1H-pyrazole-1-carboxylate To a stirred solution of 3-iodo-1H-pyrazole (1 g, 5.16 mmol, 1 eq) in DCM (10 mL) was added Boc 2 O (1.35 g, 6.19 mmol, 1.42 mL, 1.2 eq) and TEA (1.04 g, 10.31 mmol, 1.44 mL, 2 eq). The resulting mixture was stirred at 20°C for 12 h. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatograph (PE:EA=100:1-5:1) to give tert-butyl 3-iodopyrazole-1-carboxylate (1.4 g, 4.76 mmol, 92% yield) was obtained as a white solid. LCMS: MS (ESI) m/z: 194.7 [M+1-100] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.90 (d, J = 2.8 Hz, 1H), 6.54 (d, J = 2.7 Hz, 1H), 1.65 (s, 9H) Step 2. 4-(((1H-pyrazol-3-yl)thio)methyl)-3-fluorobenzonitrile To a stirred solution of 3-fluoro-4-(sulfanylmethyl)benzonitrile (341 mg, 2.04 mmol, 1.2 eq) and tert-butyl 3-iodopyrazole-1-carboxylate (500 mg, 1.70 mmol, 1 eq) in dioxane (8 mL) was added Xantphos (197 mg, 340.03 µmol, 0.2 eq), DIEA (440 mg, 3.40 mmol, 0.59 mL, 2 eq) and Pd2(dba)3 (156 mg, 0.17 mmol, 0.1 eq) under N2. The resulting mixture was stirred at 100°C for 12 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 2:1) to give 3-fluoro-4- (1H-pyrazol-3-ylsulfanylmethyl)benzonitrile (300 mg, 1.29 mmol, 76% yield) as a brown solid. LCMS: (ESI) m/z: 233.8 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 7.54 (d, J = 2.4 Hz, 1H), 7.29 - 7.36 (m, 3H), 6.25 (d, J = 2.3 Hz, 1H), 4.13 (d, J = 0.8 Hz, 2H). Step 3. 3-fluoro-4-(mercaptomethyl)benzonitrile To a stirred solution of 4-(bromomethyl)-3-fluoro-benzonitrile (1 g, 4.67 mmol, 1 eq) in EtOH (20 mL) was added thiourea (711.30 mg, 9.34 mmol, 2 eq). The resulting mixture was stirred at 80°C for 1 h. The mixture was concentrated under vacuum. The residue was dissolved into NaOH (aq.) (2M) (20 mL) and the mixture was stirred at 20°C for 2 h. The pH value of the mixture was adjusted to 6 and the aqueous was extracted with EA (150 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 100:1-5:1) to give 3-fluoro-4-(sulfanylmethyl)benzonitrile (550 mg, 3.29 mmol, 71% yield) as a white solid. 1 H NMR: (400 MHz, DMSO-d 6 ) δ 7.80 - 7.88 (m, 1H), 7.61 - 7.73 (m, 2H), 3.80 (d, J = 7.8 Hz, 2H), 3.15 (t, J = 8.0 Hz, 1H) Step 4. tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidi ne-1- carboxylate To a stirred solution of 3-fluoro-4-(1H-pyrazol-3-ylsulfanylmethyl)benzonitrile (500 mg, 2.14 mmol, 1 eq) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1.20 g, 4.29 mmol, 2 eq) in DMF (10 mL) was added Cs 2 CO 3 (1.40 g, 4.29 mmol, 2 eq). The resulting mixture was stirred at 65°C for 1 h. Water (250 mL) was added to the mixture and the aqueous was extracted with EA (100 mL x 2). The combined organic layer was washed with brine (150 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150x25mmx 10µm;mobile phase: [water(0.1%TFA)-ACN];B%: 55%-85%, 10min, then by prep-TLC (PE:EA = 3:1) to give tert-butyl 4-[3-[(4-cyano-2-fluoro- phenyl)methylsulfanyl]pyrazol-1-yl]piperidine-1-carboxylate (65 mg, 0.16 mmol, 7% yield) as a colorless oil. LCMS: MS (ESI) m/z: 361.3 [M+1-56] + , 317.3 [M+1-100] + Step 5.3-fluoro-4-(((1-(piperidin-4-yl)-1H-pyrazol-3-yl)thio)meth yl)benzonitrile
To a stirred solution of tert-butyl 4-[3-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]piperidine-1-carboxylate (65 mg, 0.16 mmol, 1 eq) in DCM (2 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 17.31 eq). The reaction mixture was stirred at 20°C for 1 h. The mixture was concentrated under vacuum to give 3-fluoro-4-[[1-(4-piperidyl)pyrazol- 3-yl]sulfanylmethyl]benzonitrile (67 mg, 0.16 mmol, 100% yield, TFA) as a light yellow oil. LCMS: MS (ESI) m/z: 317.0 [M+1] + . Intermediate 3e Step 1. tert-butyl 4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]piperidine-1-carb oxylate To a mixture of tert-butyl 4-(1-hydroxypyrazol-3-yl)piperidine-1-carboxylate (300 mg, 1.12 mmol, 1 eq) in DCM (1 mL) was added 1-(bromomethyl)-4-chloro-benzene (254 mg, 1.23 mmol, 1.1 eq) and DIEA (160 mg, 1.23 mmol, 1.1 eq), then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 60 mL/min). Compound tert- butyl 4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]piperidine-1-carb oxylate (300 mg, 0.77 mmol, 68% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 335.9 [M-55] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.36 - 7.31 (m, 2H), 7.26 - 7.20 (m, 2H), 6.91 (d, J = 2.4 Hz, 1H), 5.85 (d, J = 2.4 Hz, 1H), 5.22 (s, 2H), 4.26 - 4.11 (m, 2H), 2.85 (br t, J = 12.4 Hz, 2H), 2.76 (tt, J = 3.6, 11.6 Hz, 1H), 1.93 (br d, J = 11.2 Hz, 2H), 1.61 - 1.54 (m, 2H), 1.48 (s, 9H). Step 2.4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]piperidine To a mixture of tert-butyl 4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]piperidine-1- carboxylate (110 mg, 0.28 mmol, 1 eq) in DCM (2 mL) was added TFA (462 mg, 4.05 mmol, 0.3 mL, 14.44 eq), then the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under vacuum. Compound 4-[1-[(4-chlorophenyl)methoxy]pyrazol-3- yl]piperidine (113 mg, 0.28 mmol, 99% yield, TFA) was obtained as a colorless oil without further purification. Intermediate 3f Step 1. tert-butyl 3-((4-cyanobenzyl)oxy)-1H-pyrazole-1-carboxylate
To a stirred solution of tert-butyl 3-hydroxypyrazole-1-carboxylate (1.5 g, 8.14 mmol, 1 eq) and 4-(bromomethyl)benzonitrile (1.60 g, 8.14 mmol, 1 eq) in CH 3 CN (15 mL) was added K 2 CO 3 (2.25 g, 16.29 mmol, 2 eq). The resulting mixture was stirred at 50°C for 4 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EtOAc (100 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA=100:1-3:1) to give tert-butyl 3-[(4-cyanophenyl)methoxy]pyrazole-1-carboxylate (880 mg, 2.94 mmol, 36% yield) as a white solid. LCMS: (ESI) m/z: 244.4 [M+1-56] + , 200.4 [M+1-100] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.87 (d, J = 2.8 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 5.94 (d, J = 2.8 Hz, 1H), 5.41 (s, 2H), 1.63 (s, 9H). Step 2.4-(((1H-pyrazol-3-yl)oxy)methyl)benzonitrile To a stirred solution of tert-butyl 3-[(4-cyanophenyl)methoxy]pyrazole-1-carboxylate (880 mg, 2.94 mmol, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 9.19 eq). The resulting mixture was stirred at 20°C for 1 h. Saturated NaHCO 3 aqueous (200 mL) was added to the mixture at 0°C. The mixture was stirred at 20°C for 10 min. then the aqueous was extracted with DCM (100 mL x3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum to give 4-(1H- pyrazol-3-yloxymethyl)benzonitrile (550 mg, 2.76 mmol, 94% yield) as a white solid. LCMS: (ESI) m/z: 200.1 [M+1] + . Step 3. tert-butyl 4-(3-((4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)piperidine-1-carbo xylate To a stirred solution of 4-(1H-pyrazol-3-yloxymethyl)benzonitrile (550 mg, 2.76 mmol, 1 eq) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1.70 g, 6.07 mmol, 2.2 eq) in DMF (15 mL) was added Cs 2 CO 3 (1.80 g, 5.52 mmol, 2 eq). The resulting mixture was stirred at 100°C for 12 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EtOAc (150 mL x 2). The combined organic layer was washed with brine (100 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 100:1-2:1) to give tert-butyl 4-[3-[(4-cyanophenyl)methoxy]pyrazol-1-yl]piperidine-1-carbo xylate (630 mg, 1.65 mmol, 60% yield) as a colorless oil. LCMS: MS (ESI) m/z: 327.1 [M+1-56] + . Step 4. tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin e-1- carboxylate
To a stirred solution of tert-butyl 4-[3-[(4-cyanophenyl)methoxy]pyrazol-1-yl]piperidine-1- carboxylate (130 mg, 0.34 mmol, 1 eq) in DCM (2 mL) was added TFA (616.00 mg, 5.40 mmol, 0.4 mL, 15.89 eq). The resulting mixture was stirred at 20°C for 1 h. The mixture was concentrated under vacuum to give 4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitrile (130 mg, 0.33 mmol, 96% yield, TFA) as a yellow oil. LCMS: MS (ESI) m/z: 282.9 [M+1] + . Intermediate 3g Step 1. tert-butyl 4-[1-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-3-yl]piperidi ne-1- carboxylate To a mixture of 4-(bromomethyl)-3-fluoro-benzonitrile (79 mg, 0.37 mmol, 1.1 eq) in DCM (1 mL) was added tert-butyl 4-(1-hydroxypyrazol-3-yl)piperidine-1-carboxylate (90 mg, 0.34 mmol, 1 eq) and DIEA (48 mg, 0.37 mmol, 1.1 eq), then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=2:1) to get the product tert-butyl 4- [1-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-3-yl]piperidine -1-carboxylate (110 mg, 0.27 mmol, 82% yield) as a yellow solid. LCMS: MS (ESI) m/z: 423.3 [M+23] + . Step 2. 3-fluoro-4-[[3-(4-piperidyl)pyrazol-1-yl]oxymethyl] benzonitrile To a mixture of tert-butyl 4-[1-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-3-yl]piperidi ne- 1-carboxylate (110 mg, 0.27 mmol, 1 eq) in DCM (0.5 mL) was added TFA (385 mg, 3.38 mmol, 12.29 eq), then the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under vacuum. Compound 3-fluoro-4-[[3-(4-piperidyl)pyrazol-1- yl]oxymethyl]benzonitrile (110 mg, 0.27 mmol, 97% yield, TFA) was obtained as a yellow solid. Intermediate 3i Step 1. Tert-butyl 4-(1-((2,4-difluorobenzyl)oxy)-1H-pyrazol-3-yl)piperidine-1- carboxylate To a mixture of tert-butyl 4-(1-hydroxypyrazol-3-yl)piperidine-1-carboxylate (300 mg, 1.12 mmol, 1 eq) and 1-(bromomethyl)-2,4-difluoro-benzene (256 mg, 1.23 mmol, 1.1 eq) in DCM (3 mL) was added DIEA (217.56 mg, 1.68 mmol, 293.21 uL, 1.5 eq). The mixture was stirred at 25 °C for 12 hours. The mixture was poured into ice-water (w/w = 1/1) (30 mL) and extracted with ethyl acetate (30 mLx2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , 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, Petroleum ether/Ethyl acetate=20/1, 1/5). Tert-butyl 4-[1- [(2,4-difluorophenyl)methoxy]pyrazol-3-yl]piperidine-1-carbo xylate (320 mg, 813.37 µmol, 72.48% yield) was obtained as white solid.1H NMR: (400MHz, CDCl3) δ 7.26 - 7.17 (m, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.89 - 6.80 (m, 2H), 5.86 (d, J = 2.4 Hz, 1H), 5.29 (s, 2H), 4.15 (br d, J = 13.6 Hz, 2H), 2.91 - 2.81 (m, 2H), 2.81 - 2.71 (m, 1H), 1.93 (br dd, J = 2.0, 13.8 Hz, 2H), 1.63 - 1.54 (m, 2H), 1.48 (s, 9H). Step 2.4-(1-((2,4-difluorobenzyl)oxy)-1H-pyrazol-3-yl)piperidine To a mixture of tert-butyl 4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]piperidine-1- carboxylate (250 mg, 635.44 µmol, 1 eq) in DCM (1.5 mL) was added TFA (825 mg, 7.24 mmol, 535.71 uL, 11.39 eq). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuum. 4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]piperidine (186 mg, 634.14 µmol, 99.79% yield) was obtained as yellow oil. LCMS: MS (ESI) m/z: 294.2 [M+1] + . Intermediate 3j Step 1. Tert-butyl 4-(1-((4-fluorobenzyl)oxy)-1H-pyrazol-3-yl)piperidine-1-carb oxylate To a mixture of tert-butyl 4-(1-hydroxypyrazol-3-yl)piperidine-1-carboxylate (300 mg, 1.12 mmol, 1 eq) and 1-(bromomethyl)-4-fluoro-benzene (233 mg, 1.23 mmol, 152.51 uL, 1.1 eq) in DCM (2 mL) was added DIEA (218 mg, 1.68 mmol, 293.20 uL, 1.5 eq). The mixture was stirred at 25 °C for 12 hours. The mixture was poured into ice-water (w/w = 1/1) (30 mL) and extracted with ethyl acetate (30 mLx2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , 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, Petroleum ether/Ethyl acetate=20/1, 1/5). Tert-butyl 4-[1-[(4- fluorophenyl)methoxy]pyrazol-3-yl]piperidine-1-carboxylate (270 mg, 719.16 µmol, 64.08% yield) was obtained as white solid. 1 H NMR: (400MHz, CDCl3) δ 7.31 - 7.27 (m, 1H), 7.27 - 7.24 (m, 1H), 7.08 - 7.00 (m, 2H), 6.90 (d, J = 2.4 Hz, 1H), 5.84 (d, J = 2.4 Hz, 1H), 5.22 (s, 2H), 4.26 - 4.06 (m, 2H), 2.86 (br t, J = 12.0 Hz, 2H), 2.73 – 2.65 (m, 1H), 1.93 (br dd, J = 2.0, 13.2 Hz, 2H), 1.62 - 1.54 (m, 2H), 1.48 (s, 9H). Step 2.4-(1-((4-fluorobenzyl)oxy)-1H-pyrazol-3-yl)piperidine To a mixture of tert-butyl 4-[1-[(4-fluorophenyl)methoxy]pyrazol-3-yl]piperidine-1- carboxylate (130 mg, 346.26 µmol, 1 eq) in DCM (1.5 mL) was added TFA (462 mg, 4.05 mmol, 0.3 mL, 11.70 eq). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuum. 4-[1-[(4-fluorophenyl)methoxy]pyrazol-3-yl]piperidine (95 mg, 345.05 µmol, 99.65% yield) was obtained as yellow oil. LCMS: EW22606-199-P1A, MS (ESI) m/z: 276.2 [M+1] + . Intermediate 3k
Step 1. tert-butyl 4-[1-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-3-yl]piperid ine-1- carboxylate To a mixture of tert-butyl 4-(1-hydroxypyrazol-3-yl)piperidine-1-carboxylate (150 mg, 0.56 mmol, 1 eq) in DCM (1.1 mL) was added 1-(bromomethyl)-4-chloro-2-fluoro-benzene (138 mg, 0.62 mmol, 1.1 eq) and DIEA (80 mg, 0.62 mmol, 0.1 mL, 1.1 eq), then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ether gradient @ 60 mL/min). Compound tert-butyl 4-[1-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-3- yl]piperidine-1-carboxylate (160 mg, 0.39 mmol, 70% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 410.0 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.21 - 7.15 (m, 1H), 7.15 - 7.10 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 5.87 (d, J = 2.4 Hz, 1H), 5.30 (s, 2H), 4.23 - 4.10 (m, 2H), 2.85 (br t, J = 12.0 Hz, 2H), 2.76 (tt, J = 4.0, 11.6 Hz, 1H), 1.93 (br dd, J = 2.0, 12.8 Hz, 2H), 1.61 - 1.54 (m, 2H), 1.48 (s, 9H). Step 2.4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]piperidine To a solution of tert-butyl 4-[1-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-3- yl]piperidine-1-carboxylate (115 mg, 0.28 mmol, 1 eq) in DCM (2 mL) was added TFA (354 mg, 3.11 mmol, 0.23 mL, 11.07 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under vacuum. Compound 4-[1-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-3-yl]piperidine (118 mg, 0.28 mmol, 99% yield, TFA) was obtained as a colorless oil without further purification. Intermediate 3l Step 1. tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyrid ine-1(2H)- carboxylate To a stirred solution of tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (5 g, 23.44 mmol, 1 eq) in THF (30 mL) was added LDA (2 M, 15.24 mL, 1.3 eq) dropwise at -70°C. The reaction mixture was stirred at -70°C for 0.5 h. Then a solution of 1,1,1-trifluoro-N- phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (10.05 g, 28.13 mmol, 1.2 eq) in THF (30 mL) was added dropwise to the mixture at -70°C. The resulting mixture was warmed to 20°C slowly and stirred at 20°C for 2 h. TLC (PE:EA=5:1) showed the reaction was completed. Saturated NH 4 Cl aqueous (200 mL) was added to quench the reaction at 0°C and the aqueous was extracted with EA (100 mL x3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 100:1-10:1) to give tert-butyl 6-methyl- 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-car boxylate (5.2 g, 15.06 mmol, 64.23% yield) as a light yellow oil. LCMS: (ESI) m/z: 289.3 [M+1-15] + , 245.8 [M+1-100] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 5.63 - 5.82 (m, 1H), 4.12 - 4.80 (m, 2H), 3.64 (br d, J = 18.8 Hz, 0.5H), 2.94 - 3.08 (m, 0.5H), 2.52 - 2.89 (m, 1H), 1.99 - 2.27 (m, 1H), 1.48 (d, J = 2.6 Hz, 9H), 1.14 - 1.28 (m, 3H). Step 2. tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6 - dihydropyridine-1(2H)-carboxylate To a stirred solution of tert-butyl 6-methyl-4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H- pyridine-1-carboxylate (1 g, 2.90 mmol, 1 eq) in dioxane (15 mL) was added 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (882.41 mg, 3.47 mmol, 1.2 eq), KOAc (568.39 mg, 5.79 mmol, 2 eq) and Pd(dppf)Cl 2 (211.88 mg, 289.57 µmol, 0.1 eq) under N2. The resulting mixture was stirred at 80°C for 6 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA=100:1-10:1) to give tert-butyl 6-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine -1-carboxylate (600 mg, 1.86 mmol, 64% yield) as a light yellow oil. LCMS: (ESI) m/z: 267.1 [M+1-56] + . Step 3. tert-butyl 4-(1-(benzyloxy)-1H-pyrazol-3-yl)-2-methyl-5,6-dihydropyridi ne-1(2H)- carboxylate To a stirred solution of tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate (421.45 mg, 1.30 mmol, 1.1 eq) and 1-benzyloxy-3- bromo-pyrazole (300 mg, 1.19 mmol, 1 eq) in dioxane (5 mL) and H 2 O (1 mL) were added Pd(dppf)Cl 2 (86.73 mg, 118.53 µmol, 0.1 eq) ,Na2CO3 (376.89 mg, 3.56 mmol, 3 eq) under N2. The resulting mixture was stirred at 90°C for 2 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EA (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography(PE:EA = 100:1-4:1) to give tert-butyl 4-(1-benzyloxypyrazol-3-yl)-6-methyl-3,6-dihydro-2H- pyridine-1-carboxylate (350 mg, 0.95 mmol, 80% yield) as a colorless oil. LCMS: MS (ESI) m/z: 314.3 [M+1-56] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.30 - 7.43 (m, 5H), 6.92 (dd, J = 6.1, 2.4 Hz, 1H), 6.04 - 6.20 (m, 2H), 5.28 (s, 2H), 4.52 - 4.71 (m, 1H), 4.22 - 4.42 (m, 1H), 3.71 (s, 1H), 2.48 (br d, J = 16.3 Hz, 2H), 1.49 (s, 9H), 1.25 (d, J = 6.7 Hz, 1.3H), 1.16 (d, J = 6.8 Hz, 1.7H). Step4. tert-butyl 4-(1-hydroxy-1H-pyrazol-3-yl)-2-methylpiperidine-1-carboxyla te To a stirred solution of tert-butyl 4-(1-benzyloxypyrazol-3-yl)-6-methyl-3,6-dihydro-2H- pyridine-1-carboxylate (350 mg, 0.95 mmol, 1 eq) in MeOH (5 mL) was added Pd/C (50 mg, 20% purity) under N 2 . The reaction mixture was stirred at 20°C under H 2 (15 Psi) for 16 h. The mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl 4-(1-hydroxypyrazol-3-yl)-2-methyl-piperidine-1-carboxylate (120 mg, 0.43 mmol, 45% yield) as a colorless oil. LCMS: MS (ESI) m/z: 182.2 [M+1-100] + . Step 5. tert-butyl 4-(1-((2,4-difluorobenzyl)oxy)-1H-pyrazol-3-yl)-2-methylpipe ridine-1- carboxylate To a stirred solution of tert-butyl 4-(1-hydroxypyrazol-3-yl)-2-methyl-piperidine-1- carboxylate (120 mg, 0.43 mmol, 1 eq) in DCM (4 mL) was added 1-(bromomethyl)-2,4- difluoro-benzene (97.12 mg, 0.47 mmol, 1.1 eq) and DIEA (82.69 mg, 0.64 mmol, 0.1 mL, 1.5 eq). The resulting mixture was stirred at 20°C for 12 h. The mixture was concentrated under vacuum. The residue was purified by prep-TLC (PE:EA = 4:1) to give tert-butyl 4-[1- [(2,4-difluorophenyl)methoxy]pyrazol-3-yl]-2-methyl-piperidi ne-1-carboxylate (170 mg, 0.41 mmol, 95.47% yield, 97.6% purity) as a colorless oil. LCMS: MS (ESI) m/z: 352.1 [M+1-56] + . Step 6.4-(1-((2,4-difluorobenzyl)oxy)-1H-pyrazol-3-yl)-2-methylpi peridine To a stirred solution of tert-butyl 4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]-2- methyl-piperidine-1-carboxylate (120 mg, 0.29 mmol, 1 eq) in DCM (2 mL) was added TFA (616.00 mg, 5.40 mmol, 0.4 mL, 18.34 eq). The reaction mixture was stirred at 20°C for 1 h. The mixture was concentrated under vacuum to give 4-[1-[(2,4- difluorophenyl)methoxy]pyrazol-3-yl]-2-methyl-piperidine (124 mg, 0.29 mmol, TFA) as a colorless oil. LCMS: MS (ESI) m/z: 308.4 [M+1] + . Intermediate 3m
Step 1. tert-butyl3-[(2,4-difluorophenyl)methoxy]pyrazole-1-carboxyl ate To a solution of tert-butyl 3-hydroxypyrazole-1-carboxylate (1.78 g, 9.66 mmol, 1 eq) and 1-(bromomethyl)-2,4-difluoro-benzene (2 g, 9.66 mmol, 1 eq) in MeCN (40 mL) was added K 2 CO 3 (2.67 g, 19.32 mmol, 2 eq). The mixture was stirred at 50 °C for 6 hr. The reaction mixture was quenched by addition H 2 O (50 mL) and extracted with Ethyl acetate (100 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue, it was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 20:1 to 1:1). Compound tert-butyl 3-[(2,4-difluorophenyl)methoxy]pyrazole-1-carboxylate (1 g, 3.22 mmol, 33.36% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 311.1 [M+1] + . 1 H NMR: (400MHz, DMSO-d6) δ 7.82 (d, J = 4.0 Hz, 1H), 7.22 - 7.09 (m, 1H), 6.85 - 6.70 (m, 2H), 5.68 (d, J = 4.0 Hz, 1H), 5.32 (s, 2H), 1.52 (s, 9H) Step 2.3-[(2,4-difluorophenyl)methoxy]-1H-pyrazole
To a solution of tert-butyl 3-[(2,4-difluorophenyl)methoxy]pyrazole-1-carboxylate (1 g, 3.22 mmol, 1 eq) in CH 2 Cl 2 (5 mL) was added TFA (7.70 g, 67.53 mmol, 5 mL, 20.95 eq). The mixture was stirred at 25 °C for 1 hr. The reaction solution was concentrated under reduced pressure to give a residue. Compound 3-[(2,4-difluorophenyl)methoxy]-1H- pyrazole (600 mg, 2.85 mmol, 89% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 211.4 [M+1] + . Step 3. tert-butyl4-[3-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]pip eridine-1-carboxylate To a solution of 3-[(2,4-difluorophenyl)methoxy]-1H-pyrazole (600 mg, 2.85 mmol, 1 eq) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1.59 g, 5.71 mmol, 2 eq) in DMF (30 mL) was added Cs 2 CO 3 (2.79 g, 8.56 mmol, 3 eq). The mixture was stirred at 100 °C for 6 hr. Water (200 mL) was added to the mixture, the aqueous phase was extracted with CH 2 Cl 2 (300 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 20/1 to 1/1). Compound tert-butyl 4-[3- [(2,4-difluorophenyl)methoxy]pyrazol-1-yl]piperidine-1-carbo xylate (700 mg, 1.78 mmol, 62% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 394.3 [M+1] + . 1 H NMR: (400MHz, DMSO-d 6 ) δ 7.35 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 6.88 - 6.72 (m, 2H), 5.49 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H), 3.83 (td, J = 4.0, 8.4 Hz, 3H), 3.33 - 3.26 (m, 2H), 1.99 - 1.88 (m, 4H), 1.46 (s, 9H) Step 4.4-[3-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]piperidine To a solution of tert-butyl 4-[3-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]piperidine-1- carboxylate (300 mg, 0.76 mmol, 1 eq) in CH 2 Cl 2 (3 mL) was added TFA (4.62 g, 40.52 mmol, 3.00 mL, 53.14 eq). The mixture was stirred at 25 °C for 1 hr. The reaction solution was concentrated under reduced pressure to give a residue. Compound 4-[3-[(2,4- difluorophenyl)methoxy]pyrazol-1-yl]piperidine (250 mg, 0.61 mmol, 80% yield, TFA salt) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 294.2 [M+1] + . Intermediate 3n Step 1. tert-butyl 3-(pyridin-4-ylmethoxy)-1H-pyrazole-1-carboxylate
To a stirred solution of tert-butyl 3-hydroxypyrazole-1-carboxylate (1.5 g, 8.14 mmol, 1 eq) and 4-(chloromethyl)pyridine (1.04 g, 8.14 mmol, 1 eq) in CH 3 CN (15 mL) was added K 2 CO 3 (2.25 g, 16.29 mmol, 2 eq). The resulting mixture was stirred at 50°C for 4 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EtOAc (100 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 10:1-3:2) to give tert-butyl 3-(4-pyridylmethoxy)pyrazole-1-carboxylate (700 mg, 2.54 mmol, 31% yield) as a brown oil. LCMS: (ESI) m/z: 276.4 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 8.61 - 8.66 (m, 2H), 7.88 (d, J = 2.8 Hz, 1H), 7.34 -7.39 (m, 2H), 5.96 (d, J = 2.9 Hz, 1H), 5.38 (s, 2H), 1.63 (s, 9H). Step 2.4-(((1H-pyrazol-3-yl)oxy)methyl)pyridine To a stirred solution of tert-butyl 3-(4-pyridylmethoxy)pyrazole-1-carboxylate (700 mg, 2.54 mmol, 1 eq) in DCM (10 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 15.94 eq). The resulting mixture was stirred at 20°C for 5 h. The mixture was concentrated under vacuum to give 4-(1H-pyrazol-3-yloxymethyl)pyridine (1 g, 2.48 mmol, 98% yield, TFA) as a yellow oil. LCMS: (ESI) m/z: 176.2 [M+1] + . Step 3. tert-butyl 4-(3-(pyridin-4-ylmethoxy)-1H-pyrazol-1-yl)piperidine-1-carb oxylate To a stirred solution of 4-(1H-pyrazol-3-yloxymethyl)pyridine (1 g, 2.48 mmol, 1 eq, 2TFA) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1.52 g, 5.46 mmol, 2.2 eq) in DMF (15 mL) was added Cs 2 CO 3 (4.04 g, 12.40 mmol, 5 eq). The resulting mixture was stirred at 100°C for 12 h. Water (200 mL) was added to the mixture and the aqueous was extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (150 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 10:1-3:2) to give tert-butyl 4-[3-(4-pyridylmethoxy)pyrazol-1-yl]piperidine-1-carboxylate (320 mg, 0.89 mmol, 36.00% yield) as a yellow oil. LCMS: MS (ESI) m/z: 359.1 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 8.55 - 8.62 (m, 2H), 7.32 - 7.38 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 5.69 (d, J = 2.4 Hz, 1H), 5.22 (s, 2H), 4.16 - 4.30 (m, 2H), 4.00 - 4.08 (m, 1H), 2.78 - 2.97 (m, 2H), 2.05 - 2.11 (m, 2H), 1.78 - 1.91 (m, 2H), 1.48 (s, 9H). Step 4.4-(((1-(piperidin-4-yl)-1H-pyrazol-3-yl)oxy)methyl)pyridin e
To a stirred solution of tert-butyl 4-[3-(4-pyridylmethoxy)pyrazol-1-yl]piperidine-1- carboxylate (120 mg, 334.79 µmol, 1 eq) in DCM (2 mL) was added the solution of HCl in dioxane (4 M, 1 mL, 11.95 eq). The resulting mixture was stirred at 20°C for 2 h. The mixture was concentrated under vacuum to give 4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]pyridine (110 mg, 332.09 µmol, 99.19% yield, HCl salt) as a yellow solid. LCMS: MS (ESI) m/z: 259.2 [M+1] + . Intermediate 3o Step 1. tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1- yl]piperidine-1-carboxylate
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5 g, 25.77 mmol, 1 eq), tert-butyl 4- methylsulfonyloxypiperidine-1-carboxylate (8.6 g, 30.79 mmol, 1.19 eq) in DMF (100 mL) was added Cs 2 CO 3 (16.79 g, 51.54 mmol, 2 eq). The mixture was stirred at 90 °C for 5 hr. Water (50 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethylacetate/Petroleum ether gradient @ 60 mL/min). Compound tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1- yl]piperidine-1- carboxylate (5.32 g, 14.10 mmol, 55% yield) was obtained as a white solid. LCMS: MS (ESI) m/z: 378.2 [M+1] + . HNMR: 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (1 H, s) 7.75 (1 H, s) 4.34 - 4.25 (2 H, m) 2.90 (2 H, br s) 2.17 - 2.11 (2 H, m) 1.96 - 1.86 (2 H, m) 1.78 - 1.63 (1 H, m) 1.49 (9 H, s) 1.33 (12 H, s). Step 2. tert-butyl 4-(4-hydroxypyrazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1- yl]piperidine-1-carboxylate (1 g, 2.65 mmol, 1 eq) in THF (10 mL) at 0 °C was added NaOH (2.5 M, 2.12 mL, 2 eq). And then H 2 O 2 (680 mg, 6.00 mmol, 0.58 mL, 30% purity, 2.26 eq) was added dropwise at 0 °C for 0.1 h. The resulting mixture was stirred at 25 °C for 1hr. Water (20 mL) was added to the mixture. The aqueous phase was extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=10/1 to 1/1) Compound tert-butyl 4- (4-hydroxypyrazol-1-yl)piperidine-1-carboxylate (585 mg, 2.19 mmol, 83% yield) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 212.1 [M-56] + . 1 H NMR: (400 MHz, CDCl 3 ) δ 7.12 - 7.07 (1 H, m) 7.03 - 7.00 (1 H, m) 4.21 - 3.99 (4 H, m) 2.77 (2 H, br s), 2.00 (1 H, br s) 1.87- 1.52 (3 H, m) 1.43- 1.36 (9 H, m). Step 3. tert-butyl 4-[4-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperidi ne-1- carboxylate To a solution of tert-butyl 4-(4-hydroxypyrazol-1-yl)piperidine-1-carboxylate (585 mg, 2.19 mmol, 1 eq), 4-(bromomethyl)-3-fluoro-benzonitrile (562.06 mg, 2.63 mmol, 1.2 eq) in DMF (10 mL) was added Ag 2 CO 3 (1.21 g, 4.38 mmol, 0.20 mL, 2 eq). The mixture was stirred at 80 °C for 6 hr. Water (20 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over Na 2 SO 4 , filtered and concentrated in vacuum The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate = 10/1 to 3/1). Compound tert-butyl 4-[4-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperidi ne-1- carboxylate (387 mg, 0.97 mmol, 44% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 585.3 [M+1] + . 1 H NMR: (400 MHz, CDCl 3 ) δ 7.44 - 7.40 (2 H, m) 7.31 (1 H, dd, J = 9.2, 1.2 Hz) 7.21 (1 H, d, J = 0.8 Hz) 7.09 (1 H, d, J = 0.8 Hz) 4.97 (2 H, s) 4.23 - 4.05 (3 H, m) 2.80 (1 H, br s) 2.35 - 2.15 (1 H, m) 2.01 (2 H, br dd, J = 12.0, 2.02 Hz) 1.83 - 1.72 (2 H, m) 1.40 (9 H, s). Step 4.3-fluoro-4-[[1-(4-piperidyl)pyrazol-4-yl]oxymethyl]benzoni trile To a solution of tert-butyl 4-[4-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (387 mg, 0.97 mmol, 1 eq) in EtOAc (10 mL) was added PTSA (499.25 mg, 2.90 mmol, 3 eq). The reaction mixture was stirred at 60°C for 12 h. The mixture was filtered and the filter cake is rinsed with ethyl acetate (50 mL x 2). Crude product 3- fluoro-4-[[1-(4-piperidyl)pyrazol-4-yl]oxymethyl] benzonitrile (450 mg, crude, TsOH) was used into the next step without further purification. LCMS: MS (ESI) m/z: 585.3 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 7.50 - 7.43 (2 H, m) 7.30 (2 H, ddd, J=8.4, 4.4, 1.2 Hz) 7.25 - 7.22 (1 H, m), 5.14 (2 H, s) 3.69 - 3.55 (2 H, m) 3.39 - 3.26 (2 H, m) 2.63 - 2.50 (4 H, m) 2.32 (2 H, br d, J=12.0 Hz) Intermediate 4
Step 1. (2S)-2-(benzyloxymethyl)oxetane To a mixture of t-BuOK (13.67 g, 121.80 mmol, 2 eq) in t-BuOH (50 mL) was added trimethylsulfoxonium iodide (26.81 g, 121.80 mmol, 2 eq) at 20 °C, the mixture was stirred at 60 °C for 0.5 h. (2S)-2-(benzyloxymethyl)oxirane (10 g, 60.90 mmol, 1 eq) was added dropwise to the mixture at 60 °C, the reaction mixture was stirred at 80 °C for 2 h. The mixture was filtered through a pad of celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100:1 to 5:1). (2S)- 2-(benzyloxymethyl)oxetane (5 g, 28.05 mmol, 46% yield) was obtained as a light yellow oil. 1 H NMR: (400MHz, CDCl 3 ) δ 7.40 - 7.31 (m, 5H), 5.06 - 4.95 (m, 1H), 4.72 - 4.60 (m, 4H), 3.74 - 3.61 (m, 2H), 2.75 - 2.55 (m, 2H). Step 2. Preparation of [(2S)-oxetan-2-yl]methanol To a solution of (2S)-2-(benzyloxymethyl)oxetane (13 g, 72.94 mmol, 1 eq) in THF (150 mL) was added Pd(OH) 2 (1 g, 20% purity) under N 2 . The reaction mixture was stirred at 50 °C under H 2 (50 Psi) for 12 h. The mixture was filtered and the filtrate was concentrated in vacuum. The mixture was used into next step directly. [(2S)-oxetan-2-yl]methanol (5.2 g, 59.02 mmol, 81% yield) was obtained as a light yellow oil. Step 3. [(2S)-oxetan-2-yl]methyl methanesulfonate To a solution of [(2S)-oxetan-2-yl]methanol (5.2 g, 59.02 mmol, 1 eq), TEA (11.94 g, 118.04 mmol, 16.43 mL, 2 eq) in THF (60 mL) was added dropwise methylsulfonyl methanesulfonate (10.80 g, 61.97 mmol, 1.05 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. Water (100 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was used into next step directly. [(2S)-oxetan-2-yl]methyl methanesulfonate (9.8 g, crude) was obtained as a light yellow oil. Step 4. (2S)-2-(azidomethyl)oxetane To a solution of [(2S)-oxetan-2-yl]methyl methanesulfonate (9.8 g, 58.97 mmol, 1 eq) in DMF (50 mL) was added NaN3 (5.75 g, 88.45 mmol, 1.5 eq) under N2. The reaction mixture was stirred at 80 °C for 4 h. The mixture was filtered, and the filtrate was used into next step directly. (2S)-2-(azidomethyl)oxetane (6.8 g, crude) was obtained as a yellow oil. Step 5. [(2S)-oxetan-2-yl]methanamine To a solution of (2S)-2-(azidomethyl)oxetane (6.8 g, 60.11 mmol, 1 eq) in DMF (80 mL) and THF (100 mL) was added Pd/C (1 g, 10% purity) under N 2 . The reaction mixture was stirred at 20 °C under H 2 (15 Psi) for 12 h and 50 °C under H 2 (50 Psi) for 12 h. The mixture was filtered and the filtrate was concentrated to remove most of THF in vacuum. The mixture was used into next step directly. [(2S)-oxetan-2-yl]methanamine (5 g, crude) was obtained as a yellow oil. Step 6. methyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate To a solution of [(2S)-oxetan-2-yl]methanamine (4 g, 45.91 mmol, 1 eq) in DMF (40 mL) was added TEA (13.94 g, 137.74 mmol, 19.17 mL, 3 eq) and methyl 3-fluoro-4-nitro- benzoate (9.14 g, 45.91 mmol, 1 eq) . The reaction mixture was stirred at 20°C for 2 h. Water (100 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL x 2), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1). methyl 4-nitro-3-[[(2S)-oxetan- 2-yl]methylamino]benzoate (2.8 g, 10.52 mmol, 22% yield) was obtained as a yellow oil. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.40 (br s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.33 - 7.29 (m, 1H), 5.20 (tt, J = 4.6, 7.2 Hz, 1H), 4.84 - 4.76 (m, 1H), 4.67 (td, J = 6.0, 9.2 Hz, 1H), 3.99 (s, 3H), 3.71 - 3.63 (m, 2H), 2.82 (dtd, J = 6.0, 8.1, 11.2 Hz, 1H), 2.65 (tdd, J = 7.2, 9.1, 11.2 Hz, 1H). Step 7. methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate To a solution of methyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (2.8 g, 10.52 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (300 mg, 10% purity) under N 2 . The reaction mixture was stirred at 20 °C under H 2 (15 Psi) for 12 h. LCMS showed desired MS was detected. The mixture was filtered and the filtrate was concentrated in vacuum. The mixture was used into next step directly. methyl 4-amino-3-[[(2S)-oxetan-2- yl]methylamino]benzoate (2.6 g, crude) was obtained as a light yellow oil. LCMS: MS (ESI) m/z: 237.2 [M+1] + . 1 H NMR: (400 MHz, CDCl 3 ) δ 7.16 (dd, J = 1.9, 8.0 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.47 (s, 2H), 4.98 - 4.86 (m, 1H), 4.69 (t, J = 5.7 Hz, 1H), 4.59 - 4.43 (m, 2H), 3.72 (s, 3H), 3.38 - 3.33 (m, 1H), 3.30 - 3.23 (m, 1H), 2.73 - 2.60 (m, 1H), 2.49 - 2.37 (m, 1H). Step 8. methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl] benzimidazole-5-carboxylate To a solution of methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (2.6 g, 11.00 mmol, 1 eq), 2-chloro-1,1,1-trimethoxy-ethane (1.79 g, 11.55 mmol, 1.55 mL, 1.05 eq) in MeCN (10 mL) was added PTSA (94.75 mg, 0.55 mmol, 0.05 eq). The reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated in vacuum. The mixture was triturated with PE and EA (PE:EA = 5:1, V/V). methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (2.4 g, 8.03 mmol, 73% yield, 99% purity) was obtained as a gray solid. LCMS: MS (ESI) m/z: 251.2 [M+1] + . 1 H NMR: (400MHz, CDCl 3 ) δ 8.13 (d, J = 1.0 Hz, 1H), 8.02 (dd, J = 1.5, 8.5 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 5.22 (dq, J = 2.7, 6.8 Hz, 1H), 5.05 (s, 2H), 4.68 - 4.58 (m, 2H), 4.57 - 4.51 (m, 1H), 4.35 (td, J = 6.0, 9.2 Hz, 1H), 3.96 (s, 3H), 2.77 (dtd, J = 6.0, 8.0, 11.6 Hz, 1H), 2.43 (tdd, J = 7.3, 9.1, 11.6 Hz, 1H). Intermediate 5a Step 1.3-nitro-1-trityl-1H-1,2,4-triazole To a solution of 3-nitro-1H-1,2,4-triazole (14 g, 122.74 mmol, 1 eq) and DIEA (31.73 g, 245.48 mmol, 42.76 mL, 2.0 eq) in THF (500 mL) was added [chloro(diphenyl)methyl]benzene (40 g, 143.48 mmol, 1.17 eq) in one portion. The mixture was degassed with N 2 for three times and stirred at 20 °C for 15 h. The mixture was concentrated in reduced pressure to about 50 mL, then petroleum ether (150 mL) was added and the mixture was stirred at 20 °C for 20 min. The precipitate was filtered and the cake was washed with (Petroleum ether/Ethyl acetate = 3/1, 40 mL x 2) and dried. The residue was then partitioned by water (1000 mL) and ethyl acetate (1200 mL). The organic layer was dried over sodium sulfate and concentrated to afford 3-nitro-1-trityl-1,2,4-triazole (41 g, 115.05 mmol, 94% yield) as a yellow solid. Step 2.3-[(4-chloro-2-fluoro-phenyl)methoxy]-1-trityl-1,2,4- triazole To a solution of 3-nitro-1-trityl-1,2,4-triazole (10 g, 28.06 mmol, 1 eq) in THF (200 mL) was added NaH (1.52 g, 37.88 mmol, 60% purity, 1.35 eq) at 0 °C, and the reaction mixture was stirred at this temperature for 20 min. (4-chloro-2-fluoro-phenyl)methanol (4.73 g, 29.46 mmol, 1.05 eq) in THF (100 mL) was added dropwise to the mixture at 0 °C. The reaction was stirred at 20 °C for 12 h. Saturated NH4Cl (100 mL) and EtOAc (100 mL) was added to the mixture, the mixture was filtered and the filtrate was extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The mixture was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 100:1 to 10:1).3-[(4-chloro-2-fluoro-phenyl)methoxy]-1- trityl-1,2,4-triazole (3.5 g, 6.78 mmol, 24% yield, 91% purity) was obtained as a white solid. LCMS: EW22470-128-P1B, MS (ESI) m/z: 492.0 [M+23] + . 1 H NMR: (400MHz, DMSO- d6) δ 7.84 (s, 1H), 7.47 - 7.41 (m, 2H), 7.40 - 7.34 (m, 9H), 7.25 (dd, J = 1.8, 8.3 Hz, 1H), 7.09 - 7.02 (m, 6H), 5.25 (s, 2H). Step 3.3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H-1,2,4-triazole To a solution of 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1-trityl-1,2,4-triazol e (1.5 g, 3.19 mmol, 1 eq) in DCM (30 mL) was added TFA (9.24 g, 81.04 mmol, 6 mL, 25.39 eq) and Et3SiH (371.16 mg, 3.19 mmol, 0.51 mL, 1 eq). The reaction mixture was stirred at 20 °C for 1 h. TLC (petroleum ether: ethyl acetate = 3:1) showed new spot was detected. Saturated NaHCO 3 (100 mL) was added to the mixture. The aqueous phase was extracted with DCM (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether:Ethyl acetate = 100:1 to 10:1, Dichloromethane: Methanol = 10:1) to afford 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H-1,2,4-triazole (300 mg, 1.32 mmol, 41% yield) obtained as a light yellow solid. 1 H NMR: (400MHz, DMSO- d 6 ) δ 13.38 (s, 1H), 8.38 - 8.13 (m, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 2.0, 10.0 Hz, 1H), 7.32 (dd, J = 1.6, 8.0 Hz, 1H), 5.29 (s, 2H). Step 4. tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]-1,2,4-triazol-1-yl] piperidine-1- carboxylate To a solution of 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H-1,2,4-triazole (300 mg, 1.32 mmol, 1 eq) in DMF (5 mL) was added Cs 2 CO 3 (858.84 mg, 2.64 mmol, 2 eq) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (441.81 mg, 1.58 mmol, 1.2 eq). The reaction mixture was stirred at 80°C for 3 h. Water (50 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 1:2). tert-butyl 4-[3-[(4-chloro- 2-fluoro-phenyl)methoxy]-1,2,4-triazol-1-yl]piperidine-1-car boxylate (200 mg, 0.46 mmol, 35% yield, 95% purity) was obtained as a light yellow oil. LCMS: MS (ESI) m/z: 411.1 [M+1] + . 1 H NMR: (400MHz, CDCl 3 ) δ 7.78 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.17 - 7.08 (m, 2H), 5.34 (s, 2H), 4.32 - 4.13 (m, 3H), 2.95 - 2.83 (m, 2H), 2.17 - 2.07 (m, 2H), 1.96 - 1.87 (m, 2H), 1.48 (s, 9H). Step 5.4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]-1,2,4-triazol-1-y l]piperidine To a solution of tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]-1,2,4-triazol-1-yl] piperidine-1-carboxylate (100 mg, 0.24 mmol, 1 eq) in CH 2 Cl 2 (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 55.49 eq). The mixture was stirred at 25 °C for 1 hr. The reaction was concentrated under reduced pressure to afford crude product 4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]-1,2,4-triazol-1-yl]piperidine (90 mg, 0.21 mmol, 87% yield, TFA) as a yellow oil which was used directly. LCMS: MS (ESI) m/z: 311.2 [M+1] + . Intermediate 6
Step 1. methyl 3-(2-methoxyethylamino)-4-nitro-benzoate To a solution of methyl 3-fluoro-4-nitro-benzoate (5 g, 25.11 mmol, 1 eq) in DMF (30 mL) was added TEA (7.62 g, 75.33 mmol, 10.48 mL, 3 eq) and 2-methoxyethanamine (2.45 g, 32.64 mmol, 2.84 mL, 1.3 eq). The mixture was stirred at 30 °C for 12 h. The mixture was poured into water (80 mL), the aqueous phase was extracted with ethyl acetate (40 mLx4). The combined organic phase was washed with brine (60 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. 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 @ 60 mL/min). Compound methyl 3-(2- methoxyethylamino)-4-nitro-benzoate (6.1 g, 23.99 mmol, 96% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 254.9 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM- d) δ 8.29 - 8.08 (m, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 1.6, 8.8 Hz, 1H), 3.95 (s, 3H), 3.73 - 3.69 (m, 2H), 3.59 - 3.53 (m, 2H), 3.45 (s, 3H) Step 2. methyl 4-amino-3-(2-methoxyethylamino)benzoate To a solution of methyl 3-(2-methoxyethylamino)-4-nitro-benzoate (6.1 g, 23.99 mmol, 1 eq) in H 2 O (20 mL) and EtOH (60 mL) was added Fe (6.70 g, 119.97 mmol, 5 eq) and NH4Cl (6.42 g, 119.97 mmol, 5 eq). The mixture was stirred at 80 °C for 12 h. The mixture was filtered and concentrated under vacuum. The residue was poured into water (50 mL), the aqueous phase was extracted with ethyl acetate (20 mLx4). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. Compound methyl 4-amino-3-(2-methoxyethylamino)benzoate (5.3 g, 23.63 mmol, 99% yield) was obtained as a yellow oil without further purification. LCMS: MS (ESI) m/z: 225.2 [M+1] + . Step 3. methyl 2-(chloromethyl)-3-(2-methoxyethyl)benzimidazole-5-carboxyla te To a solution of methyl 4-amino-3-(2-methoxyethylamino)benzoate (5.2 g, 23.19 mmol, 1 eq) in MeCN (50 mL) was added PTSA (399 mg, 2.32 mmol, 0.1 eq) and 2-chloro-1,1,1- trimethoxy-ethane (4.66 g, 30.14 mmol, 4.05 mL, 1.3 eq). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 60 mL/min). Compound methyl 2- (chloromethyl)-3-(2-methoxyethyl)benzimidazole-5-carboxylate (6 g, 21.22 mmol, 92% yield) was obtained as a white solid. LCMS: MS (ESI) m/z: 283.2 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 8.13 (d, J = 0.8 Hz, 1H), 8.01 (dd, J = 1.6, 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 4.97 (s, 2H), 4.53 (t, J = 5.2 Hz, 2H), 3.97 (s, 3H), 3.74 (t, J = 5.2 Hz, 2H), 3.28 (s, 3H). Intermediate 7a Step 1. methyl 4-nitro-3-(oxazol-5-ylmethylamino)benzoate A mixture of oxazol-5-ylmethanamine (1 g, 7.43 mmol, 1 eq, HCl), methyl 3-fluoro-4-nitro- benzoate (1.63 g, 8.17 mmol, 1.1 eq) and TEA (2.26 g, 22.29 mmol, 3.10 mL, 3 eq) in DMF (30 mL) was stirred at 60 °C for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (25 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution (25 mL x 1), dried over anhydrous 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 1:0, Rf = 0.24) to give compound methyl 4-nitro-3- (oxazol-5-ylmethylamino)benzoate (1.5 g, 5.41 mmol, 73% yield) as a yellow solid. LCMS: MS (ESI) m/z: 278.3 [M+1] + . 1 H NMR: (400MHz, CDCl 3 -d) δ 8.18 (d, J = 8.8 Hz, 2H), 7.82 (s, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 1.6, 8.8 Hz, 1H), 7.03 (s, 1H), 4.60 (br d, J = 4.0 Hz, 2H), 3.88 (s, 3H). Step 2. methyl 4-amino-3-(oxazol-5-ylmethylamino)benzoate , To a solution of methyl 4-nitro-3-(oxazol-5-ylmethylamino)benzoate (1.5 g, 5.41 mmol, 1 eq) in MeOH (15 mL) was added Pd/C (200 mg, 5.41 mmol, 10% purity, 1.00 eq) under N2. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15 Psi) at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound methyl 4-amino-3-(oxazol-5- ylmethylamino)benzoate (1.3 g, 5.26 mmol, 97% yield) as a yellow solid. LCMS: MS (ESI) m/z: 248.3 [M+1] + . 1 H NMR: (400MHz, DMSO-d 6 ) δ 8.30 (s, 1H), 7.18 (dd, J = 2.0, 8.0 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.56 (d, J = 8.0 Hz, 1H), 5.47 (s, 2H), 5.20 (t, J = 5.6 Hz, 1H), 4.38 (d, J = 5.6 Hz, 2H), 3.72 (s, 3H) Step 4. methyl 2-(chloromethyl)-3-(oxazol-5-ylmethyl)benzimidazole-5-carbox ylate A mixture of methyl 4-amino-3-(oxazol-5-ylmethylamino)benzoate (0.5 g, 2.02 mmol, 1 eq), 2-chloro-1,1,1-trimethoxy-ethane (625.25 mg, 4.04 mmol, 0.54 mL, 2 eq) and PTSA (34.82 mg, 0.2 mmol, 0.1 eq) in MeCN (10 mL) was stirred at 60 °C for 4 h. LCMS showed the desired mass was detected. The reaction mixture was diluted with saturated NaHCO 3 aqueous solution (20 mL) and extracted with EA (25 mL x 2). The combined organic layers were washed with brine (25 mL x 1), dried over anhydrous 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 2:1, Rf = 0.43) to give compound methyl 2- (chloromethyl)-3-(oxazol-5-ylmethyl)benzimidazole-5-carboxyl ate (280 mg, 0.92 mmol, 45.29% yield) as a yellow solid. LCMS: MS (ESI) m/z: 305.7 [M+1] + . 1 H NMR: (400MHz, CDCl 3 -d) δ 8.20 (d, J = 0.8 Hz, 1H), 8.02 (dd, J = 1.6, 8.4 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 5.58 (s, 2H), 4.93 (s, 2H), 3.96 (s, 3H). Intermediate 7b Step 1. methyl 4-nitro-3-(oxazol-2-ylmethylamino)benzoate To a solution of oxazol-2-ylmethanamine (1 g, 7.43 mmol, 1 eq, HCl) and methyl 3-fluoro- 4-nitro-benzoate (1.48 g, 7.43 mmol, 1 eq) in DMF (10 mL) was added K 2 CO 3 (2.05 g, 14.86 mmol, 2 eq), then stirred at 60 °C for 5 h. LCMS (EW22000-252-P1A1) showed desired m/z 278.3. The reaction mixture was diluted with water 80 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine 20 mL, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate/dichloromethane=30/1/0 to 2/1/1). Methyl 4-nitro-3-(oxazol-2- ylmethylamino)benzoate (1.16 g, 4.18 mmol, 56% yield) was obtained as an orange solid. LCMS: MS (ESI) m/z: 278.3 [M+1] + . Step 2. methyl 4-amino-3-(oxazol-2-ylmethylamino)benzoate To a solution of methyl 4-nitro-3-(oxazol-2-ylmethylamino)benzoate (1.16 g, 4.18 mmol, 1 eq) in THF (15 mL) and MeOH (10 mL) was added Pd/C (200 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15 psi) at 25 °C for 3 h. LCMS showed desired m/z 248.3. The reaction mixture was filtered and the filter was concentrated to give a residue. The residue was used into next step directly. methyl 4-amino-3-(oxazol-2-ylmethylamino)benzoate (1.02 g, 4.13 mmol, 99% yield) was obtained as a yellow oil.1H NMR: (400MHz, CHLOROFORM-d) δ 7.64 (d, J = 0.8 Hz, 1H), 7.49 (dd, J = 1.6, 8.0 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.09 (d, J = 0.8 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.47 (s, 2H), 3.85 (s, 3H). Step 3. methyl 2-(chloromethyl)-3-(oxazol-2-ylmethyl)benzimidazole-5-carbox ylate To a solution of methyl 4-amino-3-(oxazol-2-ylmethylamino)benzoate (500 mg, 2.02 mmol, 1 eq) in MeCN (10 mL) was added 2-chloro-1,1,1-trimethoxy-ethane (468.93 mg, 3.03 mmol, 0.41 mL, 1.5 eq) and 4-methylbenzenesulfonic acid (17.41 mg, 0.1 mmol, 0.05 eq), then stirred at 60 °C for 2 h. LCMS showed desired m/z 306.1. The reaction mixture was concentrated to give a residue that was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate/dichloromethane = 20/1/0 to 1/1/1). methyl 2-(chloromethyl)-3-(oxazol- 2-ylmethyl)benzimidazole-5-carboxylate (565 mg, 1.85 mmol, 91.39% yield) was obtained as a light yellow solid. 1 H NMR: (400MHz, DMSO-d 6 ) δ 8.28 (d, J = 0.8 Hz, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.89 (dd, J = 1.6, 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 0.8 Hz, 1H), 5.93 (s, 2H), 5.14 (s, 2H), 3.88 (s, 3H). Intermediate 8 Step 1: Preparation 6-chloro-5-nitro-pyridine-2-carboxylic acid 2-chloro-6-methyl-3-nitro-pyridine (21.5 g, 124.59 mmol, 1 eq) was slowly added to a flask previously charged with H 2 SO 4 (18 M, 89.07 mL, 12.87 eq) with stirring. CrO 3 (37.37 g, 373.76 mmol, 13.84 mL, 3 eq) was added to the reaction mixture in small portions keeping the temperature below 50° C. The reaction mixture was stirred at 20 °C for 12 h. TLC (Petroleum ether: Ethyl acetate = 3: 1) indicated the reaction was completed. The resultant green gum was poured into 500 g of ice and the resultant solids was collected by filtration and dried under vacuum to give compound 6-chloro-5-nitro-pyridine-2- carboxylic acid (18.9 g, crude) as a pale solid. 1H NMR: (400MHz, DMSO-d6) δ: 8.71 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H). Chemical Formula: C 6 H 3 ClN 2 O 4 , Molecular Weight: 202.55 Total H count from HNMR data: 2. Step 2: Preparation of methyl 6-chloro-5-nitro-pyridine-2-carboxylate To a suspension 6-chloro-5-nitro-pyridine-2-carboxylic acid (17.9 g, 88.37 mmol, 1 eq) in CH 2 Cl 2 (150 mL) was added (COCl) 2 (22.43 g, 176.74 mmol, 15.47 mL, 2 eq) and DMF (969 mg, 13.26 mmol, 1.02 mL, 0.15 eq) at 0° C. The reaction mixture was stirred at 20° C for 1 h. Then MeOH (12 mL) was added to the reaction mixture at 20° C. The solution was stirred at 20° C for an additional 10 mm. TLC (Petroleum ether: Ethyl acetate = 3: 1) indicated the reaction was completed. The yellow solution was concentrated under reduced pressure. The resultant crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6/1 to 1/1) to give compound methyl 6-chloro-5-nitro- pyridine-2-carboxylate (12 g, 55.41 mmol, 63% yield) as a white solid. 1 H NMR: (400MHz, CD 3 OD) δ: 8.55 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 4.01 (s, 3H). Chemical Formula: C7H5ClN2O4, Molecular Weight: 216.58 Total H count from HNMR data: 5. Step 3: Preparation of methyl 5-nitro-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2- carboxylate To a solution of methyl 6-chloro-5-nitro-pyridine-2-carboxylate (1.5 g, 6.93 mmol, 1 eq) and [(2S)-oxetan-2-yl]methanamine (905 mg, 10.39 mmol, 1.5 eq) in DMF (33 mL) was added Et3N (2.10 g, 20.78 mmol, 2.89 mL, 3 eq). The mixture was stirred at 20 °C for 16 hr. LCMS indicated desired mass was detected. The reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/dichloromethane/methanol = 5/1/0/0 to 0/0/20/1) to give compound methyl 5-nitro-6-[[(2S)-oxetan-2- yl]methylamino]pyridine-2-carboxylate (1.1 g, 4.12 mmol, 59% yield) as a yellow solid. LCMS: MS (ESI) m/z: 358.4 [M+1] + 1 H NMR: (400MHz, CDCl 3 ) δ: 8.55 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.19 - 5.05 (m, 1H), 4.79 - 4.67 (m, 1H), 4.66 - 4.56 (m, 1H), 4.18 - 4.05 (m, 1H), 4.02 - 3.88 (m, 4H), 2.81 - 2.66 (m, 1H), 2.62 - 2.47 (m, 1H). Chemical Formula: C11H13N3O5, Molecular Weight: 268.1 Total H count from HNMR data: 13. Step 4: Preparation of methyl 5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2- carboxylate To a solution of methyl 5-nitro-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxyl ate (1.4 g, 5.24 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (500 mg, 5% purity) under N2. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (50psi) at 25 °C for 5 hr. TLC (Petroleum ether: Ethyl acetate = 1: 1) and LCMS showed the starting material was consumed completely. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was used directly into next step without further purification. Compound methyl 5-amino-6-[[(2S)- oxetan-2-yl]methylamino]pyridine-2-carboxylate (1.2 g, 5.06 mmol, 97% yield) was obtained as a light yellow solid. LCMS: MS (ESI) m/z: 238.1 [M+1] + 1 H NMR: (400MHz, CDCl 3 ) δ: 7.48 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.20 - 4.98 (m, 1H), 4.77 - 4.69 (m, 1H), 4.68 - 4.63 (m, 1H), 4.62 - 4.53 (m, 1H), 3.90 (s, 3H), 3.88 - 3.77 (m, 4H), 2.79 - 2.62 (m, 1H), 2.60 - 2.45 (m, 1H). Chemical Formula: C 11 H 15 N 3 O 3 , Molecular Weight: 237.26 Total H count from HNMR data: 15. Step 5: Preparation of methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5- b]pyridine-5-carboxylate To a solution of methyl 5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxyl ate (1.13 g, 4.75 mmol, 1 eq) in THF (10 mL) was added a solution of (2-chloroacetyl) 2- chloroacetate (879 mg, 5.14 mmol, 1.08 eq) in THF (10 mL) in 30 min. The mixture was stirred for 2 h at 20 °C then heated to 60°C and stirred for 7 h. LCMS indicated desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to give compound methyl 2-(chloromethyl)-3-[[(2S)- oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (1.3 g, 4.40 mmol, 92% yield) as a yellow oil. LCMS: MS (ESI) m/z: 296.0 [M+1] + 1H NMR: (400MHz, CDCl 3 ) δ: 8.33 - 7.96 (m, 2H), 5.28 - 5.19 (m, 1H), 5.17 - 4.99 (m, 2H), 4.87 - 4.71 (m, 2H), 4.67 - 4.55 (m, 1H), 4.37 - 4.26 (m, 1H), 4.02 (s, 3H), 2.87 - 2.66 (m, 1H), 2.55 - 2.33 (m, 1H). Chemical Formula: C 13 H 14 ClN 3 O 3 , Molecular Weight: 295.72 Total H count from HNMR data: 14. Intermediate 9
Step1: Preparation of methyl 3-[(3-methylimidazol-4-yl)methylamino]-4-nitro-benzoate To a solution of methyl 3-amino-4-nitro-benzoate (500 mg, 2.55 mmol, 1 eq) and TFA (3 mL) in DCM (8 mL) at 0 °C was added NaBH(OAc)3 (1.62 g, 7.65 mmol, 3 eq), followed by addition of a solution of 3-methylimidazole-4-carbaldehyde (337 mg, 3.06 mmol, 1.2 eq) in DCM (2 mL), and the mixture was stirred at 20 °C for 12 h. LCMS (EW23102-388-P1A) showed the reaction was completely. The residue was diluted with saturated sodium bicarbonate solution (20 mL), then extracted with ethyl acetate (30 mL * 2). The combined organic layers were washed with brine (20 mL * 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (Dichloromethane: Methanol = 10: 1). Compound methyl 3-[(3-methylimidazol-4-yl)methylamino]-4-nitro-benzoate (670 mg, 2.31 mmol, 91% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 291.0[M+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 8.39 (t, J = 5.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.18 (dd, J = 1.6, 8.8 Hz, 1H), 6.97 (s, 1H), 4.69 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 3.67 (s, 3H). Chemical Formula: C13H14N4O4, Molecular Weight: 290.27 Total H count from HNMR data: 14. Step 2: Preparation of methyl 4-amino-3-[(3-methylimidazol-4-yl)methylamino]benzoate To a solution of methyl 3-[(3-methylimidazol-4-yl)methylamino]-4-nitro-benzoate (670 mg, 2.31 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (70 mg, 10% purity) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15 psi) at 20 °C for 12 hours. TLC (Dichloromethane: Methanol = 10: 1) showed the reaction was completely. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound methyl 4-amino-3-[(3-methylimidazol -4-yl)methylamino]benzoate (600 mg, 2.30 mmol, 100% yield) was obtained as yellow solid. 1H NMR: (400MHz, CHLOROFORM-d) δ: 7.56 - 7.49 (m, 2H), 7.45 (d, J = 1.6 Hz, 1H), 7.02 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.28 (s, 2H), 3.93 - 3.82 (m, 3H), 3.68 (s, 3H), 3.48 (s, 2H). Chemical Formula: C 13 H 16 N 4 O 2 , Molecular Weight: 260.29 Total H count from HNMR data: 15. Step 3: Preparation of methyl 2-(chloromethyl)-3-[(3-methylimidazol-4- yl)methyl]benzimidazole-5-carboxylate To a solution of methyl 4-amino-3-[(3-methylimidazol-4-yl)methylamino]benzoate (450 mg, 1.73 mmol, 1 eq) and PTSA (30 mg, 0.17 mmol, 0.1 eq) in MeCN (5 mL) was added 2- chloro-1,1,1-trimethoxy-ethane (802 mg, 5.19 mmol, 0.70 mL, 3 eq), the mixture was stirred at 50 °C for 2 h. LCMS (EW23102-394-P1A) showed the reaction was completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water(0.1%TFA)-ACN];B%: 10%-40%,7min). Compound methyl 2-(chloromethyl)-3-[(3- methylimidazol-4-yl)methyl]benzimidazole-5-carboxylate (130 mg, 0.41 mmol, 24% yield) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 319.0[M+1] + 1H NMR: (400MHz, CHLOROFORM-d) δ: 8.62 (s, 1H), 8.12 - 7.99 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 5.63 (s, 2H), 4.85 (s, 2H), 3.95 (s, 3H), 3.79 (s, 3H). Chemical Formula: C 15 H 15 ClN 4 O 2 , Molecular Weight: 318.76 Total H count from HNMR data: 15. Intermediate 10 Step 1: Preparation of methyl 6-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5- nitropicolinate To a mixture of (3-ethylimidazol-4-yl)methanamine (910 mg, 4.59 mmol, 1 eq, 2HCl), DIEA (2.97 g, 22.97 mmol, 4.00 mL, 5 eq) in DMF (25 mL) was added methyl 6-chloro-5-nitro- pyridine-2-carboxylate (1.04 g, 4.82 mmol, 1.05 eq). The reaction was stirred at 30 °C for 12 h. LC-MS showed starting material was consumed completely and one main peak with desired m/z 306.1 was detected. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) and flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% MeOH/DCM gradient @ 40 mL/min). Compound methyl 6-[(3-ethylimidazol-4- yl)methylamino]-5-nitro-pyridine-2-carboxylate (892 mg, 2.89 mmol, 63% yield, 99% purity) was obtained as a yellow solid; LCMS: MS (ESI) m/z: 306.1 [M+1] + 1HNMR: (400MHz, CDCl 3 -d) δ = 8.56 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 4.92 (d, J = 5.2 Hz, 2H), 4.07 (q, J = 7.2, 14.4 Hz, 2H), 4.00 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). Chemical Formula: C 13 H 15 N 5 O 4 , Molecular Weight: 305.29 Total H count from HNMR data: 14. Step 2: Preparation of methyl 5-amino-6-(((1-ethyl-1H-imidazol-5- yl)methyl)amino)picolinate To a solution of methyl 6-[(3-ethylimidazol-4-yl)methylamino]-5-nitro-pyridine-2- carboxylate (892 mg, 2.92 mmol, 1 eq) in MeOH (5 mL) and THF (3 mL) was added Pd/C (90 mg, 10% purity). The suspension was degassed under vacuum and purged with H 2 for several times. The mixture was stirred at 25°C for 12 hours under H 2 (15psi). LC-MS showed no starting material was consumed completely and one main peak with desired m/z 276.0 was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound methyl 5-amino-6-[(3-ethylimidazol-4-yl)methylamino]pyridine- 2-carboxylate (790 mg, 2.41 mmol, 82% yield, 84% purity) was obtained as a brown solid. LCMS: MS (ESI) m/z: 276.0 [M+1] + Chemical Formula: C 13 H 17 N 5 O 2 , Molecular Weight: 275.31 Step 3: Preparation of methyl 2-(chloromethyl)-3-((1-ethyl-1H-imidazol-5-yl)methyl)-3H- imidazo[4,5-b]pyridine-5-carboxylate To a solution of methyl 5-amino-6-[(3-ethylimidazol-4-yl)methylamino]pyridine-2- carboxylate (50 mg, 0.18 mmol, 1 eq) in MeCN (2 mL) was added TFA (21 mg, 0.18 mmol, 0.013 mL, 1 eq) and 2-chloro-1,1,1-trimethoxy-ethane (34 mg, 0.22 mmol, 0.29 mL, 1.2 eq). The reaction was stirred at 50 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and one main peak with desired m/z 334.0 was detected. The product methyl 2- (chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]imidazo[4,5-b ]pyridine-5-carboxylate (60 mg, crude) was got as a yellow solid and used into the next step without further purification. The compound was kept in the solution. LCMS: MS (ESI) m/z: 334.0 [M+1] + Chemical Formula: C 15 H 16 ClN 5 O 2 , Molecular Weight: 333.77 Intermediate 11 Step 1: Preparation of 1-(difluoromethyl)-5-iodo-1H-imidazole To a stirred solution of 5-iodo-1H-imidazole (10 g, 51.55 mmol, 1 eq) in DMF (100 mL) was added K 2 CO 3 (14.25 g, 103.11 mmol, 2 eq) and (2-chloro-2,2-difluoro- acetyl)oxysodium (15.72 g, 103.11 mmol, 2 eq). The reaction mixture was stirred at 110 °C for 1 h. LCMS showed desired MS was detected. HPLC showed ~70% desired product in the mixture. Water (400 mL) was added to the mixture and the aqueous was extracted with EtOAc (250 mL * 2). The combined organic layer was washed with brine (200 mL * 2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*80mm*10 um; mobile phase: [water (0.1%TFA)-ACN];B%: 20%-50%,21min).1-(difluoromethyl)-5-iodo- 1H-imidazole (2.7 g, 11.07 mmol, 21.47% yield) was obtained as a light yellow solid . LCMS: MS (ESI) m/z: 244.6 [M+1] + 1 H NMR: (400 MHz, CHLOROFORM-d) δ: 8.04 (s, 1H), 7.24 (s, 0.25H), 7.22 (s, 1H), 7.09 (s, 0.5H), 6.94 (s, 0.25H) Chemical Formula: C4H3F2IN2, Molecular Weight: 243.98 Total H count from HNMR data: 3. Step 2: Preparation of methyl 1-(difluoromethyl)-1H-imidazole-5-carboxylate To a stirred solution of 1-(difluoromethyl)-5-iodo-imidazole (2.5 g, 10.25 mmol, 1 eq) in MeOH (25 mL) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (837 mg, 1.02 mmol, 0.1 eq), TEA (2.07 g, 20.49 mmol, 2.85 mL, 2 eq). The reaction mixture was stirred at 85 °C under CO (3 MPa) for 16 h. TLC (PE: EtOAc = 2: 1) showed the reactant was consumed and new spot was major in the mixture. The mixture was cooled down, then concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 2: 1). methyl 3- (difluoromethyl)imidazole-4-carboxylate (1.2 g, 6.81 mmol, 66% yield) was obtained as a light yellow solid 1H NMR: (400 MHz, CHLOROFORM-d) δ: 8.16 - 8.06 (m, 1.3H), 7.94 (s, 0.5H), 7.78 (s, 1.3H), 3.92 (s, 3H). Chemical Formula: C 6 H 6 F 2 N 2 O 2 , Molecular Weight: 176.12 Total H count from HNMR data: 6. Step 3: Preparation of 1-(difluoromethyl)-1H-imidazole-5-carbaldehyde To a stirred solution of methyl 3-(difluoromethyl)imidazole-4-carboxylate (1.1 g, 6.25 mmol, 1 eq) in DCM (10 mL) was added dropwise the solution of DIBAL-H (1 M, 9.37 mL, 1.5 eq) in toluene at -70°C. The reaction mixture was stirred at -70°C for 2 h. TLC (PE: EtOAc = 2: 1) showed reactant was consumed and one new spot formed. Saturated potassium sodium tartrate solution (300 mL) was added to the mixture and the mixture was stirred at 20°C for 12 h. The aqueous was extracted with EtOAc (150 ml * 2).The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 10: 1 - 1: 1). 3-(difluoromethyl)imidazole-4-carbaldehyde (380 mg, 2.60 mmol, 42% yield) was obtained as an off-white solid. 1 H NMR: (400 MHz, CHLOROFORM-d) δ: 9.82 (s, 1H), 8.22 (s, 1H), 8.07 (s, 0.25H), 7.90 (d, J = 8.8 Hz, 1.5H), 7.76 (s, 0.25H) Chemical Formula: C 5 H 4 F 2 N 2 O, Molecular Weight: 146.09 Total H count from HNMR data: 4. Step 4: Preparation of methyl 3-(((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)amino)-4- nitrobenzoate To a stirred solution of methyl 3-amino-4-nitro-benzoate (561 mg, 2.86 mmol, 1.1 eq) in DCM (5 mL) and TFA (3 mL) was added NaBH(OAc) 3 (1.65 g, 7.80 mmol, 3 eq) at 0°C. Then the solution of 3-(difluoromethyl)imidazole-4-carbaldehyde (380 mg, 2.60 mmol, 1 eq) in DCM (4 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 3 h. LCMS showed desired product was the major product. The mixture was poured into saturated NaHCO 3 aqueous (200 mL) and the aqueous was extracted with DCM (100 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 2: 1 - 1: 100). methyl 3-[[3-(difluoromethyl)imidazol-4-yl]methylamino]-4-nitro- benzoate (300 mg, 0.92 mmol, 35% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 327.0 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 8.49 (t, J = 6.0 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.13 - 8.06 (m, 1.3H), 7.93 (s, 0.5H), 7.79 (s, 0.3H), 7.57 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 1.6, 8.8 Hz, 1H), 7.02 (s, 1H), 4.80 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H) Chemical Formula: C 13 H 12 F 2 N 4 O 4 , Molecular Weight: 326.26 Total H count from HNMR data: 12. Step 5: Preparation of methyl 4-amino-3-(((1-(difluoromethyl)-1H-imidazol-5- yl)methyl)amino)benzoate To a stirred solution of methyl 3-[[3-(difluoromethyl)imidazol-4-yl]methylamino]-4-nitro- benzoate (300 mg, 0.92 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (50 mg, 10% purity. The resulting mixture was stirred at 20°C under H 2 (15 Psi) for 2 h. LCMS showed desired product was major in the mixture. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was used directly for next step. methyl 4-amino-3-[[3- (difluoromethyl)imidazol-4-yl]methylamino]benzoate (270 mg, 0.91 mmol, 99% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 297.1 [M+1] + Chemical Formula: C 13 H 14 F 2 N 4 O 2 , Molecular Weight: 296.27 Step 6: Preparation of methyl 2-(chloromethyl)-1-((1-(difluoromethyl)-1H-imidazol-5- yl)methyl)-1H-benzo[d]imidazole-6-carboxylate To a stirred solution of methyl 4-amino-3-[[3-(difluoromethyl)imidazol-4- yl]methylamino]benzoate (260 mg, 0.88 mmol, 1 eq) in CH 3 CN (5 mL) was added 2-chloro- 1,1,1-trimethoxy-ethane (176 mg, 1.14 mmol, 0.15 mL, 1.3 eq), TFA (100 mg, 0.88 mmol, 0.065 mL, 1 eq). The reaction mixture was stirred at 50°C for 2 h. LCMS showed reactant was consumed and desired MS was detected. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (DCM: MeOH = 100: 1 - 10:1). methyl 2-(chloromethyl)-3-[[3-(difluoromethyl)imidazol-4-yl]methyl] benzimidazole-5- carboxylate (300 mg, 0.85 mmol, 96% yield) was obtained as a yellow foam. LCMS: MS (ESI) m/z: 355.0 [M+1] + 1 H NMR: (400 MHz, CHLOROFORM-d) δ: 8.11 - 8.02 (m, 2H), 7.92 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.31 (s, 0.25H), 7.16 (s, 0.5H), 7.01 (s, 0.25H), 6.75 (s, 1H), 5.70 (s, 2H), 4.84 (s, 2H), 3.95 (s, 3H). Chemical Formula: C 15 H 13 ClF 2 N 4 O 2 , Molecular Weight: 354.74 Total H count from HNMR data: 13. Intermediate 12 Step 1: Preparation of methyl 4-bromo-2-fluoro-5-methylbenzoate To a solution of 4-bromo-2-fluoro-5-methyl-benzoic acid (7 g, 30.04 mmol, 1 eq) in MeOH (70 mL) was added SOCl 2 (10.72 g, 90.12 mmol, 6.54 mL, 3 eq) dropwise. The reaction was stirred at 80 °C for 12 h. TLC (PE: EtOAc = 3: 1) indicated Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL*3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~0.5% Ethylacetate/Petroleum ether gradient @ 60 mL/min). Compound methyl 4-bromo-2-fluoro-5-methyl-benzoate (6.59 g, 26.67 mmol, 89% yield) was obtained as a white solid. 1HNMR: (400MHz, CDCl 3 ) δ = 7.81 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 10.0 Hz, 1H), 3.93 (s, 3H), 2.40 (s, 3H). Chemical Formula: C 9 H 8 BrFO 2 , Molecular Weight: 247.06 Total H count from HNMR data: 8. Step 2: Preparation of (4-bromo-2-fluoro-5-methylphenyl)methanol To a solution of methyl 4-bromo-2-fluoro-5-methyl-benzoate (4 g, 16.19 mmol, 1 eq) in THF (40 mL) was added LiAlH4 (645 mg, 17.00 mmol, 1.05 eq) slowly at 0 °C. Then the reaction was stirred at 0 °C for 1.5 h. TLC (PE: EtOAc = 5: 1) indicated Reactant 1 was consumed completely and one new spot formed. H 2 O (0.64 mL) was added dropwise to quench the reaction, NaOH (15%, 0.64 mL) and H 2 O (1.92 mL) was added, then the mixture was filtered and the solution was needed and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ether gradient @ 40 mL/min). The residue was concentrated in vacuum. Compound (4-bromo-2-fluoro-5-methyl-phenyl)methanol (2.81 g, 12.83 mmol, 79% yield) was obtained as a colorless oil. 1HNMR: (400MHz, CDCl 3 ) δ = 7.30 (d, J = 7.6 Hz, 1H), 7.27 (br d, J = 2.0 Hz, 1H), 4.69 (s, 2H), 2.37 (s, 3H). Chemical Formula: C 8 H 8 BrFO, Molecular Weight: 219.05 Total H count from HNMR data: 7. Step 3: Preparation of 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene To a solution of PPh3 (3.87 g, 14.75 mmol, 1.15 eq) in DCM (25 mL) at 0 °C was added CBr 4 (4.89 g, 14.75 mmol, 1.15 eq). The mixture was stirred at 25 °C for 1 h. Then a solution of (4-bromo-2-fluoro-5-methyl-phenyl)methanol (2.81 g, 12.83 mmol, 1 eq) in DCM (18 mL) was added. The reaction was stirred at 25 °C for 11 h. TLC (PE: EtOAc = 10: 1) indicated Reactant 1 was consumed completely and many new spots formed. The reaction mixture was concentrated under reduced pressure to give a residue. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL*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 0~1% Ethylacetate/Petroleum ether gradient @ 30 mL/min). Compound 1-bromo-4-(bromomethyl)-5-fluoro-2-methyl- benzene (2 g, 7.09 mmol, 55% yield) was obtained as a colorless oil. 1HNMR: (400MHz, CDCl 3 ) δ = 7.33 - 7.23 (m, 2H), 4.44 (s, 2H), 2.38 - 2.34 (m, 2H), 2.39 - 2.34 (m, 1H). Chemical Formula: C 8 H 7 Br 2 F, Molecular Weight: 281.95 Total H count from HNMR data: 7. Step 4: Preparation of 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile To a solution of 1-bromo-4-(bromomethyl)-5-fluoro-2-methyl-benzene (2.36 g, 8.37 mmol, 1 eq) in DMF (16 mL), H 2 O (6 mL) was added NaCN (615 mg, 12.56 mmol, 1.5 eq). Then the reaction was stirred at 25 °C for 12 h. TLC (PE: EtOAc = 3: 1) indicated Reactant 1 was consumed completely and many new spots formed. The reaction mixture was poured into the sodium bicarbonate (100 mL), the mixed solution's pH was 8 and extracted with EtOAc (50 mL*2). 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®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ethergradient @ 20 mL/min). Compound 2-(4-bromo-2-fluoro-5- methyl-phenyl)acetonitrile (710 mg, 3.11 mmol, 37% yield) was obtained as a colorless oil. 1HNMR: (400MHz, CDCl 3 ) δ = 7.32 (dd, J = 8.4, 8.8 Hz, 2H), 3.70 (s, 2H), 2.39 (s, 3H). Chemical Formula: C9H7BrFN, Molecular Weight: 228.06 Total H count from HNMR data: 7. Step 5: Preparation of methyl 2-(4-bromo-2-fluoro-5-methylphenyl)acetate To a solution of 2-(4-bromo-2-fluoro-5-methyl-phenyl)acetonitrile (710 mg, 3.11 mmol, 1 eq) in MeOH (10 mL) was added H 2 SO 4 (5.73 g, 46.70 mmol, 3.11 mL, 80% purity, 15 eq) at 0 °C. Then the reaction was stirred at 70 °C for 12 h. TLC (PE: EtOAc = 10: 1) indicated Reactant 1 was consumed completely and one new spot formed. The solution was poured into the saturated NaHCO 3 (50 mL) slowly to quench the reaction, more NaHCO 3 (10 g) was added to quench the H 2 SO 4 . Then the aqueous phase was extracted with ethyl acetate (20 mL *3). The combined organic phase was washed with brine (20 mL*3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethylacetate/Petroleum ethergradient @ 30 mL/min). Compound methyl 2-(4-bromo-2- fluoro-5-methyl-phenyl)acetate (458 mg, 1.75 mmol, 56 % yield) was obtained as a colorless oil. 1HNMR: (400MHz, CDCl 3 ) δ = 7.28 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 3.72 (s, 3H), 3.61 (s, 2H), 2.35 (s, 3H). Chemical Formula: C 10 H 10 BrFO 2 , Molecular Weight: 261.09 Total H count from HNMR data: 10. Step 6: Preparation of methyl 2-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)acetate To a stirred solution of methyl 2-(4-bromo-2-fluoro-5-methyl-phenyl)acetate (2 g, 7.66 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2- dioxaborolane (3.89 g, 15.32 mmol, 2 eq) in dioxane (20 mL) was added potassium propanoate (3.01 g, 26.81 mmol, 3.5 eq) and Pd(dppf)Cl 2 .CH 2 Cl 2 (626 mg, 0.77 mmol, 0.1 eq). The reaction mixture was stirred at 100°C under N2 for 2 h. LCMS showed desired MS was detected. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 10: 1). methyl 2- [2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl]acetate (2.1 g, 6.81 mmol, 89% yield) was obtained as a light yellow oil. LCMS: MS (ESI) m/z: 309.2 [M+1] + 1 H NMR: (400MHz, CHLOROFORM-d) δ:7.44 (d, J = 10.2 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 3.71 - 3.69 (m, 3H), 3.64 (s, 2H), 2.48 (s, 3H), 1.34 (s, 12H) Chemical Formula: C 16 H 22 BFO 4 , Molecular Weight: 308.16 Total H count from HNMR data: 22. Intermediate 13 Step 1: Preparation of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate To a solution of 1,2-dihydropyrazol-3-one (25 g, 297.35 mmol, 1 eq) in DCM (200 mL) was added TEA (45.13 g, 446.02mmol, 62.08 mL, 1.5 eq) and (Boc) 2 O (77.88 g, 356.82 mmol, 81.97 mL, 1.2 eq), then stirred at 25 °C for 12 h. TLC (dichloromethane / methanol=10 / 1) showed the starting material was consumed completely. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate/dichloromethane/methanol=1/0/0/0 to 0/0/30/1). Tert-butyl 5- oxo-1H-pyrazole-2-carboxylate (49 g, 266.03 mmol, 89% yield) was obtained as a white solid. Chemical Formula: C 8 H 12 N 2 O 3 , Molecular Weight: 184.19 Step 2: Preparation of tert-butyl 3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazole-1- carboxylate To a solution of tert-butyl 3-hydroxypyrazole-1-carboxylate (15.0 g, 81.44 mmol, 1 eq), 1- (bromomethyl)-4-chloro-2-fluoro-benzene (18.20 g, 81.44 mmol, 1 eq) in MeCN (150 mL) was added K 2 CO 3 (22.51 g, 162.87 mmol, 2 eq). The reaction was stirred at 50 °C for 6 h. LC-MS showed starting material was consumed completely and one main peak with desired m/z 271.0 was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~7% Ethyl acetate/Petroleum ethergradient @ 85 mL/min). Compound tert-butyl 3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazole-1-carboxylate (10.81 g, 31.38 mmol, 39% yield, 95% purity) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 271.0 [M-56] + 1 HNMR: (400MHz, CDCl 3 -d) δ = 7.86 (d, J = 3.2 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.18 - 7.09 (m, 2H), 5.91 (d, J = 3.2 Hz, 1H), 5.36 (s, 2H), 1.63 (s, 9H). Chemical Formula: C15H16ClFN2O3, Molecular Weight: 326.75 Total H count from HNMR data: 16. Step 3: Preparation of 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H-pyrazole To a solution of tert-butyl 3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazole-1-carboxylate (10.81 g, 33.08 mmol, 1 eq) in DCM (200 mL) was added TFA (15.40 g, 135.06 mmol, 10 mL, 4.08 eq). The reaction was stirred at 25 °C for 3 h. TLC (PE: EA = 1: 1) indicated starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was concentrated to remove most of TFA, then diluted with 60 mL water, then NaHCO 3 was added until pH 7~8, then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine 20 mL, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. Compound 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H- pyrazole (7.13 g, 30.35 mmol, 92% yield, 96% purity) was obtained as a white solid. LCMS: . MS (ESI) m/z: 227.4 [M+1] + 1 HNMR: . (400MHz, CDCl 3 -d) δ = 7.47 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.13 (ddd, J = 2.0, 8.0, 13.6 Hz, 2H), 5.79 (d, J = 2.8 Hz, 1H), 5.26 (s, 2H). Chemical Formula: C 10 H 8 ClFN 2 O, Molecular Weight: 226.63 Total H count from HNMR data: 7. Step 4: Preparation of tert-butyl 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate
To a solution of 3-[(4-chloro-2-fluoro-phenyl)methoxy]-1H-pyrazole (7.13 g, 31.46 mmol, 1 eq), tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (21.97 g, 78.65 mmol, 2.5 eq) in DMF (150 mL) was added Cs 2 CO 3 (20.50 g, 62.92 mmol, 2 eq). The reaction was stirred at 100 °C for 6 h. LC-MS showed starting material was consumed completely and one main peak with desired m/z 410.1 was detected. The reaction mixture was filtered. The filtrate was partitioned between water (100 mL) and EA (150 mL * 3). The combined organic layers were washed with brine (50 mL * 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,15 um); mobile phase: [water(0.1%TFA)-ACN];B%: 62ACN%-86ACN%,22min). Then NaHCO 3 (2 g) solid was added to adjust pH = 8~9. Then the aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with brine (30 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. Compound tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (8.56 g, 20.84 mmol, 66.23% yield, 99.77% purity) was obtained as a white solid, checked by LCMS(EW23109-230-P1Z) and 1HNMR(EW23109- 230-P1Z). Compound tert-butyl 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (2.53 g, 6.17 mmol, 20% yield, 100% purity) was obtained as a white solid. 1HNMR: (400MHz, CDCl 3 -d) δ = 7.48 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.17 - 7.07 (m, 2H), 5.67 (d, J = 2.4 Hz, 1H), 5.21 (s, 2H), 4.36 - 4.14 (m, 2H), 4.10 - 3.98 (m, 1H), 2.87 (br t, J = 12.0 Hz, 2H), 2.08 (br dd, J = 2.0, 12.8 Hz, 2H), 1.85 (dq, J = 4.0, 12.0 Hz, 2H), 1.48 (s, 9H). Chemical Formula: C20H 2 5ClFN3O3, Molecular Weight: 409.88 Total H count from HNMR data: 25. LCMS: MS (ESI) m/z: 410.1 [M+1] + 1HNMR: (400MHz, CDCl 3 -d) δ = 7.40 - 7.34 (m, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.21 - 7.14 (m, 2H), 5.59 (d, J = 2.0 Hz, 1H), 5.11 (s, 2H), 4.36 - 4.16 (m, 3H), 2.83 (br s, 2H), 2.10 - 2.05 (m, 1H), 2.04 - 1.98 (m, 1H), 1.90 - 1.77 (m, 2H), 1.46 (s, 9H). Chemical Formula: C 20 H 25 ClFN 3 O 3 , Molecular Weight: 409.88 Total H count from HNMR data: 25. Step 5: Preparation of tert-butyl 4-(5-hydroxypyrazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (2.01 g, 4.90 mmol, 1 eq) in MeOH (5 mL) was added Pd/C (170 mg, 2.44 mmol, 10% purity) and Pd(OH) 2 (170 mg, 0.12 mmol, 10% purity, 0.1 eq) under N 2 . The suspension was degassed under vacuum and purged with H 2 for several times. The mixture was stirred under H 2 (15psi) at 20 °C for 2 hours. TLC (PE: EA = 1: 1) indicated starting material was consumed completely and new spots formed. The reaction mixture was 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 ethergradient @ 30 mL/min). Then the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/EA gradient @ 30 mL/min). Compound tert-butyl 4-(5- hydroxypyrazol-1-yl)piperidine-1-carboxylate (628 mg, 2.35 mmol, 48% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 212.2 [M-56] + 1HNMR: (400MHz, CDCl 3 -d) δ = 7.29 (d, J = 0.4 Hz, 1H), 7.27 (s, 1H), 4.38 - 4.03 (m, 3H), 2.82 (br s, 2H), 2.48 - 2.10 (m, 2H), 1.88 (dq, J = 4.4, 12.4 Hz, 2H), 1.50 - 1.46 (m, 9H). Chemical Formula: C 13 H 21 N 3 O 3 , Molecular Weight: 267.32 Total H count from HNMR data: 20. Intermediate 14
Step 1: Preparation of methyl 4-nitro-3-[[(2S)-tetrahydrofuran-2-yl]methylamino]benzoate To a solution of [(2S)-tetrahydrofuran-2-yl]methanamine (500 mg, 4.94 mmol, 0.5 mL, 1 eq) and methyl 3-fluoro-4-nitro-benzoate (984 mg, 4.94 mmol, 1 eq) in N,N- dimethylformamide (3 mL) was added triethylamine (1.50 g, 14.83 mmol, 2.06 mL, 3 eq), the mixture was stirred at 20 °C for 12 h. TLC (Petroleum ether: Ethyl acetate = 3: 1) showed the reaction was completely. The reaction mixture was quenched by water (10 mL) at 20 °C, and extracted with ethyl acetate (20 mL * 3), the combined organic layers were washed with brine (15 mL * 3), dried over anhydrous sodium sulfate, 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 @ 80 mL/min). Compound methyl 4-nitro-3-[[(2S)- tetrahydrofuran-2-yl]methylamino]benzoate (1.19 g, 4.03 mmol, 82% yield, 95% purity) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 281.4 [M+1] + Chemical Formula: C 13 H 16 N 2 O 5 , Molecular Weight: 280.28 Step 2: Preparation of methyl 4-amino-3-[[(2S)-tetrahydrofuran-2-yl]methylamino]benzoate To a solution of methyl 4-nitro-3-[[(2S)-tetrahydrofuran-2-yl]methylamino]benzoate (1.19 g, 4.25 mmol, 1 eq) in tetrahydrofuran (5 mL) and methanol (7 mL) was added palladium on carbon (200 mg, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15psi) at 20°C for 12 hours. LCMS showed the reaction was completely. The reaction mixture was filtered and the filtrate was concentrated. Compound methyl 4-amino-3-[[(2S)- tetrahydrofuran-2-yl]methylamino]benzoate (1 g, 4.00 mmol, 94% yield) was obtained as a brown oil. LCMS: MS (ESI) m/z: 251.4[M+1] + 1 H NMR: (400MHz, CHLOROFORM-d) δ: 7.71 - 7.41 (m, 2H), 6.76 - 6.66 (m, 1H), 4.24 (s, 1H), 4.06 - 3.90 (m, 2H), 3.87 (d, J = 0.8 Hz, 3H), 3.84 - 3.74 (m, 1H), 3.45 - 3.08 (m, 2H), 2.11 - 1.64 (m, 4H). Chemical Formula: C13H18N2O3, Molecular Weight: 250.29 Total H count from HNMR data: 16. Step 3: Preparation of methyl 2-(chloromethyl)-3-[[(2S)-tetrahydrofuran-2- yl]methyl]benzimidazole-5-carboxylate To a solution of methyl 4-amino-3-[[(2S)-tetrahydrofuran-2-yl]methylamino]benzoate (1 g, 4.00 mmol, 1 eq) and p-toluene sulphonic acid (69 mg, 0.40 mmol, 0.1 eq) in acetonitrile (10 mL) was added 2-chloro-1,1,1-trimethoxy-ethane (741 mg, 4.79 mmol, 0.64 mL, 1.2 eq), the mixture was stirred at 50 °C for 2 h. TLC (Petroleum ether: Ethyl acetate = 3: 1) showed the reaction was completely. 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 @ 60 mL/min). Compound methyl 2-(chloromethyl)-3-[[(2S)- tetrahydrofuran-2-yl]methyl] benzimidazole-5-carboxylate (1.1 g, 3.56 mmol, 89% yield) was obtained as a colorless oil. 1 H NMR: (400MHz, CHLOROFORM-d) δ: 8.12 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 5.06 - 4.93 (m, 2H), 4.53 - 4.45 (m, 1H), 4.42 - 4.31 (m, 1H), 4.24 (dq, J = 2.4, 7.2 Hz, 1H), 3.96 (s, 3H), 3.90 - 3.81 (m, 1H), 3.77 - 3.66 (m, 1H), 2.21 - 2.07 (m, 1H), 1.95 - 1.83 (m, 2H), 1.61 (qd, J = 8.0, 12.0 Hz, 1H). Chemical Formula: C 15 H 17 ClN 2 O 3 , Molecular Weight: 308.76 Total H count from HNMR data: 17. Intermediate 15 Step 1: Preparation of (4-chloro-2-fluorophenyl)methanethiol To a stirred solution of 1-(bromomethyl)-4-chloro-2-fluoro-benzene (2 g, 8.95 mmol, 1 eq) in EtOH (20 mL) was added thiourea (1.36 g, 17.90 mmol, 2 eq). The mixture was stirred at 80°C for 2 h. Then the mixture was concentrated under vacuum. The residue was diluted with NaOH aqueous (2 M) (40 mL). The mixture was stirred at 20°C for 1 h. TLC (PE: EtOAc = 5: 1) showed reactant was consumed and new spot was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl (1 M). The aqueous was extracted with EtOAc (100 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 3: 1). (4-chloro-2-fluoro-phenyl)methanethiol (1.5 g, 8.49 mmol, 95% yield) was obtained as a colorless oil which was confirmed by HNMR (EW22514-474-P1A). 1 H NMR: (400MHz, DMSO-d6) δ: 7.47 (t, J = 8.4 Hz, 1H), 7.39 (dd, J = 2.0, 10.0 Hz, 1H), 7.26 (dd, J = 1.6, 8.0 Hz, 1H), 3.72 (d, J = 7.2 Hz, 2H), 2.99 (t, J = 7.6 Hz, 1H) Chemical Formula: C 7 H 6 ClFS, Molecular Weight: 176.64 Total H count from HNMR data: 6. Step 2: Preparation of 3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazole To a stirred solution of 3-iodo-1H-pyrazole (1.81 g, 9.34 mmol, 1.1 eq), (4-chloro-2-fluoro- phenyl)methanethiol (1.5 g, 8.49 mmol, 1 eq) in dioxane (15 mL) was added Pd2(dba)3 (778 mg, 0.85 mmol, 0.1 eq), Xantphos (983 mg, 1.70 mmol, 0.2 eq) and DIEA (2.19 g, 16.98 mmol, 2.96 mL, 2 eq) under N2. The resulting mixture was stirred at 100°C for 16 h. LCMS showed desired product was major in the mixture. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 10: 1 - 1: 1). 3-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]-1H-pyrazole (1.2 g, 4.94 mmol, 58% yield) was obtained as a yellow oil which was confirmed by HNMR (EW22514-476-P1A). LCMS: MS (ESI) m/z: 242.7 [M+1] + 1 H NMR: (400MHz, CDCl 3 ) δ: 7.55 (s, 1H), 7.16 - 6.98 (m, 3H), 6.27 (s, 1H), 4.05 (s, 2H). Chemical Formula: C 10 H 8 ClFN 2 S, Molecular Weight: 242.70 Total H count from HNMR data: 7. Step 3: Preparation of tert-butyl 4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidine-1-carboxylate and tert-butyl 4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol- 1-yl)piperidine-1-carboxylate
To a stirred solution of 3-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]-1H-pyrazole (1.1 g, 4.53 mmol, 1 eq) in DMF (12 mL) was added Cs 2 CO 3 (2.95 g, 9.06 mmol, 2 eq) and tert- butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1.52 g, 5.44 mmol, 1.2 eq). The reaction mixture was stirred at 70°C for 1 h. LCMS showed desired product was major in the mixture. Water (250 mL) was added to the mixture and the aqueous was extracted with EtOAc (150 mL * 2). The combined organic layer was washed with brine(200 mL * 2) , dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 2: 1). tert-butyl 4- [5-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]pyrazol-1-yl]pi peridine-1-carboxylate (600 mg, 1.41 mmol, 31% yield) were obtained as a yellow oil which were confirmed by HNMR (EW22514-480-P1A) and tert-butyl 4-[3-[(4-chloro-2-fluoro- phenyl)methylsulfanyl]pyrazol-1-yl]piperidine-1-carboxylate (800 mg, 1.88 mmol, 41% yield) were obtained as a yellow oil . LCMS: MS (ESI) m/z: 370.1 [M+1-56] + 1 H NMR: (400MHz, CDCl 3 ) δ: 7.53 (d, J = 1.6 Hz, 1H), 7.14 - 6.99 (m, 2H), 6.99 - 6.85 (m, 1H), 6.30 (d, J = 1.6 Hz, 1H), 4.49 - 4.36 (m, 1H), 4.22 (br d, J = 11.6 Hz, 2H), 3.88 (s, 2H), 2.76 (br t, J = 12.8 Hz, 2H), 2.05 - 1.92 (m, 2H), 1.59 - 1.53 (m, 2H), 1.47 (s, 9H). 1H NMR: (400MHz, CDCl 3 ) δ: 7.34 (d, J = 2.4 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.15 (d, J = 2.4 Hz, 1H), 4.25 (dq, J = 4.0, 7.6 Hz, 3H), 4.09 (s, 2H), 2.88 (br t, J = 12.4 Hz, 2H), 2.09 (br dd, J = 2.4, 12.0 Hz, 2H), 1.89 (br dd, J = 4.4, 12.4 Hz, 2H), 1.48 (s, 9H). Chemical Formula: C 20 H 25 ClFN 3 O 2 S, Molecular Weight: 425.95 Total H count from HNMR data: 25. Intermediate 16
Step 1: Preparation of 3-fluoro-4-(mercaptomethyl)benzonitrile , To a stirred solution of 4-(bromomethyl)-3-fluoro-benzonitrile (2 g, 9.34 mmol, 1 eq) in EtOH (20 mL) was added thiourea (1.42 g, 18.69 mmol, 2 eq). The mixture was stirred at 80°C for 2 h. The mixture was concentrated under vacuum. The residue was diluted with NaOH aqueous (2 M) (40 mL) and the mixture was stirred at 20°C for 1 h. TLC (PE: EtOAc = 5: 1) showed reactant was consumed and new spot was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl (1 M). The aqueous was extracted with EtOAc (100 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 3: 1).3-fluoro-4-(sulfanylmethyl)benzonitrile (980 mg, 5.86 mmol, 63% yield) was obtained as a white solid which was confirmed by HNMR (EW22514-473-P1A). 1H NMR: (400MHz, DMSO-d6) δ:7.82 (d, J = 10.4 Hz, 1H), 7.72 - 7.53 (m, 2H), 3.79 (br d, J = 6.8 Hz, 2H), 3.13 (s, 1H) Chemical Formula: C8H6FNS, Molecular Weight: 167.20 Total H count from HNMR data: 6. Step 2: Preparation of 4-(((1H-pyrazol-3-yl)thio)methyl)-3-fluorobenzonitrile To a stirred solution of 3-iodo-1H-pyrazole (1.25 g, 6.45 mmol, 1.1 eq), 3-fluoro-4- (sulfanylmethyl)benzonitrile (980 mg, 5.86 mmol, 1 eq) in dioxane (10 mL) was added Pd2(dba)3 (537 mg, 0.59 Mmol, 0.1 eq), Xantphos (678 mg, 1.17 mmol, 0.2 eq) and DIEA (1.52 g, 11.72 mmol, 2.04 mL, 2 eq) under N2. The resulting mixture was stirred at 100°C for 16 h. LCMS showed desired MS was detected. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 10: 1 - 1: 1).3-fluoro-4-(1H-pyrazol-3-ylsulfanylmethyl)benzonitrile (980 mg, 4.20 mmol, 72% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 233.7 [M+1] + 1 H NMR: (400MHz, CDCl 3 ) δ: 7.55 (s, 1H), 7.37 - 7.29 (m, 3H), 6.25 (s, 1H), 4.13 (s, 2H) Chemical Formula: C 11 H 8 FN 3 S, Molecular Weight: 233.26 Total H count from HNMR data: 7. Step 3: Preparation of tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidine-1-carboxylate and tert-butyl 4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol- 1-yl)piperidine-1-carboxylate
To a stirred solution of 3-fluoro-4-(1H-pyrazol-3-ylsulfanylmethyl)benzonitrile (980 mg, 4.20 mmol, 1 eq) in DMF (10 mL) was added Cs 2 CO 3 (2.74 g, 8.40 mmol, 2 eq) and tert- butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1.41 g, 5.04 mmol, 1.2 eq). The reaction mixture was stirred at 70°C for 1 h. LCMS showed desired MS was detected. Water (250 mL) was added to the mixture and the aqueous was extracted with EtOAc (150 mL * 2). The combined organic layer was washed with brine (200 mL * 2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [water(0.1%TFA)-ACN];B%: 55%-85%,7min) to give the mixture. The ismoers was separated by SFC (EW22514-478-P1D_C1) (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O MEOH];B%: 20%- 20%,2.8;25min). tert-butyl 4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]piperidine-1-carboxylate (80 mg, 0.19 mmol, 5% yield) and tert-butyl 4-[3-[(4-cyano-2- fluoro-phenyl)methylsulfanyl]pyrazol-1-yl]piperidine-1-carbo xylate (220 mg, 0.53 mmol, 13% yield) were obtained as a colorless oil. LCMS: MS (ESI) m/z: 360.8 [M+1-56] + 1H NMR tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidi ne-1- carboxylate: (400MHz, CDCl 3 ) δ: 7.50 (d, J = 1.6 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 6.21 (d, J = 1.2 Hz, 1H), 4.54 - 4.40 (m, 1H), 4.34 - 4.13 (m, 2H), 3.92 (s, 2H), 2.88 - 2.71 (m, 2H), 2.04 (br dd, J = 4.0, 12.0 Hz, 2H), 1.67 - 1.56 (m, 2H), 1.48 (s, 9H). 1H NMR tert-butyl 4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidi ne-1- carboxylate: (400MHz, CDCl 3 ) δ: 7.39 - 7.28 (m, 4H), 6.12 (d, J = 2.0 Hz, 1H), 4.33 - 4.16 (m, 3H), 4.13 (s, 2H), 2.88 (br s, 2H), 2.07 (br d, J = 12.4 Hz, 2H), 1.89 (br dd, J = 4.0, 12.0 Hz, 2H), 1.49 (s, 9H). Chemical Formula: C 21 H 25 FN 4 O 2 S, Molecular Weight: 416.51 Total H count from HNMR data: 25. Synthesis of compounds of the invention Example 1 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}p iperidin-1-yl)methyl]- 1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylate To a stirred solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (192.39 mg, 0.41 mmol, 1 eq, TsOH) ,methyl 2-(chloromethyl)-3-[[(2R)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (120.00 mg, 0.41 mmol, 1 eq) in CH 3 CN (5 mL) was added K 2 CO 3 (225.08 mg, 1.63 mmol, 4 eq). The reaction mixture was stirred at 50 °C for 12 h. LCMS showed reactant was consumed completely and desired product was major in the mixture. Water (200 mL) was added to the mixture and the aqueous was extracted with EA (100 ml x 2). The combined organic layer was dried over Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH = 15:1) to give title compound 1 (110 mg, 0.20 mmol, 48% yield) as a yellow solid. LCMS: (ESI) m/z: 559.2 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1H), 7.98 (dd, J = 8.4, 1.0 Hz, 1H), 7.66 - 7.78 (m, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 9.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 5.68 (d, J = 2.4 Hz, 1H), 5.30 (s, 2H), 5.17 - 5.26 (m, 1H), 4.60 - 4.78 (m, 3H), 4.39 (br d, J = 9.2 Hz, 1H), 3.93 - 4.02 (m, 6H), 3.00 (br s, 2H), 2.71 - 2.81 (m, 1H), 2.40 - 2.51 (m, 1H), 2.32 (br dd, J = 11.9, 2.3 Hz, 2H), 1.93 - 2.13 (m, 4H). Step 2. Synthesis of 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylic acid, ammonium salt (Example 1) To a stirred solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol e-5-carboxylate (110 mg, 0.20 mmol, 1 eq) in CH 3 CN (3 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a]pyrimidine (82.23 mg, 0.59 mmol, 3 eq). The resulting mixture was stirred at 25 °C for 12 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted by citric acid to 6 and the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 3%-33%,10min) to give title compound e (60.83 mg, 0.11 mmol, 55% yield) as a white solid. LCMS: MS (ESI) m/z: 545.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.89 (d, J = 10.0 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 3.4 Hz, 2H), 7.56 - 7.66 (m, 2H), 5.71 (d, J = 2.2 Hz, 1H), 5.23 (s, 2H), 5.03 - 5.14 (m, 1H), 4.77 (s, 1H), 4.66 (br d, J = 2.6 Hz, 1H), 4.49 (br d, J = 5.9 Hz, 1H), 4.37 (br d, J = 8.9 Hz, 1H), 3.94 (br d, J = 13.3 Hz, 2H), 3.80 (s, 1H), 2.94 - 3.02 (m, 1H), 2.81 - 2.88 (m, 1H), 2.66 - 2.76 (m, 1H), 2.38 - 2.45 (m, 1H), 2.18 - 2.30 (m, 2H), 1.82 - 1.97 (m, 4H). Example 2 2-[(4-{4-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}p iperidin-1-yl)methyl]- 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carb oxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{4-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate To a solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-4-yl]oxymethyl]benzonitr ile (60.00 mg, 0.093 mmol, 1.03 eq, 2TsOH), methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (30 mg, 0.09 mmol, 1 eq) in ACN (1 mL) was added K 2 CO 3 (62 mg, 0.45 mmol, 5 eq). The mixture was stirred at 50 °C for 12 hours. LC-MS showed starting material was consumed completely and one main peak with desired mass was detected. The residue was poured into water (10 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO 2 , DCM : MeOH = 10:1). Title compound (50 mg, 0.083 mmol, 93% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 597.3 [M] + . Step 2. Synthesis of 2-[(4-{4-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 2) To a solution of methyl 2-[[4-[4-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (70 mg, 0.12 mmol, 1 eq) in ACN (5 mL), H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a]pyrimidine (49 mg, 0.35 mol, 3 eq). The mixture was stirred at 25 °C for 12 hours. LC-MS showed mass of desired compound was detected. The mixture was adjusted with citric acid to pH 5~6. The aqueous phase was extracted with DCM (20 mLx2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH 3 .H 2 O condition: column: Waters Xbridge 150 x 25 mm x 5 µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 7% - 37%, 10 min). Title compound (16 mg, 0.027 mmol, 23% yield, 98% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 583.3 [M+1] + . 1H NMR: SR0052-V251683 (400MHz, DMSO-d 6 ) δ 8.09 (1 H, s), 7.91 (1 H, d, J=10.4 Hz), 7.82 (1 H, dd, J=8.4, 1.2 Hz), 7.76 - 7.72 (2 H, m), 7.69 - 7.64 (2 H, m), 7.58 (1 H, s), 7.27 (1 H, s), 6.46 (1 H, s), 5.73 (2 H, s), 5.06 (2 H, s), 4.00 (3 H, q, J=7.2 Hz), 3.82 (2 H, s), 2.86 (2 H, br d, J=11.2 Hz) 2.23 - 2.16 (2 H, m) 1.88 (2 H, br d, J=9.6 Hz) 1.66 - 1.74 (2 H, m) 1.15 (3 H, t, J=7.2 Hz). Example 3 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol -1-yl}piperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol - 1-yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)met hyl]-1H-benzimidazole-6- carboxylate To a solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]-1,2,4-triazol-1-yl] piperidine (150 mg, 0.35 mmol, 1 eq, TFA), methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl] benzimidazole-5-carboxylate (130 mg, 0.35 mmol, 1 eq, HCl) in ACN (5 mL) was added K 2 CO 3 (488 mg, 3.53 mmol, 10 eq). The reaction mixture was stirred at 50 °C for 2 h. LCMS showed desired MS was detected. EtOAc (20 mL) and water (20 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (dichloromethane:methanol = 9:1). Title compound (130 mg, 0.21 mmol, 60% yield, 98.5% purity) was obtained as a light yellow oil. LCMS: MS (ESI) m/z: 607.4 [M+1] + . Step 2. Synthesis of 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol -1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 3)
To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]-1,2,4-triazol-1 -yl]- 1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (130 mg, 0.21 Mmol, 1 eq) in THF (0.5 mL), MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (45 mg, 1.07 mmol, 5 eq). The reaction was stirred at 40 °C for 2 h. LCMS showed desired MS was detected. HCl solution (2 M) was added to the mixture to adjust pH about 7. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-35%,7min). Title compound (53.17 mg, 0.08 mmol, 39.58% yield, 97.24% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 593.2 [M+1] + . 1H NMR: (400MHz, DMSO-d6) δ 8.21 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.49 (dd, J = 2.0, 10.0 Hz, 1H), 7.33 (dd, J = 1.6, 8.4 Hz, 1H), 6.40 (s, 1H), 5.68 (s, 2H), 5.25 (s, 2H), 4.11 - 3.94 (m, 3H), 3.79 (s, 2H), 2.89 - 2.79 (m, 2H), 2.23 - 2.14 (m, 2H), 1.95 - 1.86 (m, 2H), 1.76 - 1.63 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H). Example 4 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol -1-yl}piperidin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol - 1-yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H- benzimidazole-6- carboxylate
To a stirred solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]-1,2,4-triazol-1- yl]piperidine (130 mg, 031 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan- 2-yl]methyl]benzimidazole-5-carboxylate (90 mg, 0.31 mmol, 1 eq) in CH 3 CN (3 mL) was added K 2 CO 3 (212 mg, 1.53 mmol, 5 eq). The resulting mixture was stirred at 50°C for 5 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EA (80 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM:MeOH = 10:1) to give title compound (100 mg, 0.18 mmol, 57% yield) as a light yellow foam. LCMS: (ESI) m/z: 569.3 [M+1] + . Step 2. Synthesis of 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-1,2,4-triazol -1- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylic acid, ammonium salt (Example 4) To a stirred solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]-1,2,4-triazol- 1-yl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzim idazole-5-carboxylate (100 mg, 175.74 µmol, 1 eq) in THF (1 mL), MeOH (0.3 mL) and H 2 O (0.3 mL) was added LiOH (123 mg, 527.22 µmol, 3 eq). The resulting mixture was stirred at 40°C for 6 h. LCMS showed reactant was consumed completely and desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M). Then the aqueous was extracted by DCM (30 mL x3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 6%-36%,7min) to give title compound (61.50 mg, 105.87 µmol, 60.24% yield, 98.47% purity) as a white solid. LCMS: MS (ESI) m/z: 555.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.22 - 8.30 (m, 2H), 7.80 (dd, J = 8.4, 1.3 Hz, 1H), 7.54 - 7.67 (m, 2H), 7.48 (dd, J = 10.0, 2.0 Hz, 1H), 7.32 (dd, J = 8.4, 1.9 Hz, 1H), 5.25 (s, 2H), 5.03 - 5.12 (m, 1H), 4.74 - 4.84 (m, 1H), 4.60 - 4.69 (m, 1H), 4.45 - 4.53 (m, 1H), 4.32-4.41 (m, 1H), 4.08 - 4.19 (m, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.80 (d, J = 13.6 Hz, 1H), 2.93-3.03 (m, 1H), 2.81-2.89 (m, 1H), 2.63 - 2.77 (m, 1H), 2.38 - 2.45 (m, 1H), 2.18 - 2.35 (m, 2H), 1.80 - 2.04 (m, 4H). Example 5 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1-yl)methyl]- 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carb oxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate To a solution of methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]benzimidazo le- 5-carboxylate (107 mg, 0.32 mmol, 1.11 eq) and 3-fluoro-4-[[3-(4-piperidyl)pyrazol-1- yl]oxymethyl]benzonitrile (120 mg, 0.29 mmol, 1 eq, TFA) in ACN (4 mL) was added K 2 CO 3 (400 mg, 2.90 mmol, 10 eq). The mixture was stirred at 50 °C for 4 h. LCMS showed the desired mass was detected. The mixture was filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Shim-pack C18150 x 25 x 10 µm; mobile phase: [water (0.225% FA) - ACN]; B%: 9% - 31%, 11 min). Title compound (75 mg, 0.13 mmol, 43% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 597.4 [M+1] + .1H NMR: (400 MHz, CHLOROFORM-d) δ 8.09 (d, J = 1.2 Hz, 1H), 8.02 (dd, J = 1.6, 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.52 - 7.46 (m, 2H), 7.42 (d, J = 9.6 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 5.90 (d, J = 2.4 Hz, 1H), 5.70 (s, 2H), 5.40 (s, 2H), 3.96 (s, 3H), 3.95 - 3.89 (m, 2H), 3.84 (s, 2H), 2.93 (br d, J = 12.0 Hz, 1H), 2.67 (br t, J = 11.6 Hz, 2H), 2.33 (br t, J = 10.8 Hz, 2H), 1.98 (br d, J = 12.8 Hz, 2H), 1.75 - 1.58 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H). Step 2. Synthesis of 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 5) To a solution of methyl 2-[[4-[1-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (75 mg, 0.13 mmol, 1 eq) in ACN (2 mL) and H 2 O (0.4 mL) was added 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a]pyrimidine (52 mg, 0.38 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed the desired mass was detected. The reaction mixture pH was adjusted to 4-5 by citric acid and adjust to pH 8-9 by ammonium hydroxide, then the reaction mixture was concentrated under vacuum to remove most of the acetonitrile, and then filtered to get the filtrate. The filtrate was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 x 30 mm x 3 µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%- 35%, 11.5 min), the collected solution was under vacuum to remove most of the acetonitrile, and then the reaction was lyophilizated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm x3 µm; mobile phase: [water (0.225% FA) - ACN]; B%: 8%-28%, 10min), the collected solution was under vacuum to remove most of the acetonitrile, and then the reaction was lyophilizated. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 x 30 mm x 3 µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5% - 35%, 7 min), the collected solution was under vacuum to remove most of the acetonitrile, and then the reaction was lyophilizated. Title compound (35.93 mg, 0.058 mmol, 46% yield, 97.27% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 583.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.06 (s, 1H), 7.92 (dd, J = 1.2, 9.6 Hz, 1H), 7.81 (dd, J = 1.2, 8.4 Hz, 1H), 7.73 (dd, J = 1.6, 8.0 Hz, 1H), 7.69 - 7.56 (m, 3H), 7.45 (d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.72 (s, 2H), 5.37 (s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 3.79 (s, 2H), 3.31 (br s, 1H), 2.80 (br d, J = 10.8 Hz, 2H), 2.16 - 2.08 (m, 2H), 2.06 - 1.95 (m, 2H), 1.78 - 1.69 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H). Example 6 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl}p iperidin-1-yl)methyl]- 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carb oxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate To a stirred solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (170.39 mg, 0.6 mmol, 1 eq, TsOH) in ACN (5 mL) was added K 2 CO 3 (249.18 mg, 1.80 mmol, 5 eq). Then methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (120 mg, 0.36 mmol, 1 eq) was added to the mixture. The resulting mixture was stirred at 50°C for 12 h. LCMS showed desired product was major in the mixture. Water (200 mL) was added to the mixture and the aqueous was extracted with EA (150 mLx2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM:MeOH = 10:1) to give title compound (90 mg, 0.15 mmol, 42% yield) as a light yellow oil. LCMS: (ESI) m/z: 597.4 [M+1] + . Step 2. Synthesis of 2-[(4-{3-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 6) To a stirred solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimid azole-5-carboxylate (90 mg, 0.15 mmol, 1 eq) in CH 3 CN (3 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a]pyrimidine (62.99 mg, 452.52 µmol, 3 eq). The reaction mixture was stirred at 20°C for 12 h. LCMS showed starting material was consumed completely and desired product was major in the mixture. The pH value of the mixture was adjusted by citric acid. Then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-35%,7min) to givetitle compound (54.08 mg, 0.09 mmol, 59.19% yield, 99.0% purity) as a white solid. LCMS: MS (ESI) m/z: 583.3 [M+1] + . 1H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (d, J = 0.72Hz, 1H), 7.88 - 7.92 (m, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.70 - 7.74 (m, 2H), 7.62 - 7.67 (m, 2H), 7.51 (d, J = 2.2 Hz, 1H), 6.42 (s, 1H), 5.67 - 5.74 (m, 3H), 5.24 (s, 2H), 4.00 (d, J = 7.2 Hz, 2H), 3.88 - 3.95 (m, 1H), 3.81 (s, 2H), 2.80 - 2.88 (m, 2H), 2.13 - 2.21 (m, 2H), 1.81-1.88 (m, 2H), 1.58 - 1.70 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H). Example 7 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1-yl)methyl]- 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carb oxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate To a stirred solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (130 mg, 0.31 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (102 mg, 0.31 mmol, 1 eq) in CH 3 CN (4 mL) was added K 2 CO 3 (254 mg, 1.84 mmol, 6 eq). The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EA (80 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM:MeOH = 15:1) to give title compound (110 mg, 0.18 mmol, 59% yield) as a yellow oil. LCMS: MS (ESI) m/z: 606.2 [M+1] + . Step 2. Synthesis of 2-[(4-{3-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 7) To a stirred solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimid azole-5-carboxylate (110 mg, 0.18 mmol, 1 eq) in THF (2 mL), MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (23 mg, 0.54 mmol, 3 eq). The resulting mixture was stirred at 20°C for 12 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 7 by diluted HCl (1 M) and the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 11%-41%,10min) to give title compound (62.56 mg, 0.13 mmol, 56.59% yield, 100% purity) as a white solid. LCMS: MS (ESI) m/z: 592.3 [M+1] + . 1 H NMR: (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.89 - 8.00 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.45 - 7.60 (m, 3H), 7.29 - 7.34 (m, 1H), 6.55 (s, 1H), 5.76 (s, 2H), 5.68 (d, J = 2.2 Hz, 1H), 5.13 (s, 2H), 4.00 - 4.10 (m, 2H), 3.78 - 3.96 (m, 3H), 2.81 - 2.93 (m, 2H), 2.12 - 2.27 (m, 2H), 1.80 - 1.92 (m, 2H), 1.55 - 1.70 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H). Example 8 2-[(4-{3-[(4-cyanophenyl)methoxy]-1H-pyrazol-1-yl}piperidin- 1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{3-[(4-cyanophenyl)methoxy]-1H-pyrazol-1-yl}piperidin- 1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimi dazole-6-carboxylate To a stirred solution of 4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitrile (130 mg, 0.33 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (109 mg, 327.98 µmol, 1 eq) in CH 3 CN (4 mL) was added K 2 CO 3 (227 mg, 1.64 mmol, 5 eq). The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture water (150 mL) was added to the mixture and the aqueous was extracted with EA (80 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM:MeOH=10:1) to give title compound (90 mg, 0.16 mmol, 47% yield) as a yellow oil. LCMS: MS (ESI) m/z: 579.4 [M+1] + . Step 2. Synthesis of 2-[(4-{3-[(4-cyanophenyl)methoxy]-1H-pyrazol-1-yl}piperidin- 1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt (Example 8)
To a stirred solution of methyl 2-[[4-[3-[(4-cyanophenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (90 mg, 0.16 mmol, 1 eq) in CH 3 CN (2 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9-hexahydro- 2H-pyrimido[1,2-a]pyrimidine (65 mg, 0.47 mmol, 3 eq). The resulting mixture was stirred at 20°C for 12 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 7 by diluted HCl (1 M) and the aqueous was extracted with DCM (60 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC(column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (0.05% ammonia hydroxide v/v)- ACN]; B%: 2%-32%,10min) to give title compound (31.15 mg, 0.053 mmol, 34.30% yield, 99.63% purity) as a white solid. LCMS: MS (ESI) m/z: 565.3 [M+1] + . 1 H NMR: (400 MHz, DMSO-d6) δ 8.24 - 8.46 (m, 1H), 8.15 (s, 1H), 7.82 - 7.92 (m, 3H), 7.72 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 2.2 Hz, 1H), 6.72 (s, 1H), 5.80 (s, 2H), 5.70 (d, J = 2.4 Hz, 1H), 5.21 (s, 2H), 4.10 - 4.20 (m, 2H), 3.79 - 4.03 (m, 3H), 2.83 - 3.00 (m, 2H), 2.12 - 2.29 (m, 2H), 1.80 - 1.91 (m, 2H), 1.49 - 1.67 (m, 2H), 1.29 (t, J = 7.6 Hz, 3H) Example 9 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{3-[(pyridin-4-yl )methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{3-[(pyridin-4- yl)methoxy]-1H-pyrazol-1-yl}piperidin-1-yl)methyl]-1H-benzim idazole-6-carboxylate To a stirred solution of 4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]pyridine (110 mg, 0.33 mmol, 1 eq, HCl salt) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (110 mg, 0.33 mmol, 1 eq) in CH 3 CN (4 mL) was added K 2 CO 3 (275.38 mg, 1.99 mmol, 6 eq). The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EA (100 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM:MeOH = 10:1) to give title compound (80 mg, 0.14 mmol, 43% yield) as a yellow oil. LCMS: MS (ESI) m/z: 555.3 [M+1] + . Step 2. Synthesis of 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{3-[(pyridin-4- yl)methoxy]-1H-pyrazol-1-yl}piperidin-1-yl)methyl]-1H-benzim idazole-6-carboxylic acid, ammonium salt (Example 9)
To a stirred solution of methyl 3-[(3-ethylimidazol-4-yl)methyl]-2-[[4-[3-(4- pyridylmethoxy)pyrazol-1-yl]-1-piperidyl]methyl]benzimidazol e-5-carboxylate (80 mg, 0.14 mmol, 1 eq) in THF (1.5 mL), MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (18.16 mg, 0.43 mmol, 3 eq). The resulting mixture was stirred at 20°C for 12 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 7 by diluted HCl (1 M) and the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 8%-38%,10min) to give title compound (48.11 mg, 0.085 mmol, 58.99% yield, 98.63% purity) as a white solid. LCMS: MS (ESI) m/z: 541.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.57 (d, J = 6.0 Hz, 2H), 8.26 - 8.52 (m, 1H), 8.16 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 5.6 Hz, 2H), 6.70 - 6.81 (m, 1H), 5.81 (s, 2H), 5.72 (d, J = 2.2 Hz, 1H), 5.18 (s, 2H), 4.11 - 4.23 (m, 2H), 3.78 - 4.02 (m, 3H), 2.83 - 2.97 (m, 1H), 2.76 - 3.07 (m, 2H), 2.15 - 2.30 (m, 2H), 1.77 - 1.92 (m, 2H), 1.46 - 1.64 (m, 2H), 1.22 - 1.36 (m, 3H). Example 10 2-[(4-{3-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-1-yl}piper idin-1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{3-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate
To a solution of 4-[3-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]piperidine (146.88 mg, 0.36 mmol, 1.00 eq, TFA) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (120 mg, 0.36 mmol, 1 eq) in ACN (3 mL) was added K 2 CO 3 (249.18 mg, 1.80 mmol, 5 eq). The mixture was stirred at 50 °C for 2 hr. LCMS showed the reaction was completed. Water (10 mL) was added to the mixture, the aqueous phase was extracted with CH 2 Cl 2 (30 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (DCM/Methanol = 10/1, R f = 0.4). Title compound (50 mg, 0.068 mmol, 19% yield, 80% purity) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 590.2 [M+1] + . Step 2. Synthesis of 2-[(4-{3-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-1-yl}piper idin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt (Example 10)
To a solution of methyl 2-[[4-[3-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (50 mg, 0.085 mmol, 1 eq) in THF (1 mL), MeOH (1 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (10.68 mg, 0.25 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed the reaction was completed. The reaction mixture was adjusted pH = 7 with citric acid, then extracted with CH 2 Cl 2 (50 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue, it was purified by column: Phenomenex Gemini- NX C18 75x30mmx3µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 1%-31%,11.5min. Title compound (22.35 mg, 0.037 mmol, 43.62% yield, 98.07% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 576.4 [M+1] + . 1 H NMR: (400MHz, DMSO-d6) δ 7.97 (s, 1H), 7.84 - 7.73 (m, 1H), 7.63 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.33 - 7.21 (m, 2H), 7.19 - 6.98 (m, 2H), 6.33 (s, 1H), 5.68 (d, J = 1.6 Hz, 1H), 5.62 (s, 2H), 5.10 (s, 2H), 4.25 (d, J = 3.6 Hz, 1H), 3.99 (q, J = 7.2 Hz, 2H), 3.71 (s, 2H), 2.47 - 2.13 (m, 4H), 1.83 - 1.65 (m, 2H), 1.60 - 1.38 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H). Example 11 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1-yl)methyl]- 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carb oxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate To a stirred solution of 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (130 mg, 0.31 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (113 mg, 0.31 mmol, 1 eq, HCl) in CH 3 CN (4 mL) was added K 2 CO 3 (212 mg, 1.53 mmol, 5 eq). The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EA (80 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM:MeOH = 10:1) to give title compound (110 mg, 0.18 mmol, 59% yield) as a light yellow oil. LCMS: (ESI) m/z: 606.4 [M+1] + Step 2. Synthesis of 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 11)
To a stirred solution of methyl 2-[[4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimid azole-5-carboxylate (110 mg, 0.18 mmol, 1 eq) in CH 3 CN (2 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9-hexahydro- 2H-pyrimido[1,2-a]pyrimidine (76 mg, 0.54 mmol, 3 eq). The resulting mixture was stirred at 20°C for 12 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl (2 M) aqueous and the aqueous was extracted with DCM (80 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-35%,7min) to give title compound (52.29 mg, 0.085 mmol, 47.09% yield, 99.56% purity) as an off-white solid. LCMS: MS (ESI) m/z: 218.1 [M+1] + . 1H NMR: (400 MHz, DMSO-d 6 ) δ 8.04 (d, J = 0.8 Hz, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.56 - 7.68 (m, 3H), 7.52 (dd, J = 10.0, 2.0 Hz, 1H), 7.31 - 7.38 (m, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.45 (s, 1H), 5.75 (d, J = 2.0 Hz, 1H), 5.70 (s, 2H), 5.17 (s, 2H), 3.94 - 4.02 (m, 3H), 3.78 (s, 2H), 2.81 - 2.89 (m, 2H), 2.21 - 2.11 (m, 2H), 1.76 - 1.88 (m, 2H), 1.59 - 1.68 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). Example 12 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{1-[(4-fluorophen yl)methoxy]-1H-pyrazol- 3-yl}piperidin-1-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{1-[(4- fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl] -1H-benzimidazole-6- carboxylate
To a mixture of 4-[1-[(4-fluorophenyl)methoxy]pyrazol-3-yl]piperidine (83 mg, 0.30 mmol, 1 eq) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]benzimidazo le-5- carboxylate (100 mg, 0.30 mmol, 1 eq) in ACN (2 mL) was added K 2 CO 3 (125 mg, 901.49 µmol, 3 eq). The mixture was stirred at 50 °C for 3 hours. LCMS showed the reaction was completed. The mixture was cooled to 25 °C and poured into ice-water (w/w = 1/1) (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-TLC (CH 2 Cl 2 :MeOH = 10:1). Title compound (100 mg, 0.16 mmol, 53.56% yield, 92% purity) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 572.3 [M+1] + Step 2. Synthesis of 1-[(1-ethyl-1H-imidazol-5-yl)methyl]-2-[(4-{1-[(4- fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin-1-yl)methyl] -1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 12)
To a mixture of methyl 3-[(3-ethylimidazol-4-yl)methyl]-2-[[4-[1-[(4- fluorophenyl)methoxy]pyrazol-3-yl]-1-piperidyl]methyl]benzim idazole-5-carboxylate (100 mg, 0.17 mmol, 1 eq) in THF (1 mL) and H 2 O (1 mL) was added LiOH.H 2 O (22 mg, 0.52 mmol, 3 eq). The mixture was stirred at 25 °C for 12 hours. LCMS showed the reaction was completed. The mixture was cooled to 0 °C and added HCl (2N) to adjust the pH about 6. The mixture was concentrated in vacuum. The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water(10mM NH4HCO3)- ACN]; B%: 10%-40%,8min). Title compound (57.66 mg, 0.099 mmol, 56.81% yield, 99.05% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 228.3 [M+1] + . 1 H NMR: (400MHz, DMSO-d 6 ) δ 8.08 (d, J = 0.8 Hz, 1H), 7.82 (dd, J = 1.6, 8.4 Hz, 1H), 7.69 – 7.65 (m, 2H), 7.45 - 7.36 (m, 3H), 7.21 (t, J = 8.8 Hz, 2H), 6.43 (s, 1H), 5.93 (d, J = 2.4 Hz, 1H), 5.73 (s, 2H), 5.21 (s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 3.80 (s, 2H), 2.81 (br d, J = 11.2 Hz, 2H), 2.48 (br s, 1H), 2.13 (br t, J = 10.8 Hz, 2H), 1.86 - 1.68 (m, 2H), 1.47 - 1.30 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H). Example 13 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate To a solution of 4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]piperidine (110 mg, 0.27 mmol, 1 eq, TFA) in DMAC (2 mL) was added K 2 CO 3 (112 mg, 0.81 mmol, 3 eq) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]benzimidazo le-5-carboxylate (100 mg, 0.27 mmol, 1 eq, HCl). The mixture was stirred at 50 °C for 2 h. LCMS showed the reaction was completed. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 4), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol=8:1). Title compound (120 mg, crude) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 588.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt (Example 13)
To a solution of methyl 2-[[4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (120 mg, 0.20 mmol, 1 eq) in H 2 O (1 mL) and THF (0.5 mL) and MeOH (0.5 mL) was added LiOH.H 2 O (43 mg, 1.02 mmol, 5 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The reaction mixture was adjusted pH to 6-7 by 1M HCl, the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 x 30 mm x 3 µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 16% - 36%, 8 min). Title compound (34.01 mg, 0.057 mmol, 28% yield, 100% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 574.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.81 (dd, J = 1.2, 8.4 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.46 - 7.41 (m, 3H), 7.40 - 7.36 (m, 2H), 6.42 (s, 1H), 5.92 (d, J = 2.4 Hz, 1H), 5.72 (s, 2H), 5.22 (s, 2H), 3.99 (q, J = 7.2 Hz, 2H), 3.78 (s, 2H), 2.80 (br d, J = 11.2 Hz, 2H), 2.48 - 2.42 (m, 1H), 2.12 (br t, J = 10.8 Hz, 2H), 1.76 (br d, J = 11.6 Hz, 2H), 1.45 - 1.29 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H). Example 14 2-[(4-{1-[(4-cyanophenyl)methoxy]-1H-pyrazol-3-yl}piperidin- 1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-cyanophenyl)methoxy]-1H-pyrazol-3-yl}piperidin- 1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimi dazole-6-carboxylate
To a solution of 4-[[3-(4-piperidyl)pyrazol-1-yl]oxymethyl]benzonitrile (107 mg, 0.27 mmol, 1 eq, TFA) in DMAC (2 mL) was added K 2 CO 3 (112 mg, 0.81 mmol, 3 eq) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]benzimidazo le-5-carboxylate (100 mg, 0.27 mmol, 1 eq, HCl). The mixture was stirred at 50 °C for 2 h. LCMS showed the desired product was detected. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mLx4), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol=8:1). Title compound (120 mg, crude) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 579.3 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(4-cyanophenyl)methoxy]-1H-pyrazol-3-yl}piperidin- 1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt (Example 14)
To a solution of methyl 2-[[4-[1-[(4-cyanophenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (120 mg, 0.21 mmol, 1 eq) in ACN (3 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a]pyrimidine (87 mg, 0.62 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed the desired product's mass. The reaction mixture was adjusted pH to 6- 7 by citric acid, the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (10mM NH 4 HCO 3 ) - ACN]; B%: 12% - 32%, 8 min). Title compound (39.83 mg, 0.068 mmol, 33% yield, 100% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 565.3 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.08 (d, J = 0.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.6, 8.4 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 2.4 Hz, 1H), 6.43 (s, 1H), 5.95 (d, J = 2.4 Hz, 1H), 5.73 (s, 2H), 5.34 (s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 3.79 (s, 2H), 2.81 (br d, J = 11.2 Hz, 2H), 2.58 - 2.53 (m, 1H), 2.12 (br t, J = 10.8 Hz, 2H), 1.76 (br d, J = 10.4 Hz, 2H), 1.44 - 1.30 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H). Example 15 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}-2-me thylpiperidin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid , ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}-2- methylpiperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)me thyl]-1H-benzimidazole-6- carboxylate To a stirred solution of 4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]-2-methyl- piperidine (124 mg, 0.29 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[(3- ethylimidazol-4-yl)methyl]benzimidazole-5-carboxylate (108.66 mg, 0.29 mmol, 1.00 eq, HCl) in CH 3 CN (3 mL) was added K 2 CO 3 (203.36 mg, 1.47 mmol, 5 eq). The reaction mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (120 mL) was added to the mixture and the aqueous was extracted with EA (80 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM:MeOH = 10:1) to give methyl title compound (80 mg, 0.13 mmol, 45% yield) as a light yellow oil. LCMS: MS (ESI) m/z: 604.3 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}-2- methylpiperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)me thyl]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 15)
To a stirred solution of methyl 2-[[4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]-2- methyl-1-piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]b enzimidazole-5-carboxylate (80 mg, 0.13 mmol, 1 eq) in THF (1.5 mL), MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (16.68 mg, 0.40 mmol, 3 eq). The resulting mixture was stirred at 20°C for 12 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl (1 M) and the mixture was concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%- 35%,8min) to afford title compound (31.46 mg, 0.052 mmol, 39.13% yield, 100% purity) as a white solid. LCMS: MS (ESI) m/z: 590.3 [M+1] + . 1 H NMR: (400 MHz, DMSO-d6) δ 7.97 (dd, J = 15.2, 0.6 Hz, 1H), 7.80 (dd, J = 8.2, 1.3 Hz, 1H), 7.66 (dd, J = 3.6, 0.9 Hz, 1H), 7.53 (dd, J = 8.3, 0.9 Hz, 1H), 7.36 - 7.46 (m, 2H), 7.25 - 7.34 (m, 1H), 7.09 (tt, J = 8.6, 1.2 Hz, 1H), 6.22 - 6.34 (m, 1H), 5.92 (t, J = 2.0 Hz, 1H), 5.69 (br d, J = 14.1 Hz, 2H), 5.25 (s, 2H), 4.39 (d, J = 14.0 Hz, 0.5H), 4.00 - 4.09 (m, 2H), 3.76 - 3.91 (m, 1.5H), 2.86 - 2.97 (m, 1H), 2.74 - 2.81 (m, 0.5H), 2.65 (br s, 0.5H), 2.53 - 2.60 (m, 1.H), 2.38 - 2.47 (m, 1.5H), 2.34 (br s, 1H), 2.08 - 2.16 (m, 0.5H), 1.79 - 1.86 (m, 0.5H), 1.54 - 1.72 (m, 2H), 1.34 - 1.43 (m, 0.5H), 1.20 - 1.28 (m, 3H), 1.05 - 1.15 (m, 3H). Example 16 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1-yl)methyl]- 1-[(1,3-oxazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-ben zimidazole-6-carboxylate To a solution of methyl 2-(chloromethyl)-3-(oxazol-5-ylmethyl)benzimidazole-5- carboxylate (95 mg, 0.31 mmol, 1 eq) in ACN (4 mL) was added K 2 CO 3 (129 mg, 0.93 mmol, 3 eq) and 3-fluoro-4-[[3-(4-piperidyl)pyrazol-1-yl]oxymethyl]benzonitr ile (129 mg, 0.31 mmol, 1 eq, TFA). The mixture was stirred at 50 °C for 2 h. LCMS showed the desired product was detected. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 4), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol=10:1). Title compound (140 mg, 0.25 mmol, 79% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 570.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-ben zimidazole-6-carboxylic acid, ammonium salt (Example 16) To a solution of methyl 2-[[4-[1-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-(oxazol-5-ylmethyl)benzimidazole-5-carbo xylate (140 mg, 0.25 mmol, 1 eq) in ACN (3 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2- a]pyrimidine (103mg, 0.74 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed the desired product was detected. The reaction mixture was adjusted pH to 5-6 by citric acid; water (20 mL) was then added. The aqueous phase was extracted with ethyl acetate (20 mLx4), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3 µm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 8%-38%, 8min). Title compound (58.94 mg, 0.098 mmol, 40% yield, 95% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 556.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.24 (s, 1H), 7.95 - 7.89 (m, 1H), 7.82 (dd, J = 1.6, 8.4 Hz, 1H), 7.72 (dd, J = 1.2, 7.6 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.46 (d, J = 2.4 Hz, 1H), 7.22 (s, 1H), 5.98 (d, J = 2.4 Hz, 1H), 5.85 (s, 2H), 5.37 (s, 2H), 3.86 (s, 2H), 2.89 - 2.81 (m, 2H), 2.45 (br s, 1H), 2.21 - 2.11 (m, 2H), 1.82 - 1.72 (m, 2H), 1.54 - 1.41 (m, 2H) Example 17 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1-yl)methyl]-1-{[(2S)- oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of Methyl 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylate To a solution of 4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]piperidine (110 mg, 0.27 mmol, 1.00 eq, TFA) in ACN (2 mL) was added K 2 CO 3 (113 mg, 0.81 mmol, 3 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 -carboxylate (80 mg, 0.27 mmol, 1 eq). The mixture was stirred at 50 °C for 2 h. LCMS showed the reaction was completed. The residue was poured into water (20 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (20 mLx3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Ethyl acetate:Methanol = 1:0 to 20:1). Title compound (140 mg, 0.25 mmol, 94% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 550.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(4-chlorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid, ammonium salt (Example 17) To a mixture of methyl 2-[[4-[1-[(4-chlorophenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (140 mg, 0.25 mmol, 1 eq) in H 2 O (0.5 mL) and THF (0.5 mL) and MeOH (0.5 mL) was added LiOH.H 2 O (32 mg, 0.76 mmol, 3 eq), then the reaction mixture was stirred at 25°C for 1 h. LCMS showed the reaction was completed. The reaction mixture pH was adjusted to 5-6 by citric acid, then the mixture was extracted with ethyl acetate (20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep- HPLC (column: Waters Xbridge 150 x 25mm x 5µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20% - 50%, min). Title compound (58.71 mg, 0.11 mmol, 41% yield, 99% purity, ammonium salt) was obtained as a white solid. LCMS: MS (ESI) m/z: 536.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.79 (dd, J = 1.2, 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.48 - 7.40 (m, 3H), 7.40 - 7.35 (m, 2H), 5.99 (d, J = 2.0 Hz, 1H), 5.22 (s, 2H), 5.13 - 5.01 (m, 1H), 4.84 - 4.74 (m, 1H), 4.70 - 4.58 (m, 1H), 4.53 - 4.43 (m, 1H), 4.37 (td, J = 6.0, 9.2 Hz, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.75 (br d, J = 13.2 Hz, 1H), 2.92 (br d, J = 10.4 Hz, 1H), 2.84 - 2.76 (m, 1H), 2.75 - 2.67 (m, 1H), 2.46 - 2.36 (m, 2H), 2.24 - 2.11 (m, 2H), 1.88 - 1.78 (m, 2H), 1.63 - 1.46 (m, 2H). Example 18 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1-yl)methyl]- 1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylate To a solution of methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 - carboxylate (100 mg, 0.34 mmol, 1 eq) in ACN (3 mL) was added K 2 CO 3 (141 mg, 1.02 mmol, 3 eq) and 3-fluoro-4-[[3-(4-piperidyl)pyrazol-1-yl]oxymethyl]benzonitr ile (141 mg, 0.34 mmol, 1 eq, TFA).The mixture was stirred at 50 °C for 2 h. LCMS showed the desired product was detected. The residue was poured into water (20 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (20mL x 3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Ethyl acetate: Methanol = 1:0 to 20:1). Title compound (180 mg, 0.32 mmol, 95% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 559.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylic acid, ammonium salt (Example 18) To a mixture of methyl 2-[[4-[1-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (180 mg, 0.32 mmol, 1 eq) in H 2 O (1 mL) and ACN (3 mL) was added 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a]pyrimidine (135 mg, 0.97 mmol, 3 eq), then the reaction mixture was stirred at 25 °C for 1 h. LCMS showed the desired product was detected. The reaction mixture was adjusted pH to 7-8 by 1 M HCl, the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5µm; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 16%- 46%, min). Title compound (30.64 mg, 0.052 mmol, 16% yield, 95% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 545.2 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.91 (dd, J = 1.2, 9.6 Hz, 1H), 7.79 (dd, J = 1.6, 8.4 Hz, 1H), 7.71 (dd, J = 1.2, 7.6 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.45 (d, J = 2.4 Hz, 1H), 6.00 (d, J = 2.4 Hz, 1H), 5.36 (s, 2H), 5.08 (dq, J = 2.8, 7.2 Hz, 1H), 4.79 (dd, J = 7.2, 15.2 Hz, 1H), 4.64 (dd, J = 2.4, 15.2 Hz, 1H), 4.53 - 4.44 (m, 1H), 4.37 (td, J = 6.0, 9.2 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.75 (br d, J = 13.2 Hz, 1H), 2.90 (br d, J = 10.8 Hz, 1H), 2.78 (br d, J = 11.2 Hz, 1H), 2.74 - 2.65 (m, 1H), 2.45 - 2.36 (m, 2H), 2.23 - 2.11 (m, 2H), 1.81 (br t, J = 11.2 Hz, 2H), 1.60 - 1.42 (m, 2H) Example 19 2-{[4-(3-{[(4-cyano-2-fluorophenyl)methyl]sulfanyl}-1H-pyraz ol-1-yl)piperidin-1- yl]methyl}-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-{[4-(3-{[(4-cyano-2-fluorophenyl)methyl]sulfanyl}-1H- pyrazol-1-yl)piperidin-1-yl]methyl}-1-[(1-ethyl-1H-imidazol- 5-yl)methyl]-1H- benzimidazole-6-carboxylate To a stirred solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]sulfanylmethyl]benz onitrile (67 mg, 0.16 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (58 mg, 0.16 mmol, 1 eq, HCl) in CH 3 CN (3 mL) was added K 2 CO 3 (108 mg, 0.78 mmol, 5 eq). The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EA (80 mL x 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC(DCM:MeOH:10:1) to give title compound (50 mg, 0.082 mmol, 52% yield) as a light yellow oil. LCMS: MS (ESI) m/z: 613.2 [M+1] + . Step 2. Synthesis of 2-{[4-(3-{[(4-cyano-2-fluorophenyl)methyl]sulfanyl}-1H-pyraz ol-1- yl)piperidin-1-yl]methyl}-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylic acid, ammonium salt (Example 19)
To a stirred solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]-1-piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]be nzimidazole-5-carboxylate (50 mg, 81.60 µmol, 1 eq) in CH 3 CN (2 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9- hexahydro-2H-pyrimido[1,2-a]pyrimidine (34 mg, 244.81 µmol, 3 eq). The reaction mixture was stirred at 20°C for 12 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl (1 M). Then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC(column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 18%- 48%,min) to give title compound (18.84 mg, 0.031 mmol, 37.50% yield, 100% purity) as a white solid. LCMS: MS (ESI) m/z: 599.3 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.10 (d, J = 1.0 Hz, 1H), 7.66 - 7.84 (m, 5H), 7.58 (dd, J = 8.0, 1.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 6.48 (s, 1H), 6.19 (d, J = 2.3 Hz, 1H), 5.74 (s, 2H), 4.15 (s, 2H), 3.95 - 4.13 (m, 3H), 3.83 (s, 2H), 2.85 (br d, J = 11.7 Hz, 2H), 2.20 (br s, 2H), 1.85 (br d, J = 10.4 Hz, 2H), 1.67 (br s, 2H), 1.16 (t, J = 7.2 Hz, 3H). Example 20 2-[(4-{1-[(4-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1-yl)methyl]-1-{[(2S)- oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylate
To a mixture of 4-[1-[(4-fluorophenyl)methoxy]pyrazol-3-yl]piperidine (95 mg, 345.05 µmol, 1.02 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 - carboxylate (100 mg, 339.29 µmol, 1 eq) in ACN (2 mL) was added K 2 CO 3 (140.68 mg, 1.02 mmol, 3 eq). The mixture was stirred at 50 °C for3 hours. LCMS showed the reaction was completed. The mixture was cooled to 25 °C, poured into ice-water (w/w = 1/1) (20 mL) and extracted with ethyl acetate (30 mLx2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-TLC. Title compound (180 mg, 337.34 µmol, 99.42% yield, 100% purity) was obtained as yellow oil. LCMS: MS (ESI) m/z: 534.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(4-fluorophenyl)methoxy]-1H-pyrazol-3-yl}piperidin -1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid, ammonium salt (Example 20) To a mixture of methyl 2-[[4-[1-[(4-fluorophenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (180 mg, 337.34 µmol, 1 eq) in THF (1.5 mL) and H2O (1.5 mL) was added LiOH.H 2 O (42 mg, 1.01 mmol, 3 eq). The mixture was stirred at 25 °C for 12 hours. LCMS showed the reaction was completed. The mixture was cooled to 0 °C and added HCl (2N) to adjust the pH about 6. The mixture was concentrated in vacuum. The residue was purified by Prep- HPLC (column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 12%-42%,8min). Title compound (108.08 mg, 200.45 µmol, 59.42% yield, 99.52% purity) was obtained as white solid. LCMS: MS (ESI) m/z: 520.2 [M+1] + . 1 H NMR: (400MHz, DMSO-d6) δ 8.25 (d, J = 1.2 Hz, 1H), 7.81 (dd, J = 1.6, 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.47 - 7.37 (m, 3H), 7.26 - 7.15 (m, 2H), 5.99 (d, J = 2.4 Hz, 1H), 5.22 (s, 2H), 5.13 – 5.04 (m, 1H), 4.80 (dd, J = 7.2, 15.2 Hz, 1H), 4.71 - 4.60 (m, 1H), 4.54 - 4.46 (m, 1H), 4.42 – 4.34 (m, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.77 (br d, J = 13.6 Hz, 1H), 2.93 (br d, J = 10.8 Hz, 1H), 2.81 (br d, J = 11.2 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.48 - 2.37 (m, 2H), 2.27 – 2.11 (m, 2H), 1.85 (br t, J = 11.2 Hz, 2H), 1.67 - 1.47 (m, 2H). Example 21 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piper idin-1-yl)methyl]-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylate To a mixture of 4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]piperidine (100 mg, 340.93 µmol, 1.0 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 - carboxylate (100 mg, 339.29 µmol, 1 eq) in ACN (2 mL) was added K 2 CO 3 (140.68 mg, 1.02 mmol, 3 eq. The mixture was stirred at 50 °C for 3 hours. LCMS showed the reaction was completed. The mixture was cooled to 25 °C, poured into ice-water (w/w = 1/1) (20 mL) and extracted with ethyl acetate (30 mLx2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-TLC (CH 2 Cl 2 :MeOH=20:1). Title compound (180 mg, 326.33 µmol, 96.18% yield, 100% purity) was obtained as yellow oil. LCMS: MS (ESI) m/z: 552.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piper idin-1- yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-c arboxylic acid, ammonium salt (Example 21) To a mixture of methyl 2-[[4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (180 mg, 326.33 µmol, 1 eq) in THF (1.5 mL) and H 2 O (1.5 mL) was added LiOH.H 2 O (41 mg, 979.00 µmol, 3 eq). The mixture was stirred at 25 °C for 12 hours. LCMS showed the reaction was completed. The mixture was cooled to 0 °C and added HCl (2N) to adjust the pH about 6. The mixture was concentrated in vacuum. The residue was purified by Prep-HPLC (column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 13%-43%,8min). Title compound (140.82 mg, 253.92 µmol, 77.81% yield, 100% purity) was obtained as white solid. LCMS: MS (ESI) m/z: 538.2 [M+1] + . 1 H NMR: (400MHz, DMSO-d6) δ 8.25 (d, J = 1.2 Hz, 1H), 7.80 (dd, J = 1.6, 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.29 (dt, J = 2.4, 10.0 Hz, 1H), 7.08 (dt, J = 1.6, 8.4 Hz, 1H), 5.98 (d, J = 2.4 Hz, 1H), 5.26 (s, 2H), 5.13 - 5.05 (m, 1H), 4.84 - 4.75 (m, 1H), 4.69 - 4.61 (m, 1H), 4.53 - 4.45 (m, 1H), 4.42 – 4.34 (m, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.76 (d, J = 13.2 Hz, 1H), 2.91 (br d, J = 11.6 Hz, 1H), 2.79 (br d, J = 10.8 Hz, 1H), 2.74 - 2.65 (m, 1H), 2.56 - 2.51 (m, 1H), 2.46 - 2.37 (m, 1H), 2.26 - 2.10 (m, 2H), 1.82 (br t, J = 11.6 Hz, 2H), 1.63 - 1.46 (m, 2H). Example 22 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piper idin-1-yl)methyl]-1-[(1- ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methy l]-1H-benzimidazole-6- carboxylate To a mixture of 4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]piperidine (78 mg, 0.26 mmol, 1.1 eq) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (80 mg, 0.24 mmol, 1 eq) in ACN (2 mL) was added K 2 CO 3 (100 mg, 0.72 mmol, 3 eq). The mixture was stirred at 50 °C for 3 hours. LCMS showed the reaction was completed. The mixture was cooled to 25 °C, poured into ice-water (w/w = 1/1) (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Prep-TLC. Title compound (100 mg, 0.16 mmol, 64.90% yield, 92% purity) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 590.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(2,4-difluorophenyl)methoxy]-1H-pyrazol-3-yl}piper idin-1- yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimida zole-6-carboxylic acid, ammonium salt (Example 22) To a mixture of methyl 2-[[4-[1-[(2,4-difluorophenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (100 mg, 0.17 mmol, 1 eq) in THF (1 mL) and H 2 O (1 mL) was added LiOH.H 2 O (21.35 mg, 0.51 mmol, 3 eq). The mixture was stirred at 25 °C for 12 hours. LCMS showed the reaction was completed. The mixture was cooled to 0 °C and added HCl (2N) to adjust the pH about 6. The mixture was concentrated in vacuum. The residue was purified by Prep-HPLC (column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 12%-42%,8min). Title compound (39.86 mg, 0.066 mmol, 38.81% yield, 97.86% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 576.2 [M+1] + . 1 H NMR: (400MHz, DMSO-d6) δ 8.07 (d, J = 0.8 Hz, 1H), 7.81 (dd, J = 1.6, 8.4 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.45 - 7.39 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.29 (dt, J = 2.4, 10.0 Hz, 1H), 7.09 (dt, J = 2.0, 8.4 Hz, 1H), 6.42 (s, 1H), 5.92 (d, J = 2.4 Hz, 1H), 5.72 (s, 2H), 5.25 (s, 2H), 3.99 (q, J = 7.2 Hz, 2H), 3.83 - 3.76 (m, 2H), 2.80 (br d, J = 11.2 Hz, 2H), 2.44 (br s, 1H), 2.12 (br t, J = 10.4 Hz, 2H), 1.74 (br d, J = 10.8 Hz, 2H), 1.48 - 1.29 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H). Example 23 2-[(4-{1-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl} piperidin-1-yl)methyl]- 1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylate To a solution of 4-[1-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-3-yl]piperid ine (115 mg, 0.27 mmol, 1.00 eq, TFA) in ACN (3 mL) was added K 2 CO 3 (113 mg, 0.81 mmol, 3 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 -carboxylate (80 mg, 0.27 mmol, 1 eq). The mixture was stirred at 50 °C for 2 h. LCMS showed the desired product's molecular weight. The residue was poured into water (20 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Ethyl acetate: Methanol = 1:0 to 20:1). Title compound (150 mg, 0.26 mmol, 97% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 568.4 [M+1] + Step 2. Synthesis of 2-[(4-{1-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylic acid, ammonium salt late (Example 23)
To a solution of methyl 2-[[4-[1-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (150 mg, 0.26 mmol, 1 eq) in H 2 O (0.5 mL) and MeOH (0.5 mL) and THF (0.5 mL) was added LiOH.H 2 O (33 mg, 0.79 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed the desired product's mass. The reaction mixture was adjusted pH to 7-8 by 1 M HCl, then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5µm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 20% - 50%, min). Title compound (50.92 mg, 0.089 mmol, 34% yield, 100% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 554.2[M+1] + . 1 H NMR: (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.80 (br d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 2.0, 9.6 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.29 (dd, J = 2.0, 8.4 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 5.27 (s, 2H), 5.08 (dq, J = 2.8, 7.2 Hz, 1H), 4.78 (br dd, J = 7.2, 15.2 Hz, 1H), 4.63 (br dd, J = 2.4, 15.2 Hz, 1H), 4.52 - 4.44 (m, 1H), 4.37 (td, J = 6.0, 8.8 Hz, 1H), 3.91 (br d, J = 13.2 Hz, 1H), 3.75 (br d, J = 13.2 Hz, 1H), 2.91 (br d, J = 10.4 Hz, 1H), 2.78 (br d, J = 10.8 Hz, 1H), 2.74 - 2.65 (m, 1H), 2.54 (br s, 1H), 2.47 - 2.36 (m, 2H), 2.24 - 2.09 (m, 2H), 1.87 - 1.76 (m, 2H), 1.62 - 1.45 (m, 2H) Example 24 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3-yl}p iperidin-1-yl)methyl]- 1-[(1,3-oxazol-2-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1,3-oxazol-2-yl)methyl]-1H-ben zimidazole-6-carboxylate
To a solution of 3-fluoro-4-[[3-(4-piperidyl)pyrazol-1-yl]oxymethyl]benzonitr ile (122 mg, 0.29 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-(oxazol-2-ylmethyl)benzimidazole- 5-carboxylate (90 mg, 0.29 mmol, 1 eq) in ACN (2 mL) was added K 2 CO 3 (122 mg, 0.88 mmol, 3 eq). The mixture was stirred at 50 °C for 2 h. LCMS showed the desired product was detected. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mLx4), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol=10:1). Title compound (120 mg, 0.21 mmol, 72% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 570.2 [M+1] + . Step 2. Synthesis of 2-[(4-{1-[(4-cyano-2-fluorophenyl)methoxy]-1H-pyrazol-3- yl}piperidin-1-yl)methyl]-1-[(1,3-oxazol-2-yl)methyl]-1H-ben zimidazole-6-carboxylic acid, ammonium salt (Example 24) To a mixture of methyl 2-[[4-[1-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-3-yl]-1- piperidyl]methyl]-3-(oxazol-2-ylmethyl)benzimidazole-5-carbo xylate (120 mg, 0.21 mmol, 1 eq) in ACN (3 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2- a]pyrimidine (88 mg, 0.63 mmol, 3 eq), then the reaction mixture was stirred at 25 °C for 1 h. LCMS showed the desired product's mass. The reaction mixture was adjusted pH to5-6 by citric acid. Water (20 mL) was added. The aqueous phase was extracted with ethyl acetate (20 mLx4), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 x 30mm x 3µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 12% - 42%, 7 min). Title compound (55.17 mg, 0.093 mmol, 44% yield, 97. % purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 556.2 [M+1] + .1H NMR: (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 8.06 (s, 1H), 7.92 (dd, J = 1.2, 9.6 Hz, 1H), 7.83 (dd, J = 1.2, 8.4 Hz, 1H), 7.72 (dd, J = 1.2, 7.6 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.44 (d, J = 2.4 Hz, 1H), 7.16 (s, 1H), 5.92 (d, J = 2.4 Hz, 1H), 5.88 (s, 2H), 5.37 (s, 2H), 3.84 (s, 2H), 2.76 (br d, J = 11.2 Hz, 2H), 2.46 - 2.38 (m, 1H), 2.14 - 2.04 (m, 2H), 1.68 (br d, J = 11.2 Hz, 2H), 1.37 - 1.20 (m, 2H). Example 25 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1-yl)methyl]- 1-[(1,3-oxazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-ben zimidazole-6-carboxylate To a solution of 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (129 mg, 0.30 mmol, 1 eq, TFA) in ACN (5 mL) was added K 2 CO 3 (210.35 mg, 1.52 mmol, 5 eq) and methyl 2-(chloromethyl)-3-(oxazol-5-ylmethyl)benzimidazole-5-carbox ylate (93.06 mg, 0.30 mmol, 1 eq), the solution was stirred at 50 °C for 2 h. LCMS showed desired m/z 579.4. The reaction mixture was filtered and the filter was concentrated to give a residue. The residue was purified by prep-TLC (SiO 2 , Petroleum ether/Ethyl acetate = 1/3). Title compound (130 mg, 0.22 mmol, 74% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 579.4 [M+1] + . Step 2. Synthesis of 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-[(1,3-oxazol-5-yl)methyl]-1H-ben zimidazole-6-carboxylic acid, ammonium salt (Example 25) To a solution of methyl 2-[[4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-(oxazol-5-ylmethyl)benzimidazole-5-carbo xylate (130 mg, 224.52 µmol, 1 eq) in MeOH (1 mL), THF (1 mL) , H 2 O (1 mL) was added LiOH.H 2 O (47.11 mg, 1.12 mmol, 5 eq), then stirred at 40 °C for 3 h. LCMS showed desired m/z 565.2.4 M HCl was added to the reaction mixture until pH 5-6, then concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%-40%,10min). Title compound (67.32 mg, 0.11 mmol, 51.12% yield, 99.41% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 565.2 [M+1] + .1H NMR: (400MHz, DMSO-d6) δ 8.29 (s, 1H), 8.22 (d, J = 0.8 Hz, 1H), 7.81 (dd, J = 1.6, 8.4 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.52 (dd, J = 2.0, 10.0 Hz, 1H), 7.34 (dd, J = 1.6, 8.0 Hz, 1H), 7.26 - 7.20 (m, 2H), 5.83 (s, 2H), 5.76 (d, J = 2.0 Hz, 1H), 5.19 (s, 2H), 4.02 (ddd, J = 4.0, 7.6, 11.6 Hz, 1H), 3.87 (s, 2H), 2.91 (br d, J = 11.2 Hz, 2H), 2.21 (br t, J = 11.2 Hz, 2H), 1.92 (dq, J = 4.0, 12.4 Hz, 2H), 1.67 (br d, J = 10.4 Hz, 2H). Example 26 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1-yl} piperidin-1-yl)methyl]- 1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, ammonium salt Step 1. Synthesis of methyl 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylate To a solution of 4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (129 mg, 0.30 mmol, 1 eq, TFA) in ACN (5 mL) was added K 2 CO 3 (210.35 mg, 1.52 mmol, 5 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 -carboxylate (89.72 mg, 0.30 mmol, 1 eq), then stirred at 50 °C for 1.5 h. LCMS (EW22000-300-P1A1) showed desired m/z 568.4. The reaction mixture was filtered and the filter was concentrated to give a residue. The residue was purified by prep-TLC (SiO 2 , Petroleum ether/Ethyl acetate = 1/3). Title compound (150 mg, 0.26 mmol, 87% yield) was obtained as a white solid. LCMS: MS (ESI) m/z: 568.4 [M+1] + . Step 2. Synthesis of 2-[(4-{5-[(4-chloro-2-fluorophenyl)methoxy]-1H-pyrazol-1- yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-be nzimidazole-6-carboxylic acid, ammonium salt (Example 26) To a solution of methyl 2-[[4-[5-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (150 mg, 0.26 mmol, 1 eq) in MeOH (1 mL), THF (1 mL), H 2 O (1 mL) was added LiOH.H 2 O (55.41 mg, 1.32 mmol, 5 eq), the mixture was stirred at 40 °C for 3 h. LCMS showed desired m/z 554.2.4 M HCl was added to the reaction mixture until pH 5-6. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75x30mmx3µm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 10%-40%,10min). Title compound (96.99 mg, 0.17 mmol, 63.98% yield, 99.65% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 554.2 [M+1] + . 1 H NMR: (400MHz, DMSO-d 6 ) δ 8.25 (d, J = 1.2 Hz, 1H), 7.79 (dd, J = 1.6, 8.4 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.52 (dd, J = 2.0, 10.0 Hz, 1H), 7.35 (dd, J = 2.0, 8.4 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 5.76 (d, J = 2.0 Hz, 1H), 5.18 (s, 2H), 5.07 (dq, J = 2.8, 7.2 Hz, 1H), 4.79 (dd, J = 7.2, 15.2 Hz, 1H), 4.69 - 4.59 (m, 1H), 4.53 - 4.43 (m, 1H), 4.37 (td, J = 6.0, 9.2 Hz, 1H), 4.03 (tt, J = 4.0, 11.6 Hz, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 13.6 Hz, 1H), 2.95 (br d, J = 10.8 Hz, 1H), 2.82 (br d, J = 11.6 Hz, 1H), 2.73 - 2.62 (m, 1H), 2.46 - 2.36 (m, 1H), 2.29 - 2.13 (m, 2H), 2.02 - 1.84 (m, 2H), 1.69 (br t, J = 11.6 Hz, 2H). Example 27 2-((4-(5-((4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl )methyl)-1-((1-ethyl-1H- imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of tert-butyl 4-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]piperidine-1- carboxylate
To a solution of tert-butyl 4-(5-hydroxypyrazol-1-yl)piperidine-1-carboxylate (200 mg, 0.74 mmol, 1 eq) in MeCN (3 mL) was added K 2 CO 3 (206.80 mg, 1.50 mmol, 2 eq) and 4- (bromomethyl)benzonitrile (161 mg, 0.82 mmol, 1.1 eq). The reaction was stirred at 30 °C for 1 h. TLC (PE: EA = 1: 1) indicated alcohol 9 was consumed completely and one major new spot formed. Water (20 mL) was added, then the aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO 2 , PE: EA = 1: 1). Compound tert-butyl 4-[5-[(4- cyanophenyl)methoxy]pyrazol-1-yl]piperidine-1-carboxylate (270 mg, 0.70 mmol, 94% yield) was obtained as a colorless oil. 1HNMR: (400MHz, CDCl 3 -d) δ = 7.74 - 7.70 (m, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H), 4.30 - 4.22 (m, 2H), 3.79 (s, 1H), 2.92 - 2.77 (m, 2H), 2.16 - 2.06 (m, 2H), 1.95 - 1.82 (m, 2H), 1.47 - 1.46 (m, 9H). Chemical Formula: C 21 H 26 N 4 O 3 , Molecular Weight: 382.46 Total H count from HNMR data: 26. Step 2: Preparation of 4-[[2-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitrile To a solution of tert-butyl 4-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]piperidine-1- carboxylate (278 mg, 0.72 mmol, 1 eq) in DCM (2.5 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 9.29 eq). The reaction was stirred at 20 °C for 1 h. TLC (PE: EA = 1: 1 ) indicated 11 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 4-[[2-(4- piperidyl)pyrazol-3-yl]oxymethyl]benzonitrile (630 mg, crude, TFA) was obtained as a white solid. LCMS: . MS (ESI) m/z: 283.0 [M+1] + 1 HNMR: . (400MHz, CDCl 3 -d) δ = 7.77 (d, J = 8.0 Hz, 2H), 7.58 (br d, J = 8.4 Hz, 2H), 7.41 - 7.39 (m, 1H), 7.24 (d, J = 6.8 Hz, 1H), 5.37 (s, 2H), 3.88 (s, 1H), 3.73 (br d, J = 13.2 Hz, 2H), 3.43 - 3.38 (m, 2H), 2.72 - 2.66 (m, 2H), 2.41 - 2.31 (m, 2H). Chemical Formula: C 16 H 18 N 4 O, Molecular Weight: 282.34 Total H count from HNMR data: 17. Step 3: Preparation of methyl 2-[[4-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate To a solution of 4-[[2-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitrile (107 mg, 0.27 mmol, 1 eq, trifluoroacetate), potassium carbonate (187 mg, 1.35 mmol, 5 eq) in acetonitrile (1 mL) was added methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl] benzimidazole-5-carboxylate (100 mg, 0.27 mmol, 1 eq, hydrochloride). The reaction was stirred at 50 ℃ for 2 h. LCMS showed starting material was consumed completely and one main peak with desired m/z 579.3 was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by semi- preparative reverse phase HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water(10mMNH4HCO3)-ACN];B%: 25%-55%,8min). Compound methyl 2-[[4-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]-1-piperidyl]m ethyl]-3 -[(3-ethylimidazol- 4-yl)methyl]benzimidazole-5-carboxylate (50 mg, 0.09 mmol, 32% yield) was obtained as a white solid. LCMS: MS (ESI) m/z: 579.3[M+1] + Chemical Formula: C 32 H 34 N 8 O 3 , Molecular Weight: 578.66 Step 4: Preparation of 2-((4-(5-((4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl] -3-[(3-ethylimidazol-4-yl)methyl]benzimidazole-5-carboxylate (50 mg, 0.09 mmol, 1 eq) in acetonitrile (1.5 mL), tetrahydrofuran (1.5 mL) and water (0.3 mL) was added 3,4,6,7,8,9 -hexahydro-2H-pyrimido[1,2-a]pyrimidine (14 mg, 0.1 mmol, 1.16 eq), the mixture was stirred at 20 °C for 2 h. LCMS showed the reaction was completely. The citric acid (10%, 8 mL) was added to the mixture to adjust pH about 5~6, and extracted with dichloromethane (10 mL * 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by semi-preparative reverse phase HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 6%-36%,8min). Compound 2-((4-(5-((4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl )methyl)-1-((1- ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carbox ylic acid, ammonium salt (26.17 mg, 0.05 mmol, 52% yield, 100.00% purity, ammonium salt) was confirmed by 1HNMR and QC LCMS as a white solid. LCMS: MS (ESI) m/z: 565.3[M-17+1] + 1 H NMR: (400MHz, METHANOL-d4) δ: 8.15 (s, 1H), 7.99 (dd, J = 1.2, 8.4 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 2.0 Hz, 1H), 6.66 (s, 1H), 5.82 (s, 2H), 5.67 (d, J = 2.0 Hz, 1H), 5.25 (s, 2H), 4.25 - 4.15 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.86 (s, 2H), 2.93 (d, J = 11.6 Hz, 2H), 2.28 (t, J = 11.2 Hz, 2H), 2.05 - 1.92 (m, 2H), 1.80 (d, J = 11.6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H). Chemical Formula: C31H35N9O3, Molecular Weight: 581.67 Total H count from HNMR data: 31. Example 28 (R or S)-2-((4-(5-(1-(4-chloro-2-fluorophenyl)ethoxy)-1H-pyrazol-1 -yl)piperidin-1- yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt Compound of Example 28 is in the form of a single enantiomer but the absolute configuration was not established. Step 1: Preparation of 1-(4-chloro-2-fluoro-phenyl)ethanol To a mixture of 1-(4-chloro-2-fluoro-phenyl)ethanone (1 g, 5.79 mmol, 1 eq) in MeOH (10 mL) was added NaBH 4 (0.57 g, 15.07 mmol, 2.60 eq) at 5-10 °C, then the reaction mixture was stirred at 10 °C for 1 h. TLC (Petroleum ether: Ethyl acetate = 5: 1) showed the starting material was consumed. The reaction was quenched by 1 M HCl (10 mL) at 0 °C, then the mixture was adjusted pH to 7-8 by 1 M NaOH, water (10 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ethergradient @ 60 mL/min). Compound 1-(4-chloro-2-fluoro-phenyl)ethanol (0.87 g, 4.98 mmol, 86% yield) was obtained as a yellow oil. 1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.45 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.06 (dd, J = 2.0, 10.0 Hz, 1H), 5.17 (q, J = 6.4 Hz, 1H), 1.50 (d, J = 6.4 Hz, 3H) Chemical Formula: C 8 H 8 ClFO, Molecular Weight: 174.60 Total H count from HNMR data: 7 Step 2: Preparation of tert-butyl 4-[5-[1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1- yl]piperidine-1-carboxylate To a solution of 1-(4-chloro-2-fluoro-phenyl)ethanol (172 mg, 0.99 mmol, 1.1 eq) and tert- butyl 4-(5-hydroxypyrazol-1-yl)piperidine-1-carboxylate (240 mg, 0.90 mmol, 1 eq) in toluene (2 mL) was added TMAD (309 mg, 1.80 mmol, 2 eq) and tributylphosphane (363 mg, 1.80 mmol, 2 eq). The mixture was stirred at 100 °C for 12 h. LCMS showed the desired product is major. The reaction mixture was concentrated under vacuum. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 mL), 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 0~25% Ethyl acetate/Petroleum ethergradient @ 60 mL/min). Compound tert-butyl 4-[5-[1-(4-chloro-2- fluoro-phenyl)ethoxy]pyrazol-1-yl]piperidine-1-carboxylate (200 mg, 0.46 mmol, 51% yield, 96% purity) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 424.3 [M+1] + Chemical Formula: C 21 H 27 ClFN 3 O 3 , Molecular Weight: 423.91 1 H NMR: (400 MHz, CHLOROFORM-d) δ = 7.33 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.20 - 7.09 (m, 2H), 5.49 (q, J = 6.4 Hz, 1H), 5.36 (d, J = 2.0 Hz, 1H), 4.38 - 4.20 (m, 3H), 2.89 (br d, J = 1.6 Hz, 2H), 2.16 - 2.08 (m, 1H), 2.07 - 2.01 (m, 1H), 1.95 - 1.82 (m, 2H), 1.69 (d, J = 6.4 Hz, 3H), 1.49 (s, 9H) Total H count from HNMR data: 27 Step 3: Preparation of (R)-tert-butyl 4-(5-(1-(4-chloro-2-fluorophenyl)ethoxy)-1H-pyrazol- 1-yl)piperidine-1-carboxylate and (S)-tert-butyl 4-(5-(1-(4-chloro-2-fluorophenyl)ethoxy)- 1H-pyrazol-1-yl)piperidine-1-carboxylate Compound tert-butyl 4-[5-[1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1-yl]piperi dine-1- carboxylate (200 mg, 0.46 mmol,) was purified by SFC separation (column: DAICEL CHIRALPAK AY-H(250mm * 30mm,10um); mobile phase: [0.1%NH 3 H 2 O ETOH]; B%: 25%-25%, 3.6 min; 45 minmin). The collected mixture was concentrated under vacuum. Compound tert-butyl 4-[5-[(1S)-1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1- yl]piperidine-1-carboxylate (85 mg, 0.19 mmol, 80% yield, 93% purity) was obtained as a yellow oil, which was confirmed by HNMR(EW23406-293-P1A) and SFC (EW23406-293- P1A, Peak 1, Rt = 0.978 min, ee = 100%). Compound tert-butyl 4-[5-[(1R or S)-1-(4-chloro- 2-fluoro-phenyl)ethoxy]pyrazol-1-yl]piperidine-1-carboxylate (90 mg, 0.21 mmol, 88% yield, 98% purity) was obtained as a yellow oil, which was confirmed by HNMR(EW23406- 293-P2A) and SFC (EW23406-293-P2A, Peak 2, Rt = 1.204 min, ee = 99.378%). 1 H NMR: (400 MHz, CHLOROFORM-d) Chemical Formula: C 21 H 27 ClFN 3 O 3 , Molecular Weight: 423.91 δ = 7.36 - 7.31 (m, 1H), 7.27 - 7.08 (m, 3H), 5.49 (q, J = 6.4 Hz, 1H), 5.36 (d, J = 2.0 Hz, 1H), 4.29 (tdd, J = 4.0, 7.6, 15.6 Hz, 3H), 3.00 - 2.79 (m, 2H), 2.17 - 2.02 (m, 2H), 1.95 - 1.80 (m, 2H), 1.69 (d, J = 6.4 Hz, 3H), 1.49 (s, 9H) Total H count from HNMR data: 27 SFC: Peak 1, Rt = 0.978 min, ee = 100% 1 H NMR: (400 MHz, CHLOROFORM-d) Chemical Formula: C 21 H 27 ClFN 3 O 3 , Molecular Weight: 423.91 δ = 7.34 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.20 - 7.10 (m, 2H), 5.49 (q, J = 6.4 Hz, 1H), 5.36 (d, J = 2.0 Hz, 1H), 4.29 (tt, J = 4.0, 11.6 Hz, 3H), 2.89 (br s, 2H), 2.22 - 1.99 (m, 2H), 1.96 - 1.77 (m, 2H), 1.69 (d, J = 6.4 Hz, 3H), 1.49 (s, 9H) Total H count from HNMR data: 27 SFC: Peak 2, Rt=1.204, ee% value=99.378 Step 4: Preparation 4-[5-[(1R or S)-1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1- yl]piperidine To a solution of tert-butyl 4-[5-[(1R or S)-1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1- yl]piperidine-1-carboxylate (90 mg, 0.21 mmol, 1 eq) in DCM (2.5 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 31.81 eq). The mixture was stirred at 25 °C for 1 h. TLC (Petroleum ether: Ethyl acetate = 3: 1) showed the starting material was consumed. The reaction mixture was concentrated under vacuum. Compound 4-[5-[(1R)-1-(4-chloro-2- fluoro-phenyl)ethoxy]pyrazol-1-yl]piperidine (92 mg, 0.21 mmol, 99% yield, TFA) was obtained as a yellow oil without further purification. Step 5: Preparation of methyl 2-[[4-[5-[(1R or S)-1-(4-chloro-2-fluoro- phenyl)ethoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[(3-ethyli midazol-4- yl)methyl]benzimidazole-5-carboxylate To a solution of 4-[5-[(1R or S)-1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1-yl]piperidin e (90 mg, 0.21 mmol, 1 eq, TFA), methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (76 mg, 0.21 mmol, 1 eq, HCl) in MeCN (3 mL) was added K 2 CO 3 (170 mg, 1.23 mmol, 6 eq). The mixture was stirred at 50 °C for 4 h. LCMS showed the desired product is major. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol = 6: 1). Compound methyl 2-[[4-[5-[(1R)-1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1- yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (70 mg, 0.11 mmol, 55% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 620.4 [M+1] + Chemical Formula: C 32 H 35 ClFN 7 O 3 ; Molecular Weight: 620.12 Step 6: Preparation of (R or S)-2-((4-(5-(1-(4-chloro-2-fluorophenyl)ethoxy)-1H-pyrazol-1 - yl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methy l)-1H-benzo[d]imidazole-6- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[5-[(1R or S)-1-(4-chloro-2-fluoro-phenyl)ethoxy]pyrazol-1- yl]-1-piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benz imidazole-5-carboxylate (70 mg, 0.11 mmol, 1 eq) in H 2 O (0.3 mL) and MeOH (0.3 mL) and THF (0.3 mL) was added LiOH.H 2 O (24 mg, 0.56 mmol, 5 eq). The mixture was stirred at 25 °C for 2 h. LCMS showed the desired product is major. The reaction mixture was adjusted pH to 6-7 by 1 M HCl, and the mixture was adjusted pH to 7-8 by ammonium hydroxide, then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(10mM NH 4 HCO 3 )-ACN];B%: 22%- 52%,10min). Compound (R or S)-2-((4-(5-(1-(4-chloro-2-fluorophenyl)ethoxy)-1H- pyrazol-1-yl)piperidin-1-yl)methyl)-1-((1-ethyl-1H-imidazol- 5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid, ammonium salt (24.99 mg, 0.040 mmol, 35% yield, 100% purity, NH 4 +) was obtained as a white solid. LCMS: MS (ESI) m/z: 606.2 [M+1] + Chemical Formula: C31H36ClFN8O3, Molecular Weight: 623.12 1 H NMR: (400 MHz, DMSO-d 6 ) δ = 8.07 (d, J = 0.8 Hz, 1H), 7.82 (dd, J = 1.2, 8.4 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.32 (dd, J = 2.0, 8.4 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.49 (s, 1H), 5.75 (s, 2H), 5.57 - 5.50 (m, 2H), 4.16 - 4.05 (m, 1H), 4.00 (q, J = 7.2 Hz, 2H), 3.83 (s, 2H), 2.95 - 2.86 (m, 2H), 2.28 - 2.17 (m, 2H), 1.92 - 1.71 (m, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.61 - 1.53 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H) Total H count from HNMR data: 32 Example 29 2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1-((1- ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carbox ylic acid, ammonium salt Step 1: Preparation of tert-butyl 4-(5-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate To a solution of 3-bromo-1H-pyrazole (5 g, 34.02 mmol, 1 eq) and tert-butyl 4- methylsulfonyloxypiperidine-1-carboxylate (11.40 g, 40.82 mmol, 1.2 eq) in DMF (50 mL) was added Cs 2 CO 3 (22.17 g, 68.04 mmol, 2 eq). The mixture was stirred at 80 °C for 12 h. TLC (silica gel plate, Dichloromethane: Methanol = 10: 1) showed the starting material was consumed and many new spots formed. The mixture was cooled to 20 °C and filtered. The filtrate was added H 2 O (100 mL), aqueous phase was extracted with ethyl acetate (100 mL * 2). The combined organic phase was washed with brine (100 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ ethyl acetate = 15/ 1). The product tert-butyl 4- (5-bromopyrazol-1-yl)piperidine-1-carboxylate (2.8 g, 8.48 mmol, 25% yield) was obtained as a white solid and tert-butyl 4-(3-bromopyrazol-1-yl)piperidine-1-carboxylate (6.7 g, 20.29 mmol, 60% yield) was obtained as a white solid. 1H NMR: (400 MHz, CHLOROFORM-d) Chemical Formula: C13H 2 0BrN3O 2 ; Molecular Weight: 330.22 δ = 7.52 (d, J = 1.6 Hz, 1H), 6.26 (d, J = 1.6 Hz, 1H), 4.44 - 4.27 (m, 3H), 2.85 (m, 2H), 2.10-2.04 (m, 2H), 1.92-1.90 (m, 2H), 1.46 (s, 9H) Total H count from HNMR data: 20 1H NMR: (400 MHz, CHLOROFORM-d) Chemical Formula: C 13 H 20 BrN 3 O 2 ; Molecular Weight: 330.22 δ = 7.31 (d, J = 1.2 Hz, 1H), 6.26 (d, J = 1.2 Hz, 1H), 4.25 - 4.18 (m, 3H), 2.11-2.08 (m, 2H), 2.96-2.86 (m, 2H), 1.92-1.88 (m, 2H), 1.46 (s, 9H) Step 2: Preparation of tert-butyl 4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]piperidine-1-carboxylate A mixture of tert-butyl 4-(5-bromopyrazol-1-yl)piperidine-1-carboxylate (50 mg, 0.15 mmol, 1 eq), 3-fluoro-4-(sulfanylmethyl)benzonitrile (38 mg, 0.23 mmol, 1.5 eq), Cs 2 CO 3 (148 mg, 0.45 mmol, 3 eq), tBuXPhos Pd G3 (50 mg, 0.06 mmol, 4.16e-1 eq) in dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. TLC (Petroleum ether: Ethyl acetate = 3: 1) showed some new spots. Ethyl acetate (20 mL) and water (20 mL) was added. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, 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 0~30% Ethyl acetate/Petroleum ethergradient @ 45 mL/min). Compound tert-butyl 4-[5-[(4-cyano-2-fluoro- phenyl)methylsulfanyl]pyrazol-1- yl]piperidine-1-carboxylate (100 mg, 0.24 mmol, 40% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 361.0 [M-55] + Chemical Formula: C 21 H 25 FN 4 O 2 S, Molecular Weight: 416.51 Step 3: Preparation of 3-fluoro-4-[[2-(4-piperidyl)pyrazol-3-yl]sulfanylmethyl]benz onitrile A mixture of tert-butyl 4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]piperidine-1-carboxylate (80 mg, 0.19 mmol, 1 eq) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol, 0.4 mL, 28.13 eq), the mixture was stirred at 25 °C for 20 min under N 2 atmosphere. TLC (Petroleum ether: Ethyl acetate = 3: 1) showed the starting material was consumed. The mixture was concentrated under reduced pressure to give a residue. Compound 3-fluoro-4-[[2-(4-piperidyl)pyrazol-3-yl]sulfanylmethyl]benz onitrile (82 mg, 0.19 mmol, 99% yield, TFA) was obtained as a yellow oil without purification. Step 4: Preparation of methyl 2-[[4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]-1-piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]be nzimidazole-5-carboxylate To a solution of 3-fluoro-4-[[2-(4-piperidyl)pyrazol-3-yl]sulfanylmethyl]benz onitrile (80 mg, 0.19 mmol, 1 eq, TFA) in DMAc (0.3 mL) and MeCN (3 mL) was added K 2 CO 3 (257 mg, 1.86 mmol, 10 eq) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (69 mg, 0.19 mmol, 1 eq, HCl). The mixture was stirred at 50 °C for 2 h. LCMS showed the desired product's mass. The residue was added water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol = 9: 1). Compound methyl 2-[[4-[5-[(4-cyano-2-fluoro- phenyl)methylsulfanyl]pyrazol-1-yl]-1-piperidyl]methyl]-3-[( 3-ethylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (60 mg, 0.097 mmol, 53% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 613.3 [M+1] + Chemical Formula: C 32 H 33 FN 8 O 2 S, Molecular Weight: 612.72 Step 5: Preparation of 2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)pipe ridin- 1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d ]imidazole-6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (80 mg, 0.13 mmol, 1 eq) in MeCN (3 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a]pyrimidine (55 mg, 0.39 mmol, 3 eq). The mixture was stirred at 25 °C for 12 h. LCMS showed the desired product's mass. The mixture was adjusted pH to 5-6 by 1M HCl, and the mixture was adjusted pH to 7-8 by NH 3 .H 2 O, then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 * 30 mm * 3um; mobile phase: [water (10 mM NH 4 HCO 3 ) - ACN]; B%: 12% - 42%, 8 min). Compound 2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)pipe ridin-1- yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt (33.94 mg, 0.055 mmol, 42% yield, 100% purity, NH 4 +) was obtained as a white solid. LCMS: MS (ESI) m/z: 599.2 [M+1] + Chemical Formula: C 31 H 34 FN 9 O 2 S, Molecular Weight: 615.72 1 H NMR: SR0106- V472384, (400 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.87 - 7.78 (m, 2H), 7.69 - 7.58 (m, 3H), 7.49 (s, 1H), 7.35 (s, 1H), 6.46 (s, 1H), 6.30 (d, J = 1.2 Hz, 1H), 5.72 (s, 2H), 4.20 (br t, J = 11.2 Hz, 1H), 4.08 (s, 2H), 3.99 (q, J = 7.2 Hz, 2H), 3.82 (s, 2H), 2.86 (br d, J = 10.0 Hz, 2H), 2.11 (br t, J = 11.2 Hz, 2H), 1.84 - 1.69 (m, 2H), 1.39 (br dd, J = 1.6, 12.0 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). Total H count from HNMR data: 30 Example 30 2-[[4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]-1-p iperidyl]methyl]-3- [[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid Step 1: Preparation of tert-butyl 4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate To a solution of tert-butyl 4-(3-hydroxypyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.37 mmol, 1 eq), 2-(bromomethyl)-5-chloro-benzonitrile (103.47 mg, 0.44 mmol, 1.2 eq) in DMF (4 mL) was added Ag 2 CO 3 (154.73 mg, 0.56 mmol, 0.02 mL, 1.5 eq). The reaction was stirred at 80 °C for 2 h. LC-MS(EW23109-323-P1B) showed Reactant 1 was consumed completely and one main peak with desired m/z 417.1 was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO 2 , PE : EA=1 : 1). Compound tert-butyl 4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]piperidi ne-1- carboxylate (106 mg, 0.25 mmol, 67.97% yield) was obtained as a white solid. LCMS: . MS (ESI) m/z: 417.1 1HNMR: (400MHz, CDCl 3 -d) δ = 7.66 (dd, J = 2.8, 4.8 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.27 (s, 1H), 7.22 (d, J = 2.0 Hz, 1H), 5.70 (d, J = 2.4 Hz, 1H), 5.36 (s, 2H), 4.34 - 4.12 (m, 2H), 4.05 (tt, J = 4.0, 15.2 Hz, 1H), 2.94 - 2.81 (m, 2H), 2.14 - 2.00 (m, 2H), 1.85 (dq, J = 4.4, 16 Hz, 2H), 1.48 (s, 9H). Chemical Formula: C 21 H 25 ClN 4 O 3 , Molecular Weight: 417 Total H count from HNMR data: 25. Step 2: Preparation of 5-chloro-2-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile To a solution of tert-butyl 4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (106 mg, 0.25 mmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 53.12 eq). The reaction was stirred at 25 °C for 0.5 h. LC- MS(EW23109-326-P1A) showed Reactant 1 was consumed completely and one main peak with desired m/z 317.1 was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Without purification. Compound 5-chloro-2-[[1-(4- piperidyl)pyrazol-3-yl]oxymethyl]benzonitrile (109 mg, 0.25 mmol, 99.51% yield, TFA) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 317.1 [M+1] + Chemical Formula: C 16 H 17 ClN 4 O, Molecular Weight: 317 Step 3: Preparation of methyl 2-[[4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate To a solution of 5-chloro-2-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (109 mg, 0.25 mmol, 1 eq, TFA) in MeCN (5 mL) was added K 2 CO 3 (69.94 mg, 0.50 mmol, 2 eq). The solution's pH was kept 7~8. Then was added methyl 2-(chloromethyl)-3-[[(2S)-oxetan- 2-yl]methyl]benzimidazole-5-carboxylate (74.57 mg, 0.25 mmol, 1 eq). The mixed solution's pH was kept pH=7~8. The reaction was stirred at 50 °C for 2 h and then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep- TLC (SiO 2 , DCM : MeOH = 10 : 1). Compound methyl 2-[[4-[3-[(4-chloro-2-cyano- phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[[(2S)-ox etan-2- yl]methyl]benzimidazole-5-carboxylate (139 mg, 0.22 mmol, 89.28% yield, 93.45% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 575.1 [M+1] + 1 HNMR: (400MHz, CDCl 3 -d) δ = 8.16 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.60 - 7.54 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.69 (d, J = 2.4 Hz, 1H), 5.35 (s, 2H), 5.26 - 5.17 (m, 1H), 4.87 - 4.67 (m, 2H), 4.40 (td, J = 6.0, 12 Hz, 1H), 4.00 (br s, 2H), 3.96 (s, 3H), 3.11 - 2.90 (m, 2H), 2.85 - 2.67 (m, 1H), 2.53 - 2.41 (m, 1H), 2.40 - 2.24 (m, 2H), 2.15 - 1.92 (m, 4H), 1.73 - 1.51 (m, 1H), 1.40 - 1.18 (m, 1H). Chemical Formula: C30H31ClN6O4, Molecular Weight: 575 Total H count from HNMR data:31. Step 4: Preparation of 2-[[4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylic acid To a solution of methyl 2-[[4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (139 mg, 0.24 mmol, 1 eq) in MeCN (1 mL), THF (0.5 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9- hexahydro-2H-pyrimido[1,2-a]pyrimidine (67.29 mg, 0.48 mmol, 2 eq). The reaction was stirred at 40 °C for 3 h. LC-MS(EW23109-328-P1C) showed Reactant 1 was consumed completely and one main peak with desired m/z 561.2 was detected. Citric acid(40 mg) was added to adjust the solution's pH=7~8. Then the reaction mixture was concentrated under reduced pressure to remove THF. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 12%-42%,8min). NH 3 .H 2 O(0.05 mL) was added and the product was dried by lyophilization. Compound 2-[[4-[3-[(4-chloro-2-cyano-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylic acid (64.37 mg, 0.11 mmol, 45.73% yield, 99.44% purity, NH 4 + ) was obtained as a white solid. LCMS: MS (ESI) m/z: 561.2 [M+1] + 1 HNMR: (400MHz, DMSO-d6) δ = 8.25 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.80 (ddd, J = 2.4, 5.2, 6.8 Hz, 2H), 7.74 - 7.69 (m, 1H), 7.65 - 7.57 (m, 2H), 5.70 (d, J = 2.4 Hz, 1H), 4.80 (dd, J = 7.6, 15.6 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.53 - 4.45 (m, 1H), 4.38 (td, J = 6.0, 9.2 Hz, 1H), 4.04 - 3.90 (m, 2H), 3.79 (d, J = 7.6 Hz, 1H), 2.97 (br d, J = 11.6 Hz, 1H), 2.84 (br d, J = 11.2 Hz, 1H), 2.72 - 2.64 (m, 1H), 2.48 - 2.39 (m, 1H), 2.35 - 2.16 (m, 2H). Chemical Formula: C 29 H 27 ClFN 7 O 3 S, Molecular Weight: 608.09 Total H count from HNMR data: 26. Example 31 (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl) piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of 4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidi ne To a stirred solution of tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (130 mg, 0.32 mmol, 1 eq) in DCM (2 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 8.52 eq). The resulting mixture was stirred at 20°C for 1 h. LCMS showed desired product was major in the mixture. The mixture was concentrated under vacuum to give 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (130 mg, 0.31 mmol, 97% yield, TFA) as a yellow oil. LCMS: MS (ESI) m/z: 309.8 [M+1] + . Chemical Formula: C15H17ClFN3O, Molecular Weight: 309.77 Step 2: Preparation of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol e-5-carboxylate To a solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (103 mg, 0.24 mmol, 1 eq, TFA) in MeCN (4 mL) was added K 2 CO 3 (67 mg, 0.48 mmol, 2 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 -carboxylate (72 mg, 0.24 mmol, 1 eq). The reaction mixture was stirred at 50 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and one main peak with desired m/z 568.1 was detected. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep- TLC (SiO 2 , DCM: MeOH = 15: 1). Compound methyl 2-[[4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[[(2S)-ox etan-2- yl]methyl]benzimidazole-5-carboxylate (121 mg, 0.20 mmol, 85% yield, 96% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 568.2 [M+1] + 1HNMR: (400MHz, CDCl 3 -d) δ = 8.16 (d, J = 0.8 Hz, 1H), 7.98 (dd, J = 1.6, 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.17 - 7.08 (m, 2H), 5.67 (d, J = 2.4 Hz, 1H), 5.28 - 5.22 (m, 1H), 5.20 (s, 2H), 4.82 - 4.68 (m, 2H), 4.67 - 4.59 (m, 1H), 4.39 (td, J = 3.2, 6.0 Hz, 1H), 4.00 (br s, 2H), 3.96 (s, 3H), 3.50 (s, 1H), 3.09 - 2.90 (m, 2H), 2.76 (dtd, J = 6.0, 8.0, 11.2 Hz, 1H), 2.53 - 2.40 (m, 1H), 2.38 - 2.26 (m, 2H), 2.15 - 1.96 (m, 4H). Chemical Formula: C 29 H 31 ClFN 5 O 4 , Molecular Weight: 568.04 Total H count from HNMR data: 31. Step 3: Preparation of (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (121 mg, 0.21 mmol, 1 eq) in MeCN (1.5 mL), THF (0.5 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9- hexahydro-2H-pyrimido[1,2-a]pyrimidine (59 mg, 0.42 mmol, 2 eq). The reaction was stirred at 40 °C for 3 h. LC-MS showed Reactant 1 was consumed completely and one main peak with desired m/z 554.1 was detected. Citric acid (40 mg) was added to adjust the solution's pH=7~8. Then the reaction mixture was concentrated under reduced pressure to remove THF. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 23%-53%,10min). Compound (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl) piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid, ammonium salt (71.12 mg, 0.12 mmol, 58% yield, 100.00% purity, NH 4 +) was obtained as a white solid. LCMS: MS (ESI) m/z: 554.1 [M+1] + 1 HNMR: (400MHz, DMSO-d 6 ) δ = 8.24 (s, 1H), 7.80 (dd, J = 1.6, 8.4 Hz, 1H), 7.65 - 7.52 (m, 3H), 7.47 (dd, J = 2.0, 10.0 Hz, 1H), 7.31 (dd, J = 1.6, 8.0 Hz, 1H), 5.68 (d, J = 2.4 Hz, 1H), 5.13 (s, 2H), 5.10 - 5.04 (m, 1H), 4.85 - 4.74 (m, 1H), 4.70 - 4.60 (m, 1H), 4.54 - 4.44 (m, 1H), 4.37 (td, J = 6.0, 9.2 Hz, 1H), 4.03 - 3.89 (m, 2H), 3.79 (d, J = 13.6 Hz, 1H), 2.97 (br d, J = 11.6 Hz, 1H), 2.85 (br d, J = 10.8 Hz, 1H), 2.78 - 2.67 (m, 1H), 2.47 (br s, 1H), 2.35 - 2.14 (m, 2H), 2.01 - 1.75 (m, 4H). Chemical Formula: C28H32ClFN6O4, Molecular Weight: 571.04 Total H count from HNMR data: 28. Example 32 (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1-yl)methyl)-1- ((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carbox ylic acid, ammonium salt Step 1: Preparation of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-tetrahydrofuran-2-yl]methyl]benzi midazole-5-carboxylate To a solution of methyl 2-(chloromethyl)-3-[[(2S)-tetrahydrofuran-2-yl]methyl] benzimidazole-5-carboxylate (103 mg, 0.33 mmol, 1 eq) in acetonitrile (3 mL) was added potassium carbonate (138 mg, 1.00 mmol, 3 eq) and 3-fluoro-4-[[1-(4-piperidyl)pyrazol -3- yl]oxymethyl]benzonitrile (100 mg, 0.33 mmol, 1 eq, trifluoroacetate), the mixture was stirred at 50 °C for 2 h. LCMS showed the reaction was completely. The reaction mixture was quenched by water (10 mL) at 20 °C, and extracted with ethyl acetate (20 mL * 3), the combined organic layers were washed with brine (15 mL * 8), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Compound methyl 2-[[4- [3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1-piperid yl] methyl]-3-[[(2S)- tetrahydrofuran-2-yl]methyl]benzimidazole-5-carboxylate (180 mg, crude) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 573.1[M+1] + Chemical Formula: C 31 H 33 FN 6 O 4 , Molecular Weight: 572.63 Step 2: Preparation of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1 H-benzo[d]imidazole-6- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1 - piperidyl]methyl]-3-[[(2S)-tetrahydrofuran-2-yl]methyl]benzi midazole-5-carboxylate (180 mg, 0.31 mmol, 1 eq) in acetonitrile (1.5 mL), tetrahydrofuran (1 mL) and water (0.4 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (131 mg, 0.94 mmol, 3 eq), the mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completely. The citric acid (10%, 2 mL) was added to the mixture to adjust pH about 5~6, and extracted with dichloromethane (5 mL * 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by semi-preparative reverse phase HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (10mM NH4HCO3)-ACN];B%: 12%-42%,8min). Compound (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1- yl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imida zole-6-carboxylic acid, ammonium salt (81.72 mg, 0.14 mmol, 45% yield, 99.58 % purity, ammonium salt) was obtained as a white solid. LCMS: MS (ESI) m/z: 559.2 [M-17+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 8.19 (s, 1H), 7.88 (d, J = 10.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.62 - 7.56 (m, 2H), 5.70 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 4.58 - 4.51 (m, 1H), 4.49 - 4.41 (m, 1H), 4.27 - 4.19 (m, 1H), 4.03 - 3.92 (m, 2H), 3.80 (q, J = 7.2 Hz, 1H), 3.73 (d, J = 13.2 Hz, 1H), 3.66 - 3.60 (m, 1H), 2.97 (d, J = 11.6 Hz, 1H), 2.82 (d, J = 11.6 Hz, 1H), 2.33 - 2.24 (m, 1H), 2.19 (t, J = 10.8 Hz, 1H), 2.11 - 2.01 (m, 1H), 1.95 - 1.74 (m, 6H), 1.71 - 1.59 (m, 1H). Chemical Formula: C 30 H 34 FN 7 O 4 , Molecular Weight: 575.63 Total H count from HNMR data: 30. Example 33 (S)-2-((4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin -1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of tert-butyl 4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1-yl)piperidine-1- carboxylate
To a stirred solution of tert-butyl 4-(3-hydroxypyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.37 mmol, 1 eq) in DMF (4 mL) was added 1-(bromomethyl)-4-chloro-benzene (92 mg, 0.45 mmol, 1.2 eq) and Ag2CO3 (155 mg, 0.56 mmol, 0.025 mL, 1.5 eq). The resulting mixture was stirred at 80°C for 2 h. LCMS showed desired product was major in the mixture. The mixture was filtered and the filtrate was diluted with water (80 mL). The aqueous was extracted with EtOAc (50 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (PE: EtOAc = 3: 1) to give tert-butyl 4-[3-[(4-chlorophenyl)methoxy]pyrazol- 1-yl]piperidine-1-carboxylate (110 mg, 0.28 mmol, 75% yield) as a white solid. LCMS: (ESI) m/z: 336.1 [M+1-56] + Chemical Formula: C 20 H 26 ClN 3 O 3 , Molecular Weight: 391.89 1H NMR: (400 MHz, CHLOROFORM-d) δ:7.43 - 7.31 (m, 4H), 7.21 (d, J = 2.4 Hz, 1H), 5.67 (d, J = 2.4 Hz, 1H), 5.15 (s, 2H), 4.32 - 4.16 (m, 2H), 4.06 (s, 1H), 2.88 (br s, 2H), 2.09 (br d, J = 11.6 Hz, 2H), 1.86 (br dd, J = 3.6, 12.0 Hz, 2H), 1.48 (s, 9H). Total H count from HNMR data: 26 Step 2: Preparation of 4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1-yl)piperidine To a stirred solution of tert-butyl 4-[3-[(4-chlorophenyl)methoxy]pyrazol-1-yl]piperidine-1- carboxylate (100 mg, 0.26 mmol, 1 eq) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol, 0.4 mL, 21.17 eq). The reaction mixture was stirred at 20°C for 1 h. LCMS showed desired product was major in the mixture. The mixture was concentrated under vacuum to give 4- [3-[(4-chlorophenyl)methoxy]pyrazol-1-yl]piperidine (100 mg, 0.25 mmol, 97% yield, TFA) as a light yellow oil. LCMS: (ESI) m/z: 292.1 [M+1] + Chemical Formula: C15H18ClN3O, Molecular Weight: 291.78 Step 3: Preparation of (S)-methyl 2-((4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylate To a stirred solution of 4-[3-[(4-chlorophenyl)methoxy]pyrazol-1-yl]piperidine (100 mg, 0.25 mmol, 1 eq, TFA) in CH 3 CN (4 mL) was added K 2 CO 3 (170 mg, 1.23 mmol, 5 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 -carboxylate (73 mg, 0.25 mmol, 1 eq). The reaction mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (100 mL) was added to the mixture and the aqueous was extracted with EtOAc (60 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum to give methyl 2-[[4-[3-[(4-chlorophenyl)methoxy]pyrazol-1-yl]-1-piperidyl] methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (120 mg, 0.22 mmol, 89% yield) as a light yellow solid. LCMS: (ESI) m/z: 550.1 [M+1] + Chemical Formula: C29H32ClN5O4, Molecular Weight: 550.05 Step 4: Preparation of (S)-2-((4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin -1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid, ammonium salt
To a stirred solution of methyl 2-[[4-[3-[(4-chlorophenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (120 mg, 0.22 mmol, 1 eq) in THF (2 mL) , MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (55 mg, 1.31 mmol, 6 eq). The resulting mixture was stirred at 50°C for 16 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M) and the aqueous was extracted with DCM (50 mL * 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water (0.05% ammonia hydroxide v/v)- ACN];B%: 8%-38%,7min) to give (S)-2-((4-(3-((4-chlorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt (78.78 mg, 0.14 mmol, 64% yield, 98.62% purity) as a white solid. LCMS: (ESI) m/z: 536.1 [M+1] + Chemical Formula: C 28 H 33 ClN 6 O 4 , Molecular Weight: 553.05 1H NMR: (400 MHz, DMSO-d6) δ: 8.23 (s, 1H), 7.79 (dd, J = 1.6, 8.4 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.48 - 7.37 (m, 4H), 5.67 (d, J = 2.4 Hz, 1H), 5.12 - 5.05 (m, 3H), 4.76 (br d, J = 7.2 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.54 - 4.46 (m, 1H), 4.42 - 4.32 (m, 1H), 4.00 - 3.92 (m, 2H), 3.79 (d, J = 13.6 Hz, 1H), 2.97 (br d, J = 11.2 Hz, 1H), 2.85 (br d, J = 11.2 Hz, 1H), 2.75 - 2.68 (m, 1H), 2.44 (br dd, J = 2.0, 8.8 Hz, 1H), 2.33 - 2.17 (m, 2H), 2.00 - 1.83 (m, 4H). Total H count from HNMR data: 29 Example 34 (S)-2-((4-(3-((2-chloro-4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of 4-(bromomethyl)-3-chloro-benzonitrile To a solution of 3-chloro-4-methyl-benzonitrile (500 mg, 3.30 mmol, 1 eq) in CCl 4 (5 mL) was added NBS (587.05 mg, 3.30 mmol, 1 eq) and AIBN (54.16 mg, 329.83 umol, 0.1 eq) under N2. The reaction mixture was stirred at 80 °C for 12 h. TLC (petroleum ether: ethyl acetate = 5:1) showed new spot was detected. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 20:1). 4-(bromomethyl)-3-chloro-benzonitrile (470 mg, 2.04 mmol, 61% yield) was obtained as a white solid. 1H NMR: (400MHz, CDCl 3 ) δ: 7.71 (s, 1H), 7.60 - 7.54 (m, 2H), 4.58 (s, 2H). Chemical Formula: C8H5BrClN, Molecular Weight: 230.49 Total H count from HNMR data: 5. Step 2: Preparation of tert-butyl 4-[3-[(2-chloro-4-cyano-phenyl)methoxy]pyrazol- 1- yl]piperidine-1-carboxylate To a solution of 4-(bromomethyl)-3-chloro-benzonitrile (86 mg, 374.08 umol, 1 eq), tert- butyl 4-(3-hydroxypyrazol-1-yl)piperidine-1-carboxylate (100 mg, 374.08 umol, 1 eq) in DMF (2 mL) was added Ag 2 CO 3 (206.30 mg, 748.16 umol, 2 eq). The reaction mixture was stirred at 80 °C for 1 h. LCMS showed desired MS was detected. Water (20 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 2:1). tert-butyl 4-[3-[(2-chloro-4-cyano-phenyl)methoxy]pyrazol-1-yl]piperidi ne- 1-carboxylate (130 mg, 311.83 umol, 83% yield) was obtained as a light yellow oil. LCMS: MS (ESI) m/z: 361.1 [M+1-56] + 1H NMR: (400MHz, CDCl 3 ) δ: 7.75 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.59 (dd, J = 1.2, 8.0 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 5.72 (d, J = 2.4 Hz, 1H), 5.33 (s, 2H), 4.22 (br s, 2H), 4.10 - 4.02 (m, 1H), 2.87 (br t, J = 12.4 Hz, 2H), 2.15 - 2.04 (m, 2H), 1.90 - 1.80 (m, 2H), 1.48 (s, 9H). Chemical Formula: C21H 2 5ClN4O3, Molecular Weight: 416.90 Total H count from HNMR data: 25. Step 3: Preparation of 3-chloro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl] benzonitrile To a solution of tert-butyl 4-[3-[(2-chloro-4-cyano-phenyl)methoxy]pyrazol-1- yl]piperidine-1 -carboxylate (130 mg, 311.83 umol, 1 eq) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol, 0.4 mL, 17.33 eq). The reaction mixture was stirred at 20 °C for 1 h. LCMS showed desired MS was detected. The mixture was concentrated in vacuum at 20 °C. The residue was used into next step directly. 3-chloro-4-[[1-(4-piperidyl)pyrazol-3- yl]oxymethyl]benzonitrile (130 mg, crude, TFA) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 317.4 [M+1] + Chemical Formula: C 16 H 17 ClN 4 O, Molecular Weight: 316.79 Step 4: Preparation of methyl 2-[[4-[3-[(2-chloro-4-cyano-phenyl)methoxy] pyrazol-1-yl]- 1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol e-5-carboxylate To a solution of 3-chloro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (130 mg, 301.76 umol, 1 eq, TFA) in MeCN (5 mL) was added K 2 CO 3 (208 mg, 1.51 mmol, 5 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 -carboxylate (89 mg, 301.76 umol, 1 eq). The reaction mixture was stirred at 50 °C for 2 h. LCMS showed desired MS was detected. Water (20 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (dichloromethane: methanol= 12:1). Methyl 2-[[4-[3-[(2- chloro-4-cyano-phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]meth yl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (150 mg, 257.19 umol, 85% yield, 98% purity) obtained as a yellow solid. LCMS: MS (ESI) m/z: 575.5 [M+1] + Chemical Formula: C30H31ClN6O4, Molecular Weight: 575.06 Step 5: Preparation of (S)-2-((4-(3-((2-chloro-4-cyanobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(2-chloro-4-cyano-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (150 mg, 260.84 umol, 1 eq) in THF (5 mL) and H 2 O (1 mL) was added 2,3,4,6,7,8-hexahydro-1H- pyrimido[1,2-a]pyrimidine (109 mg, 782.53 umol, 3 eq). The reaction mixture was stirred at 30 °C for 2.5 h. LCMS showed desired MS was detected. Citric acid (2 M) was added to the mixture to adjust pH about 6, the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(10mM NH 4 HCO 3 )-ACN];B%: 16%-46%,9min). (S)-2-((4-(3-((2-chloro-4-cyanobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt (97.82 mg, 166.51 umol, 63.84% yield, 98.4% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 561.2 [M+1] + 1H NMR: (400MHz, DMSO-d6) δ: 8.24 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 1.6, 7.6 Hz, 1H), 7.80 (dd, J = 1.6, 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.63 - 7.59 (m, 2H), 5.73 (d, J = 2.4 Hz, 1H), 5.26 (s, 2H), 5.11- 5.05 (m, 1H), 4.82 - 4.73 (m, 1H), 4.68 - 4.59 (m, 1H), 4.52 - 4.45 (m, 1H), 4.40 - 4.35 (m, 1H), 4.00 - 3.90 (m, 2H), 3.78 (d, J = 13.6 Hz, 1H), 2.97 (br d, J = 11.2 Hz, 1H), 2.84 (br d, J = 11.6 Hz, 1H), 2.76 - 2.66 (m, 1H), 2.47 - 2.39 (m, 1H), 2.29 - 2.18 (m, 2H), 1.97 - 1.75 (m, 4H). Chemical Formula: C29H32ClN7O4, Molecular Weight: 578.06 Total H count from HNMR data: 28. Example 35 (R)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1-yl)methyl)-1- ((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carbox ylic acid, ammonium salt
Step 1: Preparation of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol- 1-yl]- 1-piperidyl]methyl]-3-[[(3R)-tetrahydrofuran-3-yl]methyl]ben zimidazole-5-carboxylate To a solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (93 mg, 224.45 umol, 1 eq, TFA) in MeCN (5 mL) was added K 2 CO 3 (155.10 mg, 1.12 mmol, 5 eq) and methyl 2-(chloromethyl)-3-[[(3R)-tetrahydrofuran-3-yl]methyl]benzim idazole-5- carboxylate (69.30 mg, 224.45 umol, 1 eq). The reaction mixture was stirred at 50 °C for 2 h. LCMS showed desired MS was detected. Water (20 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (dichloromethane: methanol = 12:1). methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1-p iperidyl]methyl]-3- [[(3R)- tetrahydrofuran-3-yl]methyl]benzimidazole-5-carboxylate (100 mg, 174.63 umol, 77% yield) was obtained as a light yellow solid. LCMS: MS (ESI) m/z: 573.3 [M+1] + Chemical Formula: C 31 H 33 FN 6 O 4 , Molecular Weight: 572.63 Step 2: Preparation of (R)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((tetrahydrofuran-3-yl)methyl)-1 H-benzo[d]imidazole-6- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(3R)-tetrahydrofuran-3-yl]methyl]benzi midazole-5-carboxylate (100 mg, 174.63 umol, 1 eq) in MeCN (3 mL) and H 2 O (0.6 mL) was added 2,3,4,6,7,8- hexahydro-1H-pyrimido[1,2-a]pyrimidine (73 mg, 523.90 umol, 3 eq). The reaction mixture was stirred at 30 °C for 2.5 h. LCMS showed desired MS was detected. citric acid (2 M) was added to the mixture to adjust pH about 6, the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(10mM NH 4 HCO 3 )-ACN];B%: 15%-45%,9min). (R)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl) piperidin-1-yl)methyl)-1- ((tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carbox ylic acid, ammonium salt (57.94 mg, 99.65 umol, 57.06% yield, 99.06% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 559.2 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 8.19 (s, 1H), 7.88 (d, J = 10.0 Hz, 1H), 7.81 (dd, J = 1.2, 8.4 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 5.70 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 4.40 (br d, J = 7.6 Hz, 2H), 4.03 - 3.94 (m, 1H), 3.92 - 3.87 (m, 1H), 3.85 - 3.77 (m, 2H), 3.69 - 3.60 (m, 2H), 3.53 (br dd, J = 5.2, 8.4 Hz, 1H), 3.00 - 2.88 (m, 3H), 2.30 - 2.17 (m, 2H), 2.01 - 1.68 (m, 6H). Chemical Formula: C30H34FN7O4, Molecular Weight: 575.63 Total H count from HNMR data: 30. Example 36 (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl )piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation 4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperid ine To a stirred solution of tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]piperidine-1-carboxylate (100 mg, 0.23 mmol, 1 eq) in DCM (2 mL) was added TFA (0.5 M, 0.47 mL, 1 eq). The reaction mixture was stirred at 20 °C for 1 h. LCMS showed desired product was major in the mixture. The mixture was concentrated under vacuum. The residue was used directly for next step. 4-[3-[(4-chloro-2-fluoro- phenyl)methylsulfanyl]pyrazol-1-yl]piperidine (100 mg, 0.23 mmol, 97% yield, TFA) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 326.1 [M+1] + Chemical Formula: C 15 H 17 ClFN 3 S, Molecular Weight: 325.83 Step 2: Preparation of (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylate To a stirred solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]piperidine (100 mg, 0.23 mmol, 1 eq, TFA) in CH 3 CN (4 mL) was added K 2 CO 3 (314 mg, 2.27 mmol, 10 eq). Then methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (67 mg, 0.23 mmol, 1 eq) was added to the mixture. The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (100 mL) was added to the mixture and the aqueous was extracted with EtOAc (60 mL * 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by prep- TLC (DCM: MeOH = 12: 1). methyl 2-[[4-[3-[(4-chloro-2-fluoro- phenyl)methylsulfanyl]pyrazol-1-yl]-1-piperidyl]methyl]-3-[[ (2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (100 mg, 0.17 mmol, 75% yield) was obtained as a light yellow foam. LCMS: MS (ESI) m/z: 584.0 [M+1] + Chemical Formula: C29H31ClFN5O3S, Molecular Weight: 584.10 Step 3: Preparation of (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt
To a stirred solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzim idazole-5-carboxylate (100 mg, 0.17 mmol, 1 eq) in THF (1.5 mL), MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (22 mg, 0.51 mmol, 3 eq). The resulting mixture was stirred at 40°C for 4 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1M). Then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 8%- 38%,10min). (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl )piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid, ammonium salt (74.95 mg, 0.13 mmol, 75% yield, 100.00% purity) was obtained as a white solid which was confirmed by HNMR. LCMS: MS (ESI) m/z: 570.1 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 8.13 (br s, 1H), 7.85 - 7.71 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 2.0, 10.0 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.16 (dd, J = 2.0, 8.4 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 5.08 (br dd, J = 3.2, 7.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.66 - 4.56 (m, 1H), 4.52 - 4.44 (m, 1H), 4.37 (td, J = 6.0, 9.2 Hz, 1H), 4.17 - 4.06 (m, 3H), 3.92 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 2.96 (br d, J = 10.8 Hz, 1H), 2.86 (br d, J = 11.2 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.46 - 2.38 (m, 1H), 2.33 - 2.16 (m, 2H), 1.99 - 1.80 (m, 4H). Chemical Formula: C28H32ClFN6O3S, Molecular Weight: 587.11 Total H count from HNMR data: 28. Example 37 (S)-2-((4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl )piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of 4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl)piperid ine To a stirred solution of tert-butyl 4-[5-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]piperidine-1-carboxylate (100 mg, 0.23 mmol, 1 eq) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol, 0.4 mL, 23.01 eq). The reaction mixture was stirred at 20°C for 1 h. LCMS showed desired product was major in the mixture. The mixture was concentrated under vacuum. The residue was used directly for next step. 4-[5-[(4-chloro-2-fluoro- phenyl)methylsulfanyl]pyrazol-1-yl]piperidine (100 mg, 0.23 mmol, 97% yield, TFA) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 325.8 [M+1] + Chemical Formula: C 15 H 17 ClFN 3 S, Molecular Weight: 325.83 Step 2: Preparation of (S)-methyl 2-((4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylate
To a stirred solution of 4-[5-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]piperidine (100 mg, 0.23 mmol, 1 eq, TFA) in CH 3 CN (4 mL) was added K 2 CO 3 (314 mg, 2.27 mmol, 10 eq). The methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (67 mg, 0.23 mmol, 1 eq) was added to the mixture. The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (100 mL) was added to the mixture and the aqueous was extracted with EtOAc (60 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep- TLC (DCM: MeOH = 12: 1). methyl 2-[[4-[5-[(4-chloro-2-fluoro- phenyl)methylsulfanyl]pyrazol-1-yl]-1-piperidyl]methyl]-3-[[ (2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (110 mg, 0.19 mmol, 83% yield) was obtained as a white foam. LCMS: MS (ESI) m/z: 584.0 [M+1] + Chemical Formula: C29H31ClFN5O3S, Molecular Weight: 584.10 Step 3: Preparation of (S)-2-((4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[5-[(4-chloro-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzim idazole-5-carboxylate (110 mg, 0.19 mmol, 1 eq) in THF (1.5 mL),MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (24 mg, 0.56 mmol, 3 eq). The resulting mixture was stirred at 40°C for 4 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1M). Then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 8%- 38%,7min). (R)-2-((4-(5-((4-chloro-2-fluorobenzyl)thio)-1H-pyrazol-1-yl )piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carb oxylic acid, salt (46.77 mg, 0.080 mmol, 42% yield, 100.00% purity) was obtained as a white solid. LCMS: . MS (ESI) m/z: 570.1 [M+1] + 1 H NMR: . (400MHz, DMSO-d 6 ) δ:8.20 (s, 1H), 7.79 (dd, J = 0.8, 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 2.0, 10.0 Hz, 1H), 7.25 - 7.09 (m, 2H), 6.34 (d, J = 1.6 Hz, 1H), 5.08 (br dd, J = 2.4, 7.2 Hz, 1H), 4.76 (dd, J = 7.2, 15.2 Hz, 1H), 4.66 - 4.58 (m, 1H), 4.53 - 4.45 (m, 1H), 4.41 - 4.33 (m, 1H), 4.21 (br s, 1H), 4.00 (s, 2H), 3.93 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 2.95 (br d, J = 11.2 Hz, 1H), 2.82 (br d, J = 10.8 Hz, 1H), 2.75 - 2.65 (m, 1H), 2.46 - 2.39 (m, 1H), 2.24 - 2.06 (m, 2H), 1.98 - 1.81 (m, 2H), 1.52 - 1.38 (m, 2H). Chemical Formula: C 28 H 32 ClFN 6 O 3 S, Molecular Weight: 587.11 Total H count from HNMR data: 28. Example 38 (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl) piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of 3-fluoro-4-(((1-(piperidin-4-yl)-1H-pyrazol-3- yl)thio)methyl)benzonitrile To a stirred solution of tert-butyl 4-[3-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]piperidine-1-carboxylate (100 mg, 0.24 mmol, 1 eq) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 28.13 eq). The resulting mixture was stirred at 20°C for 1 h. LCMS showed desired product was major in the mixture. The mixture was concentrated under vacuum. The residue was used directly for next step.3-fluoro-4-[[1-(4-piperidyl)pyrazol-3- yl]sulfanylmethyl]benzonitrile (100 mg, 0.23 mmol, 97% yield, TFA) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 316.9 [M+1] + Chemical Formula: C16H17FN4S, Molecular Weight: 316.40 Step 2: Preparation of (S)-methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylate To a stirred solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]sulfanylmethyl]benz onitrile (100 mg, 0.23 mmol, 1 eq, TFA) in CH 3 CN (4 mL) was added K 2 CO 3 (321 mg, 2.32 mmol, 10 eq). Then methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 - carboxylate (68 mg, 0.23 mmol, 1 eq) was added to the mixture. The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EtOAc (80 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM: MeOH = 12: 1). methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (100 mg, 0.17 mmol, 75% yield) was obtained as a white foam. LCMS: MS (ESI) m/z: 575.1 [M+1] + Chemical Formula: C 30 H 31 FN 6 O 3 S, Molecular Weight: 574.67 Step 3: Preparation of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzim idazole-5-carboxylate (100 mg, 0.17 mmol, 1 eq) in CH 3 CN (2 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9-hexahydro- 2H-pyrimido[1,2-a]pyrimidine (73 mg, 0.52 mmol, 3 eq). The reaction mixture was stirred at 20°C for 16 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by citric acid (2 M). The aqueous was extracted with DCM (60 mL * 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 3%-33%,7min). (S)-2-((4-(3-((4-cyano-2- fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid, ammonium salt (61.02 mg, 0.11 mmol, 61% yield, 99.87% purity) was obtained as a white solid . LCMS: MS (ESI) m/z: 561.2 [M+1] + 1 H NMR: (400MHz, DMSO-d6) ]: 8.24 (s, 1H), 7.85 - 7.73 (m, 3H), 7.65 - 7.54 (m, 2H), 7.47 - 7.36 (m, 1H), 6.19 (d, J = 2.4 Hz, 1H), 5.08 (br dd, J = 2.4, 7.6 Hz, 1H), 4.79 (br dd, J = 6.8, 15.2 Hz, 1H), 4.70 - 4.58 (m, 1H), 4.56 - 4.44 (m, 1H), 4.37 (td, J = 6.0, 8.8 Hz, 1H), 4.19 - 4.07 (m, 3H), 3.95 (br d, J = 13.6 Hz, 1H), 3.80 (br d, J = 13.6 Hz, 1H), 2.96 (br d, J = 10.8 Hz, 1H), 2.89 - 2.82 (m, 1H), 2.77 - 2.69 (m, 1H), 2.44 (br d, J = 8.8 Hz, 1H), 2.32 - 2.17 (m, 2H), 1.96 - 1.80 (m, 4H) Chemical Formula: C 29 H 32 FN 7 O 3 S, Molecular Weight: 577.67 Total H count from HNMR data: 28. Example 39 (S)-2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1-yl) piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of 3-fluoro-4-(((1-(piperidin-4-yl)-1H-pyrazol-5- yl)thio)methyl)benzonitrile To a stirred solution of tert-butyl 4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]piperidine-1-carboxylate (80 mg, 0.19 mmol, 1 eq) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol, 0.4 mL, 28.13 eq). The reaction mixture was stirred at 20°C for 1 h. LCMS showed desired product was major in the mixture. The mixture was concentrated under vacuum. The residue was used directly for next step.3-fluoro-4-[[2-(4- piperidyl)pyrazol-3-yl]sulfanylmethyl]benzonitrile (80 mg, 0.19 mmol, 97% yield, TFA) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 316.9 [M+1] + Chemical Formula: C 16 H 17 FN 4 S, Molecular Weight: 316.40 Step 2: Preparation of (S)-methyl 2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylate To a stirred solution of 3-fluoro-4-[[2-(4-piperidyl)pyrazol-3-yl]sulfanylmethyl]benz onitrile (80 mg, 0.19 mmol, 1 eq, TFA) in CH 3 CN (4 mL) was added K 2 CO 3 (257 mg, 1.86 mmol, 10 eq). Then methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 - carboxylate (55 mg, 0.19 mmol, 1 eq) was added to the mixture. The resulting mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EtOAc (80 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM: MeOH = 12: 1). methyl 2-[[4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol-1- yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole- 5-carboxylate (70 mg, 0.12 mmol, 66% yield) was obtained as a white foam. LCMS: MS (ESI) m/z: 575.1 [M+1] + Chemical Formula: C 30 H 31 FN 6 O 3 S, Molecular Weight: 574.67 Step 3: Preparation of (S)-2-((4-(5-((4-cyano-2-fluorobenzyl)thio)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[5-[(4-cyano-2-fluoro-phenyl)methylsulfanyl]pyrazol- 1-yl]-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzim idazole-5-carboxylate (70 mg, 0.12 mmol, 1 eq) in CH 3 CN (1.5 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9- hexahydro-2H-pyrimido[1,2-a]pyrimidine (51 mg, 0.37 mmol, 3 eq). The reaction mixture was stirred at 20°C for 16 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by citric acid (2 M). The aqueous was extracted with DCM (60 mL * 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 3%-33%,7min). (S)-2-((4-(5-((4-cyano-2- fluorobenzyl)thio)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid, ammonium salt (40.55 mg, 0.070 mmol, 57% yield, 99.71% purity) was obtained as a white solid which was confirmed by HNMR (EW22514- 504-P1A). LCMS: MS (ESI) m/z: 561.2 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ:8.21 (s, 1H), 7.81 (ddd, J = 1.2, 9.2, 15.2 Hz, 2H), 7.65 - 7.56 (m, 2H), 7.49 (d, J = 1.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 6.31 (d, J = 1.6 Hz, 1H), 5.08 (br dd, J = 2.8, 7.2 Hz, 1H), 4.78 (dd, J = 7.2, 15.2 Hz, 1H), 4.68 - 4.59 (m, 1H), 4.49 (br d, J = 5.2 Hz, 1H), 4.41 - 4.32 (m, 1H), 4.23 (br s, 1H), 4.08 (s, 2H), 3.94 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 2.96 (br d, J = 11.2 Hz, 1H), 2.83 (br d, J = 10.4 Hz, 1H), 2.74 - 2.64 (m, 1H), 2.43 (br d, J = 2.0 Hz, 1H), 2.23 - 2.09 (m, 2H), 1.94 - 1.85 (m, 2H), 1.45 (br s, 2H). Chemical Formula: C29H32FN7O3S, Molecular Weight: 577.67 Total H count from HNMR data: 28. Example 40 (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)p iperidin-1-yl)methyl)-3- (oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, ammonium salt
Step 1: Preparation of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b] pyridine-5-carboxylate To a solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (98 mg, 0.24 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]imidazo [4,5-b]pyridine-5-carboxylate (70 mg, 0.24 mmol, 1 eq, intermediate 8) in MeCN (3 mL) was added K 2 CO 3 (98 mg, 0.71 mmol, 3 eq), the mixture was stirred at 50 °C for 2 h. LCMS (EW23102-396-P1A) showed the reaction was completely. The reaction mixture was quenched by water (10 mL) at 20 °C, and extracted with EtOAC (20 mL * 3), the combined organic layers were washed with brine (15 mL * 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. Compound methyl 2-[[4-[3-[(4- cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]meth yl]-3-[[(2S)-oxetan-2- yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (90 mg, 0.16 mmol, 68% yield) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 560.3[M+1] + Chemical Formula: C29H30FN7O4, Molecular Weight: 559.59 Step 2: Preparation of (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4 ,5-b]pyridine-5-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1 - piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b] pyridine-5-carboxylate (90 mg, 0.16 mmol, 1 eq) in H 2 O (0.4 mL), MeCN (2 mL) and THF (1 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (67 mg, 0.48 mmol, 3 eq), the mixture was stirred at 20 °C for 2 h. LCMS (EW23102-397-P1B) showed the reaction was completely. The citric acid (10%, 2 mL) was added to the mixture to adjust pH about 5~6, and extracted with DCM (5 mL * 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 prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (10mM NH4HCO3)-ACN];B%: 10%-40%,8min). Compound (S)-2-((4-(3-((4- cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)met hyl)-3-(oxetan-2-ylmethyl)- 3H-imidazo[4,5-b]pyridine-5-carboxylic acid, ammonium salt (63.74 mg, 0.11 mmol, 70% yield, 99.35% purity, NH4+) as a white solid. LCMS: MS (ESI) m/z: 546.3[M+1] + 1H NMR: (400MHz, DMSO-d6) δ: 8.05 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 10.0 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.59 (d, J = 2.4 Hz, 1H), 5.71 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 5.20 - 5.11 (m, 1H), 4.87 - 4.78 (m, 1H), 4.76 - 4.66 (m, 1H), 4.52 - 4.44 (m, 1H), 4.35 (td, J = 6.0, 8.8 Hz, 1H), 4.02 - 3.86 (m, 3H), 2.97 - 2.87 (m, 2H), 2.73 - 2.64 (m, 1H), 2.44 (s, 1H), 2.34 - 2.21 (m, 2H), 1.97 - 1.81 (m, 4H). Chemical Formula: C28H31FN8O4, Molecular Weight: 562.60 Total H count from HNMR data: 27. Example 41 (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl) piperidin-1-yl)methyl)-3- (oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, ammonium salt Step 1: Preparation of 2, 4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidi ne To a stirred solution of tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (100 mg, 0.24 mmol, 1 eq) in DCM (1 mL) was added TFA (308mg, 2.70 mmol, 0.2 mL, 11.07 eq). The reaction mixture was stirred at 20°C for 0.5 h. LCMS showed desired product was major in the mixture. The mixture was concentrated under vacuum. The residue was used directly for next step. 4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]piperidine (100 mg, 0.24 mmol, 967% yield, TFA) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 310.1 [M+1] + Chemical Formula: C15H17ClFN3O, Molecular Weight: 309.77 Step 2: Preparation of (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4 ,5-b]pyridine-5-carboxylate To a stirred solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (100 mg, 0.24 mmol, 1 eq, TFA) in CH 3 CN (3 mL) was added K 2 CO 3 (326 mg, 2.36 mmol, 10 eq) and methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]p yridine-5- carboxylate (70 mg, 0.24 mmol, 1 eq). The reaction mixture was stirred at 50°C for 2 h. LCMS (EW22514-532-P1A) showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EtOAc (60 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was used directly for next step. methyl 2-[[4-[3- [(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1-piperidyl ]methyl]-3-[[(2S)-oxetan-2- yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (100 mg, 0.18 mmol, 74% yield) was obtained as a light yellow oil. LCMS: MS (ESI) m/z: 569.2 [M+1] + Chemical Formula: C28H30ClFN6O4, Molecular Weight: 569.03 Step 3: Preparation of (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4 ,5-b]pyridine-5-carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5- b]pyridine-5-carboxylate (100 mg, 0.18 mmol, 1 eq) in THF (1.5 mL), MeOH (0.5 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (22 mg, 0.53 mmol, 3 eq). The reaction mixture was stirred at 40°C for 3 h. LCMS (EW22514-534-P1A) showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by aq. HCl aqueous (1 M) and the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 10%-40%,9min). (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4 ,5-b]pyridine-5-carboxylic acid, ammonium salt (48.00 mg, 0.083 mmol, 47% yield, 99.40% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 555.3 [M+1] + 1H NMR: (400MHz, DMSO-d6) δ: 8.09 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.46 (dd, J = 2.0, 10.0 Hz, 1H), 7.30 (dd, J = 1.6, 8.0 Hz, 1H), 5.68 (d, J = 2.4 Hz, 1H), 5.16 - 5.05 (m, 3H), 4.85 (dd, J = 6.8, 14.8 Hz, 1H), 4.76 - 4.66 (m, 1H), 4.51 - 4.40 (m, 1H), 4.34 (td, J = 6.0, 8.8 Hz, 1H), 4.06 - 3.94 (m, 2H), 3.87 (br d, J = 13.6 Hz, 1H), 3.17 (s, 2H), 2.96 (br d, J = 10.8 Hz, 1H), 2.87 (br d, J = 11.2 Hz, 1H), 2.34 - 2.21 (m, 2H), 1.99 - 1.82 (m, 4H). Chemical Formula: C27H31ClFN7O4, Molecular Weight: 572.03 Total H count from HNMR data: 27. Example 42 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1-((1- methyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carbo xylic acid, ammonium salt
Step 1: Preparation of methyl 2-[[4-[3-[(4-cyano-2-fluoro -phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[(3-methylimidazol-4-yl)methyl]benzimi dazole-5-carboxylate To a solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (91 mg, 0.22 mmol, 1 eq, TFA) in MeCN (3 mL) was added K 2 CO 3 (91 mg, 0.66 mmol, 3 eq), and methyl 2-(chloromethyl)-3-[(3-methylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (70 mg, 0.22 mmol, 1 eq) was added to the mixture , the mixture was stirred at 50 °C for 12 h. LCMS (EW23102-402-P1A) showed the reaction was completely. The reaction mixture was quenched by water (10 mL) at 20 °C, and extracted with EtOAC (20 mL * 3), the combined organic layers were washed with brine (15 mL * 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, DCM: MeOH = 10: 1). Compound methyl 2-[[4-[3-[(4-cyano-2-fluoro - phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[(3-methy limidazol-4- yl)methyl]benzimidazole-5-carboxylate (50 mg, 0.09 mmol, 39% yield) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 583.2[M+1] + Chemical Formula: C 31 H 31 FN 8 O 3 , Molecular Weight: 582.63 Step 2: Preparation of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1- yl)methyl)-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-benzo[d] imidazole-6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1 - piperidyl]methyl]-3-[(3-methylimidazol-4-yl)methyl]benzimida zole-5-carboxylate (47 mg, 0.08 mmol, 1 eq) in H 2 O (0.4 mL) and MeCN (2 mL) was added 3,4,6,7,8,9-hexahydro-2H -pyrimido[1,2-a]pyrimidine (34 mg, 0.24 mmol, 3 eq), the mixture was stirred at 20 °C for 2 h. LCMS (EW23102-405-P1B) showed the reaction was completely. The citric acid (10%, 2 mL) was added to the mixture to adjust pH about 5~6, and extracted with DCM (5 mL * 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 prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water(10mM NH4HCO3)- ACN];B%: 10%-40%,8min). Compound 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H- pyrazol-1-yl)piperidin-1-yl)methyl)-1-((1-methyl-1H-imidazol -5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid, ammonium salt (12 mg, 0.02 mmol, 26% yield, 99.68% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 569.3[M+1] + 1H NMR: (400MHz, DMSO-d6) δ: 8.06 (s, 1H), 7.90 (d, J = 10.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 3.2 Hz, 2H), 7.66 - 7.56 (m, 2H), 7.53 (d, J = 2.4 Hz, 1H), 6.51 (s, 1H), 5.73 - 5.65 (m, 3H), 5.23 (s, 2H), 3.97 - 3.87 (m, 1H), 3.81 (s, 2H), 3.54 (s, 3H), 2.86 (d, J = 11.2 Hz, 2H), 2.18 (t, J = 11.2 Hz, 2H), 1.86 (d, J = 11.2 Hz, 2H), 1.73 - 1.60 (m, 2H). Chemical Formula: C 30 H 32 FN 9 O 3 , Molecular Weight: 585.63 Total H count from HNMR data: 28. Example 43 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1-((1- methyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carbo xylic acid, ammonium salt Step 1: Preparation of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-methylimidazol-4-yl)methyl]benzimida zole-5-carboxylate To a solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (93 mg, 0.22 mmol, 1 eq, TFA) in MeCN (3 mL) was added K 2 CO 3 (91.05 mg, 0.66 mmol, 3 eq) and methyl 2-(chloromethyl)-3-[(3-methylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate (70 mg, 0.22 mmol, 1 eq), the mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was completely. The reaction mixture was quenched by water (10 mL) at 20 °C, and extracted with EtOAC (20 mL * 3), the combined organic layers were washed with brine (15 mL * 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10: 1). Compound methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3- [(3-methylimidazol-4-yl)methyl]benzimidazole-5-carboxylate (70 mg, 0.12 mmol, 54% yield) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 592.2[M+1] + Chemical Formula: C 30 H 31 ClFN 7 O 3 , Molecular Weight: 592.06 Step 2: Preparation of 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin- 1-yl)methyl)-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-benzo[ d]imidazole-6-carboxylic acd, ammonium salt To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1 - piperidyl]methyl]-3-[(3-methylimidazol-4-yl)methyl]benzimida zole-5-carboxylate (45 mg, 0.08 mmol, 1 eq) in H 2 O (0.5 mL) and THF (2 mL) was added LiOH.H 2 O (32 mg, 0.76 mmol, 10 eq), the mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was completely. The reaction mixture was adjusted to PH = 7 with HCl solution (1 M, 3 mL), and then concentrated by vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water(10mM NH4HCO3)- ACN];B%: 12%-42%,8min). Compound 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H- pyrazol-1-yl)piperidin-1-yl)methyl)-1-((1-methyl-1H-imidazol -5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid, ammonium salt (28.89 mg, 0.05 mmol, 63% yield, 99.92% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 578.2[M+1] + 1H NMR: (400MHz, DMSO-d6) δ: 8.09 (d, J = 0.8 Hz, 1H), 7.81 (dd, J = 1.6, 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 2.0, 10.0 Hz, 1H), 7.31 (dd, J = 1.6, 8.4 Hz, 1H), 6.53 (s, 1H), 5.72 (s, 2H), 5.68 (d, J = 2.4 Hz, 1H), 5.13 (s, 2H), 3.97 - 3.87 (m, 1H), 3.83 (s, 2H), 3.55 (s, 3H), 2.87 (d, J = 11.2 Hz, 2H), 2.19 (t, J = 11.2 Hz, 2H), 1.87 (d, J = 10.4 Hz, 2H), 1.74 - 1.61 (m, 2H) Chemical Formula: C29H32ClFN8O3, Molecular Weight: 595.07 Total H count from HNMR data: 28. Example 44 2-((4-(3-((5-chloropyridin-2-yl)methoxy)-1H-pyrazol-1-yl)pip eridin-1-yl)methyl)-1- ((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-ca rboxylic acid, ammonium salt Step 1: Preparation of tert-butyl 4-(3-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]piperidine-1-carboxylate (10 g, 24.40 mmol, 1 eq) in MeOH (100 mL) was added Pd/C (500 mg, 24.40 mmol, 10% purity, 1.00 eq) and Pd(OH)2 (500 mg, 3.56 mmol, 1.46e-1 eq) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15 psi) at 20 °C for 2 hours. TLC (Petroleum ether: Ethyl acetate = 1: 1) showed the reaction was completely. The reaction mixture was filtered and the filter was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~56% Ethylacetate/Petroleum ethergradient @ 100 mL/min). Compound tert-butyl 4-(3-hydroxypyrazol-1-yl)piperidine- 1-carboxylate (2.2 g, 7.98 mmol, 33% yield, 97% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 212.2 [M+1-56] + Chemical Formula: C 13 H 21 N 3 O 3 , Molecular Weight: 267.32 Step 2: Preparation of tert-butyl 4-[3-[(5-chloro-2-pyridyl)methoxy]pyrazol-1-yl]piperidine- 1-carboxylate To a solution of tert-butyl 4-(3-hydroxypyrazol-1-yl)piperidine-1-carboxylate (200 mg, 0.75 mmol, 1 eq) in DMF (5 mL) was added Ag 2 CO 3 (309 mg, 1.12 mmol, 1.5 eq) and 5-chloro- 2-(chloromethyl)pyridine (145 mg, 0.90 mmol, 1.2 eq). The mixture was stirred at 90 °C for 3 h. LCMS showed the desired mass was detected. The residue was added water (200 mL) and ethyl acetate (15 mL). The mixture was filtered to get the filtrate, the filtrate was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethylacetate/Petroleum ethergradient @ 45 mL/min). Compound tert-butyl 4-[3-[(5-chloro-2-pyridyl)methoxy]pyrazol-1-yl]piperidine-1- carboxylate (180 mg, 0.49 mmol, 61% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 393.2 [M+1] + Chemical Formula: C 19 H 25 ClN 4 O 3 , Molecular Weight: 392.88 Step 3: Preparation of 5-chloro-2-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]pyridine
To a solution of tert-butyl 4-[3-[(5-chloro-2-pyridyl)methoxy]pyrazol-1-yl]piperidine-1- carboxylate (120 mg, 0.31 mmol, 1 eq) in DCM (3 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 22.11 eq). The mixture was stirred at 25 °C for 0.5 h. TLC (Petroleum ether: Ethyl acetate = 1: 1) showed the starting material was consumed. The reaction mixture was concentrated under vacuum. Compound 5-chloro-2-[[1-(4-piperidyl)pyrazol-3- yl]oxymethyl]pyridine (124 mg, 0.30 mmol, 100% yield, TFA) was obtained as a yellow oil without further purification. Step 4: Preparation of methyl 2-[[4-[3-[(5-chloro-2-pyridyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidaz ole-5-carboxylate To a solution of 5-chloro-2-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]pyridine (120 mg, 0.30 mmol, 1 eq, TFA) in MeCN (4 mL) was added K 2 CO 3 (204 mg, 1.47 mmol, 5 eq) and methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]benzimidazo le-5-carboxylate (132 mg, 0.32 mmol, 1.1 eq, 2HCl). The mixture was stirred at 50 °C for 3 h. TLC (Dichloromethane: Methanol = 10: 1) showed the starting material was consumed. The residue was poured into water (20 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep- TLC (Dichloromethane: Methanol = 10: 1). Compound methyl 2-[[4-[3-[(5-chloro-2- pyridyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[(3-ethy limidazol-4- yl)methyl]benzimidazole-5-carboxylate (70 mg, 0.12 mmol, 40% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 589.5 [M+1] + Chemical Formula: C30H33ClN8O3, Molecular Weight: 589.09 Step 5: Preparation of 2-((4-(3-((5-chloropyridin-2-yl)methoxy)-1H-pyrazol-1-yl)pip eridin- 1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d ]imidazole-6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(5-chloro-2-pyridyl)methoxy]pyrazol-1-yl]-1-piperi dyl] methyl]-3-[(3-ethylimidazol-4-yl)methyl]benzimidazole-5-carb oxylate (70 mg, 0.12 mmol, 1 eq) in MeOH (0.5 mL) and H 2 O (0.5 mL) and THF (0.5 mL) was added LiOH.H 2 O (5 mg, 0.18 mmol, 1 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed the desired product's mass. The mixture was adjusted pH to 7-8 by 1M HCl, and concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-35%, 8 min). 2-((4-(3-((5-chloropyridin-2-yl)methoxy)-1H-pyrazol-1-yl)pip eridin-1-yl)methyl)-1-((1- ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carbox ylic acid, ammonium salt (36.66 mg, 0.059 mmol, 50% yield, 99.08% purity, NH 4 +) was obtained as a white solid. LCMS: MS (ESI) m/z: 575.2 [M+1] + Chemical Formula: C29H34ClN9O3, Molecular Weight: 592.09 1H NMR: (400 MHz, DMSO-d 6 ) δ = 8.79 - 8.49 (m, 1H), 8.01 (s, 1H), 7.95 (dd, J = 2.4, 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.57 - 7.44 (m, 3H), 6.36 (s, 1H), 5.70 (d, J = 2.0 Hz, 1H), 5.65 (s, 2H), 5.17 (s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 3.94 - 3.86 (m, 1H), 3.76 (s, 2H), 2.82 (br d, J = 11.2 Hz, 2H), 2.14 (br t, J = 11.2 Hz, 2H), 1.83 (br d, J = 10.0 Hz, 2H), 1.70 - 1.55 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H). Total H count from HNMR data: 30 Example 45 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-3-((1- ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-c arboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]imidazo[4, 5-b]pyridine-5-carboxylate (73 mg, 0.12 mmol, 1 eq) in THF (1 mL), H 2 O (0.5 mL) and MeCN (1 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (34 mg, 0.24 mmol, 2 eq). The reaction was stirred at 25 °C for 4 h. LC-MS showed starting material was consumed completely and one main peak with desired m/z 584.3 was detected. Citric acid (12 mg) was added and then the reaction mixture was concentrated under reduced pressure to remove most of the THF. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX C18 75*30mm*3um; mobile phase: [water (10mM NH4HCO3)-ACN];B%: 8%- 38%,8min). Compound 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin- 1-yl)methyl)-3-((1-ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo [4,5-b]pyridine-5- carboxylic acid, ammonium salt (43.65 mg, 0.07 mmol, 57% yield, 95.90% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 584.3 [M+1] + 1HNMR: (400MHz, DMSO-d 6 ) δ = 8.15 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 2.8 Hz, 2H), 7.64 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.72 (s, 1H), 5.80 - 5.63 (m, 3H), 5.24 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 4.00 - 3.89 (m, 1H), 3.82 (s, 2H), 2.89 - 2.79 (m, 2H), 2.22 (br t, J = 11.2 Hz, 2H), 1.95 - 1.85 (m, 2H), 1.83 - 1.70 (m, 2H), 1.14 - 1.03 (m, 3H). Chemical Formula: C30H33FN10O3, Molecular Weight: 600.65 Total H count from HNMR data: 29. Example 46 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-3-((1- ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-c arboxylic acid, ammonium salt Step 1: Preparation of methyl 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-3-((1-ethyl-1H-imidazol-5-yl)methy l)-3H-imidazo[4,5- b]pyridine-5-carboxylate To a solution of methyl 2-(chloromethyl)-3-[(3-ethylimidazol-4-yl)methyl]imidazo[4,5 - b]pyridine-5-carboxylate (181 mg, 0.54 mmol, 1 eq) and K 2 CO 3 (375 mg, 2.71 mmol, 5 eq) in MeCN (2 mL) was added a solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol- 1-yl]piperidine (230 mg, 0.54 mmol, 1 eq, TFA). The reaction was stirred at 50 °C for 2 h. LC-MS showed starting materials consumed and one main peak with desired m/z 607.2 was detected. Water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep- TLC (SiO2, DCM: MeOH = 10: 1). Compound methyl 2-[[4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[(3-ethyl imidazol-4- yl)methyl]imidazo[4,5-b]pyridine-5-carboxylate (153 mg, 0.24 mmol, 44% yield, 95% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 607.3 [M+1] + Chemical Formula: C30H32ClFN8O3, Molecular Weight: 607.08 Step 2: Preparation of 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin- 1-yl)methyl)-3-((1-ethyl-1H-imidazol-5-yl)methyl)-3H-imidazo [4,5-b]pyridine-5- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-ethylimidazol-4-yl)methyl]imidazo[4, 5-b]pyridine-5-carboxylate (153 mg, 0.25 mmol, 1 eq) in H 2 O (0.5 mL), THF (1 mL) and MeOH (1.5 mL) was added LiOH (12 mg, 0.50 mmol, 2 eq). The reaction was stirred at 25 °C for 4 h. LC-MS showed starting material was consumed completely and one main peak with desired m/z 593.3 was detected. HCl (0.1 M, 0.15 mL) was added to adjust the solution's pH about 7. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 21%-51%,10min). Compound 2-((4-(3-((4-chloro-2- fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-3-( (1-ethyl-1H-imidazol-5- yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, ammonium salt (76.44 mg, 0.13 mmol, 50% yield, 100.00% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 593.3 [M+1] + 1 HNMR: (400MHz, DMSO-d6) δ = 8.10 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.60 - 7.52 (m, 2H), 7.47 (dd, J = 2.0, 10.0 Hz, 1H), 7.31 (dd, J = 2.0, 8.4 Hz, 1H), 6.71 (s, 1H), 5.78 - 5.61 (m, 3H), 5.19 - 5.06 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.02 - 3.89 (m, 1H), 3.85 - 3.72 (m, 2H), 2.91 - 2.77 (m, 2H), 2.21 (br t, J = 10.8 Hz, 2H), 1.98 - 1.85 (m, 2H), 1.84 - 1.69 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H) Chemical Formula: C29H33ClFN9O3, Molecular Weight: 610.08 Total H count from HNMR data: 29. Example 47 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1-((1- (difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazo le-6-carboxylic acid, ammonium salt Step 1: Preparation of methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol -5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate
To a stirred solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (100 mg, 0.24 mmol, 1 eq, TFA) in CH 3 CN (4 mL) was added K 2 CO 3 (334 mg, 2.41 mmol, 10 eq), methyl 2-(chloromethyl)-3-[[3-(difluoromethyl)imidazol-4- yl]methyl]benzimidazole-5-carboxylate (86 mg, 0.24 mmol, 1 eq). The reaction mixture was stirred at 50°C for 2 h. LCMS showed desired product was major in the mixture. Water (150 mL) was added to the mixture and the aqueous was extracted with EtOAc (70 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (DCM: MeOH = 10: 1). Methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1-p iperidyl]methyl]-3- [[3-(difluoromethyl)imidazol-4-yl]methyl]benzimidazole-5-car boxylate (80 mg, 0.13 mmol, 54% yield) was obtained as a light yellow foam. LCMS: MS (ESI) m/z: 619.3 [M+1] + Chemical Formula: C 31 H 29 F 3 N 8 O 3 , Molecular Weight: 618.61 Step 2: Preparation of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1- yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1 H-benzo[d]imidazole-6- carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 1-piperidyl]methyl]-3-[[3-(difluoromethyl)imidazol-4-yl]meth yl]benzimidazole-5- carboxylate (80 mg, 0.13 mmol, 1 eq) in CH 3 CN (1.5 mL) and H 2 O (0.3 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (54 mg, 0.39 mmol, 3 eq). The reaction mixture was stirred at 20°C for 16 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by saturated citric acid aqueous. The aqueous was extracted with DCM (50 mL * 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 5%-35%,8min). 2-((4-(3-((4-cyano-2- fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1-( (1-(difluoromethyl)-1H- imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt (17.75 mg, 0.027 mmol, 21% yield, 94.76% purity) was obtained as a white solid. LCMS:, MS (ESI) m/z: 605.2 [M+1] + 1 H NMR: (400MHz, DMSO-d 6 ) δ: 8.13 (s, 1H), 8.09 (s, 0.25H), 8.05 (s, 1H), 7.95 (s, 0.5H), 7.89 (d, J = 10.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.79 (s, 0.25H), 7.73 - 7.66 (m, 3H), 7.46 (d, J = 2.0 Hz, 1H), 6.45 (s, 1H), 5.82 (s, 2H), 5.69 (d, J = 2.0 Hz, 1H), 5.23 (s, 2H), 3.96 - 3.85 (m, 1H), 3.83 (s, 2H), 2.81 (br d, J = 11.2 Hz, 2H), 2.17 (br s, 2H), 1.83 (br d, J = 12.0 Hz, 2H), 1.63 - 1.52 (m, 2H). Chemical Formula: C30H30F3N9O3, Molecular Weight: 621.61 Total H count from HNMR data: 26. Example 48 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1-((1- (2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt
Step 1: Preparation of 1-(2,2,2-trifluoroethyl)-1H-imidazole-5-carbaldehyde A mixture of 1H-imidazole-5-carbaldehyde (10 g, 104.07 mmol, 1 eq) and K 2 CO 3 (14.38 g, 104.07 mmol, 1 eq) in MeCN (100 mL) was stirred at 60°C for 1h. Then the mixture was cooled to 20°C, 2,2,2-trifluoroethyl trifluoromethanesulfonate (48.31 g, 208.14 mmol, 2 eq) was added and stirred at 85°C for 10 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (300 mL), then extracted with ethyl acetate (300 mL * 2). The combined organic layers were washed with brine (300 mL * 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ ethyl acetate = 3/ 1 to 0/ 1) to give desired product. Compound 3-(2,2,2-trifluoroethyl)imidazole- 4-carbaldehyde (500 mg, 2.81 mmol, 3% yield) was obtained as a white solid. LCMS: MS (ESI) m/z: 178.9 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 9.79 (s, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 5.33 (q, J = 8.8 Hz, 2H). Chemical Formula: C 6 H 5 F 3 N 2 O, Molecular Weight: 178.11 Total H count from HNMR data: 5. Step 2: Preparation of methyl 4-nitro-3-(((1-(2,2,2-trifluoroethyl)-1H-imidazol-5- yl)methyl)amino)benzoate To a solution of methyl 3-amino-4-nitro-benzoate (500 mg, 2.55 mmol, 1 eq) and TFA (5 mL) in CH 2 Cl 2 (10 mL) was added NaBH(OAc) 3 (1.62 g, 7.65 mmol, 3 eq) at 0°C, then 3- (2,2,2-trifluoroethyl)imidazole-4-carbaldehyde (499.40 mg, 2.80 mmol, 1.1 eq) in CH 2 Cl 2 (5 mL) was added in at 0°C. The resulting mixture was stirred at 20°C for 12 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was basified with sat.NaHCO 3 (50 mL), then extracted with ethyl acetate (20 mL * 2). The combined organic layers were washed with brine (20 mL * 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ ethyl acetate = 3/ 1 to 0/ 1) to give desired product. Compound methyl 4-nitro-3-[[3-(2,2,2-trifluoroethyl)imidazol-4-yl]methylamin o]benzoate (730 mg, 2.04 mmol, 80% yield) was obtained as a orange solid. LCMS:, MS (ESI) m/z: 359.1 [M+1] + 1H NMR: (400MHz, DMSO-d6) δ: 8.54 (t, J = 5.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.04 - 7.94 (m, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.19 (dd, J = 1.2, 8.8 Hz, 1H), 7.10 (s, 1H), 5.22 (q, J = 8.8 Hz, 2H), 4.73 (d, J = 5.6 Hz, 2H), 3.87 (s, 3H). Chemical Formula: C 14 H 13 F 3 N 4 O 4 , Molecular Weight: 358.27 Total H count from HNMR data: 13. Step 3: Preparation of methyl 4-amino-3-(((1-(2,2,2-trifluoroethyl)-1H-imidazol-5- yl)methyl)amino)benzoate To a solution of methyl 4-nitro-3-[[3-(2,2,2-trifluoroethyl)imidazol-4- yl]methylamino]benzoate (730 mg, 2.04 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (100 mg, 5% purity) under N 2 . The suspension was degassed under vacuum and purged with H 2 for several times. The mixture was stirred under H 2 (15psi) at 20°C for 12 h. LCMS indicated desired mass was detected. The reaction mixture was filtered through celite, then concentrated to give a residue. The residue was used without further purification. Compound methyl 4-amino-3-[[3-(2,2,2-trifluoroethyl)imidazol-4-yl]methylamin o]benzoate (600 mg, 1.83 mmol, 90% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 329.1 [M+1] + Chemical Formula: C14H15F3N4O 2 , Molecular Weight: 328.29 Step 4: Preparation of methyl 2-(chloromethyl)-1-((1-(2,2,2-trifluoroethyl)-1H-imidazol-5- yl)methyl)-1H-benzo[d]imidazole-6-carboxylate To a solution of methyl 4-amino-3-[[3-(2,2,2-trifluoroethyl)imidazol-4- yl]methylamino]benzoate (540 mg, 1.64 mmol, 1 eq) and 2-chloro-1,1,1-trimethoxy-ethane (305 mg, 1.97 mmol, 0.27 mL, 1.2 eq) in CH 3 CN (10 mL) was added TFA (188 mg, 1.64 mmol, 0.12 mL, 1 eq). The mixture was stirred at 50 °C for 2 h. LCMS indicated desired mass was detected. The reaction mixture was quenched with NaHCO 3 (50 mL), then extracted with ethyl acetate (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0 to 20/1) to give desired product. Compound methyl 2- (chloromethyl)-3-[[3-(2,2,2-trifluoroethyl)imidazol-4-yl]met hyl]benzimidazole-5- carboxylate (530 mg, 0.49 mmol, 85% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 387.0 [M+1] + Chemical Formula: C16H14ClF3N4O 2 , Molecular Weight: 386.76 Step 5: Preparation of methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-(2,2,2-trifluoroethyl)-1H-im idazol-5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate To a solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (100 mg, 0.24 mmol, 1 eq, TFA) and methyl 2-(chloromethyl)-3-[[3-(2,2,2-trifluoroethyl)imidazol-4- yl]methyl]benzimidazole-5-carboxylate (260 mg, 0.24 mmol, 36% purity, 1.00 eq) in MeCN (5 mL) was added K 2 CO 3 (100 mg, 0.72 mmol, 3 eq). The mixture was stirred at 50 °C for 3 h. LCMS indicated desired mass was detected. The reaction mixture was concentrated to remove MeCN, the residue was diluted with water (20 mL), then extracted with ethyl acetate (20 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate/methanol= 1/0 to 10/1) to give desired product. Compound methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[3-(2,2,2-trifluoroethyl)imidazol-4-yl] methyl]benzimidazole-5- carboxylate (90 mg, 0.14 mmol, 57% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 651.3 [M+1] + Chemical Formula: C32H33F4N8O3, Molecular Weight: 650.63 Step 6: Preparation of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1- yl)methyl)-1-((1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)met hyl)-1H-benzo[d]imidazole-6- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[3-(2,2,2- trifluoroethyl)imidazol-4-yl]methyl]benzimidazole-5-carboxyl ate (90 mg, 0.14 mmol, 1 eq) in THF (2 mL) and H 2 O (0.6 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2- a]pyrimidine (58 mg, 0.41 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 20%-50%,10min). Compound 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1- yl)methyl)-1-((1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)met hyl)-1H-benzo[d]imidazole-6- carboxylic acid, ammonium salt (29.94 mg, 0.044 mmol, 32% yield, 96.75% purity, NH4) was obtained as a white solid. LCMS: MS (ESI) m/z: 637.2 [M+1] + 1 H NMR: (400MHz, DMSO-d 6 ) δ: 8.03 (s, 1H), 7.89 (d, J = 10.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.79 - 7.68 (m, 3H), 7.66 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 6.18 (s, 1H), 5.80 - 5.64 (m, 3H), 5.30 - 5.13 (m, 4H), 3.98 - 3.87 (m, 1H), 3.82 (s, 2H), 2.79 (d, J = 11.6 Hz, 2H), 2.15 (t, J = 11.6 Hz, 2H), 1.83 (d, J = 10.8 Hz, 2H), 1.66 - 1.46 (m, 2H). Chemical Formula: C31H31F4N9O3, Molecular Weight: 653.63 Total H count from HNMR data: 27. Example 49 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1-((1- (2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]i midazole-6-carboxylic acid, ammonium salt Step 1: Preparation of methyl 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-(2,2,2-trifluoroethyl)-1H-im idazol-5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate To a solution of methyl 2-(chloromethyl)-3-[[3-(2,2,2-trifluoroethyl)imidazol-4- yl]methyl]benzimidazole-5-carboxylate (260 mg, 0.24 mmol, 36% purity, 1.03 eq) and 4- [3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperidin e (100 mg, 0.24 mmol, 1 eq, TFA) in MeCN (5 mL) was added K 2 CO 3 (98 mg, 0.71 mmol, 3 eq). The mixture was stirred at 50 °C for 3 h. LCMS indicated desired mass was detected. The reaction mixture was concentrated to remove MeCN, the residue was diluted with water (20 mL), then extracted with ethyl acetate (20 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 to 10/1) to give desired product. Compound methyl 2-[[4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[[3-(2,2, 2-trifluoroethyl)imidazol-4- yl]methyl] benzimidazole-5- carboxylate (90 mg, 0.14 mmol, 58% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 660.1 [M+1] + Chemical Formula: C 31 H 30 ClF 4 N 7 O 3 , Molecular Weight: 660.06 Step 2: Preparation of 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin- 1-yl)methyl)-1-((1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)m ethyl)-1H-benzo[d]imidazole- 6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[3-(2,2,2-trifluoroethyl)imidazol-4-yl] methyl]benzimidazole- 5- carboxylate (90 mg, 0.14 mmol, 1 eq) in THF (2 mL) and H 2 O (0.6 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (57 mg, 0.41 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 24%-54%,10min). Compound 2-((4-(3-((4-chloro-2- fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1-( (1-(2,2,2-trifluoroethyl)-1H- imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt (41.65 mg, 0.061 mmol, 44% yield, 96.67% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 646.2 [M+1] + 1H NMR: (400MHz, DMSO-d6) 8.04 (d, J = 0.8 Hz, 1H), 7.83 (dd, J = 1.6, 8.4 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.31 (dd, J = 2.0, 8.0 Hz, 1H), 6.19 (s, 1H), 5.74 (s, 2H), 5.67 (d, J = 2.4 Hz, 1H), 5.22 (q, J = 8.8 Hz, 2H), 5.12 (s, 2H), 3.98 - 3.86 (m, 1H), 3.82 (s, 2H), 2.80 (d, J = 11.2 Hz, 2H), 2.16 (t, J = 10.8 Hz, 2H), 1.84 (d, J = 10.0 Hz, 2H), 1.67 - 1.47 (m, 2H). Chemical Formula: C 30 H 31 ClF 4 N 8 O 3 , Molecular Weight: 663.07 Total H count from HNMR data: 27. Example 50 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1-((1- isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-ca rboxylic acid, ammonium salt Step 1: Preparation of 5-bromo-1-isopropyl-1H-imidazole and 4-bromo-1-isopropyl-1H- imidazole To a solution of 1-isopropylimidazole (6.2 g, 56.28 mmol, 1 eq) in DCM (40 mL) was added dropwise a solution of 1,3- dibromo-5,5-dimethyl-imidazolidine-2,4-dione (8.05 g, 28.14 mmol, 0.5 eq) in DCM (60 mL) at 0 °C for 0.5 h. Then the reaction was stirred at 0 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and the desired m/z 188.9 was detected. The reaction mixture was concentrated at room temperature under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250*50mm*10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 12%-42%,20min). Compound 5-bromo-1-isopropyl-imidazole (2.16 g, 11.41 mmol, 20.27% yield) was obtained as brown oil, checked by 1HNMR (EW23109-400-P1A) and 2D NMR. Compound 4-bromo-1-isopropyl-imidazole (2.25 g, 11.90 mmol, 21.15% yield) was obtained as brown oil. LCMS: MS (ESI) m/z: 188.9 [M+1] + 1HNMR: 400MHz, CDCl 3 -d) δ = 7.63 (s, 1H), 7.01 (d, J = 0.8 Hz, 1H), 4.42 (td, J = 10.4, 12.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 6H). 1 HNMR: (400MHz, CDCl 3 -d) δ = 7.41 (d, J = 1.2 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 4.35 – 4.25 (m, 1H), 1.47 (d, J = 6.8 Hz, 6H). Chemical Formula: C6H9BrN2, Molecular Weight: 189.05 Total H count from HNMR data: 9. Step 2: Preparation of 1-isopropyl-1H-imidazole-5-carbaldehyde To a solution of 5-bromo-1-isopropyl-imidazole (500 mg, 2.64 mmol, 1 eq) in THF (5 mL) was added i-PrMgCl-LiCl (1.3 M, 5.09 mL, 2.5 eq) at 0 °C under N 2 . The mixture was stirred at 25 °C for 1 h under N 2 . Then DMF (580 mg, 7.93 mmol, 0.61 mL, 3 eq) was added into the solution. The reaction was stirred at 25 °C for 2 h under N2. TLC (DCM: MeOH = 10:1) indicated Reactant 1 was consumed completely and one new spot formed. Saturated NH4Cl (2 mL) was added. Then the aqueous phase was extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, PE: EtOAc = 7: 9). Compound 3-isopropylimidazole-4-carbaldehyde (132 mg, 0.88 mmol, 33% yield, 93% purity) was obtained as a light yellow oil. LCMS: MS (ESI) m/z: 139.1 [M+1] + 1 HNMR: (400MHz, CDCl 3 -d) δ = 9.74 (d, J = 0.8 Hz, 1H), 7.83 (d, J = 15.6 Hz, 2H), 5.17 (td, J = 6.8, 13.2 Hz, 1H), 1.52 (d, J = 6.8 Hz, 6H). Chemical Formula: C 7 H 10 N 2 O, Molecular Weight: 138.17 Total H count from HNMR data: 10. Step 3: Preparation of methyl 3-(((1-isopropyl-1H-imidazol-5-yl)methyl)amino)-4- nitrobenzoate To a solution of methyl 3-amino-4-nitro-benzoate (156 mg, 0.80 mmol, 1 eq) in DCM (6 mL) was added TFA (3 mL) at 0°C. Then NaBH(OAc)3 (506 mg, 2.39 mmol, 3 eq) was added at 0 °C. Then a solution of 3-isopropylimidazole-4-carbaldehyde (132 mg, 0.95 mmol, 1.2 eq) in DCM (3 mL) was added at 0 °C. The reaction was stirred at 20 °C for 12 h. LC- MS (EW23109-428-P1A) showed starting material was consumed completely and one main peak with desired m/z 319.1 was detected. Saturated NaHCO 3 (20 mL) was added dropwise to adjust the solution's pH to 8. The reaction mixture was added water (30 mL) and extracted with EtOAc (30mL * 3). The combine organic layers were washed with brine (30 mL * 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO 2 , DCM: MeOH = 10/ 1). Compound methyl 3-[(3-isopropylimidazol-4-yl)methylamino]-4-nitro-benzoate (308 mg, 0.79 mmol, 99% yield, 81%purity) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 319.1 [M+1] + 1 HNMR: (400MHz, CDCl 3 -d) δ = 8.27 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.36 (dd, J = 1.6, 8.8 Hz, 1H), 7.12 (s, 1H), 4.55 (d, J = 4.8 Hz, 2H), 4.35 (td, J = 6.8, 13.6 Hz, 1H), 3.97 (s, 3H), 1.54 (d, J = 6.8 Hz, 6H). Chemical Formula: C15H18N4O4, Molecular Weight: 318.33 Total H count from HNMR data: 17. Step 4: Preparation of methyl 4-amino-3-(((1-isopropyl-1H-imidazol-5- yl)methyl)amino)benzoate To a solution of methyl 3-[(3-isopropylimidazol-4-yl)methylamino]-4-nitro-benzoate (308 mg, 0.97 mmol, 1 eq) in MeOH (6 mL) was added Pd/C (30 mg, 0.025 mmol, 10% purity) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred at 20°C for 4 hours under H 2 (15psi). LC-MS showed starting material was consumed completely and one main peak with desired m/z 289.1 was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound methyl 4-amino-3-[(3-isopropylimidazol-4-yl)methylamino]benzoate (251 mg, 0.87 mmol, 90% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 289.1 [M+1] + Chemical Formula: C15H 2 0N4O 2 , Molecular Weight: 288.34 Step 5: Preparation methyl 2-(chloromethyl)-1-((1-isopropyl-1H-imidazol-5-yl)methyl)- 1H-benzo[d]imidazole-6-carboxylate To a solution of methyl 4-amino-3-[(3-isopropylimidazol-4-yl)methylamino]benzoate (251 mg, 0.87 mmol, 1 eq) in MeCN (6 mL) was TFA (99 mg, 0.87 mmol, 0.064 mL, 1 eq) and 2-chloro-1,1,1-trimethoxy-ethane (135 mg, 0.87 mmol, 0.12 mL, 1 eq). The reaction was stirred at 50 °C for 2 h. LC-MS showed starting material was almost consumed completely and one main peak with desired m/z 347.1 was detected. The compound was kept in the solution. The product methyl 2-(chloromethyl)-3-[(3-isopropylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (300 mg, 0.87 mmol, 99% yield) was got as a white solid and used into the next step without further purification. LCMS: MS (ESI) m/z: 347.1 [M+1] + Chemical Formula: C17H19ClN4O 2 , Molecular Weight: 346.81 Step 6: Preparation of methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-isopropyl-1H-imidazol-5-yl)m ethyl)-1H- benzo[d]imidazole-6-carboxylate To a solution of 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (180 mg, 0.43 mmol, 1 eq, TFA) in MeCN (6 mL) was added K 2 CO 3 (179 mg, 1.30 mmol, 3 eq) and methyl 2-(chloromethyl)-3-[(3-isopropylimidazol-4-yl)methyl]benzimi dazole-5- carboxylate (150 mg, 0.43 mmol, 1 eq). The reaction was stirred at 50 °C for 2 h. LC-MS showed starting material was consumed completely and one main peak with desired m/z 611.2 was detected. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO 2 , DCM: MeOH = 10: 1). Compound methyl 2-[[4-[3-[(4-cyano-2-fluoro- phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[(3-isopr opylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (91 mg, 0.11 mmol, 26% yield, 97% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 611.2 [M+1] + Chemical Formula: C33H35FN8O3, Molecular Weight: 610.68 Step 7: Preparation of 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1- yl)methyl)-1-((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo [d]imidazole-6-carboxylic acid, ammonium salt
To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-isopropylimidazol-4-yl)methyl]benzim idazole-5-carboxylate (91 mg, 0.15 mmol, 1 eq) in THF (0.5 mL), MeOH (1.5 mL), H 2 O (0.5 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (41 mg, 0.30 mmol, 2 eq). The reaction was stirred at 25 °C for 4 h. LC-MS showed Reactant 1 was consumed completely and one main peak with desired m/z 597.2 was detected. Citric acid (40 mg) was added to adjust the solution's pH to be 8. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (10mM NH4HCO3)-ACN];B%: 18%-48%,10min). Compound 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1- yl)methyl)-1-((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo [d]imidazole-6-carboxylic acid, ammonium salt (22.77 mg, 0.037 mmol, 25% yield, 98.88% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 597.2 [M+1] + 1HNMR: (400MHz, DMSO-d6) δ = 8.03 (d, J = 0.8 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.83 - 7.77 (m, 2H), 7.75 - 7.64 (m, 3H), 7.52 (d, J = 2.4 Hz, 1H), 6.45 (s, 1H), 5.77 - 5.62 (m, 3H), 5.23 (s, 2H), 4.45 (quin, J = 6.8 Hz, 1H), 4.00 - 3.88 (m, 1H), 3.82 (s, 2H), 2.87 (br d, J = 11.6 Hz, 2H), 2.19 (br t, J = 10.4 Hz, 2H), 1.86 (br d, J = 10.0 Hz, 2H), 1.68 (dq, J = 3.2, 14.8 Hz, 2H), 1.31 (d, J = 6.4 Hz, 6H). Chemical Formula: C32H36FN9O3, Molecular Weight: 613.69 Total H count from HNMR data: 32. Example 51 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1-((1- isopropyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-ca rboxylic acid, ammonium salt Step 1: Preparation of methyl 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-isopropyl-1H-imidazol-5-yl)m ethyl)-1H- benzo[d]imidazole-6-carboxylate To a solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (183 mg, 0.43 mmol, 1 eq, TFA) in MeCN (6 mL) was added K 2 CO 3 (179 mg, 1.30 mmol, 3 eq) and methyl 2-(chloromethyl)-3-[(3-isopropylimidazol-4-yl)methyl]benzimi dazole-5- carboxylate (150 mg, 0.43 mmol, 1 eq). The reaction was stirred at 50°C for 2 hours. LC- MS showed starting material was consumed completely and one main peak with desired m/z 620.2.was detected. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10: 1). Compound methyl 2-[[4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[(3-isopr opylimidazol-4- yl)methyl]benzimidazole-5-carboxylate (102 mg, 0.16 mmol, 37% yield, 97% purity) was obtained as a colorless solid. LCMS: MS (ESI) m/z: 620.1 [M+1] + Chemical Formula: C 32 H 35 ClFN 7 O 3 , Molecular Weight: 620.12 Step 2: Preparation of 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin- 1-yl)methyl)-1-((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-ben zo[d]imidazole-6- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[(3-isopropylimidazol-4-yl)methyl]benzim idazole-5-carboxylate (102 mg, 0.16 mmol, 1 eq) in THF (0.5 mL), MeOH (1.5 mL), H 2 O (0.5 mL) was added LiOH (12 mg, 0.49 mmol, 3 eq). The reaction was stirred at 25 °C for 4 h. LC-MS showed starting material was consumed completely and one main peak with desired m/z 606.2 was detected. HCl (0.1M, 0.1 mL) was added to adjust the solution's pH to 8. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 22%-52%,10min). Compound 2-((4-(3-((4-chloro-2- fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1-( (1-isopropyl-1H-imidazol-5- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt (67.42 mg, 0.11 mmol, 65% yield, 99.53% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 606.2 [M+1] + 1 HNMR: (400MHz, DMSO-d 6 ) δ = 8.03 (s, 1H), 7.84 - 7.77 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.31 (dd, J = 2.0, 8.4 Hz, 1H), 6.45 (s, 1H), 5.78 - 5.60 (m, 3H), 5.12 (s, 2H), 4.46 (td, J = 6.4, 13.2 Hz, 1H), 4.00 - 3.89 (m, 1H), 3.82 (s, 2H), 2.88 (br d, J = 11.6 Hz, 2H), 2.19 (br t, J = 11.6 Hz, 2H), 1.87 (br d, J = 10.4 Hz, 2H), 1.78 - 1.60 (m, 2H), 1.31 (d, J = 6.4 Hz, 6H). Chemical Formula: C 31 H 36 ClFN 8 O 3 , Molecular Weight: 623.12 Total H count from HNMR data: 32. Example 52 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1-((1- (difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazo le-6-carboxylic acid, ammonium salt Step 1: Preparation of methyl 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol -5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate To a solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (169 mg, 0.40 mmol, 1 eq, TFA), K 2 CO 3 (110 mg, 0.80 mmol, 2 eq) in MeCN (4 mL) was added a solution of methyl 2-(chloromethyl)-3-[[3-(difluoromethyl)imidazol-4- yl]methyl]benzimidazole-5-carboxylate (141 mg, 0.40 mmol, 1 eq), K 2 CO 3 (110 mg, 0.80 mmol, 2 eq) in MeCN (2 mL). The reaction was stirred at 50 °C for 2 h. Water (30 mL) was added, then the aqueous phase was extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/DCM gradient @ 30 mL/min). Compound methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1- yl]-1-piperidyl]methyl]-3-[[3-(difluoromethyl)imidazol-4-yl] methyl]benzimidazole-5- carboxylate (194 mg, 0.31 mmol, 77% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 628.2 [M+1] + 1 HNMR: (400MHz, CDCl 3 -d) δ = 8.13 - 7.95 (m, 2H), 7.86 - 7.73 (m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.40 - 7.31 (m, 1H), 7.24 - 7.01 (m, 4H), 6.57 (s, 1H), 5.90 - 5.76 (m, 2H), 5.66 (br s, 1H), 5.20 (s, 2H), 3.86 (br s, 2H), 3.04 - 2.78 (m, 2H), 2.46 - 2.15 (m, 2H), 2.11 - 1.98 (m, 2H), 1.88 - 1.72 (m, 2H), 1.69 - 1.44 (m, 4H). Chemical Formula: C30H 2 9ClF3N7O3, Molecular Weight: 628.04 Total H count from HNMR data: 29. Step 2: Preparation of 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin- 1-yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol-5-yl)methyl) -1H-benzo[d]imidazole-6- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[3-(difluoromethyl)imidazol-4-yl]methyl ]benzimidazole-5- carboxylate (94 mg, 0.15 mmol, 1 eq) in H 2 O (0.5 mL) and THF (3 mL) was added LiOH (18 mg, 0.75 mmol, 5 eq). The reaction was stirred at 25 °C for 2 h. Then LiOH (22 mg, 0.90 mmol, 6 eq) was added and the reaction was stirred at 40 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and one main peak with desired m/z 614.2was detected. HCl (0.1 M, 0.5 mL) was added to adjust the solution's pH to 7-8. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was kept in MeOH (1.5 mL). The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 22%-52%,7.5min). Compound 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1- yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1 H-benzo[d]imidazole-6- carboxylic acid, ammonium salt (48.36 mg, 0.076 mmol, 501% yield, 99.64% purity, NH4+) was obtained as a white solid. LCMS:, MS (ESI) m/z: 614.2 [M+1] + 1HNMR: (400MHz, DMSO-d 6 ) δ = 8.13 (s, 1H), 8.10 (s, 1H), 8.08 - 8.08 (m, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.95 (s, 1H), 7.83 (dd, J = 1.6, 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.31 (dd, J = 1.6, 8.0 Hz, 1H), 6.43 (s, 1H), 5.82 (s, 1H), 5.69 - 5.64 (m, 1H), 5.67 (d, J = 2.4 Hz, 1H), 5.12 (s, 1H), 5.23 - 4.93 (m, 1H), 3.93 - 3.85 (m, 1H), 3.82 (s, 1H), 3.85 - 3.79 (m, 1H), 2.81 (br d, J = 11.2 Hz, 2H), 2.17 (br t, J = 11.6 Hz, 2H), 1.84 (br d, J = 10.4 Hz, 2H), 1.66 - 1.49 (m, 2H). Chemical Formula: C 29 H 30 ClF 3 N 8 O 3 , Molecular Weight: 631.05 Total H count from HNMR data: 26. Example 53 (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2 ,5-difluorobenzyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt
Step 1: Preparation of 4-(((1-(4-bromo-2,5-difluorophenyl)-1H-pyrazol-3-yl)oxy)meth yl)- 3-fluorobenzonitrile To a stirred solution of 1,4-dibromo-2,5-difluoro-benzene (2.82 g, 10.36 mmol, 1.5 eq) and 3-fluoro-4-(1H-pyrazol-3-yloxymethyl)benzonitrile (1.5 g, 6.91 mmol, 1 eq) in dioxane (20 mL) was added CuI (263 mg, 1.38 mmol, 0.2 eq), (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (295 mg, 2.07 mmol, 0.3 eq) and Cs 2 CO 3 (4.50 g, 13.81 mmol, 2 eq). The reaction mixture was stirred at 120°C for 16 h. LCMS showed desired MS was detected. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 3: 1).4-[[1-(4-bromo-2,5-difluoro-phenyl)pyrazol-3-yl]oxymethyl ]-3-fluoro-benzonitrile (700 mg, 1.71 mmol, 25% yield) was obtained as a white solid which was confirmed by HNMR (EW22514-749-P1A1). LCMS: MS (ESI) m/z: 407.7,409.7 [M+1] + 1 H NMR: (400MHz, CHLOROFORM-d) δ: 7.92 (t, J = 2.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.51 (dd, J = 1.0, 8.0 Hz, 1H), 7.46 - 7.37 (m, 2H), 6.01 (d, J = 2.8 Hz, 1H), 5.45 (s, 2H) Chemical Formula: C 17 H 9 BrF 3 N 3 O, Molecular Weight: 408.18 Total H count from HNMR data: 9. Step 2: Preparation of methyl 2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2,5- difluorophenyl)acetate To a stirred solution of bromo-(2-methoxy-2-oxo-ethyl)zinc (1.07 g, 4.90 mmol, 2 eq) in THF (10 mL) was added the solution of 4-[[1-(4-bromo-2,5-difluoro-phenyl)pyrazol-3- yl]oxymethyl]-3-fluoro-benzonitrile (1 g, 2.45 mmol, 1 eq) in DMF (10 mL), Pd2(dba)3 (224 mg, 0.24 mmol, 0.1 eq) and XPhos (234 mg, 0.19 mmol, 0.2 eq). The reaction mixture was stirred at 60°C under N 2 for 1 h. LCMS showed desired product was major in the mixture. Diluted HCl aqueous (1 M) (200 mL) was added to the mixture and the aqueous was extracted with EtOAc (100 mL*2). The combined organic layer was washed with brine (150 mL*2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 2: 1). methyl 2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2,5- difluoro- phenyl]acetate (740 mg, 1.84 mmol, 75% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 401.8 [M+1] + 1 H NMR: (400MHz, CHLOROFORM-d) δ: 7.91 (t, J = 2.4 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.62 (dd, J = 6.8, 10.4 Hz, 1H), 7.50 (dd, J = 1.0, 8.0 Hz, 1H), 7.41 (dd, J = 1.2, 9.2 Hz, 1H), 7.15 (dd, J = 6.4, 12.0 Hz, 1H), 5.98 (d, J = 2.8 Hz, 1H), 5.44 (s, 2H), 3.74 (s, 3H), 3.67 (s, 2H) Chemical Formula: C20H14F3N3O3, Molecular Weight: 401.35 Total H count from HNMR data: 14. Step 3: Preparation of 2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2,5- difluorophenyl)acetic acid To a stirred solution of methyl 2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2,5-difluoro-phenyl]acetate (300 mg, 0.75 mmol, 1 eq) in THF (3 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (312 mg, 2.24 mmol, 3 eq). The reaction mixture was stirred at 45°C for 1 h. LCMS showed desired product was major in the mixture. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M) and the aqueous was extracted with DCM (70 mL*2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was used directly for next step. 2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2,5-difluoro-phenyl]acetic acid (280 mg, 0.72 mmol, 97% yield) was obtained as a yellow solid.. LCMS: MS (ESI) m/z: 388.0 [M+1] + Chemical Formula: C 19 H 12 F 3 N 3 O 3 , Molecular Weight: 387.32 Step 4: Preparation of methyl (S)-4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)-2,5-difluorophenyl)acetamido)-3-((oxetan-2-ylmethyl)amin o)benzoate
To a stirred solution of 2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2,5- difluoro-phenyl]acetic acid (100 mg, 0.26 mmol, 1 eq) and methyl 4-amino-3-[[(2S)-oxetan- 2-yl]methylamino]benzoate (67 mg, 0.28 mmol, 1.1 eq) in DMF (2 mL) was added DIEA (167 mg, 1.29 mmol, 20.22 mL, 5 eq). Then T 3 P (657 mg, 1.03 mmol, 0.61 mL, 50% purity, 4 eq) was added to the mixture at 0°C. The reaction mixture was stirred at 0°C for 1 h. LCMS showed desired MS was detected. Water (150 mL) was added to the mixture and the aqueous was extracted with EtOAc (70 Ml*2). The combined organic layer was washed with brine (80 mL*2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 3: 1 - 1: 3). methyl 4-[[2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2,5-difluoro- phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoa te (110 mg, 0.18 mmol, 70% yield) was obtained as a white solid. LCMS: MS (ESI) m/z: 606.2 [M+1] + Chemical Formula: C 31 H 26 F 3 N 5 O 5 , Molecular Weight: 605.57 Step 5: Preparation of methyl (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)- 2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazo le-6-carboxylate Methyl 4-[[2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2,5-difluoro- phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoa te (100 mg, 0.17 mmol, 1 eq) was dissolved into HOAc (4 mL). The reaction mixture was stirred at 70°C for 2 h. LCMS showed desired MS was detected. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 4: 1 - 1: 2). methyl 2-[[4- [3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2,5-diflu oro-phenyl]methyl]-3- [[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (60 mg, 0.10 mmol, 62% yield) was obtained as a yellow solid. LCMS: m/z: 588.0 [M+1] + Chemical Formula: C 31 H 24 F 3 N 5 O 4 , Molecular Weight: 587.56 Step 6: Preparation of (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2 ,5- difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benz imidazole-5-carboxylate (60 mg, 0.10 mmol, 1 eq) in THF (2 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9-hexahydro- 2H-pyrimido[1,2-a]pyrimidine (43 mg, 0.31 mmol, 3 eq). The reaction mixture was stirred at 40°C for 2 h. LCMS showed desired MS was detected. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M). The mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];B%: 24%-54%,9min). (S)-2-(4-(3-((4-cyano-2- fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2,5-difluorobenzyl)-1-(ox etan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid, ammonium salt (13.53 mg, 0.023 mmol, 22% yield, 98.77% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 574.1 [M+1] + 1 H NMR: (400MHz, DMSO-d 6 ) δ: 8.20 (s, 1H), 8.11 (t, J = 2.4 Hz, 1H), 7.92 (d, J = 10.0 Hz, 1H), 7.83 - 7.71 (m, 3H), 7.61 (dd, J = 6.4, 10.4 Hz, 1H), 7.58 - 7.43 (m, 2H), 6.18 (d, J = 2.4 Hz, 1H), 5.42 (s, 2H), 5.05 (br s, 1H), 4.69 (br d, J = 6.4 Hz, 1H), 4.60 (br d, J = 2.4 Hz, 1H), 4.53 - 4.39 (m, 3H), 4.39 - 4.33 (m, 1H), 2.67 (br s, 1H), 2.43 - 2.33 (m, 1H). Chemical Formula: C30H 2 5F3N6O4, Molecular Weight: 590.56 Total H count from HNMR data: 21. Example 54 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1-yl)methyl)-1-((1- (fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-car boxylic acid, ammonium salt Step 1: Preparation of tert-butyl ((1-(fluoromethyl)cyclopropyl)methyl)carbamate A solution of tert-butyl N-[[1-(hydroxymethyl)cyclopropyl]methyl]carbamate (900 mg, 4.47 mmol, 1 eq) in CH 2 Cl 2 (10 mL) was cooled to -78°C, then DAST (865 mg, 5.37 mmol, 0.71 mL, 1.2 eq) was added in. The mixture was allowed to warm to 20°C and stirred for 5 h. TLC (Petroleum ether: Ethyl acetate = 1: 1) indicated the reaction was completed. The reaction mixture was added into sat. NaHCO 3 (aq.) (50 mL) carefully, then extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ ethyl acetate = 30/ 1 to 10/ 1) to give desired product. Compound tert-butyl ((1- (fluoromethyl)cyclopropyl)methyl)carbamate (470 mg, 2.31 mmol, 52% yield) was obtained as a white solid. 1 H NMR: (400 MHz, CDCl 3 ) δ: 4.82 (brs, 1H), 3.55 - 3.32 (m, 2H), 2.35 - 2.19 (m, 2H), 2.18 - 2.07 (m, 2H), 1.89 - 1.77 (m, 1H), 1.56 - 1.39 (m, 10H). FNMR: (400 MHz, CDCl 3 ) δ: -134.79 ppm Chemical Formula: C 10 H 18 FNO 2 , Molecular Weight: 203.26 Total H count from HNMR data: 18. Step 2: Preparation of (1-(fluoromethyl)cyclopropyl)methanamine To a solution of tert-butyl N-[[1-(fluoromethyl)cyclopropyl]methyl]carbamate (470 mg, 2.31 mmol, 1 eq) in CH 2 Cl 2 (2 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 11.68 eq). The mixture was stirred at 20 °C for 0.5 h. TLC (Petroleum ether: Ethyl acetate = 1: 1) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was used without further purification. Compound [1- (fluoromethyl)cyclopropyl]methanamine (500 mg, 2.30 mmol, 100% yield, TFA) was obtained as a yellow oil. 1 H NMR: (400 MHz, CDCl3) δ: 8.30 - 7.38 (m, 3H), 3.43 - 3.29 (m, 2H), 2.55 - 2.35 (m, 2H), 2.33 - 2.18 (m, 2H), 2.01 - 1.88 (m, 1H), 1.71 - 1.51 (m, 1H). FNMR: (400 MHz, CDCl3) δ: -134.79 ppm and -76.026 ppm Chemical Formula: C 5 H 10 FN, Molecular Weight: 103.14 Total H count from HNMR data: 11. Step 3: Preparation of methyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4- nitrobenzoate To a solution of [1-(fluoromethyl)cyclopropyl]methanamine (500 mg, 2.30 mmol, 1 eq, TFA) and methyl 3-fluoro-4-nitrobenzoate (459 mg, 2.30 mmol, 1 eq) in DMF (10 mL) was added DIEA (893 mg, 6.91 mmol, 1.20 mL, 3 eq). The mixture was stirred at 25 °C for 12 h. LCMS indicated desired mass was detected. The reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether /ethyl acetate = 20/ 1 to 5/ 1). methyl 3-[[1- (fluoromethyl)cyclopropyl]methylamino]-4-nitro-benzoate (380 mg, 1.35 mmol, 58% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 283.0 [M+1] + Chemical Formula: C 13 H 15 FN 2 O 4 , Molecular Weight: 282.27 Step 4: Preparation of methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl) methyl)amino)benzoate To a solution of methyl 3-[[1-(fluoromethyl)cyclopropyl]methylamino]-4-nitro-benzoat e (380 mg, 1.35 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (100 mg, 10% purity, 1 eq) under N2. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15psi) at 20 °C for 3 h. LCMS indicated the reaction was completed and desired mass was detected. The mixture was filtered through celite and concentrated to give a residue. The residue was used without further purification. Compound methyl 4-amino-3-[[1-(fluoromethyl)cyclopropyl]methylamino]benzoate (330 mg, 1.31 mmol, 97% yield) was obtained as a colorless oil. LCMS: MS (ESI) m/z: 253.0 [M+1] + Chemical Formula: C 13 H 17 FN 2 O 2 , Molecular Weight: 252.29 Step 5: Preparation of methyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl) methyl)- 1H-benzo[d]imidazole-6-carboxylate To a solution of methyl 4-amino-3-[[1-(fluoromethyl)cyclopropyl]methylamino]benzoate (330 mg, 1.31 mmol, 1 eq) and 2-chloro-1,1,1-trimethoxy-ethane (263 mg, 1.70 mmol, 0.23 mL, 1.3 eq) in MeCN (5 mL) was added PTSA (23 mg, 0.13 mmol, 0.1 eq). The mixture was stirred at 50 °C for 3 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated, diluted with water (50 mL), then extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ ethyl acetate = 15/ 1 to 8/ 1) to give desired product. Compound methyl 2-(chloromethyl)- 3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carbo xylate (352 mg, 1.13 mmol, 87% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 310.9 [M+1] + Chemical Formula: C15H16ClFN2O 2 , Molecular Weight: 310.75 Step 6: Preparation of methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)me thyl)-1H-benzo[d]imidazole- 6-carboxylate To a solution of methyl 2-(chloromethyl)-3-[[1- (fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylate (105 mg, 0.34 mmol, 1 eq) and 3-fluoro-4-[[1-(4-piperidyl)pyrazol-3-yl]oxymethyl]benzonitr ile (140 mg, 0.34 mmol, 1 eq, TFA) in MeCN (5 mL) was added K 2 CO 3 (140 mg, 1.01 mmol, 3 eq). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated, diluted with water (30 mL), extracted with ethyl acetate (30 mL * 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ ethyl acetate = 3/ 1 to 1/ 2) to give desired product. Compound methyl 2- [[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1-pip eridyl]methyl]-3-[[1- (fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylate (160 mg, 0.28 mmol, 82% yield) was obtained as a yellow oil. LCMS: MS (ESI) m/z: 575.1 [M+1] + Chemical Formula: C31H32F2N6O3, Molecular Weight: 574.63 Step 7: Preparation 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piper idin-1- yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[ d]imidazole-6-carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]ben zimidazole-5-carboxylate (160 mg, 0.28 mmol, 1 eq) in THF (2 mL) and H 2 O (1 mL) was added 3,4,6,7,8,9-hexahydro- 2H-pyrimido[1,2-a]pyrimidine (116 mg, 0.84 mmol, 3 eq). The mixture was stirred at 35 °C for 2 h. LCMS indicated the reaction was completed. The mixture was concentrated to give a residue. The residue was purified by Prep-HPLC column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN];B%: 23%-53%,10min). Compound ((4-(3- ((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)piperidin-1-yl )methyl)-1-((1- (fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-car boxylic acid, ammonium salt (91.18 mg, 0.15 mmol, 55% yield, 97.32% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 561.3 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 8.26 (s, 1H), 7.88 (d, J = 10.0 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.76 - 7.67 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 5.70 (d, J = 2.0 Hz, 1H), 5.22 (s, 2H), 4.98 - 4.81 (m, 2H), 4.03 - 3.91 (m, 1H), 3.85 (s, 2H), 3.29 - 3.25 (m, 2H), 2.96 - 2.88 (m, 2H), 2.32 - 2.14 (m, 5H), 1.95 - 1.79 (m, 5H). Chemical Formula: C 30 H 33 F 2 N 7 O 3 , Molecular Weight: 577.64 Total H count from HNMR data: 29. Example 55 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1-yl)methyl)-1-((1- (difluoromethyl)-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazo le-6-carboxylic acid, ammonium salt
Step 1: Preparation of methyl 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)piperidin-1-yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol -5-yl)methyl)-1H- benzo[d]imidazole-6-carboxylate To a solution of 4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]piperid ine (169 mg, 0.40 mmol, 1 eq, TFA), K 2 CO 3 (110 mg, 0.80 mmol, 2 eq) in MeCN (4 mL) was added a solution of methyl 2-(chloromethyl)-3-[[3-(difluoromethyl)imidazol-4- yl]methyl]benzimidazole-5-carboxylate (141 mg, 0.40 mmol, 1 eq), K 2 CO 3 (110 mg, 0.80 mmol, 2 eq) in MeCN (2 mL). The reaction was stirred at 50 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and one main peak with desired m/z 628.2 was detected. Water (30 mL) was added, then the aqueous phase was extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH/DCM gradient @ 30 mL/min). Compound methyl 2-[[4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]-1-piperidyl]methyl]-3-[[3-(difl uoromethyl)imidazol-4- yl]methyl]benzimidazole-5-carboxylate (194 mg, 0.31 mmol, 77% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 628.2 [M+1] + 1 HNMR: (400MHz, CDCl 3 -d) δ = 8.13 - 7.95 (m, 2H), 7.86 - 7.73 (m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.40 - 7.31 (m, 1H), 7.24 - 7.01 (m, 4H), 6.57 (s, 1H), 5.90 - 5.76 (m, 2H), 5.66 (br s, 1H), 5.20 (s, 2H), 3.86 (br s, 2H), 3.04 - 2.78 (m, 2H), 2.46 - 2.15 (m, 2H), 2.11 - 1.98 (m, 2H), 1.88 - 1.72 (m, 2H), 1.69 - 1.44 (m, 4H). Chemical Formula: C 30 H 29 ClF 3 N 7 O 3 , Molecular Weight: 628.04 Total H count from HNMR data: 29. Step 2: Preparation of 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin- 1-yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol-5-yl)methyl) -1H-benzo[d]imidazole-6- carboxylic acid, ammonium salt To a solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-1- piperidyl]methyl]-3-[[3-(difluoromethyl)imidazol-4-yl]methyl ]benzimidazole-5- carboxylate (94 mg, 0.15 mmol, 1 eq) in H 2 O (0.5 mL) and THF (3 mL) was added LiOH (18 mg, 0.75 mmol, 5 eq). The reaction was stirred at 25 °C for 2 h. TLC (DCM: MeOH = 10: 1) indicated Reactant 1 was not consumed completely. Then LiOH (22 mg, 0.90 mmol, 6 eq) was added and the reaction was stirred at 40 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and one main peak with desired m/z 614.2was detected. HCl (0.1 M, 0.5 mL) was added to adjust the solution's pH to 7-8. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was kept in MeOH (1.5 mL). The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 22%-52%,7.5min). Compound 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)pipe ridin-1- yl)methyl)-1-((1-(difluoromethyl)-1H-imidazol-5-yl)methyl)-1 H-benzo[d]imidazole-6- carboxylic acid, ammonium salt (48.36 mg, 0.076 mmol, 501% yield, 99.64% purity, NH4+) was obtained as a white solid. LCMS: MS (ESI) m/z: 614.2 [M+1] + 1 HNMR: (400MHz, DMSO-d6) δ = 8.13 (s, 1H), 8.10 (s, 1H), 8.08 - 8.08 (m, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.95 (s, 1H), 7.83 (dd, J = 1.6, 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.31 (dd, J = 1.6, 8.0 Hz, 1H), 6.43 (s, 1H), 5.82 (s, 1H), 5.69 - 5.64 (m, 1H), 5.67 (d, J = 2.4 Hz, 1H), 5.12 (s, 1H), 5.23 - 4.93 (m, 1H), 3.93 - 3.85 (m, 1H), 3.82 (s, 1H), 3.85 - 3.79 (m, 1H), 2.81 (br d, J = 11.2 Hz, 2H), 2.17 (br t, J = 11.6 Hz, 2H), 1.84 (br d, J = 10.4 Hz, 2H), 1.66 - 1.49 (m, 2H). Chemical Formula: C29H30ClF3N8O3, Molecular Weight: 631.05 Total H count from HNMR data: 26. Example 56 (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2 -fluoro-5-methylbenzyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt
Step 1: Preparation of methyl 2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2- fluoro-5-methylphenyl)acetate To a stirred solution of methyl 2-[2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]acetate (100 mg, 0.32 mmol, 1 eq) and 3-fluoro-4-(1H-pyrazol-3- yloxymethyl)benzonitrile (99 mg, 0.45 mmol, 1.4 eq) in DCE (20 mL) was added Cu(OAc)2 (59 mg, 0.32 mmol, 1 eq), Na2CO3 (69 mg, 0.65 mmol, 2 eq) and 2-(2-pyridyl)pyridine (51 mg, 0.32 mmol, 1 eq). The reaction mixture was stirred at 80°C under O 2 (15 Psi) for 16 h. LCMS showed desired MS was detected. The mixture was filtered and the filtrate was concentrated under vacuum. The combined crude product (750 mg of 5 batches in parallel) was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 2: 1). methyl 2-[4-[3-[(4- cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2-fluoro-5-methy l-phenyl]acetate (200 mg, 0.50 mmol, 31% yield) was obtained as a light yellow solid. LCMS: MS (ESI) m/z: 398.1 [M+1] + Chemical Formula: C21H17F2N3O3, Molecular Weight: 397.38 Step 2: Preparation of 2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2-flu oro-5- methylphenyl)acetic acid To a stirred solution of methyl 2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2- fluoro-5-methyl-phenyl]acetate (200 mg, 0.50 mmol, 1 eq) in THF (2 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (210 mg, 1.51 mmol, 3 eq). The reaction mixture was stirred at 40°C for 1 h. LCMS showed desired MS was detected. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M) and the mixture was extracted with DCM (80 mL*3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was used directly for next step.2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl] -2-fluoro-5- methyl-phenyl]acetic acid (190 mg, 0.50 mmol, 98.8% yield) was obtained as a yellow solid. LCMS: MS (ESI) m/z: 384.1 [M+1] + Chemical Formula: C20H15F2N3O3, Molecular Weight: 383.35 Step 3: Preparation of methyl (S)-4-(2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)-2-fluoro-5-methylphenyl)acetamido)-3-((oxetan-2-ylmethyl )amino)benzoate To a stirred solution of 2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2-fl uoro- 5-methyl-phenyl]acetic acid (180 mg, 0.47 mmol, 1 eq) and methyl 4-amino-3-[[(2S)- oxetan-2-yl]methylamino]benzoate (122 mg, 0.52 mmol, 1.1 eq) in DMF (4 mL) was added DIEA (303 mg, 2.35 mmol, 0.41 mL, 5 eq). Then T 3 P (1.20 g, 1.88 mmol, 1.12 mL, 50% purity, 4 eq) was added to the mixture at 0°C. The reaction mixture was stirred at 0°C for 1 h. LCMS showed desired MS was detected. Water (200 mL) was added to the mixture and the aqueous was extracted with EtOAc (100 mL*2). The combined organic layer was washed with brine (100 mL*2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 4: 1 - 1: 2). methyl 4-[[2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2-fluoro-5-methyl-phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl] methylamino]benzoate (200 mg, 0.33 mmol, 71% yield) was obtained as a light yellow solid. LCMS: MS (ESI) m/z: 602.1 [M+1] + Chemical Formula: C32H 2 9F2N5O5, Molecular Weight: 601.61 Step 4: Preparation of methyl (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)- 2-fluoro-5-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]im idazole-6-carboxylate Methyl 4-[[2-[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2-fluoro-5-methyl- phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoa te (180 mg, 0.30 mmol, 1 eq) was dissolved into HOAc (5 mL). The reaction mixture was stirred at 70°C for 2 h. LCMS showed desired MS was detected. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EtOAc = 3: 1 - 1: 3). Methyl 2-[[4- [3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2-fluoro- 5-methyl-phenyl]methyl]-3- [[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (120 mg, 0.21 mmol, 69% yield) was obtained as a yellow solid. LCMS (ESI) m/z: 584.2 [M+1] + Chemical Formula: C 32 H 27 F 2 N 5 O 4 , Molecular Weight: 583.60 Step 5: Preparation of (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2 - fluoro-5-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imid azole-6-carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[3-[(4-cyano-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2-fluoro-5-methyl-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl ]benzimidazole-5- carboxylate (120 mg, 0.21 mmol, 1 eq) in THF (2 mL) and H 2 O (0.5 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (86 mg, 0.62 mmol, 3 eq). The reaction mixture was stirred at 20°C for 12 h. LCMS showed desired MS was detected. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M) and the aqueous was extracted with DCM (60 mL*3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18150*25mm*5um;mobile phase: [water( NH4HCO3)-ACN];B%: 25%-55%,9min). (S)-2-(4-(3-((4-cyano-2-fluorobenzyl)oxy)-1H- pyrazol-1-yl)-2-fluoro-5-methylbenzyl)-1-(oxetan-2-ylmethyl) -1H-benzo[d]imidazole-6- carboxylic acid, ammonium salt (39.47 mg, 0.065 mmol, 32% yield, 96.62% purity) was obtained as a white solid. LCMS: MS (ESI) m/z: 570.2 [M+1] + 1 H NMR: (400MHz, DMSO-d 6 ) δ:8.22 (s, 1H), 8.01 - 7.88 (m, 2H), 7.83 - 7.71 (m, 3H), 7.56 (d, J = 8.4 Hz, 1H), 7.41 - 7.19 (m, 2H), 6.07 (d, J = 2.6 Hz, 1H), 5.36 (s, 2H), 5.14 - 5.00 (m, 1H), 4.78 - 4.67 (m, 1H), 4.60 (br d, J = 2.2 Hz, 1H), 4.53 - 4.42 (m, 2H), 4.41 - 4.31 (m, 2H), 2.74 - 2.65 (m, 1H), 2.41 - 2.36 (m, 1H), 2.18 (s, 3H) Chemical Formula: C 31 H 28 F 2 N 6 O 4 , Molecular Weight: 586.60 Total H count from HNMR data: 24. Example 57 (S)-2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)- 2-fluoro-5-methylbenzyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, ammonium salt Step 1: Preparation of methyl 2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2- fluoro-5-methylphenyl)acetate To a stirred solution of methyl 2-[2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]acetate (100 mg, 0.32 mmol, 1 eq) and 3-[(4-chloro-2-fluoro- phenyl)methoxy]-1H-pyrazole (103 mg, 0.45 mmol, 1.4 eq) in DCE (50 mL) was added Cu(OAc)2 (59 mg, 0.32 mmol, 1 eq), Na2CO3 (69 mg, 0.65 mmol, 2 eq) and 2-(2- pyridyl)pyridine (51 mg, 0.32 mmol, 1 eq). The reaction mixture was stirred at 80°C under O 2 (15 Psi) for 16 h. LCMS showed desired MS was detected. The mixture was filtered and the filtrate was concentrated under vacuum. The crude product (750 mg of 5 batches in parallel) was purified by silica gel chromatography (PE: EtOAc = 100: 1 - 3: 1) to give methyl 2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2-f luoro-5-methyl- phenyl]acetate (160 mg, 0.39 mmol, 30% yield) as a colorless oil. LCMS: MS (ESI) m/z: 407.1 [M+1] + Chemical Formula: C 20 H 17 ClF 2 N 2 O 3 , Molecular Weight: 406.81 Step 2: Preparation of 2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2-fl uoro-5- methylphenyl)acetic acid To a stirred solution of methyl 2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2-fluoro-5-methyl-phenyl]acetate (160 mg, 0.39 mmol, 1 eq) in THF (2 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (50 mg, 1.18 mmol, 3 eq). The reaction mixture was stirred at 40°C for 1 h. LCMS showed desired MS was detected. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M) and the aqueous was extracted with DCM (70 mL*3). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum to give 2-[4-[3-[(4-chloro-2-fluoro- phenyl)methoxy]pyrazol-1-yl]-2-fluoro-5-methyl-phenyl]acetic acid (150 mg, 0.38 mmol, 97% yield) as a light yellow solid. LCMS: MS (ESI) m/z: 393.0 [M+1] + Chemical Formula: C19H15ClF2N2O3, Molecular Weight: 392.78 Step 3: Preparation of (S)-methyl 4-(2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)-2-fluoro-5-methylphenyl)acetamido)-3-((oxetan-2-ylmethyl )amino)benzoate To a stirred solution of 2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2-f luoro- 5-methyl-phenyl]acetic acid (150 mg, 0.38 mmol, 1 eq) and methyl 4-amino-3-[[(2S)- oxetan-2-yl]methylamino]benzoate (99.25 mg, 0.42 mmol, 1.1 eq) in DMF (5 mL) was added DIEA (247 mg, 1.91 mmol, 0.33 mL, 5 eq). Then T 3 P (972 mg, 1.53 mmol, 0.91 mL, 50% purity, 4 eq) was added at 0°C. The reaction mixture was stirred at 0°C for 1 h. LCMS showed desired MS was detected. Water (200 mL) was added to the mixture and the aqueous was extracted with EA (100 mL*2). The combined organic layer was washed with brine (150 mL*2), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography(PE: EtOAc = 3: 1 - 1: 3) to give methyl 4-[[2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl] -2-fluoro-5- methyl-phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino ]benzoate (180 mg, 0.29 mmol, 77% yield) as a yellow solid. LCMS: MS (ESI) m/z: 610.9 [M+1] + Chemical Formula: C 31 H 29 ClF 2 N 4 O 5 , Molecular Weight: 611.04 Step 4: Preparation of (S)-methyl 2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1-yl)- 2-fluoro-5-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]im idazole-6-carboxylate Methyl4-[[2-[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol -1-yl]-2-fluoro-5-methyl- phenyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoa te (180 mg, 0.29 mmol, 1 eq) was dissolved into the solvent of HOAc (4 mL). The reaction mixture was stirred at 70°C for 2 h. LCMS showed desired MS was detected. The mixture was concentrated under vacuum. The residue was purified by prep-TLC (DCM: EtOAc = 1: 3) to give methyl2-[[4- [3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]-2-fluoro -5-methyl-phenyl]methyl]-3- [[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (120 mg, 0.20 mmol, 69% yield) as a yellow oil. LCMS: MS (ESI) m/z: 593.0 [M+1] + Chemical Formula: C 31 H 27 ClF 2 N 4 O 4 , Molecular Weight: 593.02 Step 5: Preparation of compound (S)-2-(4-(3-((4-chloro-2-fluorobenzyl)oxy)-1H-pyrazol-1- yl)-2-fluoro-5-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d]imidazole-6-carboxylic acid, ammonium salt To a stirred solution of methyl 2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]pyrazol-1-yl]- 2-fluoro-5-methyl-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl ]benzimidazole-5- carboxylate (120 mg, 0.20 mmol, 1 eq) in THF (2 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (2 mg, 0.61 mmol, 3 eq). The reaction mixture was stirred at 40°C for 1 h. LCMS showed desired MS was detected. The pH value of the mixture was adjusted to 6 by diluted HCl aqueous (1 M). The mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxidev/v)-ACN];B%:14%-44%,9min) to give (S)-2-(4-(3-((4-chloro-2- fluorobenzyl)oxy)-1H-pyrazol-1-yl)-2-fluoro-5-methylbenzyl)- 1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid, ammonium salt (50.42 mg, 0.083 mmol, 41% yield, 98.29% purity) as a white solid. LCMS: MS (ESI) m/z: 579.1 [M+1] + 1 H NMR: (400MHz, DMSO-d6) δ: 8.07 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.75 (br d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 2.0, 10.0 Hz, 1H), 7.41 (br d, J = 8.4 Hz, 1H), 7.37 - 7.23 (m, 3H), 6.03 (d, J = 2.4 Hz, 1H), 5.25 (s, 2H), 5.05 (br dd, J = 2.4, 6.8 Hz, 1H), 4.68 - 4.58 (m, 1H), 4.55 - 4.39 (m, 3H), 4.37 - 4.29 (m, 2H), 2.70 (td, J = 2.4, 5.6 Hz, 1H), 2.41 - 2.38 (m, 1H), 2.20 (s, 3H) Chemical Formula: C 30 H 28 ClF 2 N 5 O 4 , Molecular Weight: 596.02 Total H count from HNMR data: 24. PHARMACOLOGICAL AND CLINICAL DATA Here are disclosed some representative assays illustrating the properties of the claimed compounds. The protocols and methods disclosed here may be reasonably amended by someone knowledgeable in the art without altering the relevancy of the results. Cyclic AMP (HEK293 cells) HEK293A-hGLP-1R cells (made at Monash Institute of Pharmaceutical Sciences, Monash University) were cultured in T150cm2 culture flask (Corning catalogue # 430825) in Dulbecco's Modified Eagle Medium (ThermoFisher catalogue # 11995073) supplemented with 10% foetal bovine serum (FBS; Gibco catalogue #10437-028) and 10 μg/ml puromycin (AG scientific catalogue # P-1033-SOL) in a humidified incubator at 37ºC with 5% CO 2 . On the day of the experiment cells were detached from culture flask with 2 mM EDTA in phosphate buffered saline (PBS) and centrifuged at 400xg for 3 minutes. The cell pellet was resuspended with 5ml cAMP stimulation buffer consisting of 1x HBSS (Gibco catalogue # 14065056) supplemented with 20 μM rolipram (Tocris Bioscience catalogue # 905), 5 mM HEPES, 0.1% ovalbumin (Sigma-Aldrich catalogue # A5503), at pH 7.4. Cells were counted using a haemocytometer and diluted with cAMP stimulation buffer to obtain a cell density of 20,000 cells/ml. After 30 minutes of equilibration in stimulation buffer, 5 μl of cell suspension were added to a 384-well Optiplate (PerkinElmer catalogue # 6007290) containing varying concentrations of each compound. In detail, decreasing concentrations of each compound were prepared by half-logarithmic serial dilution in the cAMP stimulation buffer, and 5 μl of diluted compounds pipetted into the 384-well Optiplate prior to addition of cells. The final concentration of DMSO in assay was 0.1%. After 30 minutes of compound stimulation at room temperature, the amount of cAMP in each well was detected using the LANCE Ultra cAMP kit (PerkinElmer catalogue # TRF024). 5 μl of europium-labelled cAMP tracer (diluted 1:50 in dilution buffer provided with kit) was added into each well, followed by 5μl of ULight anti-cAMP antibody (diluted 1:150 in dilution buffer provided with kit) and incubated for 60 minutes. Raw TR-FRET counts were obtained on Envision multiplate reader (PerkinElmer) with a setting of 320 nm (excitation) and 665 nm (emission). Molar concentrations of cAMP were determined by interpolating the raw TR-FRET counts against a cAMP standard curve performed in parallel. Data were expressed as a percentage of PF-06882961 maximal response (Emax; span of curve) and analysed with a three- parameter concentration-response equation in GraphPad Prism to obtain pEC 50 and E max values. PF-06882961 exhibits a pEC50 value of 8.6 and an Emax value of 96%. GLP1[7-36]NH 2 exhibits a pEC 50 value of 10.3 and an Emax value of 105%. Cyclic AMP (CHO cells) cAMP Hunter eXpress GLPR1 CHO-K1 Gs cells (DiscoverX catalog # 95-0062E2) were cultured in T225cm2 culture flask (Corning catalog # 431082) in Ham's F12 Nutrient Mixture with GlutaMAX (ThermoFisher catalog # 31765035) supplemented with 10% foetal bovine serum (FBS; Pan Biotech catalog # P30-193306) and 0.8 mg/ml geneticin (ThermoFisher catalog # 10131035) in a humidified incubator at 37ºC with 5% CO 2 . On the day of the experiment cells were detached from culture flask with Versen (ThermoFisher catalog # 15040-066) and centrifuged at 150xg for 5 minutes. The cell pellet was resuspended with 5ml cAMP stimulation buffer consisting of 1x HBSS (ThermoFisher catalog # 14025092) supplemented with 20 μM rolipram (Sigma-Aldrich catalogue # R6520), 5 mM HEPES, 0.1% ovalbumin (Sigma-Aldrich catalogue # A5503), at pH 7.4. Cells were counted using an automated cell counter (Vi-CELL, Beckman Coulter) and diluted with cAMP stimulation buffer to obtain a cell density of 1.2 x10E6 cells/ml. After 30 minutes of equilibration in stimulation buffer, 5 μl of cell suspension were added to a 384-well ProxiPlate (PerkinElmer catalog # 6008280) containing varying concentrations of each compound. In detail, decreasing concentrations of each compound were Echo-dispensed (Echo 525, Labcyte) in a half-logarithmic serial dilution mode into the assay plates and 5 μl of cells were then added onto the compounds. The final concentration of DMSO in assay was 0.3%. After 30 minutes of compound stimulation at room temperature, the amount of cAMP in each well was detected using the LANCE Ultra cAMP kit (PerkinElmer catalogue # TRF0262). 5 μl of europium-labelled cAMP tracer (diluted 1/100 in dilution buffer provided with kit) was added into each well, followed by 5μl of ULight anti-cAMP antibody (diluted 1/300 in dilution buffer provided with kit) and incubated for 60 minutes. Raw TR-FRET counts were obtained on PHERAstar FSX multiplate reader (BMG Labtech) with a setting of 337 nm (excitation) and 620 & 665 nm (emission). Molar concentrations of cAMP were determined by interpolating the raw TR-FRET counts against a cAMP standard curve performed in parallel. Data were expressed as a percentage of PF-06882961 maximal response (Emax; span of curve) and analyzed using the Smart Fit strategy of Genedata Screener (v16.0.7) to obtain pEC 50 and E max values. PF-06882961 exhibits a pEC50 value of 12.43. Calcium mobilization HEK293A-GLP-1R cells were cultured in T300cm2 culture flask (Sigma-Aldrich catalogue # TPP90301) in Dulbecco's Modified Eagle Medium (ThermoFisher catalogue # 11995073) supplemented with 10% foetal bovine serum (Gibco catalogue #) and 10 μg/ml puromycin (AG scientific P-1033-SOL) in a humidified incubator at 37ºC with 5% CO 2 . Assays were performed in isotonic buffer (146 mM NaCl, 5 mM KCl, 1 mM MgSO4, 1.5 mM NaHCO 3 , 10 mM D-glucose, 10 mM HEPES, 2.5 mM probenecid and 0.5 % BSA, pH 7.4). Assay buffer stock was prepared without CaCl 2 , probenecid, or ovalbumin, sterile filtered and stored at 4 °C until required. For assay, 100 mL of buffer was prepared by adding 0.625 mL of 400 mM probenecid (dissolved in 1 M NaOH) to 90 mL stock buffer, 1.3mL of 100 mM CaCl 2 and pH adjusted to 7.4, before being made to the final volume of 0.1% ovalbumin was added and buffer used within 24 h. Cells were recovered from flasks and seeded into 384- black walled plates in an assay buffer containing 1 μM Fluo-4-AM (ThermoFisher) at a density of 8,000 cells per well. After 1 h incubation at 37ºC, serially diluted compounds (prepared at 5x concentration in assay buffer) were added using the Hamamatsu FDSS. Peak change in fluorescence signal (Max-Min) was detected and data normalised to PF-06882961 maximal response (Emax; span of curve) and analysed with a three- or four-parameter concentration-response equation in GraphPad Prism to obtain pEC 50 and E max values. PF-06882961 exhibits a pEC50 value of 7.6 and an Emax value of 113%. GLP1[7-36]NH 2 exhibits a pEC 50 value of 7.5 and an Emax value of 238%.
Beta-arrestin-2 recruitment HEK293-A cells were grown in were cultured in Dulbecco's Modified Eagle Medium (DMEM; ThermoFisher catalogue # 11995073) supplemented with 10% FBS (Gibco catalogue #10437-028). Cells were detached with 2 mM EDTA in phosphate buffered saline (PBS) and centrifuged at 400xg for 3 minutes. Cell pellet was resuspended at 150,000 cells/ml in phenol-red free DMEM supplemented with 5% foetal bovine serum, and transfected with 1 μg of the Renilla luciferase (Rluc8)-tagged GLP-1R plus 4 μg of EYFP- tagged beta-arrestin-2, with 30 μg polyethylenimine (PEI) and then seeded in a poly-D- Lysine-coated, 96-well white CulturPlates at 15,000 cells/well in 100 μl of DMEM supplemented media. After 48 hours media was discarded and replaced with 80 μl/well of serum-free, phenol-red free DMEM with 0.1% ovalbumin. After 1 hour, 10 μl/well of compound dilutions prepared in phenol red-free DMEM with 0.1% ovalbumin were added to the plate and incubated for 25 minutes followed by 10 μl/well of coelenterazine h (nanolight, catalog # 301) at a final concentration of 5 μM. After 5 minutes, luminescence and fluorescence intensity of each well was measured on a PHERAStar microplate reader using detection filters 480 nm and 530 nm. End-point BRET1 signal was obtained and the BRET ratio was calculated by dividing the raw counts from the 530 nm filter by that of the 480 nm readings and then signal was normalized to that of the vehicle control. Data were expressed as a percentage of PF-06882961 maximal response (Emax; span of curve) and analysed with a three-parameter concentration-response equation in GraphPad Prism to obtain pEC50 and Emax values. PF-06882961 exhibits a pEC 50 value of 6.9 and an Emax value of 102%. GLP1[7-36]NH 2 exhibits a pEC50 value of 8.0 and an Emax value of 182%. Receptor internalization assay (FYVE) HEK293-A cells were grown in were cultured in Dulbecco's Modified Eagle Medium (DMEM; ThermoFisher catalogue # 11995073) supplemented with 10% FBS (Gibco catalogue #10437-028). Cells were detached with 2 mM EDTA in phosphate buffered saline (PBS) and centrifuged at 400xg for 3 minutes. Cell pellet was resuspended at 150,000 cells/ml in phenol-red free DMEM supplemented with 5% foetal bovine serum, and transfected with 1 μg of the Renilla luciferase (Rluc8)-tagged GLP-1R plus 4 μg of Venus- tagged FYVE with 30μg polyethylenimine (PEI) and then seeded in a poly-D-Lysine-coated, 96-well white isoplate at 15,000 cells/well in 100 μl of DMEM supplemented media. After 48 hours media was discarded and replaced with 80 μl/well of serum-free, phenol-red free DMEM with 0.1% ovalbumin. After 1 hour, 10 μl/well of compound dilutions prepared in phenol red-free DMEM with 0.1% ovalbumin were added to the plate and incubated for 30 minutes followed by 10 μl/well of Methoxy e -CTZ (Me-O-e-CTZ/Prolume Purple; NanoLight Technology, catalogue #369) at a final concentration of 5 μM. After 15 minutes, luminescence and fluorescence intensity of each well was measured on a PHERAStar microplate reader using detection filters 395 nm and 510 nm. End-point BRET2 signal was obtained and BRET ratio was calculated by dividing the raw counts from the 395 nm filter by that of the 510 nm readings and then signal was normalized to the vehicle control. Data were expressed as a percentage of PF-06882961 maximal response (Emax; span of curve) and analysed with a three-parameter concentration-response equation in GraphPad Prism to obtain pEC 50 and E max values. PF-06882961 exhibits a pEC50 value of 6.4 and an Emax value of 97%. GLP1[7-36]NH 2 exhibits a pEC 50 value of 8.4 and an Emax value of 105%.
PDE10A inhibition The test compound, reference compound or water (control) are added to a buffer containing 40 mM Tris/HCl (pH 7.4) and 8 mM MgCl 2 , 180 nM cAMP and 0.1 μCi [3H]cAMP. Thereafter, the reaction is initiated by addition of the enzyme (about 0.8U) and the mixture is incubated for 20 min at 22°C. For basal control measurements, the enzyme is omitted from the reaction mixture. Following incubation SPA beads are added. After 30 min at 22°C under shaking, the amount of [3H]5’AMP is quantified with a scintillation counter (MicroBeta, Perkin Elmer). The results are expressed as a percent inhibition of the control enzyme activity. The standard inhibitory reference compound is papaverine, which is tested in each experiment at several concentrations to obtain an inhibition curve from which its IC50 value is calculated. Q-Patch hERG CHO hERG DUO are seeded in T175 cm3 cell culture flasks (1.2 M and 0.8 M/flask respectively for 2 or 3 days of cell culture) in 25ml of hERG cell culture media in the incubator at 37°C with 5%CO 2 . Cells are used from 2 to 3 days after seeding. Cells are harvested with Accumax and resuspended with CHO-SFM II media at a cell density of 3.5M/ml. Cells are then kept in suspension in the Qpatch system in a QStirrer. Qpatch automatically picks up the amount of cells needed for the experiments, centrifuges the cells, resuspend them in External buffer (in mM, NaCl 145, KCl 4, MgCl 2 1, CaCl 2 2, Hepes 10) and apply cell suspension into the wells of the Qpatch recording plates (Qplates). The wells are filled with both external and internal buffers (in mM, KCl 120, MgCl 2 1.75, CaCl 2 5.4, EGTA 10, Hepes 10) in specific fluidic compartments beforehand. Once a gigaseal is obtained by applying negative pressure, the Qpatch goes in whole cell configuration by applying a brief suction. Then the hERG voltage protocol is applied which consists in a 5 sec depolarization step to +20mV from a holding potential of -80mV and followed by a repolarization to -50mV to assess the hERG tail current. The same voltage protocol is applied every 15 sec under application of the vehicle (external buffer with 0.3% DMSO), then with a cumulative application of a compound at three increasing concentrations and then the recording ends with application of a reference compound (Dofetilide 1µM) to get a full block of the hERG channel measured at the tail current. Inhibition percentage is then calculated from the current level obtained at each step and normalized to the vehicle and the reference compound application. Compounds of Examples 1-11, 13, 14, 16, 18, 19, 23, 31, 41, 47-52, 56 and 57 were tested and a percentage of inhibition of less than 20% is reported for all these compounds at 1 µM, 3µM and 10µM. INS-1 GSIS Rat INS-1832/8 insulinoma cells were stably transfected with the human GLP-1R receptor, and insulin secretion biosensor (Insulin-GLuc; Kalwat et al.2016, ACS Sens). Insulinoma cells were grown in RPMI 1640 media without glucose (Gibco catalogue #11879) supplemented with 10% FBS, 11 mM glucose, 10 mM HEPES, 1 mM sodium pyruvate and 50 μM 2-mercaptoethanol. Cells were detached using PBS 2 mM EDTA, counted, resuspended at 350,000 cells/ml, seeded in a poly-D-lysine-coated, 96-well plates at 30,000 cells/well in 100 μl of RPMI supplemented media. Cells were then starved in 2.8mM glucose for 4 hours prior to the addition of test agents (1-10 uM) in EBSS buffer containing 0.1% ovalbumin and 16mM glucose. After 2 hours, 45μL cell supernatant was transferred to a 384-well OptiPlate, and 5μL of coelenterazine h (nanolight, catalog # 301) was added at a final concentration of 5μM for 20min. Luminescence signal was detected in the Envision plate reader. Data were expressed as a percentage of PF-06882961 maximal response (Emax; span of curve) and analysed with a three-parameter concentration-response equation in GraphPad Prism to obtain pEC 50 and E max values. PF-06882961 exhibits a pEC50 value of 8.3 and an Emax value of 98%. GLP1[7-36]NH 2 exhibits a pEC50 value of 9.5 and an Emax value of 141%.
In Vitro ADME characterization: Intestinal permeability using Caco-2 model: The Caco-2 cell line is cultured in adapted media and used between 21 and 30 days post seeding. Compound was incubated in the apical chamber at 10 μM, 3 μM or 1μM depending on the solubility, in HBSS buffer (pH 6.8 apical and pH 7.4 basolateral). BSA 0.1% can be added in both HBSS buffers for any compounds with poor recovery (<70%) in a first experiment. Samples (duplicate) were collected at T0 and T120 min in the apical compartment and at T120 in the basolateral ones and analyzed by HPLC-LC/MS/MS across standard cuves for both compartments. The apparent permeabilities in the apical to the basolateral (A-B) and in the basolateral to the apical (B-A) direction across Caco-2 cells were calculated as follows Papp (cm/s) = K.Vr / A.60, where Vr is the volume of the receiver chamber (ml), A is the surface area of the membrane (cm2), K is the slope of the cumulated absorbed fraction as a function of time (min-1). The efflux ratio (ER) is calculated from the ratio of A-B and B-A permeabilities. Metabolic stability on microsomes (Mouse/Rat/Monkey/Human): Pooled liver microsomes from Mouse (CD-1), Rat (Sprague-Dawley), Monkey (Cynomolgus) and Human liver microsomes (mixed gender) are used with a final microsomal protein concentration of 0.3 mg/ml. Compound (0.1µM) was tested in duplicate. After pre-incubated with pooled liver microsomes (10 min, 37 ºC), the reaction is initiated by adding an NADPH-generating system and incubated in a 37 ºC shaking water bath. Samples were collected at different time points (0, 5, 15, 30, and 45 min) and the reaction was stopped by a mixture of 20 nM antipyrine, 0.1% formic acid in acetonitrile/methanol/water (35/35/30, v/v/v). Samples were analyzed LC-MS/MS. The hepatic blood clearance was extrapolated using following equation: where LW is the liver weight (g), sc is the scaling factor (g protein/g liver), Qh is the hepatic blood flow (ml/min) and fu is the blood unbound fraction (1 by default) and the intrinsic clearance (Clint): Plasma protein binding (Mouse/Rat/Monkey/Human): Each pool of mouse, human, monkey or rat plasma was spiked with the compound to obtain a final concentration of 5 μM. The experiment was performed using equilibrium dialysis with two compartments separated by a semi-permeable membrane. Buffer (Ph 7.4) was added to one side of the membrane and the plasma solution containing the compound to the other side. After equilibration, samples were taken from both sides of membrane, The test compound incubations were performed (in triplicate) using 300 μL of each plasma spiked (donor chamber) and 500 μL of phosphate buffer pH 7.4 (receiver chamber). All replicates were incubated for 3 hours at 37°C using Rapid Equilibrium Dialysis (RED device -Pierce) under orbital stirring. All plasma and buffer samples (40 μL) were analyzed with HPLC-LC-MS/MS method. The extent of plasma protein binding in each sample was calculated as follows: fu (%) = Cu/Cpl x 100 Where, fu Unbound fraction expressed as a percentage, Cpl Concentration of the compound in the plasma at the end of dialysis and Cu Concentration of the unbound compound in the buffer. The unbound fraction (fu%) was determined as the mean of the unbound fraction calculated from the triplicate. LogD pH7.4 measurement (Shake Flask): Test compound (0.5 mg) is dissolved in octanol pre-saturated with 0.1 M phosphate buffer (pH 7.4) and sonicated for 30 min. 0.1 M phosphate buffer (pH 7.4) pre-saturated with octanol is added to the octanol solution and shaken at 1000 rpm for 30 min at 37 °C. The mixed samples are then centrifuged at 1000 rpm for 5 min at 25 °C. An aliquot of the octanol fraction is removed from each mixture and diluted into DMSO. The remainder of the octanol fraction is removed, and an aliquot of the aqueous fraction is transferred into a fresh tube. The aqueous aliquot is centrifuged again at 1000 rpm for 5 min at 25 °C and an aliquot of the resulting aqueous fraction is diluted into DMSO. The resulting octanol and aqueous fraction solutions are analyzed by LC-MS/MS using Cyprotex generic conditions. The relative amount of compound in the aqueous fraction solution is quantified against a 5 point standard curve, which is produced by serially diluting the octanol fraction solution. LogD is calculated using the following equation: LogD=Log(Coct / Caq) Where: Coct = Concentration in octanol sample (corrected for dilution) Caq = Concentration in aqueous sample (corrected for dilution) In vivo characterization: standard methods for assessment of efficacy Animal Pharmacokinetics Studies Male Wistar rat (~0.25 Kg), obtained from Janvier LABS, Paris, France), male C57Bl6 mouse (~ 0.02 Kg) obtained from Charles River Laboratories Ecully, France and male and female Cynomolgus monkeys (~5 kg) obtained from Noveprim: (Mauritius) were used for these studies. Animals were fasted overnight and through the duration of the study (1.0 or 2.0 h), whereas access to water was provided ad libitum. All compounds were administered intravenously (IV) as a solution (1 mg/ml) in [polyethylene glycol 300/EtOH/NaCl 9%, 40/10/50, v/v/v) for mouse and rat and intravenously (IV) or subcutaneously (SC) as a solution in [polyethylene glycol 300/Polysorbate 80/NaCl 9%, 40/2/58, v/v/v) for monkey, and also administered by oral route (PO) gavage to rat and mouse (1 to 3 mg/Kg ) as a homogeneous suspension in [HEC1%/Polysorbate 801% in water]. Serial blood samples were collected before dosing and at 0.083, 0.25, 0.75, 1.5, 4, and 24 hours after dosing for intravenous administration, or at 0.5, 1, 2, 4, 6, and 24 hours after oral administration, or at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 hours after subcutaneous administration. Blood samples from the pharmacokinetic studies were centrifuged to generate plasma. All plasma samples were kept frozen until analysis. The samples were then analyzed by liquid chromatography tandem mass spectrometry (LC- MS/MS) and concentrations of compounds in plasma were determined by interpolation from a standard curve. Determination of Pharmacokinetic Parameters Pharmacokinetic parameters in animals were determined using noncompartmental analysis (Watson v.7.4, Thermo Scientific, Waltham, MA). Maximum plasma concentrations (Cmax) of compounds after IV, PO and SC dosing in rats, mice and monkeys were determined directly from the experimental data, with Tmax defined as the time of first occurrence of Cmax. The area under the plasma concentration-time curve from t = 0 to 24 h (AUC0-24) and t = 0 to infinity (AUC0-∞) was estimated using the linear trapezoidal rule. Systemic plasma clearance (CLp) were calculated as the intravenous dose divided by AUC0–∞IV. The terminal rate constant (kel) was calculated by a linear regression of the log-linear concentration-time curve, and the terminal elimination t1/2 was calculated as 0.693 divided by kel. Apparent steady state distribution volume (Vdss) in animals were determined as the IV dose divided by the product of AUC0–∞ and kel. The absolute bioavailability (F) of the PO or SC doses in animals was calculated by using the following equation: F = AUC0– ∞PO/AUC0–∞IV × dose IV/dose PO. Glucose tolerance test (GTT) after single or chronic administration with tested compound Male C57BL6 mice with S33W GLP-1R mutation (n>6 per group) were fasted overnight and then subjected to either oral or IP glucose tolerance test (GTT). Briefly, baseline glucose was measured in all animals using a drop of blood from a tail snip wound and Accu-check active glucometers and test strips (Roche Diagnostics). Then, mice received a dose of 2g/kg of D-glucose (Merck) by oral or IP route and blood glucose was then monitored over time up to 120 minutes after glucose administration using glucometers. Data were used to calculate the area under the curve. Plasma insulin levels were quantified using standard ELISA. High-fat diet mouse model Male humanized GLP-1R C57BL6 S33W mice (n=8-12 per group) were placed under a 60% fat diet (Research Diet # D12492) for at least 11 weeks before initiation of the compound treatment. Body weight was recorded on a weekly basis. ECHO MRI was performed at start and end of protocol to measure fat. Then, fat-fed mice mice received per oral treatment once daily vehicle (1% hydroxyethylcellulose) or tested compound(s) (X mg/kg) for 4 weeks. At the end of the treatment protocol, all the mice were subjected to GTT and mice were sacrificed the following day and blood was recovered for serum preparation. Tissue samples (liver, visceral adipose tissue) were quickly collected, frozen in liquid nitrogen and used for RNA or total protein extraction. Serum biochemistry was analyzed using standard assay kits (Sigma). Liver steatosis was determined by quantifying hepatic triglyceride content. MCD mouse model of NASH The efficacy of compounds in NASH was addressed using the murine model of NASH induced by methionine and choline deficient (MCD) diet. Treatment with compound and NASH induction by the diet started concomitantly. Male humanized GLP-1R C57BL6 S33W mice were placed under MCD diet and treatment with tested compounds (X mg/kg) started immediately for 14 days. Mice were weighed and orally administered with compounds (10 mL/kg in HEC 1%). After 14 days of treatment and diet, 4hr-fasted mice were euthanized. Blood samples were obtained for hepatic enzyme determination (ALT and AST). Liver were taken for NASH histological scoring and gene expression studies by RT-qPCR. Hepatic triglyceride content was quantified. NASH was determined by the measurement of steatosis, inflammation and by the quantification of NAS. Nutritional mouse model of NASH [AMLN diet] Male humanized GLP-1R C57BL6 S33W mice (n=67) were fed the AMLN diet [40% fat (18% trans-fat), 40% carbohydrate (20% fructose), 2% cholesterol] for 33 weeks before treatment start to induce diet-induced obesity (DIO) associated non-alcoholic steatohepatitis (NASH). Prior to treatment, all animals underwent liver biopsy for histological confirmation of liver pathology (steatosis score ≥2, fibrosis stage ≥1) and were randomized to treatment according to quantitative liver fibrosis staining (% fractional area of collagen 1a1). AMLN DIO-NASH mice (n=13-14 per group) received per oral treatment once daily with vehicle (1% hydroxyethylcellulose), tested compound(s) (X mg/kg) or Elafibranor (30 mg/kg) as positive control for 8 weeks. Within-subject comparisons (pre vs. post treatment) were performed for liver biopsy histopathological scores. Terminal quantitative endpoints included plasma/liver biochemistry and liver histology. Pharmaceutical composition - Example Formula for the preparation of 5000 tablets each containing 50 mg of active ingredient: Compound of one of Examples 1 to 26: 50 g Hydroxypropylcellulose: 10 g Wheat starch: 50 g Lactose: 500 g Magnesium stearate: 15 g Talc: 15 g
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