ZHANG BO (CN)
ZHENG XIUFANG (CN)
HOFFMANN LA ROCHE (US)
WO2013036749A1 | 2013-03-14 | |||
WO2015172099A1 | 2015-11-12 | |||
WO2013049407A2 | 2013-04-04 | |||
WO2013130703A2 | 2013-09-06 | |||
WO2018011163A1 | 2018-01-18 |
CN110483496A | 2019-11-22 | |||
US20100267717A1 | 2010-10-21 | |||
CN108904497A | 2018-11-30 | |||
RU2016148641A | 2018-06-13 |
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CAS, no. 63231-67-4
CAS , no. 2283137-86-8
CLAIMS 1. A compound of formula (I), wherein R1 is hydrogen, halogen, C2-6alkynyl, cyano, morpholinyl, or C1-6alkoxyC1-6alkoxy; L is a C5-12cycloalkyl, wherein L is a monocyclic ring or a bicyclic ring, and wherein the bicyclic ring is a bridged, spiro or fused ring; A is a 5 or 6 membered heteroaryl containing one to three heteroatoms independently selected from N, O, and S; R2 is C1-6alkylsulfonylC1-6alkyl, C1-6alkylsulfonylC3-7cycloalkyl, halo(C1-6alkylsulfonyl)C1-6alkyl, carbamoyl(C1-6alkylsulfonyl)C1-6alkyl, C1-6alkylsulfonyl, C1-6alkoxysulfonyl, (C1-6alkoxyC1- 6alkyl)sulfonyl, C3-7cycloalkylsulfonyl, C1-6alkylsulfinylC1-6alkyl, C1-6alkylsulfinyl, C3- 7cycloalkylC1-6alkylsulfinyl, C3-7cycloalkylsulfinyl, C1-6alkylsulfonimidoyl, C3-7cycloalkylC1- 6alkylsulfonimidoyl, C3-7cycloalkylsulfonimidoyl, C1-6alkylsulfanyl, C1-6alkylsulfanylC1- 6alkyl, haloC1-6alkyl, haloC1-6alkylsulfonylC1-6alkyl, C3-7cycloalkylC1-6alkylsulfonyl, or (C1- 6alkylcarbonyl)sulfamoyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R1 is halogen or C2-6alkynyl. 3. The compound according to claim 2, wherein R1 is fluoro, chloro, bromo, or ethynyl. 4. The compound according to claim 1, wherein L is ; each of x, y, and z is independently an integer of 1, 2, or 3. 5. The compound according to claim 4, wherein L is . 6. The compound according to claim 1, wherein A is furanyl, oxadiazolyl, thiadiazolyl, oxazolyl, dihydrothiazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, or pyridinyl. 7. The compound according to claim 6, wherein A is furanyl, thiadiazolyl, oxazolyl, or pyrazolyl. 8. The compound according to claim 7, wherein A is furanyl, 1,2,4-thiadiazolyl, oxazolyl, or pyrazolyl. 9. The compound according to claim 1, wherein R2 is C1-6alkylsulfonylC3-7cycloalkyl, C1-6alkylsulfonylC1-6alkyl, haloC1-6alkylsulfonylC1-6alkyl, or C1-6alkylsulfinylC1-6alkyl. 10. The compound according to claim 9, wherein R2 is methylsulfonylcyclopropyl, 1-(methylsulfonyl)propyl, 2-(methylsulfonyl)propan-2-yl, 1- (methylsulfonyl)ethyl, bromo(methylsulfonyl)methyl, or 2-(methylsulfinyl)propan-2-yl. 11. The compound according to claim 1, wherein R1 is halogen or C2-6alkynyl; L is ; A is furanyl, thiadiazolyl, oxazolyl, or pyrazolyl; and R2 is C1-6alkylsulfonylC3-7cycloalkyl, C1-6alkylsulfonylC1-6alkyl, haloC1-6alkylsulfonylC1-6alkyl, or C1-6alkylsulfinylC1-6alkyl. 12. The compound according to claim 11, wherein R1 is fluoro, chloro, bromo, or ethynyl; L is ; A is furanyl, 1,2,4-thiadiazolyl, oxazolyl, or pyrazolyl; and R2 is methylsulfonylcyclopropyl, 1-(methylsulfonyl)propyl, 2-(methylsulfonyl)propan-2-yl, 1- (methylsulfonyl)ethyl, bromo(methylsulfonyl)methyl, or 2-(methylsulfinyl)propan-2-yl. 13. A compound selected from: N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5- (methylsulfonylmethyl)furan-2-carboxamide; N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide; N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide; N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1- methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5-carboxamide; N-[3-(5-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5- (methylsulfonylmethyl)furan-2-carboxamide; N-(3-(5-bromobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(1- (methylsulfonyl)cyclopropyl)furan-2-carboxamide; N-[3-(5-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1- methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5-carboxamide; N-[3-(6-cyano-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide; N-[3-(5-cyano-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide; N-[3-(6-ethynyl-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide; N-[3-(6-fluoro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-cyclopropylsulfonyl- furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5- (methylsulfonylmethyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylpropyl)furan-2-carboxamide; N-(3-(6-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(1- (methylsulfonyl)cyclopropyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1-methyl-1- methylsulfonyl-ethyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylethyl)furan-2-carboxamide; 5-[bromo(methylsulfonyl)methyl]-N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide; 5-(2-amino-1-methylsulfonyl-2-oxo-ethyl)-N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2- (methylsulfonylmethyl)oxazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-(1- methylsulfonylethyl)oxazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-(1-methyl-1- methylsulfonyl-ethyl)oxazole-5-carboxamide; N-[6-(5-chloro-1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-2- (methylsulfamoylamino)pyridine-4-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-(1- methylsulfonylcyclopropyl)thiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-(1-methyl-1- methylsulfonyl-ethyl)thiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3- (methylsulfonylmethyl)isothiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1-methyl-1- methylsulfonyl-ethyl)isothiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1-methyl-1- methylsulfonyl-ethyl)isothiazole-3-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)isothiazole-3-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(methylsulfonylmethyl)- 1,2,4-thiadiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1-methylsulfonylethyl)- 1,2,4-thiadiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1-methyl-1- methylsulfonyl-ethyl)-1,2,4-thiadiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-1- (methylsulfonylmethyl)pyrazole-3-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-1-(1- methylsulfonylethyl)pyrazole-3-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(methylsulfonylmethyl)- 1,2,4-oxadiazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2- (methylsulfonylmethyl)triazole-4-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2- (trifluoromethyl)pyridine-4-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(methylthio)furan-2- carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(methylsulfonyl)furan-2- carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5- (cyclopropylsulfonyl)furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5- ((methylsulfonyl)methyl)furan-2-carboxamide; 5-(bromo(methylsulfonyl)methyl)-N-(3-(5-chlorobenzo[d]thiazol-2- yl)bicyclo[1.1.1]pentan-1-yl)furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(1- (methylsulfonyl)propyl)furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(2- (methylsulfonyl)propan-2-yl)furan-2-carboxamide; N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylethyl)furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(1- (methylsulfonyl)cyclopropyl)furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-((2- methoxyethyl)sulfonyl)furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5- ((methylthio)methyl)furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(2-(methylsulfinyl)propan- 2-yl)furan-2-carboxamide; N-[6-(5-chloro-1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-1,1-dioxo-thietane-3- carboxamide; N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-isopropylsulfonyl- pyridine-4-carboxamide; 2-tert-butylsulfonyl-N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]pyridine-4-carboxamide; N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-(1- methylsulfonylethyl)pyridine-4-carboxamide; N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-(1-methyl-1- methylsulfonyl-ethyl)pyridine-4-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-[(1R)-1- methylsulfonylethyl]furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-[(1S)-1- methylsulfonylethyl]furan-2-carboxamide; N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-[(1R)-1- methylsulfonylethyl]furan-2-carboxamide; N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-[(1S)-1- methylsulfonylethyl]furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1- methylsulfonylethyl)pyrazole-1-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3- (methylsulfonylmethyl)pyrazole-1-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1-methyl-1- methylsulfonyl-ethyl)pyrazole-1-carboxamide; N-[3-(5-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1-methyl-1- methylsulfonyl-ethyl)pyrazole-1-carboxamide; N-[3-(5-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1- methylsulfonylcyclopropyl)pyrazole-1-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1- methylsulfonylcyclopropyl)pyrazole-1-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(S- methylsulfonimidoyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5- (cyclopropylsulfonimidoyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5- (cyclopropylmethylsulfonimidoyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-2-(1- methylsulfonylcyclopropyl)oxazole-5-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)thiazole-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)oxazole-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5- (cyclopropylmethylsulfonyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5- (cyclopropylmethylsulfinyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-methylsulfinyl-furan-2- carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-cyclopropylsulfinyl- furan-2-carboxamide; N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5- (dichloro(methylsulfonyl)methyl)furan-2-carboxamide; 5-(chloro(methylsulfonyl)methyl)-N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan- 1-yl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide; N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide; N-[3-(5-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide; 5-(1-methylsulfonylcyclopropyl)-N-[3-(6-morpholino-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide; 5-(1-methylsulfonylcyclopropyl)-N-[3-(5-morpholino-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide; N-[3-[6-(2-methoxyethoxy)-1,3-benzothiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide; N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-3-(1-methylsulfonylethyl)- 1H-pyrazole-5-carboxamide; 5-(butanoylsulfamoyl)-N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide; or a pharmaceutically acceptable salt thereof. 14. A process for the preparation of a compound according to any one of claims 1 to 13 comprising at least one of the following steps: (a) reaction of compound of formula (II) with compound of formula (III) in the presence of a coupling reagent and a base, wherein LG is OH or C1-6alkoxyl, and wherein the coupling reagent is selected from HATU, T3P and AlMe3; the base is selected from TEA or DIPEA, or the base is absent; (b) treatment of compound of formula (II) with triphosgene in the presence of a base, then reaction with compound of formula (IV) (IV) wherein R3 is C1-6alkylsulfonylC1-6alkyl or C1-6alkylsulfonylC3-7cycloalkyl, and wherein the base is TEA or DIPEA; (c) oxidation of compound of formula (I-3) in the presence of an oxidate, wherein R4 is C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, or C1- 6alkylcarbonyl, and wherein the oxidate is selected from m-CPBA, or PhI(OAc)2 and (NH4)2CO3; (d) reaction of compound of formula (I-5) with morpholine in the presence of X-phos G3, and a base, wherein R5 is halogen, and wherein the base is Cs2CO3; (e) reaction of compound of formula (I-7) with compound CX4 in the presence of a base, wherein X is halogen, and wherein the base is NaOH or KOH; (f) reaction of compound of formula (I-10) with acyl chloride (VI) in the presence of a base, wherein R7 is C1-6alkyl, and wherein the base is TEA, DIPEA or K2CO3; wherein R1, R2, and A are as defined in any one of claims 1 to 12. 15. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, when manufactured according to the process of claim 14. 16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, and a pharmaceutically acceptable excipient. 17. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for use as therapeutically active substance. 18. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for use in the treatment or prophylaxis of HBV infection. 19. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for the treatment or prophylaxis of HBV infection. 20. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for the inhibition of HBsAg. 21. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for the inhibition of HBeAg. 22. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prophylaxis of HBV infection. 23. A method for the treatment or prophylaxis of HBV infection, which method comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 13. |
Step 1: Preparation of ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate To a solution of N,N-dimethylacetamide dimethyl acetal (11.0 g, 82.6 mmol) in DCM (10 mL) was added ethyl thiooxamate (10.0 g, 75.1 mmol, CAS No: 16982-21-1). After stirred at 25°C for 10 min, DCM was removed in vacuum. The residue was dissolved in methanol (10 mL) and then pyridine (12.2 mL, 150.2 mmol) and a solution of hydroxylamine-O-sulfonic acid (9.34 g, 82.6 mmol) in methanol (10 mL) were added at 0 °C slowly. The reaction mixture was warmed to room temperature and stirred for another 1 h. The resulting solution was concentrated in vacuum to remove methanol and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (40 mL × 2), brine (40 mL) and dried over Na 2 SO 4 . The organic layer was concentrated and the residue was purified by silica gel column eluted with PE/EtOAc = 4/1 to afford ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (8.18 g) as orange oil. MS obsd. (ESI + ) [(M+H) + ]: 173.1. Step 2: Preparation of ethyl 3-(bromomethyl)-1,2,4-thiadiazole-5-carboxylate To a solution of ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (10.0 g, 58.1 mmol) in CCl 4 (82 mL) were added NBS (12.0 g, 69.7 mmol) and BPO (21.1 g, 87.1 mmol) at 25°C. The reaction mixture was stirred at 80 °C for 16 h The resulting solution was concentrated to remove CCl 4 . The residue was re-dissolved in EtOAc ( mL) and washed with water (40 mL × 2) and brine (40 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silca gel column eluted with PE/EtOAc=4/1 to afford ethyl 3- (bromomethyl)-1,2,4-thiadiazole-5-carboxylate (7.26 g) as orange oil. MS obsd. (ESI + ) [(M+H) + ]: 250.9. Step 3: Preparation of ethyl 3-(methylsulfonylmethyl)-1,2,4-thiadiazole-5-carboxylate To a solution of ethyl 3-(bromomethyl)-1,2,4-thiadiazole-5-carboxylate (7.69 g, 30.6 mmol) in ethanol (120 mL) was added sodium methanesulfinate (4.69 g, 45.9 mmol) at 25 °C. The reaction mixture was stirred at the same temperature for 16 h. The resulting solution was concentrated in vacuum. The reisdue was dissolved in EtOAc (100 mL), washed with water (40 mL × 2) and brine (40 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 2/3 to afford ethyl 3-(methylsulfonylmethyl)-1,2,4-thiadiazole-5-carboxylate (6.12 g) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 251.1. Step 4: Preparation of ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5- carboxylate To a solution of ethyl 3-(methylsulfonylmethyl)-1,2,4-thiadiazole-5-carboxylate (500 mg, 2.00 mmol) in DMF (10 mL) was added sodium hydride in several portions (120 mg, 4.99 mmol, 60% in oil) under nitrogen atmosphere at 0°C. After stirred at 0°C for 30 min, 1,2- dibromoethane (563 mg, 3.00 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. The resulted solution was diluted with EtOAc (100 mL) at 0 °C and then ice-water (50 mL). The organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 7/3 to afford ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5-carboxyl ate (298 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 277.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 4.52 (q, J =7.2 Hz, 2H), 3.37 (s, 3H), 1.98-2.04 (m, 2H), 1.81-1.87 (m, 2H), 1.45 (t, J =7.2 Hz, 3H). Step 5: Preparation of [3-(1-methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5- carbonyl]oxylithium (Int-11) To a solution of ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5-carboxyl ate (298 mg, 1.1 mmol) in MeOH (10 mL) was added LiOH.H 2 O (88 mg, 1.1 mmol) and 1 drop of water. The reaction was stirred at 25 °C for 2 h. The resulting solution was concentrated in vacuum to give [3-(1-methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5-carbony l]oxylithium (279 mg) as a white solid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 255.0. Intermediate Int-12 5-cyclopropylsulfonylfuran-2-carboxylic acid The title compound was prepared according to the following scheme: , A mixture of 5-bromo-2-furoic acid (7.45 g, 39.0 mmol), cyclopropylsulfinyloxysodium (5.0 g, 39.0 mmol, CAS No: 910209-21-1), 2-pyrrolidinecarboxylic acid (1.8 g, 15.6 mmol), K 2 CO 3 (2.16 g, 15.6 mmol) and CuI (2.97 g, 15.6 mmol) in DMSO (60 mL) was stirred at 110 °C for 21 h. The reaction mixture was acidified by HCl (5M) to adjust pH= 3~4 and then extracted with EtOAc (50 mL × 6). The combined organic layers were washed with brine (50 mL × 3), dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 3/2 to afford 5-cyclopropylsulfonylfuran-2-carboxylic acid (4.92 g) as a yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 217.0. Intermediate Int-13 5-(1-methylsulfonylpropyl)furan-2-carboxylic acid Int-13 The title compound was prepared in analogy to the procedure described for the preparation of 5-(1-methylsulfonylcyclopropyl)furan-2-carboxylic acid (Int-9), by using iodoethane instead of 1,2-dibromoethane. Intermediates Int-14&Int-15 5-(1-methyl-1-methylsulfonyl-ethyl)furan-2-carboxylic acid and 5-(1- methylsulfonylethyl)furan-2-carboxylic acid The title compounds Int-14 and Int-15 were prepared in analogy to the procedure described for the preparation of 5-(1-methylsulfonylcyclopropyl)furan-2-carboxylic acid (Int-9), by using iodomethane instead of 1,2-dibromoethane. Intermediate Int-16 5-[bromo(methylsulfonyl)methyl]furan-2-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of ethyl 5-[bromo(methylsulfonyl)methyl]furan-2-carboxylate To a solution of ethyl 5-(methylsulfonylmethyl)furan-2-carboxylate (20.0 g, 86.1 mmol) and AIBN (1.41 g, 8.61 mmol) in CHCl 3 (500 was added NBS (18.4 g, 103.3 mmol). The reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the resulting solution was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 4/1 to afford ethyl 5-[bromo(methylsulfonyl)methyl]furan-2-carboxylate (8.5 g) as a light yellow solid. MS obsd. (ESI + ) [(M+Na) + ]: 333.0. Step 2: Preparation of ethyl 5-[bromo(methylsulfonyl)methyl]furan-2-carboxylic acid (Int- 16) To a solution of ethyl 5-[bromo(methylsulfonyl)methyl]furan-2-carboxylate (3000 mg, 9.64 mmol) in THF (30 mL) and water (10 mL) was added LiOH.H 2 O (462 mg, 19.3 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to remove the THF. The resulting solution was adjusted to pH = 2~4 with aqueous HCl solution (2 M) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 and concentrated to afford 5- [bromo(methylsulfonyl)methyl]furan-2-carboxylic acid (1000 mg) as a yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 305.0. Intermediate Int-17 5-(2-amino-1-methylsulfonyl-2-oxo-ethyl)furan-2-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 5-[cyano(hydroxy)methyl]furan-2-carboxylate To a solution of methyl 5-formylfuran-2-carboxylate (42 mg, 0.270 mmol) in THF (5 mL) was added ZnI2 (4.4 mg, 0.010 mmol) and then TMSCN (0.04 mL, 0.330 mmol) dropwise at 0 °C. After warming to 25 °C, the mixture was stirred for 1 h. The resulting solution was diluted with water (20 mL) and acidified with HCl (3 M) to pH = 3. The mixture was extracted with diisopropylether (10 mL × 3). The organic phase was dried over Na 2 SO 4 and concentrated in vacuum to afford methyl 5-[cyano(hydroxy)methyl]furan-2-carboxylate (45 mg) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 182.1. Step 2: Preparation of methyl 5-(2-amino-1-chloro-2-oxo-ethyl)furan-2-carboxylate To a solution of methyl 5-[cyano(hydroxy)methyl]furan-2-carboxylate (182 mg, 1.0 mmol) in DCM (8 mL) was added SOCl2 (0.08 mL, 1.1 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The resulting solution was concentrated in vacuum. The residue was purified by prep- TLC (PE/EtOAc = 4/1) to give methyl 5-(2-amino-1-chloro-2-oxo-ethyl)furan-2-carboxylate (80 mg) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 218.1. Step 3: Preparation of methyl 5-(2-amino-1-methylsulfonyl-2-oxo-ethyl)furan-2- carboxylate To a solution of methyl 5-(2-amino-1-chloro-2-oxo-ethyl)furan-2-carboxylate (50 mg, 0.23 mmol) in DMF (2 mL) were added sodium methanesulphinate (28.15 mg, 0.28 mmol) and TEA (0.04 mL, 0.28 mmol). The reaction was stirred at 25 °C for 2 h. The resulted solution was diluted with EtOAc (30 mL) and washed with water (20 mL × 2). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 1/1 to afford methyl 5-(2-amino-1-methylsulfonyl-2-oxo-ethyl)furan-2- carboxylate (60 mg) as a brown solid. MS obsd. (ESI + ) [(M+H) + ]: 262.0. Step 4: Preparation of 5-(2-amino-1-methylsulfonyl-2-oxo-ethyl)furan-2-carboxylic acid (Int-17) To a solution of methyl 5-(2-amino-1-methylsulfonyl-2-oxo-ethyl)furan-2-carboxylate (80 mg, 0.31 mmol) in THF (3 mL) and water (0.5 mL) was added LiOH.H 2 O (9 mg, 0.37 mmol). The reaction was stirred at 25 °C for 2 h. The resulted solution was diluted with water (20 mL), adjusted to pH = 5 with HCl (2 M) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na 2 SO 4 and concentrated to afford the crude product 5-(2-amino- 1-methylsulfonyl-2-oxo-ethyl)furan-2-carboxylic acid (50 mg) as colorless oil. MS obsd. (ESI + ) [(M+H) + ]:248.0. Intermediate Int-18 [2-(methylsulfonylmethyl)oxazole-5-carbonyl]oxylithium The title compound was prepared according to the following scheme: Step 1: Preparation of ethyl 2-(bromomethyl)oxazole-5-carboxylate A mixture of ethyl 2-methyloxazole-5-carboxylate (2.5 g, 16.1 mmol), NBS (4.3 g, 24.2 mmol) and AIBN (1.06 g, 6.45 mmol) in CCl 4 (50 mL) was stirred at 80 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 9/1 to afford ethyl 2- (bromomethyl)oxazole-5-carboxylate (3.77 g) as a light yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 234.0. Step 2: Preparation of ethyl 2-(methylsulfonylmethyl)oxazole-5-carboxylate A mixture of ethyl 2-(bromomethyl)oxazole-5-carboxylate (3.77 g, 16.1 mmol) and sodium methanesulfinate (2.47 g, 24.2 mmol) in DMF (15 mL) was stirred at 25 °C for 2 h. The mixture was concentrated in vacuum and the residue was purified by silica gel column eluted with PE/EtOAc = 7/3 to afford ethyl 2-(methylsulfonylmethyl)oxazole-5-carboxylate (600 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 234.1. Step 3: Preparation of [2-(methylsulfonylmethyl)oxazole-5-carbonyl]oxylithium (Int-18) A mixture of ethyl 2-(methylsulfonylmethyl)oxazole-5-carboxylate (50 mg, 0.21 mmol) and LiOH·H 2 O (18 mg, 0.43 mmol) in methanol (5 mL) and water (0.1 mL) was stirred at 25 °C for 2 h. After that, the mixture was concentrated in vacuum to afford [2- (methylsulfonylmethyl)oxazole-5-carbonyl]oxylithium (44 mg) as a light red solid. The crude was used for in next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 206.0. Intermediates Int-19&Int-20 2-(1-methylsulfonylethyl)oxazole-5-carboxylic acid and 2-(1-methyl-1-methylsulfonyl- ethyl)oxazole-5-carboxylic acid The title compounds Int-19 and Int-20 w epared in analogy to the procedure described for the preparation of 5-(1-methylsulfonylcyc p pyl)furan-2-carboxylic acid (Int-9), by using iodomethane instead of 1,2-dibromoethane and ethyl 2-(methylsulfonylmethyl)oxazole-5- carboxylate instead of ethyl 5-(methylsulfonylmethyl)furan-2-carboxylate. Intermediate Int-21 2-(1-methylsulfonylethyl)-4,5-dihydrothiazole-4-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of 2-methylsulfonylpropanenitrile To a solution of 2-chloropropanenitrile (1.0 g, 11.2 mmol, CAS No: 1617-17-0) in DMF (5 ml) was added sodium methanesulfinate (1.3 g, 12.3 mmol) was added. Then the reaction was stirred at 120 °C for 10 min under microwave. The reaction mixture was concentrated in vacuum to afford the crude product 2-methylsulfonylpropanenitrile (0.36 g) as brown oil. Step 2: Preparation of 2-(1-methylsulfonylethyl)-4,5-dihydrothiazole-4-carboxylic acid (Int- 21) To a mixture of cysteine hydrochloride (592 mg, 3.75 mmol) and 2- methylsulfonylpropanenitrile (500 mg, 3.75 mmol) in MeOH (5 ml) was added DIPEA (1.97 mg, 11.3 mmol). Then the mixture was stirred at 80 °C for 18 h. The solvent was removed and the residue was purified by prep-HPLC to afford 2-(1-methylsulfonylethyl)-4,5-dihydrothiazole-4- carboxylic acid (463 mg) as a white solid. Intermediate Int-22 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of ethyl 2-(bromomethyl)thiazole-5-carboxylate To a solution of ethyl 2-methylthiazole-5-carboxylate (1.0 g, 5.84 mmol) in CCl 4 (20 mL) were added NBS (1.04 g, 5.84 mmol) and AIBN (1.41 g, 5.84 mmol). The reaction was stirred at 80 °C for 3 h. The resulting solution was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 20/1 to afford ethyl 2-(bromomethyl)thiazole-5- carboxylate (960 mg) as orange oil. MS obsd. (ESI + ) [(M+H) + ]:250.0. Step 2: Preparation of ethyl 2-(methylsulfonylmethyl)thiazole-5-carboxylate To a solution of ethyl 2-(bromomethyl)thiazole-5-carboxylate (2.1 g, 8.4 mmol) in DMF (60 mL) were added TEA (1.4 mL, 10.1 mmol) and sodium methanesulfinate (1.03 g, 10.1 mmol). The reaction was stirred at 25 °C for 2 h. The resulting mixture was diluted with EtOAc (60 mL) and washed with water (20 mL × 2) and brine (20 mL × 2). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 1/1 to afford ethyl 2-(methylsulfonylmethyl)thiazole-5-carboxylate (1.3 g) as yellow oil. MS obsd. (ESI + ) [(M+H) + ]:250.0 Step 3: Preparation of ethyl 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylate To a solution of ethyl 2-(methylsulfonylmethyl)thiazole-5-carboxylate (200 mg, 0.80 mmol) in DMF (5 mL) were added sodium hydride (85 mg, 2.13 mmol, 60% in oil) and 1,2- dibromoethane (0.09 mL, 1.02 mmol). The reaction was stirred at 25 °C for 2 h. The resulted mixture was diluted with EtOAc (60 mL) and washed with water (20 mL × 2) and brine (20 mL × 2). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by reversed flash column (eluting with H 2 O/ACN = 95/5) to afford ethyl 2-(1- methylsulfonylcyclopropyl)thiazole-5-carboxylate (96 mg) as a white solid. MS obsd. (ESI+) [(M+H)+]: 276.0 Step 4: Preparation of 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylic acid (Int-22) To a solution of ethyl ethyl 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylate (96 mg, 0.349 mmol) in THF (5 mL) and water (1 mL) was added LiOH.H 2 O (20 mg, 0.480 mmol). The reaction was stirred at 25 °C for 2 h. The resulting solution was diluted with water (20 mL), adjusted to pH = 6 with HCl (2 M) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuum to afford 2-(1- methylsulfonylcyclopropyl)thiazole-5-carboxylic acid (80 mg) as a brown solid. MS obsd. (ESI + ) [(M+H) + ]: 248.0. Intermediate Int-23 2-(1-methyl-1-methylsulfonyl-ethyl)thiazole-5-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylic acid (Int-22), by using iodomethane instead of 1,2-dibromoethane. Intermediate Int-24 3-(methylsulfonylmethyl)isothiazole-5-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of [2-(methylsulfonylmethyl)oxazole-5-carbonyl]oxylithium (Int-18), by using methyl 3- methylisothiazole-5-carboxylate instead of ethyl 2-methyloxazole-5-carboxylate. Intermediate Int-25 3-(1-methyl-1-methylsulfonyl-ethyl)isothiazole-5-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylic acid (Int-22), by using methyl 3- methylisothiazole-5-carboxylate instead of ethyl 2-methylthiazole-5-carboxylate and iodomethane instead of ethylene dibromide. Intermediate Int-26 5-(1-methyl-1-methylsulfonyl-ethyl)isothiazole-3-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylic acid (Int-22), by using methyl 5- methylisothiazole-3-carboxylate instead of ethyl 2-methylthiazole-5-carboxylate and iodomethane instead of 1,2-dibromoethane. Intermediate Int-27 5-(1-methylsulfonylcyclopropyl)isothiazole-3-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylic acid (Int-22), by using methyl 5- methylisothiazole-3-carboxylate instead of ethyl 2-methylthiazole-5-carboxylate. Intermediate Int-28 3-(methylsulfonylmethyl)-1,2,4-thiadiazole-5-carboxylic acid The title compound was prepared according to the following scheme: To a solution of ethyl 3-(methylsulfonylmethyl)-1,2,4-thiadiazole-5-carboxylate (62 mg, 0.25 mmol, CAS No: 2283137-86-8) in THF (2 mL) and Water (1 mL) was added LiOH.H 2 O (16 mg, 0.37 mmol). The reaction mixture was stirred at 25 °C for 2 h. The resulting solution was diluted with water (30 mL), adjusted to pH = 5 with hydrochloric acid (2 M) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with DCM/MeOH=20/1 to afford 3-(methylsulfonylmethyl)-1,2,4-thiadiazole-5-carboxylic acid (51 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 223.1. Intermediates Int-29 & Int-30 3-(1-methylsulfonylethyl)-1,2,4-thiadiazole-5-carboxylic acid and 3-(1-methyl-1- methylsulfonyl-ethyl)-1,2,4-thiadiazole-5-carboxylic acid The title compounds were prepared in analogy to the procedure described for the preparation of [3-(1-methylsulfonylcyclopropyl)-1,2,4-thiadiazole-5-carbony l]oxylithium (Int- 11), by using iodomethane instead of 1,2-dibromoethane. Intermediate Int-31 [1-(methylsulfonylmethyl)pyrazole-3-carbonyl]oxylithium The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 1-(methylsulfanylmethyl)pyrazole-3-carboxylate To a solution of methyl 1H-pyrazole-5-carboxylate (1100 mg, 8.72 mmol, CAS No: 15366- 34-4) in DMF (15 mL) was added sodium hydride (251 mg, 10.5 mmol, 60% in oil) at 0 °C. After stirred at 0 °C for 30 min, chloromethyl methyl sulfide (1011 mg, 10.5 mmol, CAS No: 2373-51-5) was added. The reaction mixture was warmed to room temperature and stirred for another 2 h. The reaction was quenched with saturated aqueous NH4Cl solution. The resulted solution was diluted with EtOAc (100 mL) and washed with brine (50 mL × 3). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vaccum. The residue was purified by silica gel column eluted with PE/EtOAc = 3/2 to afford methyl 1- (methylsulfanylmethyl)pyrazole-3-carboxylate (417 mg) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 187.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.98 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 5.36 (s, 2H), 3.81 (s, 3H), 2.13 (s, 3H). Step 2: Preparation of methyl 1-(methylsulfonylmethyl)pyrazole-3-carboxylate A mixture of methyl 1-(methylsulfanylmethyl)pyrazole-3-carboxylate (417 mg, 2.24 mmol) and m-CPBA (1159 mg, 6.72 mmol) in DCM (10 mL) was stirred at 25 °C for 2 h. The reaction was diluted with DCM (50 mL) and washed with brine (50 mL × 3). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 1/1 to afford methyl 1-(methylsulfonylmethyl)pyrazole-3-carboxylate (347 mg) as a white solid. MS obsd. (ESI+) [(M+H)+]: 219.1. Step 3: Preparation of [1-(methylsulfonylmethyl)pyrazole-3-carbonyl]oxylithium (Int-31) To a solution of methyl 1-(methylsulfonylmethyl)pyrazole-3-carboxylate (30 mg, 0.140 mmol) in mixed solution of THF (2.5 mL) and water (0.5 mL) was added LiOH.H 2 O (7 mg, 0.160 mmol). The reaction was stirred at 25 °C for 12 h and then concentrated in vacuum to afford [1-(methylsulfonylmethyl)pyrazole-3-carbonyl]oxylithium (20 mg) as a light yellow solid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 205.1 Intermediate Int-32 [1-(1-methylsulfonylethyl)pyrazole-3-carbonyl]oxylithium The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 1-(1-methylsulfonylethyl)pyrazole-3-carboxylate To a solution of methyl 1-(methylsulfonylmethyl)pyrazole-3-carboxylate (100 mg, 0.460 mmol) in DMF (3 mL) were added sodium hydride (33 mg, 1.38 mmol, 60% in oil) and then iodomethane (0.05 mL, 0.850 mmol) at 0 °C. The reaction was stirred at 25 °C for 12 h under N 2 atmosphere and then quenched with saturated aqueous NH 4 Cl (50 mL) solution. The resulted solution was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuum to afford methyl 1-(1- methylsulfonylethyl)pyrazole-3-carboxylate (100 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 233.1. Step 2: Preparation of [1-(1-methylsulfonylethyl)pyrazole-3-carbonyl]oxylithium (Int-32) To a solution of methyl 1-(1-(methylsulfonyl)ethyl)-1H-pyrazole-3-carboxylate (100 mg, 0.5 mmol) in THF (3 mL) and water (1 mL) was added LiOH.H 2 O (23 mg). The reaction was stirred at 25 °C for 16 h and then concentrated in vacuum to give [1-(1- methylsulfonylethyl)pyrazole-3-carbonyl]oxylithium (93.5 mg) as a light yellow solid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 219.1. Intermediate Int-33 3-(methylsulfonylmethyl)-1,2,4-oxadiazole-5-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of [2-(methylsulfonylmethyl)oxazole-5-carbonyl]oxylithium (Int-18), by using ethyl 3- (chloromethyl)-1,2,4-oxadiazole-5-carboxylate instead of ethyl 2-(bromomethyl)oxazole-5- carboxylate. Intermediate Int-34 [2-(methylsulfonylmethyl)triazole-4-carbonyl]oxylithium The title compound was prepared in analogy to the procedure described for the preparation of [1-(methylsulfonylmethyl)pyrazole-3-carbonyl]oxylithium (Int-31), by using methyl 1H- triazole-4-carboxylate instead of methyl 1H-pyrazole-5-carboxylate. Intermediate Int-35 5-methylsulfanylfuran-2-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 5-methylsulfanylfuran-2-carboxylate To a solution of methyl 5-bromofuran-2-carboxylate (10 g, 48.8 mmol, Eq: 1) in DMSO (20 ml) was added the sodium thiomethoxide (6.84 g, 97.6 mmol) followed by CuI (10.2 g, 53.7 mmol). The mixture was then heated to 110 °C for 2 h. The reaction was diluted with water (100 mL) and EtOAc (100 mL) and filtered through celite. The aqueous layer was separated and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column eluted with PE/EtOAc=12/1 to afford methyl 5-methylsulfanylfuran-2-carboxylate (3.5 g) as colorless oil. Step 2: Preparation of 5-methylsulfanylfuran-2-carboxylic acid (Int-35) A mixture of methyl 5-methylsulfanylfuran-2-carboxylate (500 mg, 2.90 mmol) and NaOH (929 mg, 23.2 mmol) in MeOH (5 ml) and W ml) was stirred at room temperature for 3 h. The solution was concentrated in vacuum and the residue was re-dissolved in water (3 ml). The mixture was acidified by 1N HCl to pH = 3~4. The precipitate was collected by filtration and washed with water. The filter cake was dried in vacuum to afford 5-methylsulfanylfuran-2- carboxylic acid (232 mg) as a yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 158.9 Intermediate Int-36 5-methylsulfonylfuran-2-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 5-methylsulfonylfuran-2-carboxylate A mixture of methyl 5-methylsulfanylfuran-2-carboxylate (150 mg, 0.87 mmol) and m- CPBA (390 mg, 1.74 mmol) in DCM (5 ml) was stirred at 50 °C for 5 h. The reaction mixture was washed with saturated aqueous Na2CO3 (10 ml). The aqueous phase was extracted with DCM (5 ml × 3). The organic layers were washed with brine (15 ml), dried over Na 2 SO 4 and concentrated in vacuum. The crude product was used for next step without further purification. Step 2: Preparation of 5-methylsulfonylfuran-2-carboxylic acid (Int-36) To a mixture of methyl 5-methylsulfonylfuran-2-carboxylate (215 mg, 1.05 mmol) in a mixed solution of EtOH (5 ml) and H 2 O (2 ml) was added NaOH (337 mg, 8.42 mmol). Then the reaction mixture was stirred at 80 °C for 4 h. The solution was concentrated in vacuum to remove ethanol. The residue was acidified with 1 N HCl to pH=6~7. The precipitate was collected by filtration and dried in vacuum to afford 5-methylsulfonylfuran-2-carboxylic acid (215 mg) as a light yellow solid. Intermediate Int-37 [5-(2-methoxyethylsulfonyl)furan-2-carbonyl]oxylithium The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 5-(2-methoxyethylsulfanyl)furan-2-carboxylate To a mixture of methyl 5-sulfanylfuran-2-carboxylate (300.0 mg, 1.9 mmol, 1 eq) in DMF (3 mL) was added K 2 CO 3 (786 mg, 5.69 mmol) and 2-bromoethyl methyl ether (0.71 mL, 7.59 mmol). The reaction was stirred at 25 °C for 2 h. The mixture was diluted with DCM (30 mL × 3) and water (20 mL × 2). The organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by prep-TLC (PE/EtOAc = 19/1) to afford methyl 5-(2- methoxyethylsulfanyl)furan-2-carboxylate (40 mg) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 217.1 Step 2: Preparation of methyl 5-(2-methoxyethylsulfonyl)furan-2-carboxylate To a solution of methyl 5-(2-methoxyethylsulfanyl)furan-2-carboxylate (10.0 mg, 0.050 mmol) in DCM (2 mL) was added m-CPBA (16 mg, 0.090 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with DCM (10 mL × 3) and water (10 mL × 2). The organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by prep-TLC (PE/EtOAc = 9/1) to afford methyl 5-(2-meth thylsulfonyl)furan-2-carboxylate (7 mg, 0.030 mmol) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 249.1 Step 3: Preparation of [5-(2-methoxyethylsulfonyl)furan-2-carbonyl]oxylithium (Int-37) To a solution of methyl 5-(2-methoxyethylsulfonyl)furan-2-carboxylate (150.0 mg, 0.60 mmol) in a mixed solution of MeOH (12 mL) and H 2 O (4 mL) was added lithium hydroxide (0.04 mL, 2.42 mmol). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated to remove MeOH. The aqueous layer was lyophilized to afford [5-(2- methoxyethylsulfonyl)furan-2-carbonyl]oxylithium (130 mg) as a yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 235.1 Intermediate Int-38 5-(methylsulfanylmethyl)furan-2-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 5-methylsulfanylfuran-2-carboxylic acid (Int-35), by using ethyl 5-(chloromethyl)furan-2- carboxylate instead of methyl 5-bromofuran-2-carboxylate. Intermediate Int-39 5-(1-methyl-1-methylsulfinyl-ethyl)furan-2-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of ethyl 5-(methylsulfinylmethyl)furan-2-carboxylate To a solution of ethyl 5-((methylthio)methyl)furan-2-carboxylate (2 g, 9.99 mmol) in DCM (20 ml) was added m-CPBA (2.46 g, 9.99 mmol) portionwise at 0 °C. Then the reaction was stirred at the same temperature for 1 h. The reaction solution was washed with saturated aqueous NaHCO3 (50 ml), dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with DCM/MeOH=40/1 to afford ethyl 5-(methylsulfinylmethyl)furan- 2-carboxylate (1.9 g) as colorless oil. MS obsd. (ESI + ) [(M+H) + ]: 217.1 Step 2: Preparation of ethyl 5-(1-methyl-1-methylsulfinyl-ethyl)furan-2-carboxylate To a mixture of ethyl 5-(methylsulfinylmethyl)furan-2-carboxylate (200 mg, 0.93 mmol) in THF (2 ml) was added t-BuOK (259 mg, 2.31 mmol) portionwise. After stirring at 25 °C for 30 min, iodomethane (158 mg, 1.11 mmol) was added. The reaction was stirred at 25 °C for 3 h. The reaction was filtered and washed with DCM (10 mL). The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with DCM/MeOH=30/1 to afford ethyl 5-(1-methyl-1-methylsulfinyl-ethyl)furan-2-carboxylate (90 mg) as a white solid. MS obsd. (ESI + ) [(M+Na) + ]: 267.2 Step 3: Preparation of 5-(1-methyl-1-methylsulfinyl-ethyl)furan-2-carboxylic acid (Int-39) To a mixture of ethyl 5-(1-methyl-1-methylsulfinyl-ethyl)furan-2-carboxylate (80 mg, 0.327 mmol) in MeOH (2 ml) and Water (0.5 ml) was added lithium hydroxide hydrate (55 mg, 1.31 mmol). Then the reaction was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuum. The residue was acidified by 1N HCl to pH=3~4. The resulting mixture was concentrated in vacuum to afford 5-(1-methyl-1-methylsulfinyl-ethyl)furan-2-carboxylic acid (140 mg) as a yellow solid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 217.0 Intermediate Int-40 2-cyclopropylsulfonylpyridine-4-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 5-cyclopropylsulfonylfuran-2-carboxylic acid (Int-12), by using 2-bromoisonicotinic acid instead of 5-bromo-2-furoic acid. Intermediate Int-41 2-isopropylsulfonylpyridine-4-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 2-isopropylsulfanylpyridine-4-carboxylate , To a solution of methyl 2-bromoisonicotinate (2 g, 9.26 mmol) in DMF (19 mL) was added dipotassium carbonate (1.54 g, 11.1 mmol) and 2-propanethiol (1.41 g, 18.5 mmol). The reaction mixture was irradiated in a microwave reactor at 100 °C for 16 h. The reaction mixture was filtered and the cake was washed with DCM (20 mL). The filtrate was concentrated and the residue was purified by silica gel column eluted with DCM/MeOH = 10/1 to 5/1 to afford methyl 2-isopropylsulfanylpyridine-4-carboxylate (1.8 g) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 212.1 Step 2: Preparation of 2-isopropylsulfanylpyridine-4-carboxylic acid To a solution of methyl 2-isopropylsulfanylpyridine-4-carboxylate (1.6 g, 7.57 mmol) in methanol (32 mL) and was added LiOH.H 2 O (0.65 g, 27.2 mmol). The reaction was stirred at 25 °C for 16 h. The mixture was poured into water (20 mL), concentrated in vacuum to remove most of MeOH and adjusted to pH = 3 with 31% HCl, a white solid was formed. The mixture was filtered to give 2-isopropylsulfanylpyridine-4-carboxylic acid (1.4 g) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 198.2 Step 3: Preparation of 2-isopropylsulfonylpyridine-4-carboxylic acid To a solution of 2-isopropylsulfanylpyridine-4-carboxylic acid (1.4 g, 7.1 mmol) in DMF (10 mL) and THF (50 mL) was added 2KHSO 5 .KHSO 4. K2SO 4 (1.57 g, 25.5 mmol). The reaction mixture was stirred at 25 °C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC to give 2-isopropylsulfonylpyridine-4-carboxylic acid (1.6 g) as a light yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 230.2 Intermediate Int-42 2-cyclopropylsulfonylpyridine-4-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 2-isopropylsulfonylpyridine-4-carboxylic acid (Int-41), by using 2-methyl-2-propanethiol instead of 2-propanethiol. Intermediate Int-43 2-(1-methylsulfonylethyl)pyridine-4-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 2-(chloromethyl)pyridine-4-carboxylate To a solution of methyl 2-(hydroxymethyl)pyridine-4-carboxylate (10.0 g, 59.8 mmol) in DCM (250 mL) was added thionyl chloride (8.68 mL, 119.7 mmol). The reaction mixture was stirred at 25 °C for 4 h. The mixture was concentrated in vacuum to afford methyl 2- (chloromethyl)pyridine-4-carboxylate (11.1 g) as a light yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 186.0 Step 2: Preparation of methyl 2-(methylsulfonylmethyl)pyridine-4-carboxylate To a solution of methylsulfinyloxysodium (9.2 g, 89.7 mmol) in DMF (250 mL) was added methyl 2-(chloromethyl)pyridine-4-carboxylate (11.1 g, 59.8 mmol) and TEA (16.7 ml, 119.7 mmol). The reaction mixture was stirred for 16 h at 25 °C. The reaction mixture was concentrated to dryness and the residue was diluted with EtOAc (80 mL).1 N HCl was added to adjust pH = 2~3. The separated organic phase was washed with brine (80 mL), dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=1/1 to give methyl 2-(methylsulfonylmethyl)pyridine-4-carboxylate (6.0 g) as a light yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 230.1 Step 3: Preparation of methyl 2-(1-methylsulfonylethyl)pyridine-4-carboxylate To a solution of methyl 2-(methylsulfonylmethyl)pyridine-4-carboxylate (4.7 g, 20.5 mmol) in THF (150 mL) was added sodium hydride (820 mg, 20.5 mmol). The reaction was stirred for 30 min, then iodomethane (2.55 mL, 41 mmol) was added and stirred for 2 h at 25 °C. The reaction mixture was quenched with MeOH (15 mL), concentrated and purified by silica gel column eluted with PE/EtOAc=4/1 to give the product methyl 2-(1- methylsulfonylethyl)pyridine-4-carboxylate (2.18 g) as a light yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 244.1 Step 4: Preparation of 2-(1-methylsulfonylcyclopropyl)thiazole-5-carboxylic acid (Int-43) To a solution of methyl 2-(1-methylsulfonylethyl)pyridine-4-carboxylate (760 mg, 3.12 mmol) in MeOH (20 mL) was added LiOH.H 2 O (300 mg, 12.5 mmol). The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated and purified by prep-HPLC to afford 2-(1- methylsulfonylethyl)pyridine-4-carboxylic acid (523 mg) (Int-43) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 230.1 Intermediate Int-44 2-(1-methyl-1-methylsulfonyl-ethyl)pyridine-4-carboxylic acid The title compound was prepared in analogy to the procedure described for the preparation of 2-isopropylsulfonylpyridine-4-carboxylic acid (Int-43), by extending the reaction time from 2 h to 16 h of step 3. Intermediate Int-45 3-(1-methylsulfonylethyl)-1H-pyrazole Int-45 The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 1H-pyrazole-3-carboxylate (20.0 g, 159 mmol) in DMF (200 mL) was added sodium hydride (4.57 g, 190 mmol, 60% in oil) at 0°C. After stirring at 0°C for 30 min, SEMCl (31.7 g, 190 mmol) was added portionwise at 0°C. Then the reaction mixture was stirred at 0°C for another 2 h. The reaction was quenched with water (10 mL). The resulting solution was diluted with EtOAc (500 mL), washed with water (800 mL × 2) and brine (1000 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=4/1 to give methyl 1-(2- trimethylsilylethoxymethyl) pyrazole-3-carboxylate (40 g) as light yellow oil MS obsd. (ESI + ) [(M+H) + ]: 257.2. Step 2: Preparation of [1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methanol To a solution of methyl 1-(2-trimethylsilylethoxymethyl) pyrazole-3-carboxylate (3.0 g, 11.1 mmol) in THF (30 mL) was added LiAlH 4 (0.51 g, 13.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with H 2 O (1 mL). After filtered through celite, the filtrate was concentrated in vacuum to give [1-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methanol (1.7 g) as light yellow oil. The crude was used directly in next step. MS obsd. (ESI + ) [(M+H) + ]: 229.2. Step 3: Preparation of 2-[[3-(chloromethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-sil ane To a solution of [1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methanol (1.7 g, 7.44 mmol) in DCM (20 mL) was added SOCl 2 (0.81 mL, 11.2 mmol) slowly. The mixture was stirred at 25 °C for 2 h and then concentrated in vacuum to give 2-[[3-(chloromethyl)pyrazol-1- yl]methoxy]ethyl-trimethyl-silane (1.85 g) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 247.2. Step 4: Preparation of trimethyl-[2-[[3-(methylsulfonylmethyl)pyrazol-1- yl]methoxy]ethyl]silane A mixture of 2-[[3-(chloromethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-sil ane (1.85 g, 7.5 mmol), sodium methanesulfinate (1.15 g, 11.2 mmol) and TEA (3.1 mL, 22.5 mmol) in DMF (15 mL) was stirred at 25 °C for 2 h. After filtration, the filtrate was purified by reversed flash column (eluting with ACN/H 2 O = 50/50) to give trimethyl-[2-[[3- (methylsulfonylmethyl)pyrazol-1-yl]methoxy]ethyl]silane (600 mg) as a light yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 313.1. Step 5: Preparation of trimethyl-[2-[[3-(1-methylsulfonylethyl)pyrazol-1- yl]methoxy]ethyl]silane To a solution of trimethyl-[2-[[3-(methylsulfonylmethyl)pyrazol-1-yl]methoxy] ethyl]silane (150 mg, 0.52 mmol) in DMF (5 mL) was added sodium hydride (25 mg, 0.62 mmol). After stirring at 25 °C for 1 h, iodomethane (88 mg, 0.62 mmol) was added. The reaction mixture was stirred for another 3 h. The resulting solution rified by reversed flash column (eluting with acetonitrile/H 2 O = 50/50) to give trimethyl-[2-[[3-(1-methylsulfonylethyl)pyrazol-1- yl]methoxy]ethyl]silane (100 mg) as light yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 305.2. Step 6: Preparation of 3-(1-methylsulfonylethyl)-1H-pyrazole A mixture of trimethyl-[2-[[3-(1-methylsulfonylethyl)pyrazol-1-yl]methoxy ]ethyl]silane (150 mg, 0.49 mmol) and TFA (1.0 mL, 13.5 mmol) in DCM (3 mL) was stirred at 25 °C for 2 h. After filtration, the filtrate was concentrated in vacuum to give 3-(1-methylsulfonylethyl)-1H- pyrazole (85 mg) (Int-45) as light red oil. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 175.1. Intermediate Int-46 3-(methylsulfonylmethyl)-1H-pyrazole The title compound was prepared according to the following scheme: A mixture of trimethyl-[2-[[3-(methylsulfonylmethyl)pyrazol-1-yl]methoxy] ethyl]silane (150 mg, 0.52 mmol) and TFA (1.0 mL, 13.5 mmol) in DCM (3 mL) was stirred at 25 °C for 2 h. After filtration, the filtrate was concentrated in vacuum to give 3-(methylsulfonylmethyl)-1H- pyrazole (80 mg) (Int-46) as light red oil. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 161.1. Intermediate Int-47 3-(methylsulfonylmethyl)-1H-pyrazole The title compound was prepared in analogy to the procedure described for the preparation of 2-isopropylsulfonylpyridine-4-carboxylic acid (Int-45), by increasing the equivalent of the sodium hydride and iodomethane from 1.2 to 5. Intermediate Int-48 3-(1-methylsulfonylcyclopropyl)-1H-pyrazole The title compound was prepared according to the following scheme: Step 1: Preparation of 1-(1-methylsulfonylcyclopropyl)ethanone To a solution of methylsulfonylacetone (10.0 g, 73.4 mmol, CAS No: 5000-46-4) and K 2 CO 3 (3.04 g, 220.3 mmol) in DMF (120 mL) was added 1,2-dibromoethane (9.49 mL, 110.2 mmol). The resulting mixture was heated to 60 °C and stirred for 48 h. After cooling to ambient temperature, the resulting solution was diluted with water (1000 mL) and extracted with EtOAc (150 mL × 5). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=3/2 to give 1-(1-methylsulfonylcyclopropyl)ethanone (5.1 g) as a colorless solid. MS obsd. (ESI + ) [(M+H) + ]: 163.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 3.12 (s, 3H), 2.18 (s, 3H), 1.84-1.88 (m, 2H), 1.59-1.63 (m, 2H). Step 2: Preparation of (E)-3-(dimethylamino)-1-(1-methylsulfonylcyclopropyl)prop-2- en-1- one To a solution of 1-(1-methylsulfonylcyclopropyl)ethanone (5.0 g, 30.8 mmol) in 1,4- dioxane (50 mL) was added DMF-DMA (12.3 mL, 92.5 mmol). The resulting mixture was heated to 100 °C and stirred for 4 h. The resulting solution was concentrated in vacuum to give (E)-3-(dimethylamino)-1-(1-methylsulfonylcyclopropyl)prop-2- en-1-one (7.5 g) as yellow liquid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 218.1. Step 3: Preparation of 3-(1-methylsulfonylcyclopropyl)-1H-pyrazole To a solution of (E)-3-(dimethylamino)-1-(1-methylsulfonylcyclopropyl)prop-2- en-1-one (3.29 g, 12.9 mmol) in 1,4-dioxane (50 mL) was added N 2 H 4 -HCl (0.93 g, 13.5 mmol) under nitrogen atmosphere. The reaction mixture was refluxed for 6 h. The resulting solution was concentrated in vacuum to give 3-(1-methylsulfonylcyclopropyl)-1H-pyrazole (2.8 g) (Int-48) as yellow liquid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]:187.2. Intermediate Int-49 5-cyclopropylsulfanylfuran-2-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of cyclopropanethiol To a solution of cyclopropylmagnesium bromide (10 mL, 5 mmol) in THF was added sulfur (160 mg, 0.63 mmol) at 0 °C. Then the solution was heated at 50 °C with stirring for 3 h. After being cooled in an ice-bath, lithium aluminum hydride (5 mL, 5 mmol) in THF was added. The resulting mixture was stirred at 65 °C for 0.5 h and quenched by H 2 O (0.5 mL) at 0 °C, then acidified by H2SO 4 (5% v/v, 20 mL). The organic phase containing cyclopropanethiol was separated, dried over anhydrous Na 2 SO 4 and used for the next step without purification. Step 2: Preparation of methyl 5-cyclopropylsulfanylfuran-2-carboxylate To a mixture of methyl 5-bromo-2-furoate (410 mg, 2 mmol), tris(dibenzylideneacetone)dipalladium (0) (183 mg, 0.2 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (116 mg, 0.2 mmol) and N,N-diisopropylethylamine (1.74 mL, 10 mmol) in 1,4-dioxane (15 mL) was added the above solution containing cyclopropanethiol. After being stirred at 110 °C for 6 h, the mixture was filtered through a short silica gel column. The filtration was concentrated and purified by silica gel column eluted with PE/EtOAc = 99/1 to give methyl 5-cyclopropylsulfanylfuran-2-carboxylate (120 mg) as colorless oil. MS obsd. (ESI + ) [(M+H) + ]: 199.1. Step 3: Preparation of 5-cyclopropylsulfanylfuran-2-carboxylic acid To a solution of methyl 5-cyclopropylsulfanylfuran-2-carboxylate (50 mg, 0.25 mmol) in a mixed solvent of THF (2 mL) and MeOH (2 mL) was added a solution of LiOH in water (1.9 mL, 2 M). After being stirred at 25 °C for 2 h, the mixture was acidified by HCl (1 M) to pH = 5, then extracted by EtOAc (10 mL × 3). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to give 5-cyclopropylsulfanylfuran-2-carboxylic acid (46 mg) (Int-49) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 185.1. Intermediate Int-50 5-(cyclopropylmethylsulfanyl)furan-2-carboxylic acid The title compound was prepared according to the following scheme: Step 1: Preparation of methyl 5-(cyclopropylmethylsulfanyl)furan-2-carboxylate 120 C, 12 h To a solution of methyl 5-bromo-2-furoate (2 g, 9.76 mmol) in 1,4-dioxane (20 mL) was added sodium hydrosulfide (5.5 g, 97.6 mmol) and (bromomethyl)cyclopropane (3.3 mL, 34.1 mmol). After being stirred at 120 °C for 12 h, the reaction mixture was quenched with H 2 O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column (eluting with 100% PE) to afford methyl 5-(cyclopropylmethylsulfanyl)furan-2-carboxylate (580 mg) as colorless oil. MS obsd. (ESI + ) [(M+H) + ]: 213.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.14 (d, J = 3.5 Hz, 1 H), 6.50 (d, J = 3.5 Hz, 1 H), 3.89 (s, 3 H), 2.86 (d, J = 7.2 Hz, 2 H), 0.95 - 1.10 (m, 1 H), 0.51 - 0.61 (m, 2 H), 0.14 - 0.24 (m, 2 H). Step 2: Preparation of 5-(cyclopropylmethylsulfanyl)furan-2-carboxylic acid To a solution of methyl 5-(cyclopropylmethylsulfanyl)furan-2-carboxylate (308 mg, 1.45 mmol) in a mixed solvent of THF (2 mL) and methanol (2 mL) was added a solution of LiOH in water (2.2 mL, 2 M). After being stirred at 20 °C for 1 h, the mixture was acidified by HCl (2.5 mL, 2 M). The solvent was evaporated and the residue was separated by EtOAc (20 mL) and water (20 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give the 5- (cyclopropylmethylsulfanyl)furan-2-carboxylic acid (280 mg) (Int-50) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 199.1. Intermediate Int-51 methyl 5-(methylsulfonylmethyl)thiazole-2-carboxylate The title compound was prepared in analogy to the procedure described for the preparation of [2-(methylsulfonylmethyl)oxazole-5-carbonyl]oxylithium (Int-18), by using 5- methylthiazole-2-carboxylate instead of ethyl 2-methyloxazole-5-carboxylate. Intermediate Int-52 ethyl 5-(methylsulfonylmethyl)oxazole-2-carboxylate The title compound was prepared in analogy to the procedure described for the preparation of [2-(methylsulfonylmethyl)oxazole-5-carbonyl]oxylithium (Int-18), by using ethyl 5- methyloxazole-2-carboxylate instead of ethyl 2-methyloxazole-5-carboxylate. Intermediate Int-53 Ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-5-carboxyla te The title compound was prepared according to the following scheme: Step 1: Preparation of 1-methylsulfonylcyclopropanecarbonitrile To a mixture of 2-(methylsulfonyl)acetonitrile (5.0 g, 42.0 mmol, CAS No: 2274-42-2) in DMF (50 mL) was added K 2 CO 3 (11.6 g, 84.0 mmol) and 1,2-dibromoethane (15.61 g, 84.0 mmol). The mixture was stirred at 80 °C for 12 h. The resulting solution was diluted with water (300 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vaccum to give 1- methylsulfonylcyclopropanecarbonitrile (4.5 g) as a white solid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 146.1. Step 2: Preparation of N-hydroxy-1-methylsulfonyl-cyclopropanecarboxamidine A solution of 1-(methylsulfonyl)cyclopropane-1-carbonitrile (500 mg, 3.45 mmol), hydroxylamine hydrochloride (476 mg, 6.9 mmol) and K 2 CO 3 (952 mg, 6.9 mmol) in a mixed solvent of EtOH and H 2 O (10 mL, v/v = 4/1) was stirred at 25 °C for 2 h. The resulting solution was diluted with water (200 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (30 mL), dried over N a2 SO 4 and concentrated in vacuum to give N-hydroxy-1-methylsulfonyl-cyclopropanecarboxamidine (310 mg) as a white solid. The crude was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 179.1. Step 3: Preparation of ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-5- carboxylate To a mixture of N-hydroxy-1-methylsulfonyl-cyclopropanecarboxamidine (250 mg, 1.4 mmol) in DCM (20 mL) were added Et3N (283 mg, 2.8 mmol) and ethyl 2-chloro-2-oxoacetate (228 mg, 1.68 mmol). The reaction was stirred at 25 °C for 4 h. The resulting solution was diluted with DCM (100 mL) and washed with water (20 mL × 3) and brine (10 mL). The organic layer was dried over Na 2 SO 4 and concentrated i ccum. The residue was purified by silica gel column eluted with PE/EtOAc=1/1 to give ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4- oxadiazole-5-carboxylate (155 mg) (Int-53) as yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 261.1. Intermediate Int-54 Methyl 5-(1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxyla te The title compound was prepared according to the following scheme: Step 1: Preparation o f methyl 2-(hydroxyamino)-2-imino-acetate A solution of methyl cyanoformate (8.0 g, 94.1 mmol), sodium carbonate (19.94 g, 188.1 mmol) and NH 2 OH.HCl (7.83 mL, 188.1 mmol) in a mixed solution of ethanol and water (250mL, v/v=4/1) was heated at 80 °C for 6 h. After removed ethanol in vacuum, the resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated in vacuum to give methyl 2-(hydroxyamino)-2-imino-acetate (5.4 g) as a light yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 119.1. Step 2: Preparation of [(2-methoxy-2-oxo-ethanimidoyl)amino] 1- methylsulfonylcyclopropanecarboxylate To a solution of 1-methylsulfonylcyclopropanecarboxylic acid (4.17 g, 25.4 mmol) in DMF (40 mL) were added triethylamine (10.6 mL, 76.21 mmol), HATU (10.6 g, 27.94 mmol) and methyl 2-(hydroxyamino)-2-imino-acetate (3.0 g, 25.4 mmol). The reaction mixture was stirred at 25 °C for 1 h. The resulting solution was diluted with H 2 O (200 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuum to give [(2-methoxy-2-oxo-ethanimidoyl)amino] 1- methylsulfonylcyclopropanecarboxylate (6 g) as a red solid. The crude product was used for next step without further purification. MS obsd. (ESI + ) [(M+H) + ]: 265.1. Step 3: Preparation of methyl 5-(1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3- carboxylate A solution of [(2-methoxy-2-oxo-ethanimidoyl)amino] 1- methylsulfonylcyclopropanecarboxylate (700 mg, 2.65 mmol) in DMF (10 mL) was heated to 100 °C and stirred for 12 h. After cooled to room temperature, the reaction mixture was filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give methyl 5-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (200 mg) (Int-54) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 247.0. Intermediate Int-55 5-(1-methylsulfonylethyl)-1-(2-trimethylsilylethoxymethyl)py razole-3-carboxylic acid The title compound was prepared according to the following scheme:
Step 1: Preparation of methyl 4-bromo-5-(bromomethyl)-1H-pyrazole-3-carboxylate To a solution of methyl 5-methyl-1H-pyrazole-3-carboxylate (4000 mg, 28.54 mmol, CAS No: 25016-17-5) in CCl 4 (50 mL) were added NBS (10161 mg, 57.09 mmol) and BPO (1381 mg, 5.71 mmol). The reaction mixture was stirred for 12 h at 80 °C. The resulting mixture was diluted with DCM (300 mL) and washed with water (100 mL × 2) and brine (100 mL × 2). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with DCM/MeOH = 19/1 to give methyl 4-bromo-5-(bromomethyl)-1H- pyrazole-3-carboxylate (2500 mg) as an off-white solid. MS obsd. (ESI + ) [(M+H) + ]: 299.1. Step 2: Preparation of methyl 4-bromo-5-(methylsulfonylmethyl)-1H-pyrazole-3- carboxylate To a solution of methyl 4-bromo-5-(bromomethyl)-1H-pyrazole-3-carboxylate (2000 mg, 6.71 mmol) in ethanol (50 mL) was added sodium methanesulfinate (822 mg, 8.06 mmol). The mixture was stirred at 80 °C for 2h. After removed ethanol in vacuum, the resulting mixture was diluted with EtOAc (400 mL) and washed wi r (100 mL × 2) and brine (100 mL × 2). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with DCM/MeOH = 19/1 to give methyl 4-bromo-5- (methylsulfonylmethyl)-1H-pyrazole-3-carboxylate (1300 mg) as an off-white solid. MS obsd. (ESI + ) [(M+H) + ]: 297.1. Step 3: Preparation of methyl 4-bromo-5-(methylsulfonylmethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 4-bromo-5-(methylsulfonylmethyl)-1H-pyrazole-3-carboxylate (2000 mg, 6.73 mmol) in THF (80 mL) was added sodium hydride (323 mg, 8.08 mmol, 60% in oil) at 0 °C under N 2 atmosphere. After stirred for 0.5 h at 0 °C, SEM-Cl (1349 mg, 8.08 mmol) was added. The reaction mixture was warmed to 25 °C and stirred for another 10 h. The resulting solution was diluted with EtOAc (300 mL) and washed with water (100 mL × 2) and brine (100 mL × 2). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with DCM/MeOH = 19/1 to give methyl 4-bromo-5- (methylsulfonylmethyl)-1-(2-trimethylsilylethoxymethyl)pyraz ole-3-carboxylate (1702 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 427.1. Step 4: Preparation of methyl 5-(methylsulfonylmethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 4-bromo-5-(methylsulfonylmethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1700 mg, 3.98 mmol) in methanol (30 mL) was added Pd/C (170 mg, 10% w/w). The reaction mixture was stirred at room temperature for 2 h under hydrogen atmosphere. After filtered through a celite pad, the filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with DCM/MeOH = 19/1 to give methyl 5-(methylsulfonylmethyl)-1-(2-trimethylsilylethoxymethyl)pyr azole-3-carboxylate (830 mg) as a yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 349.1. Step 5: Preparation of methyl 5-(1-methylsulfonylethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 5-(methylsulfonylmethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate (100 mg, 0.29 mmol) in DMF (10 mL) was added sodium hydride (28.7 mg, 0.720 mmol, 60% in oil) at 0 °C under nitrogen atmosphere. After stirring for 30 min at 0 °C, CH 3 I (102 mg, 0.720 mmol) was added. The reaction mixture was warmed to 25 °C and stirred for another 2 h. The resulted mixture was diluted with EtOAc (200 mL) and washed with water (60 mL × 2) and brine (100 mL × 2). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 1/1 to give methyl 5-(1-methylsulfonyl-ethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate (93 mg) as yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 363.1. Step 6: Preparation of 5-(1-methylsulfonylethyl)-1-(2-trimethylsilylethoxymethyl)py razole- 3-carboxylic acid To a solution of methyl 5-(1-methylsulfonyl-ethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate (93 mg, 0.250 mmol) in a mixed solution of THF (2 mL) and water (1 mL) was added lithium hydroxide (16 mg, 0.370 mmol). The reaction mixture was stirred at 25 °C for 2 h. The resulting solution was diluted with water (20 mL), adjusted to pH = 6 with HCl (2 M) and extracted with EtOAc (20 mL × 2). The organic layers were dried over Na 2 SO 4 and concentrated in vacuum to give 5-(1-methylsulfonyl-ethyl)-1-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid (52 mg) (Int-55) as a yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 349.1. Example 1 N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentany l]-5- (methylsulfonylmethyl)furan-2-carboxamide The title compound was prepared according to the following scheme: To a solution of 3-(6-bromo-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-1-amin e (Int-1, as the “AMINE” in Table 1) (100 mg, 0.340 mmol), 5-(methylsulfonylmethyl)furan-2-carboxylic acid (69 mg, 0.340 mmol, as the “ACID” in Table 1) in DMF (4 mL) were added HATU (154 mg, 0.410 mmol) and TEA (102 mg, 1.02 mmol). The reaction mixture was stirred at 25 °C for 1 h. The resulting solution was diluted with EtOAc (60 mL) and washed with water (15 mL × 2) and brine (15 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by prep-HPLC (Chromatographic columns: Kromasil-C18100 × 21.2 mm 5um (mobile phase: ACN-H 2 O (0.1%FA)) to give N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]-5-(methylsulfonylmethyl)furan-2-carb oxamide (56 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 480.9. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.99 (d, J = 1.8 Hz, 1 H), 7.86 (dd, J = 8.8, 1.8 Hz, 1 H), 7.55-7.59 (m, 1 H), 7.15 (d, J = 3.2, 1 H), 6.88 (s, 1 H), 6.64 (d, J = 3.2 Hz, 1 H), 4.39 (s, 2H), 2.92 (s, 3 H), 2.70 (s, 6 H). The following Example 2 to Example 53 were prepared in analogy to the procedure described for the preparation of Example 1, replacing 3-(6-bromo-1,3-benzothiazol-2- yl)bicyclo[1.1.1]pentan-1-amine (Int-1) with “AMINE”, and replacing 5- (methylsulfonylmethyl)furan-2-carboxylic acid (Int-9) with “ACID”. The “AMINE” and “ACID” are the reagents indicated in Table 1. Table 1: Compounds synthesis and characterization
Example 56-a and 56-b The two enantiomers (Example 56-a and Example 56-b) were obtained through SFC [Instrument: MG Ⅱ preparative SFC (SFC-1); Column: ChiralPak OD, 250×30mm I.D., 5µm; Mobile phase: A for CO2 and B for Ethanol; Gradient: B 50%; Flow rate: 50 mL /min; Back pressure: 100 bar Column temperature: 38℃; Wavelength: 254nm] chiral separation of N-[3-(6- chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(1 -methylsulfonylethyl)furan-2- carboxamide (Example 17), Example 56-a was faster eluting than Example 56-b. N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-[(1R)-1- methylsulfonylethyl]furan-2-carboxamide and N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]-5-[(1S)-1-methylsulfonylethyl]furan- 2-carboxamide (Example 56-a and Example 56-b) Example 56-a: white solid. MS obsd. (ESI + ) [(M+H) + ]: 451.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.01 (d, J = 1.8 Hz, 1H, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8, 1.8 Hz, 1H), 7.15 (d, J = 3.4 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 4.65 (q, J = 7.4 Hz, 1H), 2.92 (s, 3H), 2.66 (s, 6H), 1.77 (d, J = 7.4 Hz, 3H). Example 56-b: white solid. MS obsd. (ESI + ) [(M+H) + ]: 451.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.02 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H), 4.65 7.4 Hz, 1H), 2.92 (s, 3H), 2.66 (s, 6H), 1.77 (d, J = 7.4 Hz, 3H). Example 57-a and 57-b The two enantiomers (Example 57-a and Example 57-b) were obtained through SFC [Instrument: SFC-80; Column: ChiralPak OD, 250×20mm I.D., 5µm; Mobile phase: A for CO2 and B for IPA; Gradient: B 40%; Flow rate: 50 mL /min; Back pressure: 100 bar Column temperature: 40℃; Wavelength: 254nm] chiral separation of N-[3-(6-chloro-1,3-benzothiazol-2- yl)-1-bicyclo[1.1.1]pentanyl]-5-(1-methylsulfonylethyl)furan -2-carboxamide (Example 46). Example 57-a was faster eluting than Example 57-b. N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-[(1R)-1- methylsulfonylethyl]furan-2-carboxamide and N-[3-(5-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]-5-[(1S)-1-methylsulfonylethyl]furan- 2-carboxamide (Example 57-a and 57-b) Example 57-a: white solid. MS obsd. (ESI + ) [(M+H) + ]: 451.0. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.10 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.6, 2.1 Hz, 1H), 7.16 (d, J = 3.5 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 4.73 (q, J = 7.1 Hz, 1H), 2.97 (s, 3H), 2.57 (s, 6H), 1.66 (d, J = 7.2 Hz, 3H). Example 57-b: white solid. MS obsd. (ESI + ) [(M+H) + ]: 451.1. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.11 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.7, 2.1 Hz, 1H), 7.16 (d, J = 3.4 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 4.73 (q, J = 7.2 Hz, 1H), 2.97 (s, 3H), 2.57 (s, 6H), 1.66 (d, J = 7.2 Hz, 3H). Example 58 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-3-(1- methylsulfonylethyl)pyrazole-1-carboxamide The title compound was prepared according to the following scheme: To a solution of triphosgene (105 mg, 0.35 mmol) in THF (4 mL) was added 1-(6-chloro- 1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-amine (89.0 mg, 0.350 mmol) (Int-7, as the “AMINE-1” in Table 2) and TEA (0.3 mL, 2.13 mmol) at 0 °C. After stirring at 0 °C for 1 h, 3- (1-methylsulfonylethyl)-1H-pyrazole (Int-45, as the “AMINE-2” in Table 2) (62 mg, 0.35 mmol) was added. The reaction mixture was warmed to 25 °C and stirred for another 1 h. The resulting solution was concentrated in vacuum. The residue was purified by prep-HPLC (Chromatographic columns: Kromasil-C18100 × 21.2 mm 5um Mobile Phase: ACN--H2O (0.1% FA) Gradient: 50%-60%) to give N-[1-(6-chloro-1,3-benzothiazol-2-yl)-3- bicyclo[1.1.1]pentanyl]-3-(1-methylsulfonylethyl)pyrazole-1- carboxamide (5.4 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 451.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.26 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 4.73-4.81 (m, 1H), 2.88 (s, 3H), 2.68 (s, 6H), 1.77 (d, J = 7.2 Hz, 3H). The following Example 59 to Example 63 were prepared in analogy to the procedure described for the preparation of Example 58, replacing 1-(6-chloro-1,3-benzothiazol-2- yl)bicyclo[1.1.1]pentan-3-amine (Int-7) with “AMINE-1”, and replacing 3-(1- methylsulfonylethyl)-1H-pyrazole (Int-45) with “AMINE-2”. The “AMINE-1” and “AMINE- 2” are the reagents indicated in Table 2 Table 2: Compounds synthesis and characterization Example 64 N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl )-5-(S- methylsulfonimidoyl)furan-2-carboxamide The title compound was prepared according to the following scheme: Step 1: Preparation of N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl )-5- (methylthio)furan-2-carboxamide To a mixture of 3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (100 mg, 399 µmol, Int-8) and 5-(methylthio)furan-2-carboxylic acid (69 mg, 439 µmol, Int-35) in DCM (4 ml) was added EDCI (115 mg, 598 µmol) and DMAP (73 mg, 598 µmol). Then the reaction was stirred at 25 °C for 18 h. The reaction solution was purified by silica gel column eluted with DCM/MeOH=60/1 to give N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl )-5- (methylthio)furan-2-carboxamide (130 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 390.9. Step 2: Preparation of [1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methanol A mixture of N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl )-5- (methylthio)furan-2-carboxamide (100 mg, 256 µmol), PIDA (173 mg, 537 µmol) and NH 2 COONH 4 (37 mg, 384 µmol) in MeOH ( was stirred at 25 °C for 2h. The reaction was concentrated in vacuum and the residue was purified by silica gel column eluted with DCM/MeOH=40/1 to give N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl )-5-(S- methylsulfonimidoyl)furan-2-carboxamide (95 mg) (Example 64) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 422.1. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.43 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.6, 2.1 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H), 7.16 (d, J = 3.5 Hz, 1H), 4.88 (s, 1H), 3.14-3.23 (m, 3H), 2.59 (s, 6H). Example 65 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- (cyclopropylsulfonimidoyl)furan-2-carboxamide 65 The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using 3-(6-chloro-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-1-ami ne (Int-7) instead of 3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (Int-8) and 5- cyclopropylsulfanylfuran-2-carboxylic acid (Int-49) instead of 5-(methylthio)furan-2-carboxylic acid (Int-35). The product was purified by preparative HPLC to afford Example 65 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 448.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.03 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.22-7.26 (m, 2H), 3.72-3.76 (m, 1H), 2.67 (s, 6H), 0.91- 1.55 (m, 4H). Example 66 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- (cyclopropylmethylsulfonimidoyl)furan-2-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using 3-(6-chloro-1,3-ben zol-2-yl)bicyclo[1.1.1]pentan-1-amine (Int-7) instead of 3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (Int-8) and 5- (cyclopropylmethylsulfanyl)furan-2-carboxylic acid (Int-45) instead of 5-(methylthio)furan-2- carboxylic acid (Int-35). The product was purified by preparative HPLC to afford Example 66 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 462.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.42 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.8, 2.0 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 7.20 (d, J = 3.6 Hz, 1H), 4.89 (s, 1H), 3.26 (d, J = 7.2 Hz, 2H), 2.52 (s, 4H), 2.09 (s, 2H), 0.96- 1.00 (m, 1H), 0.45 (q, J = 5.6 Hz, 2H), 0.11 (q, J = 5.6 Hz, 2H). Example 67 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-2-(1- methylsulfonylcyclopropyl)oxazole-5-carboxamide The title compound was prepared according to the following scheme: To a solution of ethyl 2-(methylsulfonylmethyl)oxazole-5-carboxylate (50 mg, 0.21 mmol) in DMF (3 mL) was added sodium hydride (13 mg, 0.54 mmol, 60% in oil) at 0 °C. After stirred at 0 °C for 0.5 h, 1,2-dibromoethane (60 mg, 0.32 mmol) was added. The reaction mixture was stirred at 25 °C for 12 h. To the stirred solution, HATU (36.18 mg, 0.100 mmol), DIEA (33.54 mg, 0.260 mmol) and 1-(6-chloro-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-ami ne (22 mg, 0.090 mmol) were added. The reaction mixture was stirred at 25 °C for 1 h. The resulted mixture was purified by prep-HPLC to give N-[1-(6-chloro-1,3-benzothiazol-2-yl)-3- bicyclo[1.1.1]pentanyl]-2-(1-methylsulfonylcyclopropyl)oxazo le-5-carboxamide (2.8 mg) (Example 67) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 464.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.41 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.51 (dd J = 8.8, 2.0 Hz, 1H), 3.29 (s, 3H), 2.67 (s, 6H), 1.87-1.90 (m, 2H), 1.73-1.77 (m, 2H). Example 68 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-(1- methylsulfonylcyclopropyl)thiazole-2-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 67, by using methyl 5-(methylsulfonylmethyl)thiazole-2-carboxylate (Int-51) instead of ethyl 2-(methylsulfonylmethyl)oxazole-5-carboxylate. The product was purified by preparative HPLC to afford Example 68 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 480.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.05 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 2.93 (s, 3H), 2.68 (s, 6H), 1.87-1.91 (m, 2H), 1.52-1.56 (m, 2H). Example 69 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-(1- methylsulfonylcyclopropyl)oxazole-2-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 67, by using ethyl 5-(methylsulfonylmethyl)oxazole-2-carboxylate (Int-52) instead of ethyl 2-(methylsulfonylmethyl)oxazole-5-carboxylate. The product was purified by preparative HPLC to afford Example 69 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 464.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.02 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.47 (s, 1H), 3.08 (s, 3H), 2.68 (s, 6H), 1.81-1.90 (m, 2H), 1.53-1.63 (m, 2H). Example 70 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- (cyclopropylmethylsulfonyl)furan-2-carboxamide The title compound was prepared according to the following scheme: Step 1: Preparation of N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- (cyclopropylmethylsulfanyl)furan-2-carboxamide To a solution of 1-(6-chloro-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-ami ne (414 mg, 1.65 mmol) and 5-(cyclopropylmethylsulfanyl)furan-2-carboxylic acid (654 mg, 3.3 mmol, Int- 50) in DCM (30 mL) was added triethylamine (1.38 mL, 9.9 mmol) and T 3 P (6.3 g, 9.9 mmol). The reaction mixture was stirred at 30 °C for 16 h. The resulting solution was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc = 4/1 to give N-[3- (6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5 -(cyclopropylmethylsulfanyl) furan- 2-carboxamide (610 mg) as an off-white solid. MS obsd. (ESI + ) [(M+H) + ]: 433.0. Step 2: Preparation of N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- (cyclopropylmethylsulfonyl)furan-2-carboxamide To a solution of N-[1-(6-chloro-1,3-benzothiazol-2-yl)-3-bicyclo[1.1.1]pentan yl]-5- (cyclopropylmethylsulfanyl)furan-2-carboxamide (150 mg, 0.35 mmol) in DCM (15 mL) was added m-CPBA (132 mg, 0.77 mmol). The reaction was stirred at 25 °C for 6 h. After concentration, the residue was purified by prep-HPLC (Chromatographic columns: Kromasil- C18100 x 21.2 mm 5um Mobile Phase: ACN--H 2 O (0.1%FA) Gradient: 55-65) to give N-[3-(6- chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]-5-(c yclopropylmethylsulfonyl)furan-2- carboxamide (129 mg) (Example 70) as white solid. MS obsd. (ESI + ) [(M+H) + ]: 463.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.49 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.0 Hz, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 3.44 (d, J = 7.2 Hz, 2H), 2.59 (s, 6H), 0.92-0.96 (m, 1H), 0.59-0.41 (m, 2H), 0.16 (q, J = 4.6 Hz, 2H). Example 71 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- (cyclopropylmethylsulfinyl)furan-2-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 70, by decreasing the equivalent of the m-CPBA from 2 to 1.1. The product was purified by preparative HPLC to afford Example 71 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 447.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.45 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.27-7.31 (m, 2H), 3.36 (d, J = 7.2 Hz, 1H), 3.21-3.26 (m, 1H), 2.59 (s, 6H), 0.72-0.90 (m, 1H), 0.53-0.56 (m, 2H), 0.32- 0.45 (m, 1H), 0.24-0.28 (m, 1H). Example 72 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-methylsulfinyl-furan-2- carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 71, by using 5-methylsulfanylfuran-2-carboxylic acid (Int-35) instead of 5- (cyclopropylmethylsulfanyl)furan-2-carboxylic acid (Int-50). The product was purified by preparative HPLC to afford Example 72 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 407.0. 1 H NMR (400 MHz, CD 3 OD) δ 8.02 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.21-7.25 (m, 2H), 3.10 (s, 3H), 2.68 (s, 6H). Example 73 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-cyclopropylsulfinyl-furan- 2-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 71, by using 5-cyclopropylsulfanylfuran-2-carboxylic acid (Int-49) instead of 5- (cyclopropylmethylsulfanyl)furan-2-carboxylic acid (Int-50). The product was purified by preparative HPLC to afford Example 73 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 433.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.02 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 8.6, 2.0 Hz, 1H), 7.25 (d, J = 3.6 Hz, 1H), 7.20 (d, J = 3.6 Hz, 1H), 2.86-2.95 (m, 1H), 2.67 (s, 6H), 1.20-1.35 (m, 2H), 1.10-1.14 (m, 1H), 0.91-1.00 (m, 1H). Example 74 and 75 N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl )-5- (dichloro(methylsulfonyl)methyl)furan-2-carboxamide 5-(chloro(methylsulfonyl)methyl)-N-(3-(5-chlorobenzo[d]thiaz ol-2-yl)bicyclo[1.1.1]pentan- 1-yl)furan-2-carboxamide The title compounds were prepared according to the following scheme: To a mixture of CCl 4 (106 mg, 66.3 µl, 687 µmol) and NaOH (34.3 mg, 858 µmol) in DMF (6 ml) was added N-(3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl )-5- ((methylsulfonyl)methyl)furan-2-carboxamide (300 mg, 687 µmol, Example 42) in one portion at 0 °C. Then the reaction was stirred at the same temperature for 3 h. The reaction solution was poured into 50 ml of saturated aqueous NH 4 Cl. The resulting mixture was extracted with DCM (15 ml × 4). The organic layers were washed with brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuum. The residue purified by prep-HPLC to give N-(3-(5- chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(dic hloro(methylsulfonyl)methyl)furan- 2-carboxamide (47 mg) (Example 74) as a white solid and 5-(chloro(methylsulfonyl)methyl)-N- (3-(5-chlorobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)f uran-2-carboxamide (17 mg) (Example 75) as a white solid. Example 74: MS obsd. (ESI + ) [(M+H) + ]: 505.0. 1 H NMR (DMSO-d 6 , 400 MHz): δ (ppm) 9.34 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.7, 2.1 Hz, 1H), 7.31 (d, J = 3.7 Hz, 1H), 7.22 (d, J = 3.8 Hz, 1H), 3.45 (s 3H), 2.58 (s, 6H). Example 75: MS obsd. (ESI + ) [(M+H) + ]: 470.9. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.25 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.6, 2.1 Hz, 1H), 7.24 (d, J = 3.5 Hz, 1H), 6.93 (d, J = 3.5 Hz, 1H), 6.88 (s, 1H), 3.25 (s, 3H), 2.57 (s, 6H). Example 76 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-3-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared according to the following scheme: To a solution of 1-(6-chloro-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-ami ne (125 mg, 0.500 mmol, Int-7) and ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-5-carboxyla te (100 mg, 0.380 mmol) (Int-53) in toluene (10 mL) was added trimethylaluminium (0.58 mL, 0.580 mmol, 1.0 M in hexane) at 25 °C under N 2 atmosphere. The resulting mixture was heated to 100°C and stirred for 16 h. After cooled to room temperature, the resulting solution was concentrated in vacuum. The residue was purified by pre-HPLC to give N-[1-(6-chloro-1,3- benzothiazol-2-yl)-3-bicyclo[1.1.1]pentanyl]-3-(1-methylsulf onylcyclopropyl)-1,2,4-oxadiazole- 5-carboxamide (25.9 mg) (Example 76) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 465.1. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.92 (d, J = 8.6 Hz, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.42-7.47 (m, 1H), 3.24 (s, 3H), 2.74 (s, 6H), 1.99-2.06 (m, 2H), 1.68- 1.74 (m, 2H). Example 77 N-[3-(6-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentany l]-5-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 76, by using 3-(6-bromo-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-1-amin e (Int-1) instead of 1-(6-chloro-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-ami ne (Int-7) and methyl 5-(1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxyla te (Int-54) instead of ethyl 3-(1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-5-carboxyla te (Int-53). The product was purified by preparative HPLC to afford Example 77 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 509.0. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.92 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.48-7.54 (m, 1H), 7.41 (s, 1H), 3.25 (s, 3H), 2.67 (s, 6H), 2.02-2.08 (m, 2H), 1.81- 1.85 (m, 2H). Example 78 N-[3-(5-bromo-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentany l]-5-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 76, by using 3-(5-bromo-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-1-amin e (Int-2) instead of 1-(6-chloro-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-ami ne (Int-7) and methyl 5- (1-methylsulfonylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (Int-54) instead of ethyl 3-(1- methylsulfonylcyclopropyl)-1,2,4-oxadiazole-5-carboxylate (Int-53). The product was purified by preparative HPLC to afford Example 78 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 509.0. 1 H NMR (400 MHz, CDCl3) δ ppm: 8.16 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.6, 1.8 Hz, 1H), 7.37 (s, 1H), 3.32 (s, 3H), 2.74 (s, 6H), 2.12-2.16 (m, 2H), 1.88-1.90 (m, 2H). Example 79 5-(1-methylsulfonylcyclopropyl)-N-[3-(6-morpholino-1,3-benzo thiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide The title compound was prepared accord he following scheme: A mixture of N-[1-(6-bromo-1,3-benzothiazol-2-yl)-3-bicyclo[1.1.1]pentany l]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide (50 mg, 0.10 mmol, Example 2), morpholine (13 mg, 0.15 mmol), XPhos G 3 (8.33 mg, 0.010 mmol), Cesium carbonate (96 mg, 0.30 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. After cooled to 25°C, the resulting solution was diluted with EtOAc (30 mL) and filtered through a celite pad. The filtrate was washed with brine (20 mL × 3), dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by prep-HPLC to give 5-(1-methylsulfonylcyclopropyl)-N-[1-(6- morpholino-1,3-benzothiazol-2-yl)-3-bicyclo[1.1.1]pentanyl]f uran-2-carboxamide (21.2 mg) (Example 79) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 514.2. 1 H NMR (400 MHz, CD 3 OD) d ppm: 7.79 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.4 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 3.81-3.89 (m, 4H), 3.16-3.25 (m, 4H), 3.02 (s, 3H), 2.63 (s, 6H), 1.79 (q, J = 4.8 Hz, 2H), 1.56 (q, J = 5.2 Hz, 2H). Example 80 5-(1-methylsulfonylcyclopropyl)-N-[3-(5-morpholino-1,3-benzo thiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide The title compound was prepared in analogy to the procedure described for the preparation of Example 79, by using N-(3-(5-bromobenzo[d]thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl) -5-(1- (methylsulfonyl)cyclopropyl)furan-2-carboxamide (Example 6) instead of N-[1-(6-bromo-1,3- benzothiazol-2-yl)-3-bicyclo[1.1.1]pentanyl]-5-(1-methylsulf onylcyclopropyl)furan-2- carboxamide (Example 2). The product was purified by preparative HPLC to afford Example 80 as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 514.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 7.81 (d, J = 8.6 Hz, 1H), 7.45 (s, 1H), 7.14-7.22 (m, 2H), 6.80 (br. s, 1H), 3.85-3.42 (m, 4H), 3.20-3.25 (m, 4H), 3.03 (s, 3H), 2.65 (s, 6H), 1.80 (d, J = 5.0 Hz, 2H), 1. J = 5.0 Hz, 2H). Example 81 N-[3-[6-(2-methoxyethoxy)-1,3-benzothiazol-2-yl]-1-bicyclo[1 .1.1]pentanyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide The title compound was prepared according to the following scheme: Step 1: Preparation of 5-(1-methylsulfonylcyclopropyl)-N-[3-[6-(4,4,5,5-tetramethyl -1,3,2- dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]-1-bicyclo[1.1.1]pe ntanyl]furan-2-carboxamide To a solution of N-[1-(6-bromo-1,3-benzothiazol-2-yl)-3-bicyclo[1.1.1]pentany l]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide (500 mg, 0.99 mmol, Example 2) in 1,4- dioxane (15 mL) were added bis(pinacolato)diboron (299 mg, 1.18 mmol), potassium acetate (193 mg, 1.97 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (72 mg, 0.10 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 18 h under nitrogen atmosphere. After cooled to room temperature, the resulting mixture was diluted with EtOAc (60 mL) and washed with water (15 mL × 2) and brine (15 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by silica gel column eluted with DCM/MeOH=20/1 to give 5-(1-methylsulfonylcyclopropyl)-N-[3-[6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]- 1-bicyclo[1.1.1]pentanyl]furan-2- carboxamide (444 mg) as yellow oil. MS obsd. (ESI + ) [(M+H) + ]: 555.1. Step 2: Preparation of N-[3-(6-hydroxy-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]penta nyl]-5- (1-methylsulfonylcyclopropyl)furan-2-carboxamide A mixture of 5-(1-methylsulfonylcyclopropyl)-N-[3-[6-(4,4,5,5-tetramethyl -1,3,2- dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]-1-bicyclo[1.1.1]pe ntanyl]furan-2-carboxamide (307 mg, 0.55 mmol) and hydrogen peroxide (0.06 mL, 0.66 mmol) in THF (10 ml) was stirred at 25 °C for 18 h. The reaction solution was diluted with EtOAc (50 mL). The resulting solution was washed with saturated aqueous Na 2 S 2 O 3 (10 mL × 2) and brine (15 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by prep-HPLC to give N-[3-(6-hydroxy-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]penta nyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide (210 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 445.1. Step 3: Preparation of N-[3-[6-(2-methoxyethoxy)-1,3-benzothiazol-2-yl]-1- bicyclo[1.1.1]pentanyl]-5-(1-methylsulfonylcyclopropyl)furan -2-carboxamide To a solution of N-[3-(6-hydroxy-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]penta nyl]-5-(1- methylsulfonylcyclopropyl)furan-2-carboxamide (100 mg, 0.22 mmol) in DMF (10 mL) were added potassium carbonate (62 mg, 0.45 mmol) and 1-bromo-2-methoxyethane (31 mL, 0.22 mmol). The reaction mixture was stirred at 50 °C for 16 h. After cooled to room temperature, the resulting solution was diluted with EtOAc (100 mL × 3) and washed with water (100 mL × 2) and brine (150 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by prep-HPLC to give N-[3-[6-(2-methoxyethoxy)-1,3-benzothiazol-2-yl]- 1-bicyclo[1.1.1]pentanyl]-5-(1-methylsulfonylcyclopropyl)fur an-2-carboxamide (2.5 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 503.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 7.81 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.11-7.17 (m, 2H), 6.78 (d, J = 3.6 Hz, 1H), 4.16-4.22 (m, 2H), 3.75-3.80 (m, 2H), 3.43 (s, 3H), 3.02 (s, 3H), 264 ( , 6H), 1.79 (q, J = 5.0 Hz, 2H), 1.56 (q, J = 5.0 Hz, 2H). Example 82 N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-3-(1-methylsulfonylethyl)- 1H-pyrazole-5-carboxamide The title compound was prepared according to the following scheme: Step 1: Preparation of N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-(1- methylsulfonylethyl)-1-(2-trimethylsilylethoxymethyl)pyrazol e-3-carboxamide To a solution of 5-(1-methylsulfonylethyl)-1-(2-trimethylsilylethoxymethyl)py razole-3- carboxylic acid (50 mg, 0.140 mmol, Int-55) in DCM (5 mL) was added oxalyl chloride (20 mg, 0.160 mmol). After stirring at 25 °C for 30 min, the reaction mixture was concentrated in vacuum. The residue was dissolved in DCM (5 mL) and a solution of 1-(6-chloro-1,3- benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-amine (35.98 mg, 0.140 mmol, Int-7) in DCM (5 mL) was added slowly. The reaction was stirred at room temperature for 1 h. The resulted solution was concentrated in vacuum to give N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]-5-(1-methylsulfonylethyl)-1-(2-trime thylsilylethoxymethyl)pyrazole-3- carboxamide (50 mg) as a grey solid. MS obsd. (ESI + ) [(M+H) + ]: 581.0. Step 2: Preparation of N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-(1- methylsulfonylethyl)-1H-pyrazole-3-carboxamide To a solution of N-[1-(6-chloro-1,3-benzothiazol-2-yl)-3-bicyclo[1.1.1]pentan yl]-2-(3,3- dimethylbutoxymethyl)-5-(1-methylsulfonylethyl)pyrazole-3-ca rboxamide (50 mg, 0.090 mmol) in DCM (2 mL) was added TFA (2.0 mL, 26.93 mmol) at 25 °C. The reaction was stirred at room temperature for 2 h and then concentrated in vacuum. The residue was purified by prep- HPLC to give N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5-(1- methylsulfonylethyl)-1H-pyrazole-3-carboxamide (2.4 mg) (Example 82) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 451.0. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.34 (s, 1H), 9.00 (s, 1H), 8.31 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.03 (s, 1H), 3.35 (q, J = 6.4 Hz, 1H), 2.91 (s, 3H), 2.62 (s, 6H), 1.66 (d, J = 6.4 Hz, 3H). Example 83 5-(butanoylsulfamoyl)-N-[3-(6-chloro-1,3-benzothiazol-2-yl)- 1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide The title compound was prepared according to the following scheme: Step 1: Preparation of N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- sulfamoyl-furan-2-carboxamide To a solution of 1-(6-chloro-1,3-benzothiazol-2-yl)bicyclo[1.1.1]pentan-3-ami ne (656 mg, 2.62 mmol, Int-7) and 5-sulfamoylfuran-2-carboxylic acid (500 mg, 2.62 mmol) in DMF (20 mL) were added HATU (995 mg, 2.62 mmol) and TEA (265 mg, 2.62 mmol). The reaction was stirred at 25 °C for 2 h. The reaction mixture was diluted with DCM (40 mL) and washed with water (20 mL × 3). The organic phase was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by prep-HPLC to give N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1- bicyclo[1.1.1]pentanyl]-5-sulfamoyl-furan-2-carboxamide (108 mg) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 424.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.02 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.18 (d, J = 3.6 Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 2.66 (s, 6H). Step 2: Preparation of 5-(butanoylsulfamoyl)-N-[3-(6-chloro-1,3-benzothiazol-2-yl)- 1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide To a solution of butyryl chloride (0.06 mL, 0.54 mmol) in DCM (3 mL) were added TEA (0.15 mL, 1.09 mmol) and N-[3-(6-chloro-1,3-benzothiazol-2-yl)-1-bicyclo[1.1.1]pentan yl]-5- sulfamoyl-furan-2-carboxamide (100 mg, 0.54 mmol). The reaction was stirred at 25 °C for 2 h. The resulted solution was diluted with DCM (20 mL) and washed water (15 mL) and brine (15 mL). The organic phase was dried over Na 2 SO 4 and concentrated in vacuum. The residue was purified by prep-HPLC to give 5-(butanoylsulfamoyl)-N-[3-(6-chloro-1,3-benzothiazol-2-yl)- 1- bicyclo[1.1.1]pentanyl]furan-2-carboxamide (17.5 mg) (Example 83) as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 494.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm: 8.02 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 3.6 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), 2.66 (s, 6H), 2.20 (t, J = 7.4 Hz, 2H), 1.53-1.65 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). BIOLOGICAL EXAMPLES Example 84 PHH Natural Infection Assay Detailed procedures regarding primary human hepatocyte (PHH) HBV natural infection assay are described as below. One tube of frozen PHH (10 million cells) is thawed in 37 °C water bath and then transferred to 20 mL of PHH thawing medium (Sigma, InVitroGRO HT Medium, Cat. S03319) with gently mixing. The cells were then centrifuged at 80 g/min for 5 min, the supernatant was discarded and the tube was refilled with 25 mL of PHH plating medium (Sigma , InVitroGRO CP Medium, Cat. S03317). The tube was shaken very gently to re-suspend all cells, and then 50 µl of cells were transferred to each well 384-well collagen I coated plate with appropriate liquid handling equipment, e.g. Integra VIAFLO384 or Agilent Bravo. The cells were then cultured for 24 hours in a cell incubator. For HBV infection, after PHH attachment on the culture plate, the plating medium was removed and replenished with PHH culture medium containing HBV virus. The PHH culture medium was prepared with Dulbecco's Modified Eagle Medium (DMEM)/F12 (1: 1 in volume ratio) containing 10% fetal bovine serum (Gibco, Cat.10099141), 5 ng/mL human epidermal growth factor (Gibco, Cat.PHG0311L), 20 ng/mL dexamethasone (Sigma, Cat.D4902-100mg), 250 ng/mL human recombinant insulin (Gibco, Cat.41400045) and 100 U/mL penicillin. HBV virus at 200 genome equivalent (GE) per cell with 4% PEG8000 (Sigma, Cat.P1458) containing culture medium were added to the PHH culture medium for infection. The cells were then cultured for 24 hours in cell incubator. Then the cell culture supernatant was removed. The HBV-infected PHH were cultured with sandwich culture method with PHH culture medium containing 1% DMSO and 0.25 mg/mL matrix gel for 72 hours. The supernatant was then refreshed with PHH culture medium containing different concentrations of testing compounds for two times with 72-hour interval. At the end of treatment, the supernatant was collected for viral markers measurements, including HBsAg, HBeAg, HBV DNA and cytotoxicity. HBsAg and HBeAg were detected using alphalisa method using their specific antibodies. For HBV DNA detection, HBV DNA Quantitative Fluorescence Diagnostic Kit (Sansure Biotech Inc.) was used following the manufacture’s protocol. Cytotoxicity was determined using Cell Counting Kit-8 (CCK8, Dojindo Molecular Technologies, Inc.). The compounds of the present invention were tested for their capacity to inhibit HBsAg and HBeAg as described herein. The Examples were tested in the above assay and found to have IC 50 below 10 µM. Results of PHH assay are given in Table 3. Table 3: Activity data of compounds of this invention