EA039459B1 - Heterocyclic compound and use thereof as an agent for the treatment of diseases associated with an orexin type 2 receptor - Google Patents

Abstract

The invention relates to a heterocyclic compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I), wherein each symbol is as described in the specification, or a salt thereof is useful as an agent for the prophylaxis or the treatment of narcolepsy.

Description

The invention relates to a heterocyclic compound, in particular to a heterocyclic compound having orexin type 2 receptor agonist activity.

State of the art invention

Orexin is a neuropeptide specifically produced in individual neurons scattered in the lateral hypothalamus and surrounding area, and includes two subtypes, orexin A and orexin B. Orexin A and orexin B are endogenous ligands of orexin receptors, which are G-linked receptors. -protein and present mainly in the brain, and two types of orexin receptor subtypes are known, type 1 and type 2 (non-patent document 1).

Since orexin-producing neurons (orexin neurons) are localized in close proximity to the center of eating behavior and intraventricular administration of orexin peptide leads to an increase in food intake, orexin initially attracted attention as a neuropeptide with the ability to regulate eating behavior. However, a genetic variation of the orexin type 2 receptor has subsequently been reported to cause narcolepsy in dogs (Non-Patent Document 2), and the role of orexin in controlling sleep and wakefulness has attracted attention.

As a result of studies using a transgenic mouse with denatured orexin neurons and a double transgenic mouse obtained by crossing this mouse with a transgenic mouse with orexin overexpression, it was found that symptoms similar to those of narcolepsy that occur with degeneration of oxerin neurons disappear as a result of maintained expression of orexin. Similarly, when an orexin peptide is intraventricularly administered to a transgenic mouse with a denatured orexin neuron, a positive trend in symptoms similar to those of narcolepsy is also observed (Non-Patent Document 3). Studies of oxerin type 2 receptor knockout mice have suggested that the type 2 orexin receptor is essential for maintaining arousal (Non-Patent Document 4, Non-Patent Document 5). Such data suggest that orexin type 2 receptor agonists can be used as drugs for the treatment of narcolepsy or as therapeutic agents for the treatment of other sleep disorders with excessive sleepiness (Non-Patent Document 6).

In addition, a peptide agonist that selectively acts on orexin type 2 receptors is expected to reduce obesity in mice resulting from a high-fat diet (Non-Patent Document 7).

It is also believed that intraventricular administration of orexin peptide shortens the time of systemic anesthesia in the rat (Non-Patent Document 8).

It is also assumed that patients with sleep apnea syndrome show low plasma levels of orexin A (Non-Patent Document 9).

It is also believed that intraventricular administration of orexin peptide improves memory retention in a mouse model of accelerated aging (SAMP8) with cognitive dysfunction (Non-Patent Document 10).

An orexin type 2 receptor agonist is also expected to be a therapeutic drug for treating heart failure (Patent Document 1, Non-Patent Document 11).

It is also believed that the daytime sleepiness of patients with Parkinson's disease is caused by damage to the orexin nerve (Non-Patent Document 12).

Orexin is also expected to regulate bone formation and loss, and an orexin type 2 receptor agonist will be a therapeutic drug for bone loss diseases such as osteoporosis, rheumatoid arthritis, and the like. (patent document 2).

It is also contemplated that an orexin receptor agonist can be used to prevent or treat sepsis, severe sepsis and septic shock, since in a mouse model of septic shock, mortality is greatly reduced simply by continuous administration of orexin from the periphery (Patent Document 3).

Thus, a compound having an orexin type 2 receptor agonist activity is expected to be useful as a novel therapeutic drug for the treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, mental disorders such as coma, and the like. narcolepsy syndrome with symptoms of narcolepsy, hypersomnia syndrome with daytime hypersomnia (eg, Parkinson's disease, Guillain-Barré syndrome, and Kleine-Lewin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss disorders, sepsis and the like, and as an anesthetic antagonist, prophylactic or therapeutic drug for treating side effects.

As sulfonamide derivatives, a compound represented by the formula

- 1 039459 where each symbol takes on the meaning defined in the document (patent document 4) and the compound represented by the formula

RN 1422063-50-0. The latter compound is an optically active form of N-(2-benzylpyrrolidin-3-yl)methanesulfonamide, which is excluded from the compound (I) of the present invention. In addition, compounds represented by the formulas are described.

- 2 039459

- 3 039459

- 4 039459

(RN 2180637-97-0)

In addition, the following compounds are described as compounds having orexin type 2 receptor agonist activity:

- 5 039459 a compound represented by the formula

R ³

Η Ί Η ι ?

W ^Ν R ⁵ °* m where each character takes on the meaning defined in the document (patent document 5); compound represented by the formula

(0 where each character takes on the meaning defined in the document (patent document 6); the compound represented by the formula

where each character takes on the meaning defined in the document (patent document 7); compound represented by the formula

where each character takes on the meaning defined in the document (patent document 8).

However, these compounds are not considered to be adequate in terms of potency, pharmacokinetics and safety, and it is still desirable to develop a compound having orexin type 2 receptor agonist activity.

List of documents

Patent Documents.

Patent document 1. WO 2015/073707 A1.

Patent document 2. WO 2015/048091 A1.

Patent document 3. WO 2015/147240 A1.

Patent document 4. WO 2012/137982 A9.

Patent document 5. WO 2015/088000 A1.

Patent document 6. WO 2016/133160 A1.

Patent document 7. WO 2016/199906 A1.

Patent document 8. WO 2017/135306 A1.

non-patent documents.

Non-Patent Document 1. Cell, Vol. 92, 573-585, 1998.

Non-Patent Document 2. Cell, Vol. 98, 365-376, 1999.

Non-Patent Document 3. Proc. Natl. Acad. sci. USA, Vol.101, 4649-4654, 2004.

Non-Patent Document 4. Cell, Vol. 98, 437-451, 1999.

Non-Patent Document 5. Neuron, Vol. 38, 715-730, 2003.

Non-Patent Document 6. CNS Drugs, Vol.27, 83-90, 2013.

Non-Patent Document 7. Cell Metabolism, Vol. 9, 64-76, 2009.

Non-Patent Document 8. Neuroscience, Vol. 121, 855-863, 2003.

Non-Patent Document 9. Respiration, Vol. 71, 575-579, 2004.

Non-Patent Document 10. Peptides, Vol. 23, 1683-1688, 2002.

Non-Patent Document 11. Journal of the American College of Cardiology. Vol. 66, 2015, pages 25222533.

Non-Patent Document 12. Brain. Vol. 130, 2007, Pages 1586-1595.

- 6 039459

The essence of the invention

Problems Solved by the Invention.

The subject of the present invention is a heterocyclic compound having agonistic activity against type 2 oxerine receptors.

Problem solving tools.

The present inventors found that the compound represented by the following formula (I) or a pharmacologically acceptable salt thereof (herein referred to as compound (I)) has an oxerine type 2 receptor agonist activity. As a result of further research, they completed the present invention.

Accordingly, the present invention provides the following items.

1) The compound represented by the formula

where R ¹ is:

(1) C _1-6 alkyl group optionally substituted with 1-3 substituents selected from:

(a) a halogen atom, and (b) a C _1-6 alkoxy group, (2) a C _3-6 cycloalkyl group optionally substituted with 1-3 halogen atoms, or (3) a mono- or di-C _1-6 alkylamino group;

R ² represents a hydrogen atom;

^R3 is:

(1) C _1-6 alkoxycarbonyl group, (2) C _1-6 alkylcarbonyl group optionally substituted with 1-3 hydroxyl groups, (3) mono- or di-C _1-6 alkylcarbamoyl group, (4) NC _1-6 alkyl-N-C _1-6 alkoxycarbamoyl group, (5) C _3-6 cycloalkylcarbonyl group (wherein C _3-6 cycloalkyl in C _3-6 cycloalkylcarbonyl group may be a ring bridging group) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom, (b) a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms, (c) a hydroxyl group, (d) a C _1-6 alkoxy group, and (e) a cyano group, (6) an oxetanylcarbonyl group , (7) an azetidinylcarbonyl group optionally substituted with 1-3 substituents selected from:

(a) a halogen atom, and (b) a C _1-6 alkyl group, or (8) a 5-azaspiro[2.3]hexylcarbonyl group;

R ⁴ and R ⁵ are both hydrogen atoms;

ring A is:

(1) a pyrrolidine ring, or (2) a piperidine ring; ring B is (1) a benzene ring further substituted with one phenyl group optionally substituted with 1-3 substituents selected from:

(i) a halogen atom, and (ii) a C _1-6 alkyl group, and optionally further substituted with one halogen atom, (2) a pyridine ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms, (3) a thiazole ring , optionally substituted with one phenyl group optionally substituted with 1-3 halogen atoms, or (4) piperidine ring optionally substituted with one phenyl group, provided that N-((2S,3S)-2-((2,3'- difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide and its pharmacologically acceptable salt are excluded.

2) A compound or a pharmacologically acceptable salt thereof according to claim 1 above, wherein

R ¹ is:

(1) C _1-6 alkyl group,

- 7 039459 (2) a C _3-6 cycloalkyl group optionally substituted with 1-3 halogen atoms, or (3) a mono- or di-C _1-6 alkylamino group;

R ² represents a hydrogen atom;

^R3 is:

(1) C _1-6 alkylcarbonyl group optionally substituted with 1-3 hydroxyl groups, (2) mono- or di-C _1-6 alkylcarbamoyl group, (3) N-Ci.6 alkyl-K-C _1-6 alkoxycarbamoyl a group or (4) an azetidinylcarbonyl group;

R ⁴ and R ⁵ are both hydrogen atoms;

ring A is a pyrrolidine ring; and ring B is a benzene ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms and optionally further substituted with one halogen atom.

[3] N-((2S,3S)-1 -(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl )methanesulfonamide or a pharmacologically acceptable salt thereof.

[4] N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl )ethanesulfonamide or a pharmacologically acceptable salt thereof.

[5] A compound selected from the following compounds:

(1) N-((2S, 3S)-1-(azetidin-1-ylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide, ( 2) N-((2S,3 S)-1 -(azetidin-1 -ylcarbonyl)-2-((3', 5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide, (3 ) N-((2 S,3 S)-1 -(azetidin-1 -ylcarbonyl)-2-(biphenyl-3 -ylmethyl)pyrrolidin-3 - yl)ethanesulfonamide, (4) N-((2 S, 3 S)-1 -(azetidin-1 -ylcarbonyl)-2-((2,3'-difluorobiphenyl-3 - yl)methyl)pyrrolidin-3-yl)ethanesulfonamide, (5) (2S,3 8)-2- ((2,3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-H N-dimethylpyrrolidine-1-carboxamide, (6) (2S,3 8)-2-((2,3' -difluorobiphenyl-3-yl)methyl)-3-((dimethylsulfamoyl)amino)A, N-dimethylpyrrolidine-1-carboxamide, (7) (28.38)-3-((ethylsulfonyl)amino)-G4, N- dimethyl-2-((2,3',5'-trifluorobiphenyl-3yl)methyl)pyrrolidine-1-carboxamide, (8) (28.38)-2-(biphenyl-3-ylmethyl)-3-((ethylsulfonyl )amino)-M-methoxy-Mmethylpyrrolidine-1-carboxamide, (9) N-[(2S, 3 S)-2-[(2,3'-difluoro [ 1, G-biphenyl]-3-yl)methyl ]-1-(2-hydroxy-2-methylpropanoyl)pyr rolidin-3-yl]-1-fluorocyclopropane-1-sulfonamide, (10) N- { (2 S, 3 S)-1 -(azetidine-1-carbonyl)-2-[(2-fluoro [ 1, G-biphenyl] -3 - yl)methyl]pyrrolidin-3-yl}ethanesulfonamide, (11) (2S,3S)-3 - [(ethanesulfonyl)amino] -2- [(3'-fluoro [ 1, G - biphenyl]-3-yl)methyl]-N-methoxy-M-methylpyrrolidine-1-carboxamide, (12) (28.38)-3-[(dimethylsulfamoyl)amino]-2-[(2-fluoro[1, G-biphenyl]-3-yl)methyl]-

N, N-dimethylpyrrolidine-1-carboxamide, (13) (2S,3 S)-3 -[(dimethylsulfamoyl)amino]-K, Xdimethyl-2- [(2,3', 5'-trifluoro[ 1, G biphenyl]-3-yl)methyl]pyrrolidin-1-carboxamide, (14) (28.38)-2-[(3',5'-difluoro[1,G-biphenyl]-3-yl)methyl]- 3-[(ethanesulfonyl)amino]N-MeTOKcn-N-methylpyrrolidine-1-carboxamide, or a pharmacologically acceptable salt thereof.

[6] An orexin type 2 receptor agonist drug containing the compound or pharmacologically acceptable salt of the above items 1 to 5.

[7] The drug according to the above item 6 for the prevention or treatment of narcolepsy.

[8] The use of a compound or a pharmacologically acceptable salt thereof according to the above items 1 to 5 for the prevention or treatment of narcolepsy.

[9] A method for activating a type 2 orexin receptor in a mammal, which comprises administering to the mammal an effective amount of a compound or a pharmacologically acceptable salt thereof according to

- 8 039459 above paragraphs 1-5.

[10] A method for preventing or treating narcolepsy in a mammal, which comprises administering to the mammal an effective amount of a compound or a pharmacologically acceptable salt thereof according to the above claims 1 to 5.

[11] The use of a compound or a pharmacologically acceptable salt thereof according to the above items 1 to 5 for the manufacture of a medicament for the prevention or treatment of narcolepsy.

Invention effect.

The compound of the present invention has an orexin type 2 receptor agonist activity and can be used as an agent for the prevention or treatment of narcolepsy.

Detailed description of the invention

The following is a definition of each substituent used in the present description. Unless otherwise stated, each substituent has the following definition.

In the present specification, examples of the halogen atom include fluorine, chlorine, bromine, and iodine.

In the present description, examples of the C _1-6 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl , 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

In the present specification, examples of an optionally halogenated C _1-6 alkyl group include a C _ ₆ alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples of such a group include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl , 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.

In the present specification, examples of the C2-6 alkenyl group include ethenyl, 1-propenyl, 2propenyl, ₂ -methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl , 2pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

In the present specification, examples of the C ₂ _ ₆ alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1hexynyl, 2 -hexynyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and 4-methyl-2-pentynyl.

In the present specification, examples of the C ₃ _ ₁₀ cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

As used herein, examples of an optionally halogenated C ₃ .o cycloalkyl group include a C ₃ .1o cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples of such a group include cyclopropyl, 2,2difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the present description, examples C ₃ . The ₁₀ cycloalkenyl group includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

In the present specification, examples of the C ₆ _ ₁₄ aryl group include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

In the present specification, examples of the C _7-16 aralkyl group include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

As used herein, examples of C _1-6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

In the present specification, examples of the optionally halogenated C _1-6 alkoxy group include a C _1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples of such a group include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy.

In the present description, examples of C ₃ - ₁₀ cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

As used herein, examples of the _{C1_6} alkylthio group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, t-butylthio, pentylthio, and hexylthio.

In the present specification, examples of the optionally halogenated _{C1_6} alkylthio group include a C _1-6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples of such a group include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

In the present specification, examples of the C _1-6 alkylcarbonyl group include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.

In the present specification, examples of an optionally halogenated _{C1_6} alkylcarbonyl group include a _{C1_6} alkylcarbonyl group optionally containing 1 to 7, preferably

- 9 039459 from 1 to 5, halogen atoms. Specific examples of such a group include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl.

In the present specification, examples of the C _1-6 alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

In the present specification, examples of the C _6-14 arylcarbonyl group include benzoyl, 1-naphthoyl, and 2-naphthoyl.

In the present specification, examples of the C _7-16 aralkylcarbonyl group include phenylacetyl and phenylpropionyl.

In the present specification, examples of the 5-14 membered aromatic heterocyclylcarbonyl group include nicotinoyl, isonicotinoyl, thienyl, and furoyl.

In the present specification, examples of the 3-14 membered non-aromatic heterocyclylcarbonyl group include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

As used herein, examples of a mono- or di-C _1-6 alkylcarbamoyl group include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and K-ethyl-K-methylcarbamoyl.

As used herein, examples of the mono- or di- _{C7_16} aralkylcarbamoyl group include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the C _1-6 alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and t-butylsulfonyl.

In the present specification, examples of the optionally halogenated C _1-6 alkylsulfonyl group include a C _1-6 alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples of such a group include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

In the present specification, examples of the C _6-14 arylsulfonyl group include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

In the present description, examples of the substituent include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxyl group, an optionally substituted sulfanyl (SH) group; and an optionally substituted silyl group.

In the present description, examples of a hydrocarbon group (including a hydrocarbon group, an optionally substituted hydrocarbon group) include a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _{3- 10} cycloalkenyl group, C6-14 aryl group and C _7-16 aralkyl group.

As used herein, examples of an optionally substituted hydrocarbon group include a hydrocarbon group optionally having a substituent(s) selected from substituent group A below.

A group of deputies

(1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxyl group, (6) an optionally halogenated C _1-6 alkoxy group, (7) a C _6-14 aryloxy group (e.g., phenoxy , naphthoxy), (8) C _7-16 aralkyloxy (e.g. benzyloxy), (9) 5-14 membered aromatic heterocyclyloxy (e.g. pyridyloxy), (10) 3-14 membered non-aromatic heterocyclyloxy (e.g. morpholinyloxy, piperidinyloxy ), (11) C _1-6 alkylcarbonyloxy (e.g. acetoxy, propanoyloxy), (12) C _6-14 arylcarbonyloxy (e.g. benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C _1-6 alkoxycarbonyloxy (e.g. , methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) mono- or di-C _1-6 alkylcarbamoyloxy group (for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) C _6-14 arylcarbamoyloxy group (for example, phenylcarbamoyloxy, naphthylcarbamoyloxy) , (16) 5-14-membered aromatic heterocyclylcarbonyloxy group (e.g. nicotinoyloxy), (17) 3-14 membered non-aromatic heterocyclylcarbonyloxy group (e.g. morpholinylcarbonyloxy, piperidinylcarbonyloxy),

- 10 039459 (18) optionally halogenated C _1-6 alkylsulfonyloxy group (eg methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) C ₆ . ₁₄ arylsulfonyloxy group optionally substituted with C _1-6 alkyl group (e.g. phenylsulfonyloxy, toluenesulfonyloxy), (20) optionally halogenated C _1-6 alkylthio group, (21) 5-14 membered aromatic heterocyclic group, (22) 3-14 membered non-aromatic heterocyclic group, (23) formyl group, (24) carboxyl group, (25) optionally halogenated C _1-6 alkylcarbonyl group, (26) C _6-14 arylcarbonyl group, (27) 5-14 membered aromatic heterocyclylcarbonyl group, (28) 3-14 membered non-aromatic heterocyclylcarbonyl group, (29) C _1-6 alkoxycarbonyl group, (30) C _6-14 aryloxycarbonyl group (e.g. phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2naphthyloxycarbonyl), (31) C _7-16 aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) carbamoyl group, (33) thiocarbamoyl group, (34) mono- or di-C _1-6 alkylcarbamoyl group, (35) C _6-14 arylcarbamoyl group (e.g., f enylcarbamoyl), (36) 5-14 membered aromatic heterocyclylcarbamoyl group (e.g. pyridylcarbamoyl, thienylcarbamoyl), (37) 3-14 membered non-aromatic heterocyclylcarbamoyl group (e.g. morpholinylcarbamoyl, piperidinylcarbamoyl), (38) optionally halogenated C _1-6 alkylsulfonyl group, (39) C _6-14 arylsulfonyl group, (40) 5-14 membered aromatic heterocyclylsulfonyl group (e.g. pyridylsulfonyl, thienylsulfonyl), (41) optionally halogenated C _1-6 alkylsulfonyl group, (42) C _{6- 14} arylsulfinyl group (e.g. phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5-14 membered aromatic heterocyclylsulfinyl group (e.g. pyridylsulfinyl, thienylsulfinyl), (44) amino group, (45) mono- or di-C1 -6 alkylamino group (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, K-ethyl-K-methylamino), (46) mono- or di-C _6-14 arylamino uppa (e.g. phenylamino), (47) 5-14 membered aromatic heterocyclylamino (e.g. pyridylamino), (48) C _7-16 aralkylamino (e.g. benzylamino), (49) formylamino, (50) C _1-6 alkylcarbonylamino (e.g. acetylamino, propanoylamino, butanoylamino), (51) (C _1-6 alkyl) (C _1-6 alkylcarbonyl)amino (e.g. N-acetyl-C-methylamino), (52) C _6-14 arycarbonylamino (e.g. , phenylcarbonylamino, naphthylcarbonylamino), (53) C _1-6 alkoxycarbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, t-butoxycarbonylamino), (54) C _{7-16 aralkyloxycarbonylamino} group (e.g., benzyloxycarbonylamino), (55) ₆ alkylsulfonylamino group (e.g. methylsulfonylamino, ethylsulfonylamino), (56) C _6-14 arylsulfonylamino group optionally substituted with C _1-6 alkyl group (e.g. phenylsulfonylamino, toluenesulfonylamino), (57) optionally halogenated C _1-6 alkyl group, (58) C _2-6 alkenyl group, (59) C _2-6 alkynyl group, (60) C _3-10 cycloalkyl group, (61) C _3-10 cycloalkenyl group, (62) C _6-14 aryl group. The number of the above substituents in the optionally substituted hydrocarbon group is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the respective substituents may be the same or different.

In the present specification, examples of a heterocyclic group (including a heterocyclic group of an optionally substituted heterocyclic group) include: (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7-10 membered heterocyclic bridging group, each of which contains, as ring-forming atoms, in addition to carbon atoms, from 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms.

In the present specification, examples of an aromatic heterocyclic group (including a 5-14 membered aromatic heterocyclic group) include 5-14 membered (preferably 5-10 membered) aromatic heterocyclic groups having 1 to 4 heteroatoms as ring-forming atoms in addition to carbon atoms. selected from nitrogen, sulfur and oxygen atoms.

Preferred examples of the aromatic heterocyclic group include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4 -oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and the like; and 8-14 membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, opazolopyridinyl, , imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, SH-indazolyl, purinyl, isoquinolyl, quinolidinyl, quinolidinyl, quinolidinyl , quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

In the present specification, examples of a non-aromatic heterocyclic group (including a 3-14 membered aromatic heterocyclic group) include a 3-14 membered (preferably 4-10 membered) non-aromatic heterocyclic group having, as ring-forming atoms, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms.

Preferred examples of the non-aromatic heterocyclic group include 3-8 membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazole, tetrahydroisoxazole, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, digidrotiopiranil, tetrahydropyrimidine, tetrahydropyridazine, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oksepanil, azocanyl, and the like diazokanil ; and 9-14 membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl , isoindolinyl, tetrahydrothieno [2,3-c] pyridinyl, tetrahydrobenzazepin, tetrahydroquinoxalinyl, tetragidrofenantridinil, geksagidrofenotiazinil, geksagidrofenoksazinil, tetrahydrophthalazine, tetragidronaftiridinil, tetrahydroquinazoline, tetragidrotsinnolinil, tetrahydrocarbazole, tetrahydro-a-carbolinyl, tetrahydro, tetragidrofenazinil, tetragidrotioksantenil, etc oktagidroizohinolil .

As used herein, preferred examples of the 7-10 membered heterocyclic bridge group include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the nitrogen-containing heterocyclic group include a heterocyclic group containing at least one nitrogen atom as ring-forming atoms.

In the present specification, examples of an optionally substituted heterocyclic group include a heterocyclic group optionally having a substituent(s) selected from substituent group A above.

The number of substituents on the optionally substituted heterocyclic group is, for example, 1 to 3. When the number of substituents is two or more, the respective substituents may be the same or different.

In the present specification, examples of the acyl group include a formyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has 1 or ₂ substituents selected from a C1.6 alkyl group, C2. ₆ alkenyl group, C ₃ _ ₁₀ cycloalkyl group, C ₃ .u cycloalkenyl group, C ₆ _ ₁₄ aryl group, C ₇ _ ₁₆ aralkyl group, 5-14 membered aromatic heterocyclic group and 3-14 membered non-aromatic heterocyclic group, each of which optionally contains 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, and a carbamoyl group.

Examples of the acyl group also include a hydrocarbon sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon sulfinyl group, and a heterocyclylsulfinyl group.

- 12 039459 group.

In the present specification, the term hydrocarbon sulfonyl group means a sulfonyl group linked to a hydrocarbon group, the term heterocyclylsulfonyl group means a sulfonyl group linked to a heterocyclic group, the term hydrocarbon sulfinyl group means a sulfinyl group linked to a hydrocarbon group, and the term heterocyclylsulfinyl group means a sulfinyl group linked to with a heterocyclic group.

Preferred examples of the acyl group include formyl group, carboxyl group, C1-6 alkylcarbonyl group, _C2-6 alkenylcarbonyl group (e.g. _crotonoyl ), _C3-10 cycloalkylcarbonyl group (e.g. cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), _{C3 - 10} cycloalkenylcarbonyl group (e.g. 2-cyclohexenecarbonyl), C _6-14 arylcarbonyl group, C _7-16 aralkylcarbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered non-aromatic heterocyclylcarbonyl group, C _1-6 alkoxycarbonyl group, C _6-14 aryloxycarbonyl group (for example, phenyloxycarbonyl, naphthyloxycarbonyl), C _7-16 aralkyloxycarbonyl group (for example, benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, mono- or di- C ₂ _ ₆ alkenylcarbamoyl group (for example, diallylcarbamoyl), mono- or di-C ₃ _ ₁₀ cycloalkylcarbamoyl group (for example, c iclopropylcarbamoyl), mono- or di- _{C6_14 arylcarbamoyl} group (e.g. phenylcarbamoyl), mono- or di- _{C7_16} aralkylcarbamoyl group, 5-14 membered aromatic heterocyclylarbamoyl group (e.g. pyridylcarbamoyl), thiocarbamoyl group, mono- or di- C _1-6 thiocarbamoyl group (for example, methylthiocarbamoyl, N-ethylN-methylthiocarbamoyl), mono- or di-C _2-6 alkenylthiocarbamoyl group (for example, diallylthiocarbamoyl), mono- or di-C ₃ _ ₁₀ cycloalkylthiocarbamoyl group (for example, cyclopropylthiocarbamoyl , cyclohexylthiocarbamoyl), a mono- or di-C _6-14 arylthiocarbamoyl group (e.g. phenylthiocarbamoyl), a mono- or di-C _7-16 aralkylthiocarbamoyl group (e.g. benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5-14 membered aromatic heterocyclylthiocarbamoyl group (e.g. , pyridylthiocarbamoyl), a sulfino group, a C _1-6 alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), a sulfonic group, a C _1-6 alkylsulfonyl group, a C _6-14 arylsulfonyl group th group, a phosphonic group and a mono- or di-C _1-6 alkylphosphono group (eg dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the optionally substituted amino group include an amino group optionally having 1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _{7- 16} aralkyl group, C _1-6 alkylcarbonyl group, C ₆ .14 arylcarbonyl group, C _7-16 aralkylcarbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered non-aromatic heterocyclylcarbonyl group, C _1-6 alkoxycarbonyl group, 5-14 membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group, mono- or di-C7_ ₁₆ aralkylcarbamoyl group, C _1-6 alkylsulfonyl group and C _6-14 arylsulfonyl group, each of which optionally contains from 1 to 3 substituents selected from substituent group A.

Preferred examples of an optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C _1-6 alkyl) amino group (for example, methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C ₂ _ ₆ an alkenylamino group (e.g. diallylamine), a mono- or di-C ₃ _ ₁₀ cycloalkylamino group (e.g. cyclopropylamino, cyclohexylamino), a mono- or di-C ₆ _ ₁₄ arylamino group (e.g. phenylamino), a mono- or di-C 7_ ₁₆ aralkylamino group (e.g. benzylamino, dibenzylamino), mono- or di-(optionally halogenated C _1-6 alkyl) carbonylamino group (e.g. acetylamino, propionylamino), mono- or di-C _6-14 arylcarbonylamino group (e.g. benzoylamino), mono- or a diC _7-16 aralkylcarbonylamino group (e.g., benzylcarbonylamino), a mono- or di-5-14 membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), a mono- or di-3-14-membered non-aromatic hetero ocyclylcarbonylamino group (e.g. piperidinylcarbonylamino), mono- or di-C _1-6 alkoxycarbonylamino group (e.g. t-butoxycarbonylamino), 5-14 membered aromatic heterocyclylamino group (e.g. pyridylamino), carbamoylamino group, (mono- or di-C _1-6 alkylcarbamoyl)amino group (e.g. methylcarbamoylamino), (mono- or di-C7_ ₁₆ aralkylcarbamoyl)amino group (e.g. benzylcarbamoylamino), C _1-6 alkylsulfonylamino group (e.g. methylsulfonylamino, ethylsulfonylamino), C6-1 ₄ arylsulfonylamino group (e.g. phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkylcarbonyl) amino group (for example, N-acetyl-N-methylamino) and (C _1-6 alkyl) (C _6-14 arylcarbonyl) amino group (for example, N-benzoyl-N -methylamine).

In the present specification, examples of the optionally substituted carbamoyl group include a carbamoyl group optionally having 1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkylcarbonyl group, C _6-14 arylcarbonyl group, C _7-16 aralkylcarbonyl group

- 13 039459 group, 5-14-membered aromatic heterocyclylcarbonyl group, 3-14-membered non-aromatic heterocyclylcarbonyl group, C1- _b alkoxycarbonyl group, 5-14-membered aromatic heterocyclic group, carbamoyl group, mono-or di- _{C1_b} alkylcarbamoyl group and a mono- or di-C ₇ _ _1b aralkylcarbamoyl group, each of which optionally contains from 1 to substituents selected from substituent group A.

Preferred examples of an optionally substituted carbamoyl group include a carbamoyl group, a mono- or di- _{C1_b} alkylcarbamoyl group, a mono- or di- _{C2_b} alkenylcarbamoyl group (e.g., _{diallylcarbamoyl} ), a mono- or di- _{C3_10} cycloalkylcarbamoyl group (e.g., cyclopropylcarbamoyl , cyclohexylcarbamoyl), mono- or di-C _b - ₁₄ arylcarbamoyl group (for example, phenylcarbamoyl), mono- or di-C ₇ - _1b aralkylcarbamoyl group, mono- or di-C1_ _b alkylcarbonylcarbamoyl group (for example, acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C _b - ₁₄ arylcarbonylcarbamoyl group (eg benzoylcarbamoyl); and a 5-14 membered aromatic heterocyclylcarbamoyl group (eg pyridylcarbamoyl).

As used herein, examples of an optionally substituted thiocarbamoyl group include a thiocarbamoyl group optionally having 1 or ₂ substituents selected from C1- _b alkyl group, C2-6 alkenyl group, _{C3_1o} cycloalkyl group, _{Cb_14 aryl} group, _C7 . _1b aralkyl group, C1- _b alkylcarbonyl group, _Cb _ ₁₄ arylcarbonyl group, C ₇ _ _1b aralkylcarbonyl group, 5-14-membered aromatic heterocyclylcarbonyl group, 3-14-membered non-aromatic heterocyclylcarbonyl group, C1- _b alkoxycarbonyl group, 5- A 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di- _{C1_b} alkylcarbamoyl group, and a mono- or di- _{C7-1b aralkylcarbamoyl} group, each of which optionally contains 1 to 3 substituents selected from substituent group A.

Preferred examples of an optionally substituted thiocarbamoyl group include a thiocarbamoyl group, mono- or di-C1. _b alkylthiocarbamoyl group (for example, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C ₂ -b alkenylthiocarbamoyl group (for example, diallylthiocarbamoyl), mono- or di-C ₃ _ ₆ cycloalkylthiocarbamoyl group (e.g. cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di- _{C6_14 arylthiocarbamoyl} group (e.g. phenylthiocarbamoyl), mono- or di- _{C7_1b aralkylthiocarbamoyl} group (e.g. benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di- _{C1_b} an alkylcarbonylthiocarbamoyl group (eg, acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di- _{C6_14} arylcarbonylthiocarbamoyl group (eg, _{benzoylthiocarbamoyl} ), and a 5-14 membered aromatic heterocyclylthiocarbamoyl group (eg, pyridylthiocarbamoyl).

As used herein, examples of an optionally substituted sulfamoyl group include a sulfamoyl group optionally having 1 or 2 substituents selected from C _1-b alkyl group, C 2- _b alkenyl group, C ₃ _ _1o cycloalkyl group, C _b - ₁₄ aryl group, C ₇ - _1b aralkyl group, C _1-b alkylcarbonyl group, C _b - ₁₄ arylcarbonyl group, C ₇ - _1b aralkylcarbonyl group, 5-14-membered aromatic heterocyclylcarbonyl group, 3-14-membered non-aromatic heterocyclylcarbonyl group, C1_ _b alkoxycarbonyl group, 5 -14-membered aromatic heterocyclic group, carbamoyl group, mono-or di- _{C1_b} alkylcarbamoyl group and mono- or di- _{C7_1b aralkylcarbamoyl} group, each of which optionally contains from 1 to 3 substituents selected from substituent group A.

Preferred examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di- _{C1-6 alkylsulfamoyl} group (e.g. , diallylsulfamoyl), mono- or di-C ₃ - ₁₀ cycloalkylsulfamoyl group (for example, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or diC _b - ₁₄ arylsulfamoyl group (for example, phenylsulfamoyl), mono- or di-C ₇ - _1b aralkylsulfamoyl group ( e.g., benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C1- _b alkylcarbonylsulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), a mono- or di- _{Cb_14} arylcarbonylsulfamoyl group (e.g., _{benzoylsulfamoyl} ), and a 5-14 membered aromatic heterocyclylsulfamoyl group (for example, pyridylsulfamoyl).

In the present specification, examples of the optionally substituted hydroxyl group include a hydroxyl group optionally having a substituent selected from _{C1_b} alkyl group, _{C2_b} alkenyl group, _{C3_1o cycloalkyl} group, _{Cb_14 aryl} group, _{C7_1b aralkyl group} , C _1-b alkylcarbonyl group, C _b - ₁₄ arylcarbonyl group, C ₇ - _1b aralkylcarbonyl group, 5-14-membered aromatic heterocyclylcarbonyl group, 3-14-membered non-aromatic heterocyclylcarbonyl group, C _1-b alkoxycarbonyl group, 5-14 -membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkylcarbamoyl group, a mono- or di- _C7-1b aralkylcarbamoyl group, a _{C1 -b alkylsulfonyl group} , and a _C6-14 arylsulfonyl group, each of which is optional contains from 1 to 3 substituents selected from substituent group A.

Preferred examples of an optionally substituted hydroxyl group include a hydroxyl group, a C _1-6 alkoxy group, a C _2-6 alkenyloxy group (for example, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C ₃ . ), C _{6-1 4} aryloxy (e.g. phenoxy, naphthyloxy), C _7-16 aralkyloxy (e.g. benzyloxy, phenethyloxy), C _1-6 alkylcarbonyloxy (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _{6 -14} arylcarbonyloxy (e.g. benzoyloxy), C _7-16 aralkylcarbonyloxy (e.g. benzylcarbonyloxy), 5-14 membered aromatic heterocyclylcarbonyloxy (e.g. nicotinoyloxy), 3-14 membered non-aromatic heterocyclylcarbonyloxy (e.g. piperidinylcarbonyloxy), C _1-6 alkoxycarbonyloxy (e.g. t-butoxycarbonyloxy), 5-14 membered aromatic heterocyclyloxy (e.g. pyridyloxy), carbamoyloxy, C1.6 alkylcarb a moyloxy group (eg methylcarbamoyloxy), a C _7-16 aralkylcarbamoyloxy group (eg benzylcarbamoyloxy, a C _1-6 alkylsulfonyloxy group (eg methylsulfonyloxy, ethylsulfonyloxy) and a C6-14 arylsulfonyloxy group (eg phenylsulfonyloxy).

In the present specification, examples of the optionally substituted sulfanyl group include a sulfanyl group optionally having a substituent selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 an aralkyl group, a C _1-6 alkylcarbonyl group, a C _6-14 arylcarbonyl group, and a 5-14 membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from substituent group A and a halogenated sulfanyl group.

Preferred examples of an optionally substituted sulfanyl group include a sulfanyl (-SH) group, a C _1-6 alkylthio group, a C _2-6 alkenylthio group (for example, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C ₃ . , cyclohexylthio), C _6-14 arylthio (e.g. phenylthio, naphthylthio), C _7-16 aralkylthio (e.g. benzylthio, phenethylthio), C _1-6 alkylcarbonylthio (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C a _6-14 arylcarbonylthio group (eg benzoylthio), a 5-14 membered aromatic heterocyclylthio group (eg pyridylthio) and a halogenated thio group (eg pentafluorothio).

In the present specification, examples of the optionally substituted silyl group include a silyl group optionally having 1 to 3 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, and C _7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A.

Preferred examples of an optionally substituted silyl group include a tri-C _1-6 alkylsilyl group (eg trimethylsilyl, t-butyl(dimethyl)silyl).

In the present specification, examples of the hydrocarbon ring include C _6-14 aromatic hydrocarbon ring, C _3-10 cycloalkane, and C ₃ .u cycloalkene.

In the present description, examples of the C _6-14 aromatic hydrocarbon ring include benzene and naphthalene.

In the present specification, examples of the C _3-10 cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

In the present specification, examples of the C _3-10 cycloalkene include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

In the present specification, examples of the heterocycle include an aromatic heterocycle and a non-aromatic heterocycle, each of which contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen as ring-forming atoms.

In the present specification, examples of the aromatic heterocycle include a 5-14-membered (preferably 5-10-membered) aromatic heterocycle having, as ring-forming atoms, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms. Preferred examples of the aromatic heterocycle include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole , 1,3,4-oxadiazole, 1,2,4thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and 8-14 membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazol, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiine, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, naphthalazine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine, and the like.

As used herein, examples of the non-aromatic heterocycle include a 3-14-membered (preferably 4-10-membered) non-aromatic heterocycle having, as ring-forming atoms, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen.

- 15 039459

Preferred examples of the non-aromatic heterocycle include 3-8 membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepan, diazepan, azepine, azocan, diazocan, oxepan, and the like; and 9-14 membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazol, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolysine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquino.

In the present description, examples of a nitrogen-containing heterocycle from the heterocycle group include a heterocycle containing at least one nitrogen atom as a ring-forming atom.

In the present description, examples of a 4-7 membered nitrogen-containing saturated monocyclic heterocycle from the group of 3-8 membered monocyclic non-aromatic heterocycle include a 4-7 membered saturated heterocycle containing at least one nitrogen atom as a ring-forming atom.

In the present description, examples of the ring include a hydrocarbon ring and a heterocycle. The definition of each symbol in formula (I) is described in detail below.

R ¹ is:

( ₁ ) a C1-6 alkyl group (eg methyl, ethyl) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom), and (b) a C _1-6 alkoxy group (eg methoxy), (2) a C ₃ - ₆ cycloalkyl group (eg cyclopropyl) optionally substituted with 1-3 halogen atoms (eg , a fluorine atom), or (3) a mono- or di- _{C1_6} alkylamino group (eg dimethylamino). R ¹ is preferably:

(1) a C _1-6 alkyl group (eg methyl, ethyl), (2) a C ₃ - ₆ cycloalkyl group (eg cyclopropyl) optionally substituted with 1-3 halogen atoms (eg fluorine atom), or (3) mono - or a di-C1-6 alkylamino _group (eg dimethylamino).

Or, particularly preferably, R ¹ is a _C1-6 alkyl group (eg methyl, ethyl). R ¹ is even more preferably:

( ₁ ) a C1-6 alkyl group (eg methyl, ethyl, propyl) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom, chlorine atom), and (b) a _{C1_6} alkoxy group (eg methoxy), (2) a C _{3 -6} cycloalkyl group (eg cyclopropyl) or (3) mono- or di -C1_6 alkylamino group ₍ eg dimethylamino). R ¹ is particularly preferably:

(1) a C1-6 alkyl group (eg methyl, ethyl) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom), and (b) a C _1-6 alkoxy group (eg methoxy), or (2) a C ₃ - ₆ cycloalkyl group (eg cyclopropyl). R ² represents a hydrogen atom. ^R3 is:

(1) _{C1_6} alkoxycarbonyl group (eg ethoxycarbonyl, isopropoxycarbonyl), ( ₂ ) C1-6 alkylcarbonyl group (eg 2-methylpropanoyl, pivaloyl) optionally substituted with 1-3 hydroxyl groups, (3) mono- or di-C1_ ₆ alkylcarbamoyl group (eg dimethylcarbamoyl), (4) N-Ci. ₆ alkyl-K-C1. ₆ alkoxycarbamoyl group (e.g. N-methoxy-N-methylcarbamoyl), ( ₅ ) C3-6 cycloalkylcarbonyl group (wherein C3-6 cycloalkyl in the C ₃ _ ₆ cycloalkylcarbonyl group may be a ring bridging group, e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo[ 1.1.1]pentylcarbonyl), optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom), (b) a C _1-6 alkyl group (eg methyl) optionally substituted with 1-3 halogen atoms (eg fluorine atoms),

- 16 039459 (c) a hydroxyl group, (d) a C _1-6 alkoxy group (e.g. methoxy), and (e) a cyano group, (6) an oxetanylcarbonyl group, (7) an azetidinylcarbonyl group optionally substituted with 1-3 substituents selected from :

(a) a halogen atom (eg, a fluorine atom), and (b) a C _1-6 alkyl group (eg, methyl), or (8) a 5-azaspiro[2.3]hexylcarbonyl group. R ³ is preferably:

(1) C _1-6 alkylcarbonyl group (eg 2-methylpropanoyl) optionally substituted with 1-3 hydroxyl groups, (2) mono- or di-C _1-6 alkylcarbamoyl group (eg dimethylcarbamoyl), (3) N- Ci. ₆ αlkyl-N-Cl. ₆ alkoxycarbamoyl group (eg N-methoxy-N-methylcarbamoyl), or (4) azetidinylcarbonyl group.

Or R ³ is particularly preferably a C _1-6 alkylcarbonyl group (eg 2-methylpropanoyl) optionally substituted with 1-3 hydroxyl groups.

R ³ is particularly preferably:

(1) C _1-6 alkoxycarbonyl group (for example, ethoxycarbonyl, isopropoxycarbonyl), (2) C _1-6 alkylcarbonyl group (for example, 2-methylpropanoyl, pivaloyl), (3) C _3-6 cycloalkylcarbonyl group (wherein C _3- The ₆ cycloalkyl in the C _3-6 cycloalkylcarbonyl group may be a ring bridging group, eg cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo[1.1.1]pentylcarbonyl), optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, methyl) optionally substituted with 1-3 halogen atoms (for example, a fluorine atom), (c) a hydroxyl group, (d) C _1-6 alkoxy (e.g. methoxy), and (e) cyano, (4) oxetanylcarbonyl group, (5) azetidinylcarbonyl group optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom), and (b) a C1-6 alkyl group (eg methyl), or (6) a 5-azaspiro[2.3]hexylcarbonyl group. In this embodiment, R ³ is particularly preferably:

(1) C _1-6 alkoxycarbonyl group (eg ethoxycarbonyl, isopropoxycarbonyl), (2) C _1-6 alkylcarbonyl group (eg 2-methylpropanoyl, pivaloyl) optionally substituted with 1-3 hydroxyl groups, (3) mono- or a di-C _1-6 alkylcarbamoyl group (e.g., dimethylcarbamoyl), (4) a C _3-6 cycloalkylcarbonyl group (wherein the C _3-6 cycloalkyl in the C _3-6 cycloalkylcarbonyl group may be a ring bridging group, e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo [1.1.1]pentylcarbonyl) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, methyl) optionally substituted with 1-3 halogen atoms (for example, a fluorine atom), (c) a hydroxyl group, (d) C1-6 alkoxy (e.g. methoxy), and (e) cyano, (5) oxetanylcarbonyl group, (6) azetidinylcarbonyl group optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom), and (b) a C _1-6 alkyl group (eg methyl), or (7) a 5-azaspiro[2.3]hexylcarbonyl group.

Both R ⁴ and R ⁵ represent a hydrogen atom.

Ring A is:

(1) a pyrrolidine ring, or (2) a piperidine ring. Ring B is (1) a benzene ring further substituted with one phenyl group optionally substituted with 1-3 substituents selected from:

(i) a halogen atom (eg fluorine atom, chlorine atom), and (ii) a C _1-6 alkyl group (eg methyl), and optionally further substituted with one halogen atom (eg fluorine atom),

- 17 039459 (2) a pyridine ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms (e.g. fluorine atom), (3) a thiazole ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms (e.g. , a fluorine atom), or (4) a piperidine ring further substituted with one phenyl group. Ring B is preferably a benzene ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms (eg fluorine atoms) and optionally further substituted with one halogen atom (eg fluorine atom).

With respect to the A ring of compound (I), the configuration with respect to the carbon atom to which the -NR2SO2R ¹ group is attached and the carbon atom to which the -CR ⁴ R ⁵ -ring B group is attached (for example, when ring A is a pyrrolidine ring or piperidine ring, configuration of positions 2 and 3) is preferably the cis form. Those. compound (I) is preferably a compound represented by formula (IA) or (IB)

where each symbol takes on the meaning defined above, more preferably represented by formula (IA)

where each character takes on the value defined above.

Preferred examples of the compound (I) include the compounds shown below. These compounds are preferably represented by the above formula (IA) or (IB), more preferably the above formula (IA).

Compound F-3.

Compound (I), in which

R ¹ is:

(1) C _1-6 alkyl group (eg methyl, ethyl) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom), and (b) a C _1-6 alkoxy group (eg methoxy), (2) a C _3-6 cycloalkyl group (eg cyclopropyl) optionally substituted with 1-3 halogen atoms ( eg a fluorine atom), or (3) a mono- or di-C _1-6 alkylamino group (eg dimethylamino);

R ² represents a hydrogen atom;

^R3 is:

(1) a C _1-6 alkoxycarbonyl group (eg ethoxycarbonyl, isopropoxycarbonyl), (2) a C _1-6 alkylcarbonyl group (eg 2-methylpropanoyl, pivaloyl) optionally substituted with 1-3 hydroxyl groups, (3) mono- or di-C _1-6 alkylcarbamoyl group (eg dimethylcarbamoyl), (4) NC _1-6 alkyl-N-C _1-6 alkoxycarbamoyl group (eg N-methoxy-N-methylcarbamoyl), (5) C _3-6 a cycloalkylcarbonyl group (wherein the C _3-6 cycloalkyl in the C _3-6 cycloalkylcarbonyl group may be a ring bridging group, e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, bicyclo[1.1.1]pentylcarbonyl) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, methyl) optionally substituted with 1-3 halogen atoms (for example, a fluorine atom), (c) a hydroxyl group, (d) C _1-6 alkoxy groups (e.g. methoxy), and

- 18 039459 (e) cyano groups, (6) oxetanylcarbonyl group, (7) azetidinylcarbonyl group optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (eg fluorine atom), and (b) a C1.6 alkyl group (eg methyl), or (8) a 5-azaspiro[2.3]hexylcarbonyl group;

R ⁴ and R ⁵ are both hydrogen atoms;

Ring A is:

(1) a pyrrolidine ring, or (2) a piperidine ring;

ring B is (1) a benzene ring further substituted with one phenyl group optionally substituted with 1-3 substituents selected from:

(i) a halogen atom (eg fluorine atom, chlorine atom), and (ii) a C1-6 alkyl group (eg methyl), and optionally further substituted with one halogen atom (eg fluorine atom), (2) a pyridine ring, optionally substituted with one phenyl group optionally substituted with 1-3 halogen atoms (e.g. fluorine atom), (3) thiazole ring optionally substituted with one phenyl group optionally substituted with 1-3 halogen atoms (e.g. fluorine atom), or (4) a piperidine ring further substituted with one phenyl group.

Compound G-1.

Compound (I), in which

R ¹ is:

(1) C1-6 alkyl group (eg methyl, ethyl), (2) C ₃ . ₆ a cycloalkyl group (eg cyclopropyl) optionally substituted with 1-3 halogen atoms (eg fluorine atom), or (3) a mono- or di-C1-6 alkylamino group (eg dimethylamino);

R ² represents a hydrogen atom;

^R3 is:

(1) C1. ₆ alkylcarbonyl group (eg 2-methylpropanoyl) optionally substituted with 1-3 hydroxyl groups, (2) mono- or di-C1. ₆ alkylcarbamoyl group (eg dimethylcarbamoyl), (3) NC^ αkyl-N-C ₁ . ₆ alkoxycarbamoyl group (eg N-methoxy-N-methylcarbamoyl), or (4) azetidinylcarbonyl group;

R ⁴ and R ⁵ are both hydrogen atoms;

ring A is a pyrrolidine ring;

ring B is a benzene ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms (eg fluorine atoms) and optionally further substituted with one halogen atom (eg fluorine atom).

Compound G-2.

Compound (I), in which

R ¹ is a C1.6 alkyl group (eg methyl, ethyl);

R ² represents a hydrogen atom;

R ³ is C1. ₆ alkylcarbonyl group (eg 2-methylpropanoyl) optionally substituted with 1-3 hydroxyl groups;

R ⁴ and R ⁵ are both hydrogen atoms;

ring A is a pyrrolidine ring;

ring B is a benzene ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms (eg fluorine atoms) and optionally further substituted with one halogen atom (eg fluorine atom).

Compound I

N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide or its pharmacologically acceptable salt.

Compound J

N-((2S,3 S)-1 -(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3 yl)methyl)pyrrolidin-3-yl)ethanesulfonamide or its pharmacologically acceptable salt.

Compound K.

Connection selected from

- 19 039459 (1) N-((2S,3 S)-1 -(azetidin-1 -ylcarbonyl)-2-((2,3'-difluorobiphenyl-3 yl)methyl)pyrrolidin-3-yl)methanesulfonamide, (2) N-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-((3', 5'-difluorobiphenyl-3 yl)methyl)pyrrolidin-3-yl)ethanesulfonamide, (3 ) N-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-(biphenyl-3-ylmethyl)pyrrolidin-3yl)ethanesulfonamide, (4) N-((2S,3S)- 1 -(azetidin-1 -ylcarbonyl)-2-((2,3'-difluorobiphenyl-3 - yl)methyl)pyrrolidin-3-yl)ethanesulfonamide, (5) (2S,3 8)-2-((2 ,3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-X Ndimethylpyrrolidine-1-carboxamide, (6) (2S,3 8)-2-((2,3'-difluorobiphenyl- 3-yl)methyl)-3-((dimethylsulfamoyl)amino)-X N-dimethylpyrrolidine-1-carboxamide, (7) (28.38)-3-((ethylsulfonyl)amino)^, M-dimethyl-2- ((2,3',5'-trifluorobiphenyl-3yl)methyl)pyrrolidine-1-carboxamide, (8) (28.38)-2-(biphenyl-3-ylmethyl)-3-((ethylsulfonyl)amino)- M-methoxy-Mmethylpyrrolidine-1-carboxamide, (9) N-[(2S, 3 S)-2-[(2,3'-difluoro [ 1, G-biphenyl] -3 -yl)methyl]-1 - (2-hydroxy-2-methylpropano yl)pyrrolidin-3 -yl]-1-fluoro cyclopropan-1-sulfonamide, (10) N- { (2 S, 3 S)-1 -(azetidine-1-carbonyl)-2-[(2-fluoro [ 1, G-biphenyl] -3 - yl)methyl]pyrrolidin-3-yl}ethanesulfonamide, (11) (2S,3S)-3 - [(ethanesulfonyl)amino] -2- [(3'-fluoro [ 1, G-biphenyl]-3-yl)methyl]-N-methoxy-M-methylpyrrolidine-1-carboxamide, (12) (28.38)-3-[(dimethylsulfamoyl)amino]-2-[(2-fluoro[ 1,G-biphenyl]-3-yl)methyl]-

N, N-dimethylpyrrolidine-1-carboxamide, (13) (2 S, 3 S)-3 -[(dimethylsulfamoyl)amino] -N, N-dimethyl-2- [(2,3', 5'-trifluoro [ 1 , G biphenyl]-3-yl)methyl]pyrrolidin-1-carboxamide and (14) (2S,3S)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl) methyl]-3-[(ethanesulfonyl)amino]-

M-methoxy-M-methyl pyrrole id in-1-carboxamide, or a pharmacologically acceptable salt thereof.

Compound L.

A compound selected from (1) (2S,3 8)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-X Ndimethylpyrrolidine-1-carboxamide, (2 ) (28.38)-3-((ethylsulfonyl)amino)^, ^dimethyl-2-((2,3',5'-trifluorobiphenyl-3yl)methyl)pyrrolidine-1-carboxamide, (3) ^[( 28.38)-2-[(2,3'-difluoro[1,G-biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-1 - cyclopropane-1-sulfonamide fluorine, (4) N- {(2S,3 S)-1 -(azetidine-1-carbonyl)-2-[(2-fluoro[1,1'-biphenyl]-3-yl) methyl]pyrrolidin-3-yl}ethanesulfonamide, (5) (28.38)-3-[(ethanesulfonyl)amino]-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl ]-Hmethoxy-N-methylpyrrolidine-1-carboxamide and (6) (28.38)-3-[(dimethylsulfamoyl)amino]-2-[(2-fluoro[1,G-biphenyl]-3-yl)methyl ]-

N,N-dimethylpyrrolidine-1-carboxamide, or a pharmacologically acceptable salt thereof.

Specific examples of Compound (I) include the compounds of Examples 1-488 below.

As the salt of the compound represented by formula (I), a pharmacologically acceptable salt thereof is preferable, and examples of such a salt include an inorganic base salt, an organic base salt, an inorganic acid salt, an organic acid salt, a basic or acidic amino acid salt, etc. .P.

Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salts, ammonium salts and the like.

Preferred examples of the organic base salt include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc. P.

Preferred examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

Preferred examples of organic acid salts include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid; and the like.

Preferred examples of the basic amino acid salt include salts with arginine, lysine, ornithine, and the like.

Preferred examples of the acidic amino acid salt include salts with aspartic acid, glutamic acid, and the like.

The following describes a method for producing the compound of the present invention.

The starting compound and the reagent used, as well as the compound obtained in each step in the following production method, may be in the form of a salt, and examples of such a salt include salts similar to those of the compound of formula (I), and the like.

When the compound obtained in each step is a free form compound, it can be converted to the desired salt according to a known method. When the compound obtained in each step is a salt, it may be converted to the desired free form or other salt according to a known method.

The compound obtained in each step can be used directly in the next step as a reaction mixture or as a crude product. Alternatively, the compound obtained in each step can be isolated from the reaction mixture and purified according to known methods, such as separation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography, and the like.

When the starting compound and the reagent used in each step are commercially available, the commercially available product can also be used directly.

Although the reaction time varies in each step depending on the reagent and solvent used, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours, unless otherwise indicated.

Although the reaction temperature varies in each step depending on the reagent and solvent used, it is generally in the range -78 to 300°C, preferably -78 to 150°C, unless otherwise indicated.

Although the pressure varies in each step depending on the reagent and solvent used, it is usually between 1 atm (101.325 kPa) and 20 atm (2026.5 kPa), preferably between 1 atm (101.325 kPa) and 3 atm (303.975 kPa), unless otherwise specified.

At any stage of the synthesis, a microwave reaction reactor such as Biotage's Initiator and the like can be used. Although the reaction temperature varies in each step depending on the reagent and solvent used, it is generally in the range of room temperature to 300°C, preferably 50 to 250°C, unless otherwise indicated. Although the reaction time varies in each step depending on the reagents and solvents used, it is usually from 1 minute to 48 hours, preferably from 1 minute to 8 hours, unless otherwise indicated.

At any stage in the reaction, the reagent is used in an amount of from 0.5 equivalents to 20 equivalents, preferably from 0.8 equivalents to 5 equivalents, relative to the substrate, unless otherwise indicated. When the reagent is used as a catalyst, it is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When a reagent is used as a reaction solvent, the reagent is used in the amount in which the solvent is used.

Unless otherwise indicated, the reaction at any stage of the synthesis is carried out without solvent or with dissolution or suspension of the starting compound in a suitable solvent. Examples of solvents include the solvents described in the examples and the solvents below.

Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like; aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.;

saturated hydrocarbons: cyclohexane, hexane, etc.;

amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;

- 21 039459 halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

nitriles: acetonitrile and the like;

sulfoxides: dimethyl sulfoxide and the like;

aromatic organic bases: pyridine and the like;

anhydrides: acetic anhydride and the like;

organic acids: formic acid, acetic acid, trifluoroacetic acid, and the like;

inorganic acids: hydrochloric acid, sulfuric acid, etc.;

esters: ethyl acetate and the like;

ketones: acetone, methyl ethyl ketone, etc.;

water.

The above solvents can be used as a mixture of two or more solvents in a suitable ratio.

When a base is used in the reaction at any stage of the synthesis, examples of such a base include the bases described in the examples and the bases below.

Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.;

organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine and etc.;

metal alkoxides: sodium ethoxide, potassium t-butoxide, and the like;

alkali metal hydrides: sodium hydride and the like;

metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like; organic lithium compounds: n-butyllithium, etc.

When an acid or an acid catalyst is used in the reaction at any stage of the synthesis, examples of such acid and acid catalyst include the acids and acid catalysts described in the examples, as well as the acids and acid catalysts below.

Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.;

organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like;

Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, and the like.

Unless otherwise indicated, the reactions in each synthesis step are carried out according to a known method, for example, the method described in Jikken Kagaku ^Kouza , 5th Edition, vol. 13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza Vol. 14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, ^Nankodo ); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol.1-Vol.14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, etc., or in the manner described in the examples.

The functional group protection or deprotection reaction at any stage of the synthesis is carried out in accordance with a known method, for example, the method described in Protective Groups in Organic Synthesis, 4 ^th Ed, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter GM Wuts ); Protecting Groups 3rd Ed. Thieme, 2004 (PJ Kocienski), or the like, or in the manner described in the examples.

Examples of a protecting group for the hydroxyl group of an alcohol, and the like. and phenol hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; ester carboxylate type protecting groups such as an acetic acid ester group and the like; ester sulfonate type protecting groups such as a methanesulfonic acid ester group and the like; ester-type protecting groups of carboxylic acids such as a t-butyl carbonate group and the like.

Examples of a protecting group for an aldehyde carbonyl group include acetal-type protecting groups such as a dimethyl acetal group and the like; cyclic acetal type protecting groups such as 1,3-dioxane and the like.

Examples of a protecting group for a ketone carbonyl group include ketal-type protecting groups such as a dimethylketal group and the like; cyclic ketal type protecting groups such as a 1,3-dioxane group and the like; oxime-type protecting groups such as the O-methyloxime group and the like; hydrazone type protecting groups such as N,N-dimethylhydrazone group and the like.

Examples of a protecting group for a carboxyl group include an ester-type protecting group such as a methyl ester group and the like; amide type protecting groups such as N,N-dimethylamide group and the like.

- 22 039459

Examples of a protecting group for a thiol include ether-type protecting groups such as a benzyl thioether group and the like; ester-type protecting groups such as a thioacetate, thiocarbonate, thiocarbamate group, and the like.

Examples of a protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate-type protecting groups such as a benzyl carbamate group and the like; amide type protecting groups such as an acetamide group and the like; alkylamine type protecting groups such as N-triphenylmethylamine group and the like; sulfonamide-type protecting groups such as a methanesulfonamide group, and the like.

Protecting groups can be removed according to a known method, for example, using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilylyl iodide, trimethylsilyl bromide) and the like, by the method recovery, etc.

When a reduction reaction is carried out at any stage of the synthesis, examples of reducing agents that can be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride, and the like; boranes such as a complex of tetrahydrofuran and borane; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. When a carbon-carbon double or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar's catalyst, and the like can be used.

When an oxidation reaction is carried out at any stage of the synthesis, examples of an oxidizing agent that can be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, t-butyl hydroperoxide, and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese, such as manganese dioxide, potassium permanganate, and the like; lead compounds such as lead tetraacetate and the like; reagents containing chromium, such as pyridinium chlorochromate (pyridinium chlorochromate - PCC), pyridinium dichromate (pyridinium dichromate - PDC), Jones reagent, etc.; halogenated compounds such as N-bromosuccinimide (N-bromosuccinimide NBS) and the like; oxygen; ozone; complex of sulfur trioxide and pyridian; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2,3-dichloro-5,6-dicyano-1,4-benzoquinone - DDQ) and the like.

When a radical reaction is carried out at any stage of the synthesis, examples of the radical initiator that can be used include an azo compound such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4,4'-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboron in the presence of air or oxygen; benzoyl peroxide; and the like. Examples of the radical reagent that can be used include tributylstannan, tris(trimethylsilyl)silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, and the like.

When a Wittig reaction is carried out at any stage of the synthesis, examples of the Wittig reagent that can be used include alkylidene phosphoranes and the like. Alkylidene phosphoranes can be prepared according to a known method, for example by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is carried out at any stage of the synthesis, examples of reagents that can be used include phosphonoacetates such as methyldimethylphosphonoacetate, ethyldiethylphosphonoacetate, and the like; and bases such as alkali metal hydrides, organic lithium compounds, and the like.

When a Friedel-Crafts reaction is carried out at any stage of the synthesis, a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (eg, alkyl halide, alcohol, olefin, etc.) is used as a reactant. Alternatively, an organic acid or an inorganic acid may be used in place of the Lewis acid, and an anhydride such as acetic anhydride and the like may be used in place of the acid chloride.

When an aromatic nucleophilic substitution reaction is carried out at any stage of the synthesis, a nucleophile (eg, amine, imidazole, etc.) and a base (eg, organic base, etc.) are used as reactants.

When a nucleophilic addition reaction using a carboanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) using a carboanion, or a nucleophilic substitution reaction using a carboanion is carried out in any step of the synthesis, examples of the base used to prepare the carboanion include organic lithium compounds, alkoxides metals, inorganic bases, organic bases, etc.

When the Grignard reaction is carried out at any stage of the synthesis, examples of the Grignard reagent that can be used include aryl magnesium halides such as phenyl magnesium bromide and the like; and alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared in accordance with a known method, for example by reacting an alkyl halide or an aryl halide with

- 23 039459 magnesium metal in ether or tetrahydrofuran as solvent.

When a Knoevenagel condensation reaction is carried out at any stage of the synthesis, a compound containing an activated methylene group with two electron withdrawing groups (for example, malonic acid, malonic acid diethyl ester, malononitrile, etc.) and a base (for example, an organic base, metal alkoxide, inorganic base).

When the Vilsmeier-Haack reaction is carried out at any stage of the synthesis, phosphoryl chloride and an amide derivative (eg, K,K-dimethylformamide, etc.) are used as reagents.

When an azidation reaction of an alcohol, an alkyl halide, or a sulfonate is carried out at any stage of the synthesis, examples of the azidation reagent that can be used include diphenylphosphorylazide (DPPA), trimethylsilyl azide, sodium azide, and the like. For example, for the alcohol azidation reaction, a method using diphenylphosphoryl azide and 1,8diazabicyclo[5.4.0]undec-7-ene (DBUY) and a method using trimethylsilyl azide and a Lewis acid, and the like can be used.

When a reductive amination reaction is carried out at any stage of the synthesis, examples of a reducing agent that can be used include sodium triacetoxyboroide, sodium cyanobororide, hydrogen, formic acid, and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine, and the like; secondary amines such as dimethylamine and the like.

When the Mitsunobu reaction is carried out at any stage of the synthesis, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as a reactant.

When an esterification reaction, an amidation reaction, or a urea production reaction is carried out in any synthetic step, examples of a reagent that can be used include acyl halides such as acid chlorides, acid bromides, and the like; activated carboxylic acids such as acid anhydrides, activated esters, sulfates, and the like. Examples of the carboxylic acid activating agent include carbodiimide condensing reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing reagents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMTMM) and the like; carbonate condensing reagents such as 1,1-carbonyldiimidazole (CDI), and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trivdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Muqayyama's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N',N'tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; their combinations, etc. When a carbodiimide condensing agent is used, 1-hydroxybenzotriazole (HOBt), Nhydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be added to the reaction system.

When a coupling reaction is carried out at any stage of the synthesis, examples of the metal catalyst that can be used include palladium compounds such as palladium(P) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(P), dichlorobis(triethylphosphine )palladium(II), tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and the like; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide and the like; platinum compounds, etc. In addition, a base may be added to the reaction system, and examples thereof include inorganic bases and the like.

When a thiocarbonylation reaction is carried out at any stage of the synthesis, phosphorus pentasulfide is usually used as the thiocarbonylating reagent. Alternatively, instead of phosphorus pentasulfide, a reagent containing the structure of 1,3,2,4-dithiadiphosphetane-2,4-disulfide (for example, 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane) can be used. -2,4-disulfide (Lavesson's reagent), etc.).

When the Wohl-Ziegler reaction is carried out at any stage of the synthesis, examples of the halogenating agent that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, and the like. In addition, the reaction can be accelerated by exposing the reaction system to a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile, and the like.

When the reaction of halogenation of the hydroxyl group is carried out at any stage of the synthesis, examples of the halogenating agent that can be used include hydrohalic acids and inorganic acid halides, in particular, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., for bromination, 48% hydrobromic acid; and the like. In addition, a method for producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can be used. Alternatively, a two-step process for producing an alkyl halide can be used, comprising the transformation

- 24 039459 alcohol into the corresponding sulfonate and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide.

When the Arbuzov reaction is carried out at any stage of the synthesis, examples of reagents that can be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite, and the like.

When a sulfonate esterification reaction is carried out at any stage of the synthesis, examples of the sulfonating agent that can be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

When a hydrolysis reaction is carried out at any stage of the synthesis, an acid or a base is used as a reactant. In the t-butyl ester acid hydrolysis reaction, formic acid, triethylsilane, and the like may be added to reductively capture the t-butyl cation which is a by-product.

When a dehydration reaction is carried out at any stage of the synthesis, examples of a dehydrating agent that can be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

Compound (7) used in Reaction Scheme 3 below can be obtained from compound (1) according to the method shown in Reaction Scheme 1 below. In the present description, when the symbol M is used, it means magnesium halide or alkali metal , such as lithium, etc., and other symbols have the meanings indicated above. Reaction Scheme 1

Compound (1) may be commercially available, or may be produced according to a known method or the like.

Compound (3) can be obtained by reacting compound (2) with an organometallic reagent according to a nucleophilic addition reaction. Examples of the organometallic reagent that can be used include organic magnesium halides, organic lithium compounds, and the like.

The organometallic reagent can be produced according to a known method.

The compound (4) can be obtained, for example, by oxidizing the compound (3), where R ⁴ represents a hydrogen atom.

The compound (5), where R ⁵ represents a hydrogen atom, can be obtained, for example, by reducing the compound (3).

The compound (5), where R ⁵ is a C _1-6 alkoxy group, can be obtained, for example, by a nucleophilic substitution reaction of the compound (3) with an electrophile in the presence of a base. Examples of an electrophile that can be used include alkyl halides and the like. Examples of the base that can be used include alkali metal hydrides and the like.

The compound (5), where R ⁴ and R ⁵ both represent fluorine atoms, can be obtained, for example, by fluorination of the compound (4). Examples of reagents that can be used include fluorinating agents such as diethylaminosulfur trifluoride (DAST), bis(2-methoxyethylaminosulfur trifluoride (BAST), 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA), etc. .P.

Compound (7) can be obtained by a coupling reaction of compound (5) and compound (6). Compound (6) may be commercially available, or may be produced according to a known method or the like.

Compound (7) can also be obtained from compound (8) according to the method shown in Reaction Scheme 2 below. The symbol Hal when used in the present description means a halogen atom, the symbols LG ¹ and LG ² are independently denote the group to be removed, and the other characters take on the meanings defined above.

Reaction Scheme 2

Examples of the leaving group represented by LG ¹ or LG ² include halogen atoms, optionally halogenated C _1-6 alkylsulfonyloxy groups (e.g. methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C _6-14 arylsulfonyloxy groups optionally substituted with C _1-6 alkyl (e.g. benzenesulfonyloxy, toluenesulfonyloxy) and the like.

Compound (8) may be commercially available, or may be produced according to a known method or the like.

Compound (11) can be obtained by reacting compound (9) with compound (10) according to the nucleophilic substitution reaction. Examples of the compound (10) that can be used include cyclic amines (eg, pyrrolidine, piperidine), pyrazole, and the like. In addition, a base may be added to the reaction system. Examples of bases include inorganic bases, organic bases, alkali metal hydrides, and the like.

Compound (14) can be obtained by reacting compound (12) with compound (13) according to a sulfanilamide reaction in the presence of a base. Examples of the base that can be used include organic bases and the like. Compound (13) may be commercially available or may be produced according to a known method.

Compound (7) can be obtained by reacting compound (14) according to a nucleophilic substitution reaction with an electrophile in the presence of a base. Examples of an electrophile that can be used include alkyl halides and the like. Examples of the base that can be used include alkali metal hydrides and the like.

The compound (Ia) and the compound (Ib), which are the compound (I), where ring A is a piperidine ring, can be obtained from compound (7) according to the method shown in the following reaction scheme 3. Symbol LG ³ , when used in the present description, means the group to be deleted, and other symbols take on the meanings defined above.

Reaction Scheme 3

^R3 - ^LG3

(7) (la) (lb)

Examples of the leaving group represented as LG ³ include the groups that are given as examples of the leaving group represented as LG ¹ or LG ² .

Compound (Ia) can be obtained by reduction reaction of compound (7). Examples of a reducing agent that can be used include catalysts such as palladium-carbon, rhodium, platinum-carbon, and the like.

Compound (Ib) can be obtained by a condensation reaction of compound (Ia) and compound (15).

- 26 039459

Examples of compound (15) that can be used include acyl halides such as acid chlorides, acid bromides, alkyl chloroformates, carbamoyl chlorides, and the like; activated carboxylic acids such as acid anhydrides, activated esters, sulfate esters, and the like. Examples of the carboxylic acid activating agent include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate ester condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Muqayyama's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; their combinations, etc. In addition, a base may be added to the reaction system. Examples of bases include inorganic bases, organic bases, and the like. When a carbodiimide condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like can also be added to the reaction system.

Compound (Ic) and compound (Id), which are compound (I), where R ² represents a hydrogen atom, and compound (I) can be obtained from compound (16) according to the method shown in Reaction Scheme 4. The symbol P ¹ when used herein is a protecting group, LG ⁴ is a leaving group, and other symbols have the meanings defined above.

Reaction Scheme 4

Examples of the protecting group represented by P ¹ include those exemplified by the above-mentioned protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole, and the like.

Examples of the leaving group represented as LG ⁴ include those shown as examples of the leaving group represented as LG ¹ or LG ² .

Compound (16) and compound (17) may be commercially available or may be prepared according to a known method or the like.

Compound (18) can be obtained by reacting compound (16) with compound (17) according to a nucleophilic substitution reaction in the presence of a base. Examples of the base that can be used include alkali metal hydrides, organic lithium compounds, and the like. Alternatively, compound (18) can also be obtained by a two-step reaction, i.e. conversion of compound (16) into the corresponding enamine, followed by reaction of the enamine with compound (17).

Examples of an amine that can be used to produce an enamine include pyrrolidine, morpholine, N,N-dimethylhydrazine, and the like. A base may be added to the reaction system of enamine and compound (17). Examples of the base include alkali metal hydrides, organic lithium compounds, and the like. In addition, a catalyst may be added to the reaction system to speed up the reaction. Examples of a catalyst that can be used include tetrabutylammonium iodide and the like.

Compound (19) can be obtained by a reductive amination reaction of compound (18). Examples of the reducing agent that can be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, and the like. Examples of an amine that can be used include ammonia and the like. In addition, a metal catalyst may be added to the reaction system. Examples of a catalyst that can be used include iridium catalysts and the like. Alternatively, compound (19) can also be obtained by a two-step reaction, i.e. conversion of compound (18) to the corresponding oxime, followed by reduction of the oxime to

- 27 039459 according to the reduction reaction. Examples of amines that can be used to form an oxime include hydroxylamine, O-methylhydroxylamine, and the like. Examples of the reducing agent that can be used include boranes such as borane-tetrahydrofuran complex and the like, sodium borohydride and the like. In addition, a metal catalyst may be added to the reaction system.

Examples of a catalyst that can be used include molybdenum trioxide and the like.

Compound (21) can be obtained by reacting compound (19) with compound (20) according to the sulfanylamide reaction in the presence of a base. Examples of the base that can be used include organic bases and the like. Compound (20) may be commercially available or may be produced by a known method.

Compound (Id) can be obtained by reacting compound (Ic) and compound (15) according to a condensation reaction. Examples of compound (15) that can be used include acyl halides such as acid chlorides, acid bromides, alkyl chloroformates, carbamoyl chlorides, and the like; activated carboxylic acids such as acid anhydrides, activated esters, sulfate esters, and the like. Examples of the carboxylic acid activating agent include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate ester condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Muqayyama's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; N,N',N'-tetramethyluronium O-(7-azabenzotriazol-1-yl)-H hexafluorophosphorate (HATU); sulfuric acid; their combinations, etc. In addition, a base may be added to the reaction system. Examples of the base include inorganic bases, organic bases, and the like. When a carbodiimide condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like can also be added to the reaction system.

Compound (I) can be obtained from compound (Id) by a nucleophilic substitution reaction with an electrophile in the presence of a base. Examples of an electrophile that can be used include an alkyl halide and the like. Examples of the base that can be used include alkali metal hydrides and the like.

In the compound (I) thus obtained, the intramolecular functional group can also be converted to the target functional group by known combinations of chemical reactions. Examples of the chemical reaction include an oxidation reaction, a reduction reaction, an alkylation reaction, an acylation reaction, a urea formation reaction, a hydrolysis reaction, an amination reaction, an esterification reaction, an aryl coupling reaction, deprotection reactions, and the like.

In the above production method, when the starting compound contains an amino group, a carboxyl group, a hydroxyl group, a carbonyl group, or a mercapto group as a substituent, a protecting group commonly used in peptide chemistry can be introduced into these groups, and if necessary, the target compound can be obtained by removing the protective groups after the reaction.

Compound (I) obtained by the above production method can be isolated and purified by known methods such as solvent extraction, liquid transformation, phase change, crystallization, recrystallization, chromatography, and the like.

When the compound (I) has an optical isomer, a stereoisomer, a regioisomer and a rotamer, these compounds are also included in the definition of the compound (I), and each of them can be obtained as a single product by a known synthetic method or a known separation method. For example, when compound (I) exists in the form of an optical isomer, the isolated optical isomer is also compound (I).

The optical isomer according to the present invention can be obtained by a known method.

Compound (I) may be crystalline.

The crystalline compound (I) (hereinafter sometimes abbreviated as the crystal of the present invention) can be obtained by crystallizing the compound (I) using a crystallization method which is known as such.

In the present description, the term melting point means the melting point measured, for example, using a micromelting point apparatus (Yanako, MP-500D or Buchi, B-545), a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1), etc. .P.

Generally, the melting point may vary in some cases depending on the measuring apparatus, the state under which the measurement is performed, and the like. The crystal in the present description may be a crystal with a melting point that differs from the values described in the present description, provided that the difference is within the range of common errors.

- 28 039459

The crystal of the present invention is excellent in physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy), and is extremely useful as a drug. facilities,

Compound (I) can be used as a prodrug. The term "prodrug of the compound (I)" means a compound which is converted into the compound (I) of the present invention by interaction with an enzyme, gastric acid, etc. in the physiological conditions of a living organism, i.e. a compound which is converted into the compound (I) of the present invention by oxidation, reduction, hydrolysis, etc. under the action of an enzyme; a compound which is converted into the compound (I) of the present invention by hydrolysis, etc. under the action of stomach acid, etc.

The prodrug of compound (I) may be a compound obtained by acylation, alkylation or phosphorylation of an amino group in compound (I) (for example, a compound obtained by eicosanylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolene-4 -yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylation and the like of the amino group in the compound (I));

a compound obtained by acylation, alkylation, phosphorylation or boronation of the hydroxyl group in compound (I) (for example, a compound obtained by acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc. of the hydroxyl group in compound (I) );

a compound obtained by esterification or amidation of a carboxyl group in compound (I) (for example, a compound obtained by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonyl ethyl esterification, methylamidation, etc. of the carboxyl group in the compound (I)) and the like. Any of these compounds can be obtained from the compound (I) in accordance with a known method.

The prodrug of compound (I) may also be a compound that is converted to compound (I) under physiological conditions such as those described in IYAKUHIN by KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, a prodrug may form a salt, and as such a salt, salts exemplified as salts of the compound represented by formula (I) may be mentioned.

Compound (I) may be labeled with an isotope (eg ³ H, ¹³ C, ¹⁴ C, 1 F, ³⁵ S, ¹²⁵ I) and the like.

Compound (I) labeled or substituted with an isotope can be used, for example, as an indicator in positron emission tomography (PET) (PET imaging), and can be used in the field of medical diagnosis and the like.

In addition, the compound (I) may be a hydrate or not a hydrate or not a solvate (eg an anhydride) or a solvate (eg a hydrate).

Compound (I) also includes a deuterium conversion form in which 1H is converted to ² H(D).

In addition, the compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. The term co-crystal or co-crystal salt means a crystalline substance that is composed of two or more solids at room temperature whose physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility, and stability) are different. The co-crystal and the co-crystal salt can be obtained by the co-crystallization method, which is known per se.

Compound (I) or its prodrug (hereinafter abbreviated as the compound of the present invention for simplicity) may be administered to a mammal (e.g., human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey) by itself or in the form of a pharmaceutical composition (also referred to as a drug) when mixed with a pharmacologically acceptable carrier, etc. as an agent for the prevention or treatment of various diseases indicated below.

As pharmacologically acceptable carriers, various organic or inorganic carrier materials commonly used as preparation materials can be used. They are introduced as an excipient, lubricant, binder and disintegrant for solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonic additive, buffer and emollient for liquid preparations; etc.; and, if necessary, additives such as a preservative, an antioxidant, a coloring agent, a sweetener, and the like, may be added to the preparation.

Preferred excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminometasilicate.

Preferred examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silicon dioxide.

Preferred examples of the binder include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium salt, sodium croscarmellose, sodium carboxymethyl starch, light anhydrous silicic acid, and low substituted hydroxypropyl cellulose.

Preferred solvent examples include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferred examples of solubilizing additives include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

Preferred examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl amino propionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, and the like; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like, polysorbates; and polyoxyethylene hydrogenated castor oil.

Preferred examples of an isotonic supplement include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose.

Preferred examples of buffers include phosphate, acetate, carbonate, citrate buffers, etc.

Preferred examples of an emollient include benzyl alcohol.

Preferred examples of the preservative include p-hydroxybenzoate esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

Preferred examples of antioxidants include sulfite salts and ascorbate salts.

Preferred examples of the coloring agent include aqueous aniline food colorings (for example, food colorings such as red food coloring Nos. 2 and 3, yellow food coloring Nos. 4 and 5, blue food coloring Nos. 1 and 2, etc. food coloring), insoluble in water mordant lacquer dyes (eg aluminum salt of the above aqueous food aniline dye), natural dyes (eg β-carotene, chlorophyll, iron oxide red), and the like.

Preferred sweetener examples include sodium saccharin, potassium double glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the above pharmaceutical composition include preparations for oral administration such as tablets (including sugar-coated tablets, coated tablets, sublingual tablets, lozenges, buccal dissolving tablets), capsules (including soft capsules, microcapsules) , pills, granules, powders, lozenges, syrups, liquids, emulsions, suspensions, aerosols, films (eg, absorbable films, adhesive films for the oral mucosa), etc.; and preparations for parenteral administration such as injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), topical preparations (eg, absorption-type transdermal preparation, ointment, lotion, adhesive preparation), suppositories ( eg rectal suppositories, vaginal suppositories), granules, intranasal preparations, lung preparations (inhalation dosage form), eye drops, and the like. The compound and the medicament of the present invention may, respectively, be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraorganically, nasally, intradermally, by instillation, intracerebral, intravaginally, intraperitoneally, intratumorally, near a tumor, and into wound).

These formulations may be controlled release formulations (eg, sustained release microcapsules) such as immediate release formulations, sustained release formulations, and the like.

The pharmaceutical composition can be prepared according to a method commonly used in the field of pharmaceutical production, such as the method described in Japanese Pharmacopoeia and the like.

Although the content of the compound of the invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dose of the compound of the present invention, and the like, it is, for example, about 0.1 to 100% by weight.

When preparing a formulation for oral administration, the formulation may be coated when necessary for taste masking, enteral solubility, or stability.

Examples of the coating base used for coating include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a slow release coating base.

Sucrose is used as the base of the sugar coating, and additionally, one or more types of talc, as well as precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, and the like can be used in combination.

Examples of the water-soluble film coating base include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and the like; synthetic polymers such as polyvinyl acetal-diethylaminoacetate-aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone and the like; and polysaccharides such as pullulan and the like.

Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, and the like; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], etc. .P.; as well as natural substances such as shellac and the like.

Examples of the slow release film coating base include cellulose polymers such as ethyl cellulose and the like; and acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate and methyl methacrylate suspension [Eudragit NE (trade name)], and the like.

Two or more types of the above coating bases can be used in a mixture in a suitable ratio. In addition, for example, light shielding additives such as titanium oxide, red iron oxide, and the like can be used in the coating process.

Since the compound of the present invention exhibits low toxicity (e.g., low acute toxicity, low chronic toxicity, low genetic toxicity, low reproductive toxicity, low cardiotoxicity, low carcinogenicity) and weaker side effects, it can be used as a prophylactic or therapeutic agent or for diagnosis of various diseases in mammals (for example, in humans, cattle, horses, dogs, cats, monkeys, mice, rats).

The compound of the present invention has excellent orexin type 2 receptor agonist activity and can treat or prevent or reduce the risk of various neurological and psychiatric diseases associated with orexin type 2 receptor. The compound of the present invention can be used as an agent for the prevention or treatment of various diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with symptoms similar to narcolepsy, hypersomnia syndrome with excessive daytime sleepiness (for example, Kleine-Levin syndrome, major depressive episode with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick type C disease, cerebral contusion, cerebral infarction, brain tumor brain, muscular dystrophy, multiple sclerosis, acute multiple encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (eg, malignant mastocytosis, exogenous obesity, hyperinsulinemic obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, mental disorder , such as coma, etc., side effects and complications due to anesthesia, sleep disturbance, insomnia, interrupted sleep, nocturnal myoclonus, interruption of REM sleep, jet lag, jet lag syndrome, shift worker sleep disorders, disorder sleep disorder, nightmare, depression, major depressive episode, somnambulism, enuresis, sleep disturbance, Alzheimer's disorder of consciousness, circadian rhythm disorders, fibromyalgia, sleep deprivation condition, binge eating, obsessive o-compulsive eating disorder, obesity-related disease, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer,

- 31 039459 cancer, osteoarthritis, obstructive sleep apnea syndrome, cholelithiasis, gallstones, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, ischemic heart disease, cardiovascular disorder, sudden death, polycystic ovaries, craniopharyngioma, Froelich syndrome, growth hormone deficiency, normal mutant short stature, Turner syndrome, childhood acute lymphoblastic leukemia, syndrome X, sex hormone abnormality, reduced fertility, infertility, decreased male gonadal function, sexual and reproductive dysfunction such as hirsutism in women and men, fetal defects associated with obesity in pregnant women, gastrointestinal motility disorders such as gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick's syndrome), respiratory diseases such as shortness of breath, inflammation such as systemic vascular inflammation systems, at erosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, kidney cancer, risk of secondary obesity outcomes such as decreased risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, flushing persons, night sweats, diseases of the genital/urinary system, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress, agoraphobia, generalized anxiety disorder, obsessive disorder, acute anxiety disorder with panic response, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorders such as coronary artery bypass grafting and transplantation cerebral disorder, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, muscle spasticity disorder, delirium, amnesic disorder, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, drug-induced parkinsonism syndrome, syndrome Gill-Touretta, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing impairment, tinnitus, nerve damage, retinop atia, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and traumatic brain injury (TBI).

In particular, the compound of the present invention can be used as an agent for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by symptoms similar to narcolepsy, hypersomnia syndrome accompanied by excessive daytime sleepiness (for example, Parkinson's disease, Guillain-Barré syndrome and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness such as coma, etc., side effects and complications associated with anesthesia, etc. or as an antagonist to an anesthetic.

Although the dose of the compound of the present invention varies depending on the subject to which it is administered, the route of administration, the target disease, the symptom, and the like, when the compound of the present invention is administered, for example, orally or parenterally to an adult patient, its dose is, for example , from about 0.01 to 100 mg/kg body weight per dose, preferably from 0.1 to 50 mg/kg body weight per dose, more preferably from 0.5 to 20 mg/kg body weight per dose. This amount is desirable to enter one to three portions daily.

The compound of the present invention can be used in combination with other drugs (hereinafter, abbreviated as concomitant drug).

By combining the compound of the present invention and a concomitant drug, an excellent effect can be achieved, for example:

(1) the dose of application may be reduced compared to the administration of one compound of the present invention or one concomitant drug;

(2) the drug to be combined with the compound of the invention may be selected according to the condition of the patient (mild case, severe case, etc.);

(3) by selecting a concomitant drug with a mechanism of action different from the mechanism of action of the compound of the present invention, a longer period of treatment can be established;

(4) by selecting a concomitant drug with an action and mechanism of action different from the action and mechanism of action of the compound of the present invention, a long-term treatment effect can be achieved;

(5) using the combined use of the compound of the present invention and concomitant

- 32 039459 a synergistic effect can be achieved.

In the present description, the compound of the present invention and the concomitant drug used in combination are hereinafter referred to as the combined drug of the present invention.

When using the combination drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or its pharmaceutical composition and the concomitant drug or its pharmaceutical composition may be administered to the subject at the same time or at different times. The dose of the concomitant drug may be determined according to the clinically used dose, and may be appropriately selected depending on the subject to which it is administered, route of administration, disease, type of combination, and the like.

The method of administration of the combination drug of the present invention and the concomitant drug is not particularly limited, and the compound of the present invention and the concomitant drug must be combined when administered. Examples of such an administration method are: (1) administration of a single preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two preparations, the preparation of the compound of the present invention and the preparation of the concomitant drug, which are produced separately, by the same route of administration, (3) the administration of two preparations - the preparation of the compound of the invention and the preparation of the concomitant drug, which are produced separately, by the same route of administration at different times, (4) the simultaneous administration of two preparations - the preparation of the compound of the present of the invention and the drug of the concomitant drug, which are produced separately, by different routes of administration, (5) the administration of two drugs - the drug of the compound of the present invention and the drug of the concomitant drug, which are produced separately, by different ways administering at different times (eg, administering the compound of the present invention first and then the concomitant drug, or in reverse order), and the like.

The dose of the concomitant drug may be appropriately determined based on the dose used in the clinical setting. The mixing ratio of the compound of the present invention and the concomitant drug may be appropriately determined depending on the administration subject, administration route, target disease, symptom, combination, and the like.

For example, the content of the compound of the invention in the combination drug of the present invention varies depending on the form of the preparation and is usually from about 0.01 to about 100 wt.%, preferably from about 0.1 to about 50 wt.%, even more preferably from about 0.5 to about 20 wt.%, based on the total weight of the drug.

The content of the concomitant drug in the combination drug of the present invention varies depending on the form of the drug and is usually from about 0.01 to about 100 wt.%, preferably from about 0.1 to about 50 wt.%, more preferably from about 0 .5 to about 20 wt.%, based on the total weight of the drug.

The content of additives, such as a carrier and the like, in the combination drug of the present invention varies depending on the form of the preparation and is usually from about 1 to about 99.99 wt.%, preferably from about 10 to about 90 wt.%. , based on the total weight of the drug.

A similar content can be used even when the compound of the present invention and the concomitant drug are administered in separate formulations.

Examples of concomitant drug include the following drugs: narcolepsy therapeutic drug (eg, methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium hydroxybutyrate, modafinil, caffeine), anti-obesity drug (amphetamine, benzphetamine, bromocriptine, bupropion, diethylpropion , exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine recombinant leptin, simbutramineli , zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitor (eg donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), antidementia drug (eg memantine), inhibitor of β- production, secretion, accumulation, aggregation and/or precipitation amyloid protein, secretion, accumulation, aggregation and/or precipitation, β-secretase inhibitor (e.g. 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, (N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4- yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'- methylbiphenyl-4yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6(2',4'-dimethoxybiphenyl-4-yl)methoxy -2-[2-(N,K-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-33 039459 yl)phenyl]methoxy-2-[2-(N,N-dimethylamino) )ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2(N,N-dimethylamino)ethyl]tetralin, its optically active form, salt and hydrate, OM99-2 ( WO 0100663)), γ-secretase inhibitor, β-amyloid protein aggregation inhibitor (e.g. PTI-00703, ALZHEMED (NC-531), PPI-368 (National Publication of International Patent Application No. 11514333), PPI-558 (National Publication of International Patent Application No. 2001-500852), SKF74652 (Biochem. J. (1999), 340 (1), 283-289)), β-amyloid vaccine, β-amyloid degrading enzyme, etc., brain function stimulant (eg, aniracetam, nicergoline), therapeutic drug for treatment of Parkinson's disease [(eg, dopamine receptor agonist (eg, LDOPA, bromocriptine, pergolide, talipexol, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) enzyme inhibitor (eg, deprenyl, selegiline, remacemide, riluzole), anticholinergic (eg, trihexyphenidyl, biperiden), catechol-O-methyltransferase inhibitor (eg, entacapone)], amyotrophic lateral sclerosis therapeutic drug (eg, riluzole, etc., neurotrophic factor), therapeutic agent for abnormal behavior, erratic movement, and the like accompanying the development of dementia (eg, sedative drug, tranquilizer), apoptosis inhibitor (eg, CPI-1189, IDN-6556, CEP-1347), neuronal differentiation-regeneration promoter ( eg leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)- 2,3dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl2,3-dihydro-1-benzofuran -5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro1-benzofuran-5-yl]-6,7-dihydro-5H -[1,3]dioxolo[4,5-1]isoindole and their optically active forms, salts or hydrates), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc. ), steroid drug (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARD), anti-cytokine drug (eg, TNF inhibitor, MAP kinase), therapeutic drug for incontinence urine, urinary frequency (eg, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), ing phosphodiesterase inhibitor (eg, sildenafil (citrate)), dopamine receptor agonists (eg, apomorphine), antiarrhythmic drugs (eg, mexiletine), sex hormone or derivative (eg, progesterone, estradiol, estradiol benzoate), therapeutic drug for the treatment osteoporosis (eg, alfacalcidol, calcitriol, elkatonin, salmon calcitonin, estriol, ipriflavon, disodium pamidronate, sodium alendronate hydrate, disodium incadronate), parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drug for insomnia (eg, drugs benzodiazepine-based, non-benzodiazepine drugs, melatonin agonist, orexin receptor antagonists), therapeutic drug for schizophrenia (eg typical antipsychotics such as haloperidol and the like; atypical antipsychotics such as clozapine, olanzapine, risperidone, aripiprazole, and the like; a drug acting on metabotropic glutamate receptors or glutamate receptors coupled to ion channels; phosphodiesterase inhibitor), drugs based on benzodizepines (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitor (pregabalin, etc.), tricyclic or tetracyclic antidepressant (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), reuptake inhibitor norepinephrine and serotonin (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), norepinephrine reuptake inhibitor (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, sepiptyline maleate, agonist 5- HT _1A (buspirone hydrochloride, tandospirone citrate, osemozotane hydrochloride, etc.), 5-HT _2A antagonist, 5-HT ₂ inverse agonist, 5HT ₃ antagonist (cyamemazine, etc.), non-selective inhibitor of cardiac β-adrenergic receptors (propranolol hydrochloride, oxprenolol hydrochloride, etc.), histamine H1 antagonist (hydroxyzine hydrochloride etc.), CRF antagonist, other anxolytic drugs (meprobamate, etc.), tachykinin antagonist (MK-869, saredutant, etc.), drug that acts on metabotropic glutamate receptors, CCK antagonist , β3 adrenaline antagonist (amibegron hydrochloride, etc.), GAT-1 inhibitor (tiagabine hydrochloride, etc.), N-type calcium channel inhibitor, carbonic anhydrase II inhibitor, NMDA glycine fragment agonist, NMDA antagonist (memantine, etc. .d.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1a antagonist, phosphodiesterase inhibitor, opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone iron (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamot

- 34 039459 rigine, riluzole, felbamate, etc.), CB1 cannabinoid antagonist (rimonabant, etc.), FAAH inhibitor, sodium channel inhibitor, drug for the treatment of attention deficit hyperactivity disorder (ADHD) (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), alcoholism drug, autism therapeutic drug, chronic fatigue syndrome therapeutic drug, seizure therapeutic drug, fibromyalgia syndrome therapeutic drug, headache therapeutic drug pain, therapeutic drug for smoking cessation, therapeutic drug for myasthenia gravis, therapeutic drug for cerebral infarction, therapeutic drug for mania, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for ataxia of the autonomic nervous system, therapeutic drug for male and female sexual dysfunction, therapeutic drug for migraine, therapeutic drug for pathological gambling, therapeutic drug for restless leg syndrome, therapeutic drug for drug addiction, therapeutic drug for alcohol abuse syndrome, therapeutic drug for irritable bowel syndrome, therapeutic drug for lipid disorders, such as cholesterol lowering agent (statins (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrate (clofibr at, etc.), a squalene synthetase inhibitor), a therapeutic drug for the treatment of pathological behavior or a suppressive drug for the treatment of dromomania associated with dementia (sedative drugs, anxiolytic, etc.), a therapeutic drug for the treatment of diabetes, a therapeutic drug for complications of diabetes, a therapeutic drug for hypertension, a therapeutic drug for hypotension, a diuretic, a chemotherapeutic drug, an immunotherapy drug, an antithrombotic drug, an anticancer drug, and the like.

Two or more kinds of the above concomitant drug can be used in a mixture at a suitable ratio.

When the compound of the present invention is used to treat each of the above diseases, it can also be used in combination with a biological drug (for example, an antibody-based drug, a nucleic acid or nucleic acid derivative drug, an aptamer drug, a vaccine drug), in combination with the method of gene therapy, etc. or in combination with non-drug psychiatric treatment.

Examples of an antibody-based drug and a vaccine preparation include an angiotensin II vaccine preparation, an anti-CETP vaccine preparation, an anti-CETP antibody, an antibody against TNFa antibody and other cytokines, an amyloid-β vaccine preparation, a type 1 diabetes vaccine (e.g., DIAPEP-277 manufactured by Peptor), an HIV antibody and an HIV vaccine preparation, as well as antibodies or vaccine preparations against cytokines, enzymes of the renin-angiotensin system and their products, antibody-based preparations or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines relating to enzymes and proteins involved in blood coagulation or fibrinolysis systems, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, and the like. In addition, biologics associated with growth factors such as GH, IGF, and the like can be used in combination.

Examples of a gene therapy method include a method of treatment using a gene related to a cytokine, a renin-angiotensin type enzyme and its product, a G protein, a G protein coupled receptor and its phosphorylating enzyme, a method of treatment using a DNA decoy such as NFkB trap and the like, antisense treatment method, treatment method using a gene related to an enzyme or protein involved in blood lipid metabolism (for example, a gene related to metabolism, excretion and absorption of cholesterol, triglyceride, high-density lipoprotein cholesterol or blood phospholipid), a treatment method using a gene associated with an enzyme or protein involved in angiogenic therapy for peripheral vascular obstruction, and the like. (for example, with a growth factor such as hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), etc.), a treatment method using a gene related to a protein involved in glucose metabolism and inulin resistance, an antisense molecule, directed against cytokines such as FIO, etc. etc.

Examples of the drug-free psychiatric treatment method include modified electroshock therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, psychotherapy including cognitive behavioral therapy, and the like.

- 35 039459

The compound of the invention can also be used in combination with various methods of organ regeneration, such as heart, kidney, pancreas, revascularization, etc., with methods of cell transplantation therapy using bone marrow (mononuclear cells derived from bone marrow, myelogenous stem cells) or tissue engineering technology using artificial organs (for example, an artificial blood vessel, a cardiomyocyte layer).

Examples

The invention is explained in detail below with reference to examples, experimental examples and examples of preparations. However, these examples do not limit the present invention and may be modified within the scope of the present invention.

The term room temperature in the following examples usually means a temperature from about 10 to about 35°C. The ratio of the components in the mixed solvent, unless otherwise indicated, is the volume ratio of the components in the mixture, and % means % by weight, unless otherwise indicated.

Column chromatography elution in the examples was carried out with thin layer chromatography (TLC) control, unless otherwise indicated. TLC monitoring uses Merck 60 F ₂₅₄ plates, column chromatography uses an elution solvent as eluent, and a UV detector is used for detection. In silica gel column chromatography, NH means using aminopropylsilane-bound silica gel, Diol (diol) means using 3-(2,3-dihydroxypropoxy)propylsilane-bound silica gel. In preparative high performance liquid chromatography (HPLC), C18 means the use of octadecyl-bonded silica gel. The ratio of the components in the elution solvent, unless otherwise indicated, is a volume ratio.

1H NMR spectra were obtained using a Fourier NMR spectrometer. For 1H NMR analysis, ACD/SpecManager (trade name) software and the like are used. Weak proton peaks of the hydroxyl group, amino group, etc. groups in some cases are not described.

MS is obtained by LC/MS. As the ionization method, an electrospray method (ESI) or an atmospheric pressure chemical ionization (APCI) method is used. The data shows the actual value obtained (found). Although a molecular ion peak is usually observed, in some cases a fragment ion peak is observed. In the case of a salt, there is usually a molecular ion peak or a free-form ion fragment peak.

Sample concentration unit (c) for optical rotation ([a] _D ) is g/100 ml.

Elemental analysis data (anal.) is presented as a calculated value (calculated) and an actual value obtained (found).

In the examples, cis/trans in the names of compounds generally means a cis or trans mixture of two kinds of optical isomers when the corresponding structure contains two asymmetric centers. In exceptional cases, the prefixes cis/trans mean a single optical isomer when optically active is indicated.

In the examples, the X-ray powder diffraction peaks are those obtained at room temperature with an Ultima IV (Rigaku Corporation, Japan) using CuKa radiation as the radiation source. The measurement conditions are given below.

Electric voltage/electric current: 40 kV/50 mA.

Scanning speed: 6°/min.

Scan range 2θ: 2-35°.

Crystallinity in the method of powder x-ray diffraction in the examples is calculated by the method of Hermans (Hermans).

In the following examples, the following abbreviations are used.

- 36 039459

Mp: melting point

MS: mass spectrum

M: molar concentration

Ν: normality

CDC1 ₃ : deuterochloroform

DMSO-th ₆ : deuterodimethyl sulfoxide

Ή NMR: proton nuclear magnetic resonance

LC/MS: liquid chromatograph/mass spectrometer,

ESI: electrospray ionization, electrospray ionization

APCI: atmospheric pressure chemical ionization

Pd ₂ (dba) ₃ : tris (dibenzylideneacetone) dipalladium (O)

TFA: trifluoroacetic acid

DIPEA: X-ethyl-X-isopropylpropan-2-amine

DMF: N,N-dimethylformamide

THF: tetrahydrofuran

CH ₃ CN: acetonitrile

DME: 1,2-dimethoxyethane

BON: methanol

EtOH: ethanol t-AmOH: 2-methyl-2-butanol

Pd(PPh ₃ ) ₄ : palladium-triphenylphosphine (1:4) tBuXphos: 2-di-tert-butylphosphino-2'4',6'-triisopropylbiphenyl

XPhos Pd G3: methanesulfonate (2-dicyclohexylphosphino-2'4',6'-triisopropyl-

1, G-biphenyl)[2-(2'-amino-1, G-biphenyl)]palladium(II)

PPh ₃ : triphenylphosphine

AcOH: acetic acid

TBAI: tetrabutylammonium iodide

TEA: triethylamine (A-taPhos) ₂ PdCl ₂ : 4-(di-tert-butylphosphino)-X, N-dimethylaniline-dichloropalladium (2:1)

TFR: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatrifosphine-2,4,6-trioxide

HATU: O-(7-azabenzotriazol-1-yl)-X, N,N'N'-tetramethyluronium hexafluorophosphate

DMAP: N, X-dimethyl-4-aminopyridine

CPME: methoxycyclopentane tBu: tert-butyl

Vos: tert-butoxycarbonyl

Example 1 cis-2-(3-Benzylbenzyl)-X-ethyl-3-((methylsulfonyl)amino)piperidine-1-carboxamide.

A) 1-Benzyl-3-bromobenzene.

A mixture of (chloromethyl)benzene (3.78 g), (3-bromophenyl)boronic acid (6.00 g), Pd(PPh ₃ ) ₄ (1.73 g), sodium carbonate (3.16 g), DME ( 60 ml) and water (30 ml) were stirred at 100° C. for 15 hours. The reaction mixture was added to water and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel (petroleum ether) column chromatography to give the title compound (4.50 g).

¹ H NMR (400 MHz, CDCl3) δ 3.94 (2H, s), 7.10-7.25 (5H, m), 7.28-7.40 (4H, m).

B) (3-Benzylphenyl)(3-bromopyridin-2-yl)methanol.

To a mixture of magnesium (147 mg) and THF (10 ml) was added iodine (catalytic amount) and 1-benzyl-3-bromobenzene (1.49 g). The mixture is refluxed for 1 hour and then cooled to 20°C. 3-Bromopyridine-2-carbaldehyde (750 mg) was added to the mixture, and the resulting mixture was stirred under nitrogen atmosphere at 20° C. for 15 hours. The reaction mixture was added to a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (900 mg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.97 (2H, s), 5.23 (1H, d, J=6.8 Hz), 5.94 (1H, d, J=5.2 Hz ), 7.03-7.08 (1H,

m), 7.10 -7.31 (9H, m), 7.83-7.90 (1H, m), 8.59 (1H, dd, J=4.4, 1.2 Hz).

C) 2-(3-Benzylbenzyl)-3-bromopyridine.

Triethylsilane (10 ml) was added to a mixture of (3-benzylphenyl)(3-bromopyridin-2-yl)methanol (900 mg) and TFA (5 ml). The mixture is stirred at 60° C. for 40 hours and then concentrated under reduced pressure. The resulting residue was made basic to pH 7-8 with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (1.10 g).

¹ H NMR (400 MHz, CDCl3) 53.95 (2H, s), 4.32 (2H, s), 7.00-7.08 (2H, m), 7.10-7.23 (6H, m), 7.25-7.30 (2H, m), 8.83 (1H, dd, J=8.0, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

D) N-(2-(3-Benzylbenzyl)pyridin-3-yl)methanesulfonamide.

Mixture of 2-(3-benzylbenzyl)-3-bromopyridine (1.10 g), methanesulfonamide (464 mg), tBuXphos (166 mg), Pd ₂ (dba) ₃ (149 mg), cesium carbonate (1.59 g) and DME (20 ml) was stirred under nitrogen at 85° C. for 15 hours. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (260 mg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.39 (3H, s), 3.93 (2H, s), 4.22 (2H, s), 6.21 (1H, br. s), 7 .00-7.35 (10H, m), 8.87 (1H, d, J=7.2 Hz), 8.44 (1H, d, J=3.6 Hz).

E) N-(cis-2-(3-Benzylbenzyl)piperidin-3-yl)methanesulfonamide.

A mixture of N-(2-(3-benzylbenzyl)pyridin-3-yl)methanesulfonamide (200 mg), 5% rhodium on carbon (350 mg), THF (9 ml) and acetic acid (1 ml) was stirred for 15 h in a hydrogen atmosphere with a pressure of 35 pounds per square inch (0.24 Pa) at a temperature of 20°C. The reaction mixture is filtered and the filtrate is added to water. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) and preparative thin layer chromatography to give the title compound (30 mg).

MS: [M+H]+ 359.0.

F) cis-2-(3-Benzylbenzyl)-N-ethyl-3-((methylsulfonyl)amino)piperidine-1-carboxamide.

A mixture of N-(cis-2-(3-benzylbenzyl)piperidin-3-yl)methanesulfonamide (30 mg), TEA (25 mg) and isocyanatoethane (8 mg) in THF (5 ml) was stirred at 20° C. for 15 h. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Fuji C18 (300x25), YMC 25x20, mobile phase: water/acetonitrile (0.1% aqueous ammonia solution)). The resulting fraction was concentrated under reduced pressure and freeze-dried to give the title compound (6 mg).

¹ H NMR (400 MHz, CDCU) δ 0.72 (3H, t, J=7.2 Hz), 1.60-1.90 (4H, m), 2.75-3.00 (8H, m ), 3.50-3.60(2H, m), 3.93(2H, s), 4.05-4.15(1H, m), 4.22-4.32(1H, m), 4.59 (1H, d, J=7.2 Hz), 7.03-7.08 (3H, m), 7.15-7.35 (6H, m).

Example 19 tert-Butyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

A) tert-Butyl-2-(biphenyl-3-ylmethyl-3-oxo-piperidine-1-carboxylate.

Pyrrolidine (1.87 g) was added to a mixture of tert-butyl 3-oxo-piperidine-1-carboxylate (3.49 g) and toluene (38 ml) at room temperature. The mixture was stirred at room temperature for 30 minutes, then refluxed for 1 hour using a Dean-Stark trap and then concentrated under reduced pressure. The resulting residue was mixed with CH3CN (38 ml), and 3-(bromomethyl)biphenyl (5.19 g) was added to the resulting mixture at room temperature. The mixture is refluxed for 1 hour, then the reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.42 g).

MS: [M+H-(tBu)] ⁺ 310.2.

B) tert-Butyl cis-3-amino-2-(biphenyl-3-ylmethyl)piperidine-1-carboxylate.

Ammonium acetate (7, 19 g). The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride was added to the mixture.

- 38 039459 (3.56 g). The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution at 0° C. and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.67 g).

MS: [M+H]+ 367.2.

C) tert-Butyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

To a mixture of tert-butyl cis-3-amino-2-(biphenyl-3-ylmethyl)piperidine-1-carboxylate (1.66 g), THF (15 ml) and TEA (0.917 g) at 0°C was added methanesulfonyl chloride (0.623 g). The mixture was stirred at room temperature for 1 hour, then poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.75 g).

¹ H NMR (300 MHz, CDCl ,) δ 1.11 (9H, s), 1.61-1.74 (2H, m), 1.75-1.84 (1H, m), 1.88 -1.97(1H, m), 2.832.98(3H, m), 3.00(3H, s), 3.57-3.68(1H, m), 4.04-4.12(1H , m), 4.41 (1H, d, J=7.9 Hz), 4.73-4.83 (1H, m), 7.17 (1H, d, J=7.2 Hz), 7 .30-7.39(3H, m), 7.39-7.46(3H, m), 7.52-7.58(2H, m).

Example 24 Methyl cis-2-(3-iodobenzyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate

A) tert-Butyl-2-(3-iodobenzyl)-3-oxo-piperidine-1-carboxylate.

Pyrrolidine (4.28 g) was added to a mixture of tert-butyl 3-oxo-piperidine-1-carboxylate (10 g) and toluene (100 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was mixed with CH3CN (100 ml) and 1-(bromomethyl)-3-iodobenzene (17.9 g) was added to the mixture. The mixture is stirred overnight at 80° C. and concentrated under reduced pressure. The residue was taken up in ethyl acetate and 1M hydrochloric acid, the resulting solution was stirred for 30 minutes and then extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.7 g).

MS: [M+H-Bos] + 316.0.

B) tert-Butyl cis-3-amino-2-(3-iodobenzyl)piperidine-1-carboxylate.

Ammonium acetate (7.24 g ). The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (3.58 g) was added to the mixture, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate . The separated organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.14 g). MS: [M+H]+417.1.

C) tert-Butyl cis-2-(3-iodobenzyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

TEA (0.972 g) and methanesulfonyl chloride (0.660 G). The mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.66 g).

MS: [M-N] ^- 493.1.

D) N-(cis-2-(3-iodobenzyl)piperidin-3-yl)methanesulfonamide hydrochloride.

To a mixture of tert-butyl cis-2-(3-iodobenzyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate (1.66 g) and THF (8 ml) at room temperature was added a 4M solution of hydrochloric acid in ethyl acetate (8.39 ml). The mixture is stirred overnight at room temperature and concentrated under reduced pressure. The residue is suspended in ethyl acetate and the solid is collected by filtration. The solid was washed with ethyl acetate to give the title compound (1.29 g).

MS: [M+H]+ 395.0.

E) Methyl cis-2-(3-iodobenzyl)-3-((methylsulfonyl)aminopiperidine-1-carboxylate.

Methyl chloroformate (0.570 g ). The mixture is stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.30 g).

- 39 039459 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.35-1.56 (1H, m), 1.59-1.76 (3H, m), 2.78-2.87 ( 2H, m), 2.89-3.04 (4H,

m), 3.05-3.23 (2H, m), 3.33-3.52 (2H, m), 3.67-3.87 (1H, m), 4.37-4.65 ( 1H, m), 7.00-7.10(1H, m), 7.12-7.21(1H, m), 7.34(1H, s), 7.48-7.56(2H, m).

Example 27 Methyl cis-3-((methylsulfonyl)amino)-2-(3-(pyrrolidin-1-yl)benzyl)piperidine-1 carboxylate.

A mixture of methyl cis-2-(3-iodobenzyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate (40 mg), pyrrolidine (12.6 mg), Pd ₂ (dba) ₃ (8.10 mg ), dicyclohexyl(2'6'-diisopropoxybiphenyl-2-yl)phosphine (12.4 mg), cesium carbonate (86 mg) and t-AmOH (1 ml) were subjected to microwave irradiation at 100°C for 1 hour. After the mixture is poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (19.0 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 1.32-1.57 (1H, m), 1.61-1.76 (3H, m), 1.86-1.99 (4H, m) , 2.68-2.84 (2H, m), 2.90-3.03 (4H, m), 3.08-3.23 (5H, m), 3.34-3.52 (2H, m), 3.61-3.89 (1H, m), 4.39-4.71 (1H, m), 6.23-6.47 (3H, m), 6.92-7.06 ( 1H, m), 7.28-7.40 (1H, m).

Example 64 Isopropyl cis-3-((methylsulfonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate.

A) (6-Phenylpyridin-2-yl)methanol.

Mixture of (6-bromopyridin-2-yl)methanol (5.10 g), phenylboronic acid (4.96 g), Pd(PPh ₃ ) ₄ (1.25 g), 2M aqueous sodium carbonate solution (33.9 ml ) and DME (55 ml) are refluxed for 15 h under argon. The reaction mixture was poured into water and extracted with ethyl acetate-THF. The insoluble matter was removed by filtration, the organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.76 g).

MS: [M+H]+ 186.1.

B) 2-(Bromomethyl)-6-phenylpyridine.

To a mixture of (6-phenylpyridin-2-yl)methanol (3.74 g), PPh ₃ (6.36 g) and benzotrifluoride (150 ml) was added tetrabromomethane (8.04 g) at 0°C. The mixture is stirred at 0°C for 3 hours, the insoluble matter is removed by filtration and washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.03 g).

MS: [M+H]+ 248.0.

C) tert-Butyl 3-oxo-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate.

Pyrrolidine (1.44 g) was added to a mixture of tert-butyl 3-oxo-piperidine-1-carboxylate (2.69 g) and toluene (29 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes, refluxed for 1 hour using a Dean-Stark trap and concentrated under reduced pressure. The residue was mixed with CH3CN (29 ml), and 2-(bromomethyl)-6-phenylpyridine (4.02 g) was added to the mixture at room temperature. The mixture is stirred at room temperature for 15 hours, then the reaction mixture is poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.56 g).

MS: [M+H]+ 367.2.

D) tert-Butyl cis-3-amino-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate.

To a mixture of tert-butyl 3-oxo-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate (2.55 g), methanol (19 ml) and THF (19 ml) at room temperature ammonium acetate (5.36 g) is added. The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (2.65 g) was added to the mixture. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (977 mg).

MS: [M+H]+ 368.2.

E) tert-Butyl cis-3-((methylsulfonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate (973 mg), TEA (536 mg) and THF (9 ml) at 0° Add methanesulfonyl chloride (364 mg). The mixture was stirred at room temperature for 1 hour, then the reaction mixture was poured into ice water and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.05 g).

MS: [M+H]+ 446.2.

F) N-(cis-2-((6-Phenylpyridin-2-yl)methyl)piperidin-3-yl)methanesulfonamide.

TFA was added to a mixture of tert-butyl cis-3-((methylsulfonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate (991 mg) and toluene (11 ml) at room temperature. (11 ml). The mixture was stirred at room temperature for 1 hour and then poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The resulting mixture was adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate/THF. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (671 mg).

MS: [M+H] ⁺ 346.1.

G) Isopropyl cis-3-((methylsulfonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate.

To a mixture of N-(cis-2-((6-phenylpyridin-2-yl)methyl)piperidin-3-yl)methanesulfonamide (150 mg) and THF (2.17 ml) was added TEA (132 mg) at room temperature and isopropyl chloroformate (0.326 ml). The mixture was stirred at room temperature for 1 hour, the resulting reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (157 mg).

1H NMR (300 MHz, CDC13) δ 1.12 (6H, d, J=6.4 Hz), 1.75 (4H, br.s), 2.05-2.19 (1H, m), 2 .67-2.90 (3H, m), 2.88-3.06 (2H, m), 3.35 (1H, dd, J=13.9, 5.7 Hz), 3.53-3 .68 (1H, m), 3.96-4.14 (1H, m), 4.84 (2H, d, J=5.7 Hz), 7.14-7.22 (1H, m), 7.38-7.52(3H, m), 7.55-7.59(1H, m), 7.66-7.74(1H, m), 7.90-7.98(2H, m ).

Example 75 Ethyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate

A) tert-Butyl 2-(biphenyl-3-ylmethyl)-3-oxopyrrolidine-1-carboxylate.

Pyrrolidine (1.61 g) was added to a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.5 g) and toluene (30 ml) at room temperature. The mixture is stirred at 100° C. for 3 hours and concentrated. CH3CN (30 ml) and 3-(bromomethyl)biphenyl (4.67 g) were added to the residue at room temperature. The mixture is stirred overnight under nitrogen at 80° C. and then concentrated. The resulting residue is diluted with water and the resulting mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.92 g).

MS: [M+H-Bos] + 252.2.

B) tert-Butyl cis-2-(biphenyl-3-ylmethyl)-3-((1-phenylethyl)amino)pyrrolidine-1-carboxylate.

Mixture of tert-butyl 2-(biphenyl-3-ylmethyl)-3-oxopyrrolidine-1-carboxylate (2.38 g), 1phenylethanamine (0.903 g), ytterbium(3+) tris(trifluoromethanesulfonate) (0.420 g) and toluene (20 ml) stirred at 100° C. for 4 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine and concentrated under reduced pressure. To a mixture of the resulting residue (3.08 g), CH3CN (30 ml) and acetic acid (5 ml) was added sodium triacetoxyborohydride (4.30 g) at 0°C. The mixture was stirred at room temperature for 1 hour and neutralized with 4M aqueous sodium hydroxide. The resulting mixture was partitioned between ethyl acetate and an aqueous sodium hydrogen carbonate solution, the organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.29 g).

MS: [M+H]+ 457.3.

C) tert-Butyl cis-3-amino-2-(biphenyl-3-ylmethyl)pyrrolidine-1-carboxylate.

tert-Butyl cis-2-(biphenyl-3-ylmethyl)-3-((1-phenylethyl)amino)pyrrolidine-1-carboxylate mixture (2.29g), 20% palladium hydroxide on charcoal (3.52g ), 1M hydrochloric acid (10.0 ml) and MeOH (50 ml) were stirred overnight under a normal hydrogen atmosphere at room temperature. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (865 mg).

MS, found: 297.2.

D) tert-Butyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-(biphenyl-3-ylmethyl)pyrrolidine-1-carboxylate (865 mg), TEA

- 41 039459 (497 mg) and THF (50 ml) at 0° C. methanesulfonyl chloride (337 mg) is added. The mixture was stirred at room temperature for 1 hour, then poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (750 mg).

MS: [M-N] ^- 429.2.

E) N-(cis-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride.

A mixture of tert-butyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (750 mg) and 4M hydrochloric acid in ethyl acetate (20 ml) was stirred at room temperature for within 3 days. The precipitate was collected by filtration to give the title compound (500 mg).

MS: [M+H] ⁺ 331.1.

F) Ethyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

Ethyl chloroformate (23, 7 mg). The mixture was stirred at room temperature for 30 minutes, then the reaction solution was poured into a saturated sodium hydrogen carbonate solution at room temperature, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was crystallized from ethyl acetate-heptane to give the title compound (32.0 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 0.64-1.23 (3H, m), 1.72-2.25 (2H, m), 2.60-3.48 (8H, m) , 3.54-4.25(3H, m), 7.11-7.69(10H, m).

Example 76 Optically active isopropyl cis-3-((methylsulfonyl)amino)-2-((6-phenylpyridin2-yl)methyl)piperidine-1-carboxylate.

Racemate (120 mg) isopropyl cis-3-((methylsulfonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate separated by HPLC (column: CHIRALPAK AD-H (UG065 ), 4.6 mm IDx250 mm L, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give the title compound (49.4 mg) (lower retention time fraction). The title compound was purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), saturated aqueous sodium hydrogen carbonate was added to the resulting fraction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (43.0 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 0.47 (2H, br.s), 0.64-1.12 (4H, m), 1.48 (1H, br.s), 1.74 (3H, br.s), 2.93-3.24 (6H, m), 3.43 (1H, d, J=6.1 Hz), 3.86 (1H, br.s), 4, 31 (1H, br.s), 4.76 (1H, br.s), 7.11-7.22 (1H, m), 7.34-7.54 (4H, m), 7.73 ( 2H, br.s), 8.00-8.11 (2H, m).

Example 81 N-(cis-2-(Biphenyl-3-ylmethyl)pyrrolidin-3-yl)methanesulfonamide m.p.

A mixture of tert-butyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (0.950 g), TFA (3.08 g) and dichloromethane (10 ml) was stirred in nitrogen atmosphere at 15°C for 2 hours.

The reaction solution was neutralized (pH 7) with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethanol/ethyl acetate) to give the title compound (0.378 g).

1H NMR (400 MHz, CDCl ,) δ 1.85-1.96 (1H, m), 2.22-2.34 (1H, m), 2.74-2.86 (2H, m), 2.94 (3H, s), 3.003.15 (2H, m), 3.25-3.33 (1H, m), 3.90-3.96 (1H, m), 7.18-7, 25(1H, m), 7.30-7.48(6H, m), 7.54-7.63(2H, m).

Example 88 tert-Butyl cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate

A) 4-(Chloromethyl)-2-phenyl-1,3-thiazole.

A mixture of benzenecarbothioamide (6.86 g), 1,3-dichloroacetone (6.35 g) and toluene (50 ml) was refluxed for 3 hours. The reaction mixture was cooled and water was added. The resulting mixture was extracted with ethyl acetate, the extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.77 g).

MS: [M+H] ⁺ 210.1.

B) tert-Butyl-3-oxo-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate.

Pyrrolidine (0.509 g) was added to a mixture of tert-butyl 3-oxo-piperidine-1-carboxylate (0.950 g) and toluene (10 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes and concentrated. The residue is mixed with CH3CN (10 ml) and to the mixture at room temperature

- 42 039459 4-(chloromethyl)-2-phenyl-1,3-thiazole (1 g) and TBAI (0.352 g) are added. The mixture is stirred overnight at 80° C. and then concentrated. The resulting residue is partitioned between ethyl acetate and water, and the mixture is extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (0.580 g).

MS: [M+H]+ 373.1.

C) tert-Butyl-cis-3-amino-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate.

To a mixture of tert-butyl 3-oxo-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate (580 mg), ammonium acetate (1200 mg), MeOH (5 ml) and THF (5 ml) sodium triacetoxyborohydride (495 mg) was added at room temperature. The mixture is stirred overnight at room temperature and then concentrated. The resulting residue was mixed with a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (213 mg).

MS: [M+H]+ 374.2.

D) tert-Butyl-cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate (212 mg), TEA (86 mg) and THF ( 5 ml) at room temperature, methanesulfonic anhydride (119 mg) is added. The mixture is stirred at room temperature for 10 minutes and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (212 mg).

1H NMR (300 MHz, CDC13) δ 1.33 (9H, s), 1.58-1.83 (3H, m), 2.00-2.11 (1H, m), 2.75-3, 07 (5H, m), 3.27 (1H, dd, J=14.4, 6.1 Hz), 3.54-3.69 (1H, m), 4.01 (1H, d, J= 11.4 Hz), 4.75 (1H, d, J=5.8 Hz), 6.14 (1H, br. s), 7.01 (1H, s), 7.39-7.49 ( 3H, m), 7.86-8.01 (2H, m).

Example 89 Isopropyl cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate.

A) N-(cis-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidin-3-yl)methanesulfonamide dihydrochloride.

To a mixture of tert-butyl cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine 1-carboxylate (207 mg) and ethyl acetate (5 ml) at room temperature, a 4M solution of hydrochloric acid in ethyl acetate (2 ml) is added. The mixture was stirred overnight at room temperature and then concentrated to give the title compound (200 mg).

MS: [M+H]+ 352.1.

B) Isopropyl cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1carboxylate.

To a mixture of N-(cis-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidin-3-yl)methanesulfonamide (60 mg), TEA (71.5 mg) and THF (2 ml) add a 2M solution of isopropyl chloroformate in toluene (0.106 ml) at room temperature. The mixture was stirred at room temperature for 3 hours and then purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (43.0 mg).

1H NMR (300 MHz, CDCl ,) δ 1.04-1.21 (6H, m), 1.59-1.83 (3H, m), 2.03-2.15 (1H, m), 2.81-3.05 (5H, m), 3.30 (1H, dd, J=14.8, 6.4 Hz), 3.53-3.71 (1H, m), 3.98- 4.09 (1H, m), 4.69-4.91 (2H, m), 6.38 (1H, br.s), 7.02 (1H, s), 7.38-7.53 ( 3H, m), 7.90-8.02 (2H, m).

Example 93 N-(cis-2-(Biphenyl-3-ylmethyl)-1-(cyclopropylcarbonyl)piperidin-3-yl)methanesulfonamide

Cyclopropanecarbonyl chloride was added to a mixture of N-(cis-2-(biphenyl-3-ylmethyl)piperidin-3-yl)methanesulfonamide (100 mg), TEA (58.8 mg) and dichloromethane (1 ml) under nitrogen at 0°C. (45.5 mg). The mixture was stirred at 0° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Phenomenex Gemini, mobile phase: water/CH ₃ CN (containing 0.05% NH3-H2O)) to give the title compound (56.0 mg).

1H NMR (400 MHz, DMSO-d6) δ 0.53-0.40 (4H, m), 1.26-1.76 (5H, m), 2.90-3.05 (6H, m), 3.23-3.52(1H, m), 4.28-4.66(1H, m), 4.88-5.18(1H, m), 7.16(1H, d, J=7 .6 Hz), 7.27-7.47 (7H, m), 7.57-7.62 (2H, m).

Example 100 Isopropyl cis-2-((6-(2,5-difluorophenyl)pyridin-2-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

A) 3-Isopropyloxpiperidine-1-carboxylate.

To a mixture of 1-benzylpiperidin-3-one hydrochloride (15.0 g), TEA (7.40 g) and CH3CN (100 ml) at 0° C.

- 43 039459 dropwise add a 2M solution of isopropyl chloroformate in toluene (59.8 ml). The mixture was stirred at room temperature for 2 hours, the insoluble precipitate was removed by filtration and washed with CH3CN. The filtrate is concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.0 g).

1H NMR (300 MHz, CDCl ,) δ 1.25 (6H, d, J=6.4 Hz), 1.95-2.04 (2H, m), 2.48 (2H, t, J= 6.6 Hz), 3.60-3.66 (2H, m), 4.04 (2H, s), 4.94 (1H, spt, J=6.2 Hz).

B) 2-Bromo-6-(bromomethyl)pyridine.

To a mixture of (6-bromopyridin-2-yl)methanol (5.22 g), PPh ₃ (8.74 g) and benzotrifluoride (210 ml) was added tetrabromomethane (11.1 g) at 0°C. The mixture is stirred at 0°C for 2 hours, the insoluble precipitate is removed by filtration and washed with a mixture of ethyl acetate and diethyl ether. The filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (7.33 g).

1 H NMR (300 MHz, CDCl ,) δ 4.50 (2H, s), 7.39-7.45 (2H, m), 7.52-7.60 (1H, m).

C) Isopropyl 2-((6-bromopyridin-2-yl)methyl)-3-oxo-piperidine-1-carboxylate.

Pyrrolidine (2.59 g) was added to a mixture of isopropyl-3-oxo-piperidine-1-carboxylate (4.50 g) and toluene (52 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes and then concentrated. Toluene and CH ₃ CN are added to the mixture, and the resulting mixture is concentrated. The residue was mixed with CH3CN (52 ml) and 2-bromo-6(bromomethyl)pyridine (7.32 g) was added to the mixture at room temperature. The mixture is refluxed for 15 hours, the reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (2.72 g).

MS: [M+H] + 355.0.

D) Isopropyl cis-3-amino-2-((6-bromopyridin-2-yl)methyl)piperidine-1-carboxylate.

Ammonium acetate was added to a mixture of isopropyl 2-((6-bromopyridin-2-yl)methyl)-3-oxo-piperidine-1-carboxylate (2.71 g), methanol (23 ml) and THF (23 ml) at room temperature (5.88 g). The mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (3.23 g) was added to the mixture. The mixture was stirred at room temperature for 15 hours. The mixture was poured into saturated aqueous sodium hydrogen carbonate under ice-cooling and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (373 mg).

MS: [M+H]+ 356.0.

E) Isopropyl cis-2-((6-bromopyridin-2-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

To a mixture of isopropyl cis-3-amino-2-((6-bromopyridin-2-yl)methyl)piperidine-1-carboxylate (369 mg), TEA (210 mg) and THF (3.5 ml) at room temperature methanesulfonyl chloride (142 mg) is added. The mixture was stirred at room temperature for 1 hour, the reaction solution was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (340 mg).

MS: [M+H]+ 434.0.

F) Isopropyl cis-2-((6-(2,5-difluorophenyl)pyridin-2-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

Mixture of isopropyl cis-2-((6-bromopyridin-2-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1 carboxylate (73 mg), (2,5-difluorophenyl)boronic acid (39.8 mg), 2M aqueous sodium carbonate solution (0.210 ml) and DME (1.1 ml) are refluxed under argon for 9 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (58.6 mg).

1H NMR (300 MHz, CDCI3) δ 0.92-1.12 (6H, m), 1.60-1.83 (3H, m), 2.02-2.07 (1H, m), 2, 91 (3H, s), 2.943.06 (2H, m), 3.30 (1H, dd, J=14.0, 5.7 Hz), 3.57-3.68 (1H, m), 3 .99-4.13 (1H, m), 4.73 (1H, st, J=6.2 Hz), 4.844.92 (1H, m), 5.64 (1H, br.s), 7, 01-7.16(2H, m), 7.22-7.26(1H, m), 7.62-7.74(3H, m).

- 44 039459

Example 101 Ethyl-(2S,3S)-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)pyrrolidin-1-carboxylate

The racemate (146 mg) of ethyl cis-2-(biphenyl-3-ylmethyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate was separated by HPLC (column: Chiralcel OD (IK001), 50 mm IDx500 mm L, manufactured Daicel Chemical Industries, mobile phase: hexane/2-propanol=450/550) to give the title compound (47 mg) (lower retention time fraction).

1H NMR (300 MHz, DMSO-d6) δ 0.62-1.16 (3H, m), 1.71-2.23 (2H, m), 2.67-3.50 (8H, m), 3.55-4.26 (3N, m), 7.10 -7.68 (10N, m).

Example 116 Isopropyl cis-2-((2',3'-difluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

Isopropyl cis-2-(3-iodobenzyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate (96mg), (2,3-difluorophenyl)boronic acid (95mg), XPhos Pd G3 (8 46 mg), 1M aqueous solution of tripotassium phosphate (0.6 ml) and THF (1 ml) are refluxed for 1 h. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (71.0 mg).

1H NMR (300 MHz, CDCl ₃ ) δ 0.82 (3H, br. s), 1.03 (3H, d, J=6.4 Hz), 1.59-1.99 (4H, m), 2.98(6H, s), 3.56-3.73(1H, m), 4.01-4.13(1H, m), 4.38(1H, d, J=7.6Hz) , 4.54-4.69(1H, m), 4.74-4.89(1H, m), 7.07-7.25(4H, m), 7.30-7.42(3H, m).

Example 117 Isopropyl cis-2-(3-iodobenzyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate

A 2M solution of isopropyl chloroformate in toluene ( 1.80 ml). Saturated aqueous sodium hydrogen carbonate was added to the mixture at room temperature, and the resulting mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.16 g).

1H NMR (300 MHz, CDCl ₃ ) δ 0.83-1.00 (3H, m), 1.10 (3H, d, J=6.1 Hz), 1.58-1.98 (4H, m ), 2.70-2.92(3H, m), 3.00(3H, s), 3.51-3.68(1H, m), 4.03-4.14(1H, m), 4.22-4.38(1H, m), 4.58-4.82(2H, m), 6.92-7.07(1H, m), 7.15(1H, d, J=7 .6 Hz), 7.48-7.58 (2H, m).

Example 122 Isopropyl cis-3-((methylsulfonyl)amino)-2-((3-phenyl-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate.

A) 3-Nitro-2-((3-phenyl-1H-pyrazol-1-yl)methyl)pyridine.

A mixture of 2-(bromomethyl)-3-nitropyridine (100 mg), 3-phenyl-1H-pyrazole (69.8 mg) and DMF (2 ml) was stirred at 60° C. for 17 hours. The mixture was partitioned between ethyl acetate and water , the organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (87 mg).

MS: [M+H]+ 281.0.

B) 2-((3-Phenyl-1H-pyrazol-1-yl)methyl)pyridine-3-amine.

A mixture of 3-nitro-2-((3-phenyl-1H-pyrazol-1-yl)methyl)pyridine (793 mg), 10% palladium-carbon (301 mg) and ethanol (35 ml) was stirred under normal hydrogen atmosphere at room temperature for 1 hour. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (509 mg).

MS: [M+H] ⁺ 251.0.

C) N-(2-((3-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methanesulfonamide.

A mixture of 2-((3-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-amine (550 mg), TEA (667 mg), methanesulfonyl chloride (629 mg) and THF (10 ml) was stirred at room temperature over 1 hour. MeOH (5 ml) and 2M aqueous sodium hydroxide solution (2.20 ml) were added to the mixture. The mixture was stirred at 50° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water, the organic layer was washed with brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (650 mg).

MS: [M+H]+ 329.0.

D) N-(cis-2-((3-Phenyl-1H-pyrazol-1-yl)methyl)piperidin-3-yl)methanesulfonamide.

A mixture of N-(2-((3-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methanesulfonamide (648 mg), 5% platinum on carbon (150 mg), 35% hydrochloric acid (411 mg), MeOH (23 ml) and water (7 ml) were stirred under a hydrogen atmosphere (3 MPa) at 50°C for 2 hours. 5% platinum on charcoal (75 mg) was added to the mixture, and the resulting mixture was stirred under a hydrogen atmosphere at 3 MPa and 50° C. for 2 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue was partitioned between aqueous sodium hydrogen carbonate and THF, and the organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and crystallized from ethyl acetate to give the title compound (110 mg).

MS: [M+H]+335.1.

E) Isopropyl cis-3-((methylsulfonyl)amino)-2-((3-phenyl-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate.

Mixture of N-(cis-2-((3-phenyl-1H-pyrazol-1-yl)methyl)piperidin-3-yl)methanesulfonamide (110 mg), TEA (66.6 mg), 2M solution of isopropyl chloroformate in toluene ( 0.247 ml) and THF (3 ml) were stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and an aqueous sodium hydrogen carbonate solution, the organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (93 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 0.62 (6H, d, J=5.3 Hz, minor peak), 0.81-1.12 (6H, m, major peak), 1.41 -1.83(4H, m), 3.03(3H, s), 3.06-3.21(1H, m), 3.41-3.54(1H, m), 3.74-3 .96 (1H, m), 4.26-4.59 (3H, m), 4.60-4.80 (1H, m), 6.62 (1H, d, J=1.5 Hz), 7.21-7.30(1H, m), 7.32-7.41(2H, m), 7.47(1H, br.s), 7.60(1H, d, J=2.3 Hz), 7.76 (2H, d, J=7.6 Hz).

Example 178 Isopropyl cis-3-((cyclopropylsulfonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate.

A) tert-Butyl cis-3-(((benzyloxy)carbonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate (1.05 g), sodium bicarbonate (0.360 g), THF (7 ml) and water (7 ml), 1(((benzyloxy)carbonyl)oxy)pyrrolidine-2,5-dione (0.748 g) was added at room temperature. The mixture was stirred vigorously at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.37 g).

MS: [M+H]+ 502.2.

B) Benzyl(cis-2-((6-phenylpyridin-2-yl)methyl)piperidin-3-yl)carbamate.

To a mixture of tert-butyl cis-3-(((benzyloxy)carbonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate (1.37 g) and toluene (15 ml ) at room temperature, add TFA (15 ml). The mixture was stirred at room temperature for 1 hour and then added under ice-cooling to a saturated aqueous sodium hydrogen carbonate solution. The mixture is adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (966 mg).

MS: [M+H]+ 402.1.

C) Isopropyl cis-3-(((benzyloxy)carbonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1carboxylate.

To a mixture of benzyl(cis-2-((6-phenylpyridin-2-yl)methyl)piperidin-3-yl)carbamate (960 mg), TEA (726 mg) and THF (20 ml) was added 2M isopropyl chloroformate solution at room temperature in toluene (2.39 ml). The mixture was stirred at room temperature for 1 hour, then added to an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.11 g).

MS: [M+H]+ 488.2.

D) Isopropyl cis-3-amino-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate.

Isopropyl cis-3-(((benzyloxy)carbonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate mixture (1.09 g), 10% palladium on charcoal (0 36 g) and MeOH (22 ml) were stirred at room temperature under normal hydrogen atmosphere for 1.5 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (703 mg).

MS: [M+H]+ 354.1.

E) Isopropyl cis-3-((cyclopropylsulfonyl)amino)-2-((6-phenylpyridin-2-yl)methyl)piperidine 1-carboxylate.

To a mixture of isopropyl cis-3-amino-2-((6-phenylpyridin-2-yl)methyl)piperidine-1-carboxylate (28 mg), TEA (0.00971 mg) and THF (1.0 ml) was added cyclopropanesulfonyl chloride (13.5 mg). The mixture was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was filtered using a Top-Phase Separation Filter Tube, and the filtrate was concentrated by blowing air at 60°C. The residue is purified by HPLC

- 46 039459 (YMCTriartC18, mobile phase: water/MeCN (10 mM ammonium bicarbonate)). The resulting fraction was concentrated by blowing air at 60° C. to give the title compound (12.7 mg).

MS: [M+H]+458.1.

Example 206 N-(cis-2-(Biphenyl-3-ylmethyl)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl)methanesulfonamide m.p.

Cyclopropanecarbonyl chloride was added to a mixture of N-(cis-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)methanesulfonamide (52.0 mg), TEA (47.8 mg) and THF (1.2 ml) at room temperature. (32.9 mg). The mixture was stirred at room temperature for 50 minutes, then poured into an aqueous sodium hydrogen carbonate solution and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give a solid. The solid was collected by filtration and washed with isopropyl ether/hexane to give the title compound (38.0 mg).

1H NMR (300 MHz, CDC13) δ 0.07-0.62 (2H, m), 0.72-1.08 (3H, m), 1.71-1.91 (1H, m), 2, 23-2.36(1H, m), 2.49-2.74(2H, m), 2.92-3.06(2H, m), 3.22(1H, td, J=13.1 , 3.0 Hz), 3.47-3.76(2H, m), 3.96-4.10(1H, m), 4.524.80(2H, m), 7.17(1H, d, J=7.6 Hz), 7.30-7.49(6H, m), 7.52-7.58(2H, m).

Example 209 N-(cis-2-(Biphenyl-3-ylmethyl)-1-isobutyrylpyrrolidin-3-yl)methanesulfonamide m.p.

2- methylpropanoyl chloride (24.8 mg). The mixture was stirred at 0°C for 30 minutes, then water was added to the mixture at 0°C and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (methanol/ethyl acetate). The resulting solid was recrystallized from ethyl acetate/hexane to give the title compound (29.0 mg).

1H NMR (300 MHz, CDCl ₃ ) δ 0.50-1.19 (6H, m), 1.71-2.51 (4H, m), 2.54-2.74 (1H, m), 2 .87-3.09 (2H, m), 3.11-3.27 (1H, m), 3.38-3.84 (2H, m), 3.91-4.09 (1H, m) , 4.23-4.55(1H, m), 4.57-4.74(1H, m), 7.09-7.62(9H, m).

Example 210 Optically active isopropyl cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3thiazol-4-yl)methyl)piperidine-1-carboxylate.

The racemate (82 mg) isopropyl-cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylate was separated by supercritical fluid chromatography ( SFC) (column: CHIRALCEL ODH (TB001), 4.6 mm IDx150 mm L, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide/methanol=770/230) to give the title compound (381 mg) (large fraction) holding time).

1H NMR (300 MHz, CDCl ,) δ 0.96-1.24 (6H, m), 1.60-1.87 (3H, m), 2.08 (1H, d, J=9.5 Hz), 2.78-3.07 (5H, m), 3.30 (1H, dd, J=14.6, 6.2 Hz), 3.52-3.76 (1H, m), 4 .05 (1H, d, J=14.8 Hz), 4.67-4.90 (2H, m), 6.31 (1H, br.s), 7.02 (1H, s), 7, 38-7.52 (3H, m), 7.89-8.04 (2H, m).

Example 213 Isopropyl cis-3-((methylsulfonyl)amino)-2-(pyridin-3-ylmethyl)piperidine-1-carboxylate

A) tert-Butyl-2-((6-chloropyridin-3-yl)methyl)-3-oxo-piperidine-1-carboxylate.

Pyrrolidine (0.857 g) was added to a mixture of tert-butyl 3-oxo-piperidine-1-carboxylate (2.00 g) and toluene (20 ml) at room temperature. The mixture is stirred for 15 minutes and concentrated under reduced pressure. The residue was dissolved in CH3CN (20 ml) and 2chloro-5-(chloromethyl)pyridine (1.63 g) and TBAI (0.742 g) were added to the resulting solution. The mixture is refluxed for 1 h and the reaction mixture is diluted with water. The mixture is extracted with ethyl acetate and the extract is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.61 g).

MS: [M+H]+ 325.3.

B) tert-Butyl cis-3-amino-2-((6-chloropyridin-3-yl)methyl)piperidine-1-carboxylate.

To a mixture of tert-butyl 2-((6-chloropyridin-3-yl)methyl)-3-oxo-piperidine-1-carboxylate (1.61 g), THF (15 ml) and MeOH (15 ml) was added at room temperature ammonium acetate (3.82 g). The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (2.10 g) was added to the mixture. The mixture was stirred overnight at room temperature, poured into saturated aqueous sodium hydrogen carbonate under ice-cooling, and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (567 mg).

MS: [M+H]+ 326.2.

C) tert-Butyl cis-2-((6-chloropyridin-3-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((6-chloropyridin-3-yl)methyl)piperidine-1-carboxylate (567

- 47 039459 mg), TEA (264 mg) and THF (8 ml) at room temperature add methanesulfonic anhydride (364 mg). The mixture is stirred at room temperature for 2 hours and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (650 mg).

MS: [M+H]+ 404.2.

D) N-(cis-2-((6-chloropyridin-3-yl)methyl)piperidin-3-yl)methanesulfonamide dihydrochloride.

A mixture of tert-butyl cis-2-((6-chloropyridin-3-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate (645 mg) and a solution of hydrochloric acid in methanol (776 mg) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to give the title compound (557 mg).

MS: [M+H] ⁺ 304.1.

E) Isopropyl cis-2-((6-chloropyridin-3-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate.

A 2M solution of isopropyl chloroformate in toluene (0.319 ml). The mixture is stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (222 mg).

MS: [M+H]+ 390.2.

F) Isopropyl cis-3-((methylsulfonyl)amino)-2-(pyridin-3-ylmethyl)piperidine-1-carboxylate.

Isopropyl cis-2-((6-chloropyridin-3-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate mixture (91.0 mg), 5.5% palladium on charcoal (30 mg ) and ethanol (5 ml) was stirred at room temperature under a normal hydrogen atmosphere for 2 days. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. A similar reaction was carried out using isopropyl cis-2-((6-chloropyridin-3-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate (117 mg), 5.5% palladium on charcoal ( 40 mg) and ethanol (5 ml). The combined residues were purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (144 mg).

1H NMR (300 MHz, DMSO-d6) δ 0.49-1.13 (6H, m), 1.49 (1H, br.s), 1.60-1.82 (3H, m), 2, 81-2.91(2H, m), 2.92-3.07(4H, m), 3.35-3.50(1H, m), 3.85(1H, d, J=14.4 Hz), 4.26-4.67 (2H, m), 7.27 (1H, br.s), 7.39 (1H, br.s), 7.54 (1H, dt, J=7, 8, 2.0 Hz), 8.36 (2H, d, J=2.3 Hz).

Example 214 Isopropyl cis-3-((methylsulfonyl)amino)-2-((1-phenylpiperidin-3-yl)methyl)piperidine-1-carboxylate

A) Isopropyl cis-3-((methylsulfonyl)amino)-2-(piperidin-3-ylmethyl)piperidine-1-carboxylate.

Isopropyl-cis-3-((methylsulfonyl)amino)-2-(pyridin-3-ylmethyl)piperidine-1-carboxylate mixture (142mg), 5% rhodium on charcoal (50% moisture, 30mg), MeOH (25 ml) and acetic acid (5 ml) were stirred under hydrogen atmosphere (3 MPa) at 50° C. for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (140 mg).

MS: [M+H]+ 362.2.

C) Isopropyl-cis-3-((methylsulfonyl)amino)-2-((1-phenylpiperidin-3-yl)methyl)piperidine-1-carboxylate.

To a mixture of isopropyl-cis-3-((methylsulfonyl)amino)-2-(piperidin-3-ylmethyl)piperidine-1-carboxylate (28.6 mg), bromobenzene (24.8 mg), cesium carbonate (103 mg) and t-AmOH (1 ml) Pd ₂ (dba) ₃ (7.24 mg) and dicyclohexyl-(2',6'-diisopropoxybiphenyl-2-yl)phosphine (7.38 mg) are added at room temperature. The mixture is refluxed under nitrogen atmosphere for 4 hours. Water is added to the mixture and the resulting mixture is extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (23.6 mg).

1H NMR (300 MHz, DMSO-d6) δ 0.92-2.04 (18H, m), 2.22-2.45 (1H, m), 2.55-2.87 (2H, m), 2.92 (3H, s), 3.20-3.64 (2H, m), 3.79 (1H, br.s), 4.43 (1H, br.s), 4.76 (1H, quin, J=6.2 Hz), 6.72 (1H, t, J=7.2 Hz), 6.90 (2H, dd, J=8.5, 3.2 Hz), 7.09- 7.27 (3H, m).

Example 227 N-(cis-2-(Biphenyl-3-ylmethyl)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl)methanesulfonamide m.p.

To a mixture of N-(cis-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (40 mg), pivalic acid (13.4 mg), HATU (49.7 mg) and DMF (0. 5 ml) at 0° C. TEA (33.1 mg) is added. The mixture was stirred at room temperature for 30 minutes, then a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (39 mg).

¹ H NMR (300 MHz, CDCl ,) δ 1.26 (9H, s), 1.89-2.05 (1H, m), 2.20-2.34 (1H, m), 2.45 (3H, s), 2.78-2.93 (1H, m), 3.19-3.29 (1H, m), 3.62-3.77 (2H, m), 3.89-4 .04 (1H, m), 4.45 (1H, d, J=8.3 Hz), 4.70-4.80 (1H, m), 7.30-7.49 (6H, m), 7.52-7.62 (3H, m).

Example 254 N-(cis-1-(Cyclobugylcarbonyl)-2-((2-(3-fluorophenyl)-1,3-thiazol-4-yl)methyl)-irrolidin-3-yl)methanesulfonamide.

A) 2-Bromo-4-(bromomethyl)-1,3-thiazole.

Phosphorus tribromide (6.97 g) was added to a mixture of (2-bromo-1,3-thiazol-4-yl)methanol (5.0 g) and THF (50 ml) at 0°C. The mixture is stirred overnight under nitrogen at room temperature. The mixture was poured into ice water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.90 g).

MS: [M+H]+ 255.7.

B) tert-Butyl 2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-oxopyrrolidine-1-carboxylate.

Pyrrolidine (8.53 g) was added to a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (20.2 g) and toluene (200 ml) at room temperature. The mixture is refluxed overnight and then concentrated. The residue is mixed with CH3CN (200 ml) and 2-bromo-4(bromomethyl)-1,3-thiazole (14.0 g), TBAI (4.03 g) and CH3CN (200 ml) are added to the resulting mixture at 80° WITH. The mixture is stirred under nitrogen at 80° C. for 3 hours and then concentrated under reduced pressure. The mixture is poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.5 g).

MS: [M-N] ^- 358.8.

C) tert-Butyl-cis-3-amino-2-((2-bromo-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl 2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-oxopyrrolidine-1-carboxylate (13.6 g), ammonium formate (25.0 g) and MeOH (40 ml) chloro[N-[4(dimethylamino)phenyl]-2-pyridinecarboxamidateto](pentamethylcyclopentadienyl)iridium(III) (0.454 g) was added at room temperature. The mixture is refluxed for 2 hours. The reaction solution is concentrated. The resulting residue was diluted with ethyl acetate, washed with a mixture of saturated brine and saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (6.18 g).

MS: [M+H] ⁺ 362.1.

D) tert-Butyl cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1carboxylate.

A mixture of tert-butyl-cis-3-amino-2-((2-bromo-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (145 mg), TEA (81 mg) and THF (2 ml) was stirred at 0°C and then methanesulfonic anhydride (91 mg) was added to the mixture at 0°C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (53 mg).

MS: [M+H] + 440.0.

E) N-(cis-2-((2-Bromo-1,3-thiazol-4-yl)methyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide.

tert-Butyl-cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (650 mg) and 4M hydrochloric acid solution in ethyl acetate (7.38 ml) was mixed at room temperature. After 30 minutes, the reaction solution was concentrated. The resulting residue was mixed with THF (7.5 ml) and TEA (747 mg), and cyclobutanecarbonyl chloride (262 mg) was added to the mixture at 0°C. The mixture was stirred at room temperature for 1 hour, then saturated brine was added to the reaction solution, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (422 mg).

MS: [M+H] ⁺ 422.1.

F) N-(cis-1-(Cyclobutylcarbonyl)-2-((2-(3-fluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-(cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (60.0 mg), 3-( (A-taPhos) ₂ PdCl2 (5.7 mg). The mixture was stirred under nitrogen at 80° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane) and the resulting compound was triturated into the mixture. diethyl ether/hexane to give the title compound (35.2 mg).

¹ H NMR (300 MHz, CDCl ,) δ 1.33-1.52 (1H, m), 1.81-2.58 (7H, m), 2.94-3.45 (7H, m) , 3.61 (1H, dd, J=14.8, 6.1 Hz), 4.00-4.21 (1H, m), 4.30-4.59 (1H, m), 6.94 -7.04(1H, m), 7.10-7.20(1H, m), 7.39-7.51(1H, m), 7.59-7.68(1H, m), 7 .69-7.79 (1H, m), 8.12 (1H, d, J=9.1 Hz).

Example 255 N-(cis-1-(Cyclobutylcarbonyl)-2-((2-(2-fluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-(cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (60.0 mg), (2- (A-taPhos) ₂ PdCl2 (6.0 mg). The mixture was stirred under nitrogen at 80° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane), and then the resulting compound was triturated in diethyl ether/ hexane to give the title compound (38.2 mg).

¹ H NMR (300 MHz, CDC13) δ 1.23-1.43 (1H, m), 1.82-2.59 (7H, m), 2.94-3.46 (7H, m), 3 .66 (1H, dd, J=14.8, 5.7 Hz), 4.01-4.19 (1H, m), 4.30-4.62 (1H, m), 7.02-7 .12(1H, m), 7.16-7.25(1H, m), 7.28-7.36(1H, m), 7.38-7.49(1H, m), 8.14 -8.29 (2H, m).

Example 256 N-(cis-1-(Cyclobutylcarbonyl)-2-((2-(2,3-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-(cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (60.0 mg), (2, (A-taPhos) 2 PdCl 2 (A-taPhos) ₂ PdCl ₂ ( 6.0 mg). The mixture was stirred under nitrogen at 80° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane) and the resulting compound was triturated in diethyl ether/hexane to give the title compound (38.4 mg).

¹ H NMR (300 MHz, CDCI3) δ 1.20-1.44 (1H, m), 1.81-2.03 (2H, m), 2.06-2.61 (5H, m), 2 .94-3.44 (7H, m), 3.67 (1H, dd, J=14.6, 5.9 Hz), 4.00-4.19 (1H, m), 4.30-4 .60 (1H, m), 7.05-7.51 (3H, m), 7.89-8.12 (2H, m).

Example 258 N-(cis-1-(Cyclobutylcarbonyl)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-(cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (51.1 mg), (3, (A-taPhos) 2 PdCl 2 (A-taPhos) ₂ PdCl ₂ ( 3.7 mg). The mixture is stirred overnight under nitrogen at 80°C. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane), and the resulting compound was triturated in diethyl ether/hexane to give the title compound (30.2 mg).

¹ H NMR (300 MHz, CDC13) δ 1.33-1.52 (1H, m), 1.80-2.03 (2H, m), 2.06-2.58 (5H, m), 2 .96-3.05 (3H, m), 3.07-3.45 (4H, m), 3.60 (1H, dd, J=14.8, 6.4 Hz), 3.98-4 .20 (1H, m), 4.30-4.57 (1H, m), 6.84-6.95 (1H, m), 6.997.10 (1H, m), 7.42-7.53 (2H, m), 7.94 (1H, d, J=8.7 Hz).

Example 259 N-(cis-1-(Cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)cyclopropanesulfonamide.

A) tert-Butyl-3-oxo-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate.

Pyrrolidine (85 mg) was added to a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (185 mg) and toluene (2.00 ml) at room temperature. The mixture is stirred at room temperature for 15 minutes and concentrated under reduced pressure. The residue was mixed with CH3CN (2 ml) and 4-(chloromethyl)-2-phenyl-1,3-thiazole (105 mg) and TBAI (36.9 mg) were added to the resulting mixture. The mixture is refluxed for 1.5 h and then the reaction mixture is diluted with water. The mixture is extracted with ethyl acetate, and the resulting extract is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (45.3 mg).

MS: [M+H]+ 359.1.

B) tert-Butyl-cis-3-amino-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-3-oxo-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (3.66 g), ammonium formate (6.44 g) and MeOH (30 mL) chloro[N-[4(dimethylamino)phenyl]-2-pyridinecarboxamidateto](pentamethylcyclopentadienyl)iridium(III) (123 mg) was added at room temperature. The mixture was stirred under argon at 70° C. for 2 hours. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate and brine, and concentrated under reduced pressure to give the title compound (3, 42 g).

- 50 039459

MS: [M+H]+ 360.1.

C) tert-Butyl cis-3-((cyclopropylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-1-carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (810 mg), TEA (0.81 ml), DMAP (91.0 mg) add THF (5.0 ml) and DMF (6.0 ml) at room temperature add cyclopropanesulfonyl chloride (0.57 ml). The mixture was stirred at room temperature for 2 hours. A 5% aqueous acetic acid solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (317 mg).

MS: [M+H]+ 464.3.

D) N-(cis-1-(Cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)cyclopropanesulfonamide.

To a mixture of tert-butyl-cis-3-((cyclopropylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-1-carboxylate (72.0 mg), cyclopentylmethyl - (2.0 ml) and MeOH (2.0 ml) at room temperature, add a 4M solution of hydrochloric acid in cyclopentylmethyl ether (2.0 ml). The mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. DMF (2.0 ml), THF (2.0 ml), TEA (0.088 ml) and cyclobutanecarbonyl chloride (0.050 ml) were added to the residue, and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane). The resulting compound was purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), a saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure, the residue was triturated in diethyl ether/hexane to give the title compound (15.5 mg).

¹ H NMR (300 MHz, CDCl ,) δ 0.81-1.44 (6H, m), 1.80-2.53 (7H, m), 3.03-3.53 (4H, m) , 3.65 (1H, dd, J=14.8, 5.7 Hz), 4.03-4.21 (1H, m), 4.45-4.58 (1H, m), 6.88 -6.98(1H, m), 7.41-7.52(3H, m), 7.88-8.00(2H, m), 8.11(1H, d, J=9.5Hz ).

Example 261 N-((2S,3S)-2-(Biphenyl-3-ylmethyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide m.p.

A) tert-Butyl-2-(3-bromobenzyl)-3-oxopyrrolidine-1-carboxylate.

Pyrrolidine (2.49 g) was added to a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (5.4 g) and toluene (50.0 ml) at room temperature. The mixture is stirred for 15 minutes and then concentrated. The residue was mixed with CH3CN (50 ml) and 1-bromo-3-(bromomethyl)benzene (7.29 g) and TBAI (2.15 g) were added to the mixture. The mixture is refluxed for 1 hour and then diluted with water. The mixture is extracted with ethyl acetate and the extract is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.00 g).

MS, found: 254.2.

B) tert-Butyl cis-3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate.

Chloro[N- [4-(dimethylamino)phenyl]-2pyridinecarboxamidateto](pentamethylcyclopentadienyl)iridium(111) (0.026 g). The mixture was stirred under nitrogen at 70° C. for 2 hours. The mixture was then neutralized with saturated aqueous sodium hydrogen carbonate at 0° C. and concentrated under reduced pressure. The residue is extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (565 mg).

MS, found: 299.2.

C) tert-Butyl-(2S,3S)-3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate.

The racemate (1.5 g) of tert-butyl cis-3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate was separated by HPLC (column: CHIRALPAK AD (AK001), 50 mm IDx500 mm L, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol/diethylamine=850/150/1) to give the title compound (650 mg) (lower retention time fraction).

MS, found: 299.0.

D) tert-Butyl-(2S,3S)-2-(3-bromobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate (920 mg), TEA

- 51 039459 (786 mg) and THF (10 ml) with stirring at room temperature, add methanesulfonic anhydride (541 mg). After 0.5 h, the reaction mixture is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.05 g).

MS, found: 333.1.

E) N-((2S,3S)-2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride.

To a 4M solution of hydrochloric acid in ethyl acetate (5.42 ml) at room temperature was added tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (470 mg). The mixture was stirred for 1 hour and then concentrated to give the title compound (370 mg). MS: [M+H]+333.1.

F) N-((2S,3S)-2-(3-Bromobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide.

Cyclobutanecarbonyl chloride (96 mg ). The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (220 mg).

MS: [M+H]+ 415.2.

G) N-((2S,3S)-2-(Biphenyl-3-ylmethyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (55 mg), phenylboronic acid (48.4 mg), XPhos Pd G3 (5, 60 mg), 1M aqueous solution of tripotassium phosphate (0.397 ml) and THF (1 ml) are refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue is diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and purified by silica gel column chromatography (methanol/ethyl acetate). The resulting solid was crystallized from ethyl acetate diisopropyl ether-hexane to give the title compound (31 mg).

1H NMR (300 MHz, CDCl ,) δ 1.31-3.01 (11H, m), 3.04-3.79 (4H, m), 3.89-4.74 (3H, m), 7.07-7.63 (10N, m).

Example 262 N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

A) tert-Butyl-(2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (2.38 g), (3-fluorophenyl)boronic acid (1.15 d), XPhos Pd G3 (0.139 g), 1M tripotassium phosphate aqueous solution (16.5 ml) and THF (50 ml) were stirred at 70° C. for 2 h. The mixture was concentrated under reduced pressure, the residue was diluted with saturated aqueous sodium bicarbonate and extract the mixture with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.37 g).

MS: [M+H-Bos] + 349.3.

B) N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride.

To a mixture of tert-butyl-(2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (2.37 g) and ethyl acetate ( 10 ml) at room temperature, add a 4M solution of hydrochloric acid in ethyl acetate (26.4 ml). The mixture is stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure and the resulting solid is collected by filtration with ethyl acetate. The resulting solid was washed with ethyl acetate and dried to give the title compound (1.88 g).

MS: [M+H]+ 349.3.

C) N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (1.10 g), TEA (1.45 g) and THF (20 ml) at 0° C., cyclobutanecarbonyl chloride (0.508 g) was added dropwise. The mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was concentrated under reduced pressure to remove THF. The remaining aqueous layer is extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). The residue was crystallized from ethyl acetate-hexane to give the title compound (1.10 g).

1H NMR (300 MHz, DMSO-d ₆ ) δ 0.91-2.41 (9H, m), 2.53-3.05 (5H, m), 3.09-3.58 (2H, m) , 3.75-3.96 (1H,

- 52 039459

m), 4.04 4.46 (1H, m), 7.03-7.77 (9H, m).

Example 266 N-((2S,3S)-2-((3-Fluorobiphenyl-3-yl)methyl)-1-((1-fluorocyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

A) N-((2S,3S)-2-(3-Bromobenzyl)-1-((1-fluorocyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (100 mg), 1-fluorocyclobutanecarboxylic acid (50 mg) and DMF (2 ml), HATU was added dropwise (154 mg) and DIPEA (105 mg). The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (109 mg).

MS: [M+H]+433.1.

B) N-((2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-1-((1-fluorocyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide.

Mixture of N-((2S,3S)-2-(3-bromobenzyl)-1-((1-fluorocyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide (54.4 mg), (3-fluorophenyl)boronic acid (52.7 mg), XPhos Pd G3 (5.31 mg), 1M tripotassium phosphate (0.377 ml) and THF (1 ml) were stirred at 70° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the obtained ethyl acetate mixture. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (NH, ethyl acetate/hexane). The residue was crystallized from ethyl acetate-hexane to give the title compound (42.4 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 1.28-2.41 (7H, m), 2.52-2.64 (1H, m), 2.70-2.86 (4H, m) , 3.00 (1H, dd, J=13.8, 6.6 Hz), 3.38-3.63 (2H, m), 3.81-4.00 (1H, m, J=10, 2 Hz), 4.37-4.58(1H, m), 7.12-7.23(1H, m), 7.247.41(2H, m), 7.43-7.63(6H, m ).

Example 269 N-(cis-1-(Cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)1-fluoromethanesulfonamide.

A) tert-Butyl-cis-3-(((fluoromethyl)sulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (108 mg), DIPEA (58.2 mg) and THF (1 ml) at 0° C., fluoromethanesulfonyl chloride (31.8 mg) was added. Water was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, the resulting mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (62.5 mg).

MS: [M+H]+ 456.1.

B) N-(cis-1-(Cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide.

To a mixture of tert-butyl-cis-3-(((fluoromethyl)sulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (31.2 mg ) and MeOH (0.200 ml), 4M hydrochloric acid in cyclopentylmethyl ether (0.342 ml) was added at room temperature. The mixture is stirred at room temperature for 1 hour and then concentrated. The residue was mixed with THF (0.7 ml) and TEA (34.7 mg) and cyclobutanecarbonyl chloride (12.2 mg) was added to the mixture at 0°C. The mixture was stirred at room temperature for 1 hour, brine was added to the mixture, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (22.2 mg). 1H NMR (300 MHz, CDCl ₃ ) δ ppm 1.35-1.53 (1H, m), 1.81-2.02 (2H, m), 2.14 (5H, br.s), 3.03-3.39 (4H, m), 3.67 (1H, dd, J=14.8, 5.7 Hz), 4.13-4.28 (1H, m), 4.42-4.59 (1H, m), 4.92- 5.32(2H, m), 6.98(1H, s), 7.41-7.51(3H, m), 7.908.03(2H, m), 8.96(1H, d, J= 8.7 Hz).

Example 293 N-(cis-2-((2-Fluoro-biphenyl-3-yl)methyl)-1-isobutyrylpyrrolidin-3-yl)methanesulfonamide m.p.

A) 1-Bromo-3-(bromomethyl)-2-fluorobenzene.

To a mixture of (3-bromo-2-fluorophenyl)methanol (5.13 g), PPh ₃ (7.88 g) and trifluoromethylbenzene (180 ml) was added tetrabromomethane (9.96 g) at 0°C. The mixture is stirred at 0° C. for 2 hours, the insoluble precipitate is removed by filtration and washed with diethyl ether. The filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.70 g).

1H NMR (300 MHz, CDCl ₃ ) δ 4.51 (2H, d, J=1.1 Hz), 7.02 (1H, td, J=8.0, 1.4 Hz), 7.30- 7.37 (1H, m), 7.51

- 53 039459 (1H, ddd, J=8.1, 6.4, 1.7 Hz).

B) tert-Butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate.

Pyrrolidine (1.52 g) was added to a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.30 g) and toluene (28 ml) at room temperature. The mixture was stirred at room temperature for 30 minutes, refluxed using a Dean-Stark trap for 30 minutes and then concentrated under reduced pressure. The residue was mixed with CH3CN (28 ml) and 1-bromo-3-(bromomethyl)-2-fluorobenzene (4.77 g) and TBAI (1.32 g) were added to the resulting mixture at room temperature. The mixture is refluxed for 4.5 hours, then poured into water and the resulting mixture is extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g).

1H NMR (300 MHz, CDCl ₃ ) δ 1.45 (9H, s), 2.12-2.30 (1H, m), 2.44-2.59 (1H, m), 2.97-3 .40 (3H, m), 3.744.02 (1H, m), 4.21 (1H, t, J=5.1 Hz), 6.89-6.96 (1H, m), 7.05 ( 1H, t, J=6.7 Hz), 7.43 (1H, dd, J=8.0, 6.4, 1.9 Hz).

C) tert-Butyl cis-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate.

Mixture of tert-butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate (941 mg), ammonium formate (1.28 g), chloro[N-[4-(dimethylamino)phenyl] -2-pyridinecarboxamidateto](pentamethylcyclopentadienyl)iridium(III) (30.5 mg) and MeOH (20 ml) were stirred under argon at 70° C. for 2.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution with cooling ice and extract the resulting mixture with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (427 mg).

MS: [M+H(tBu)]+316.9.

D) tert-Butyl cis-2-(3-bromo-2-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl cis-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (421 mg), TEA (228 mg) and THF (4 ml) was added methanesulfonyl chloride ( 155 mg). The mixture was stirred at room temperature for 1 hour, then poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (437 mg).

MS: [M-N]' 448.9.

E) N-(cis-2-(3-Bromo-2-fluorobenzyl)pyrrolidin-3-yl)methanesulfonamide.

TFA was added to a mixture of tert-butyl cis-2-(3-bromo-2-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (434 mg) and toluene (4.8 ml) at room temperature . The mixture was stirred at room temperature for 1 hour, and then the resulting reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture is adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (245 mg).

MS: [M+H] + 350.9.

F) N-(cis-2-(3-Bromo-2-fluorobenzyl)-1-isobutyrylpyrrolidin-3-yl)methanesulfonamide.

2-methylpropanoyl chloride (72 .8 mg). The mixture was stirred at room temperature for 1 hour, then added to aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (132 mg).

MS: [M+H] ⁺ 421.0.

G) N-(cis-2-((2-Fluoro-biphenyl-3-yl)methyl)-1-isobutyrylpyrrolidin-3-yl)methanesulfonamide.

Mixture of N-(cis-2-(3-bromo-2-fluorobenzyl)-1-isobutyrylpyrrolidin-3-yl)methanesulfonamide (63 mg), phenylboronic acid (36.5 mg), XPhos Pd G3 (6.33 mg) , 1M aqueous solution of tripotassium phosphate (0.449 ml) and THF (1.5 ml) was stirred under argon at 70° C. for 1 hour. The mixture was poured into aqueous sodium hydrogen carbonate and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (52.8 mg).

1H NMR (300 MHz, CDC13) δ 0.57-1.14 (6H, m), 1.83-2.13 (1H, m), 2.27-2.41 (1H, m), 2, 53-3.20 (6N, m),

- 54 039459

3.40-3.55(2H, m), 3.65-4.11(1H, m), 4.35-4.67(1H, m), 4.81-4.89(1H, m ), 7.10-7.20(1H, m), 7.28-7.54(7H, m).

Example 294 N-(cis-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-isobutyrylpyrrolidin-3-yl)methanesulfonamide

Mixture of N-(cis-2-(3-bromo-2-fluorobenzyl)-1-isobutyrylpyrrolidin-3-yl)methanesulfonamide (62 mg), (3-fluorophenyl)boronic acid (41.2 mg), XPhos Pd G3 ( 6.23 mg), 1M aqueous tripotassium phosphate (0.441 ml) and THF (1.5 ml) were stirred under argon at 70° C. for 1 hour. The mixture was poured into aqueous sodium hydrogen carbonate and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (53.2 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.56-1.13 (6H, m), 1.86-2.08 (1H, m), 2.29-2.3 (1H, m), 2.55-3.21(6H, m), 3.41-3.78(2H, m), 3.97-4.11(1H, m), 4.36-4.67(1H, m ), 4.77-4.86(1H, m), 7.03-7.11(1H, m), 7.14-7.23(2H, m), 7.27-7.51(4H , m).

Example 299 N-(cis-1-(Cyclobutylcarbonyl)-2-((5-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide

A) tert-Butyl-2-(3-bromo-5-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate.

Pyrrolidine (1.59 g) was added to a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.44 g) and toluene (30 ml) at room temperature. The mixture was stirred at room temperature for 20 minutes, refluxed for 20 minutes using a Dean-Stark trap, and then concentrated under reduced pressure. The residue was mixed with CH3CN (30 ml), and 1-bromo-3-(bromomethyl)-5-fluorobenzene (4.98 g) and TBAI (1.37 g) were added to the mixture at room temperature. The mixture is refluxed for 4.5 hours, then poured into water and the resulting mixture is extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.83 g).

MS: [M+N-Sun]+271.9.

B) tert-Butyl cis-3-amino-2-(3-bromo-5-fluorobenzyl)pyrrolidine-1-carboxylate.

Mixture of tert-butyl 2-(3-bromo-5-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate (2.82 g), ammonium formate (3.82 g), chloro[N-[4-(dimethylamino) phenyl]-2-pyridinecarboxamidateto](pentamethylcyclopentadienyl)iridium(III), (0.069 g) and MeOH (60 ml) were stirred under argon at 70° C. for 2.5 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution at ice-cooling and extract the resulting mixture with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.07 g). MS: [M+H-(tBu)]+316.9.

C) tert-Butyl cis-2-(3-bromo-5-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl cis-3-amino-2-(3-bromo-5-fluorobenzyl)pyrrolidine-1-carboxylate (1.06 g), TEA (0.575 g) and THF (10 ml) was added at room temperature methanesulfonyl chloride (0.390 g). The mixture was stirred at room temperature for 1 hour, then the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (1.09 g).

MS: [M-N] ^- 448.8.

D) N-(cis-2-(3-Bromo-5-fluorobenzyl)pyrrolidin-3-yl)methanesulfonamide.

TFA was added to a mixture of tert-butyl cis-2-(3-bromo-5-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (1.09 g) and toluene (12 ml) at room temperature (12 ml). The mixture was stirred at room temperature for 1 hour and then, under ice-cooling, poured into a saturated aqueous sodium hydrogen carbonate solution. The mixture is adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (245 mg).

MS: [M+H] + 350.9.

E) N-(cis-2-(3-Bromo-5-fluorobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide.

Cyclobutanecarbonyl chloride (155 mg). The mixture was stirred at room temperature for 1 hour, added to aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals are collected by filtration and washed with a mixture of diisopropyl

- 55 039459 ether-hexane to give the title compound (261 mg).

MS: [M+H]+ 433.0.

F) Na(cis-1-(Cyclobutylcarbonyl)-2-((5-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

Mixture of N(cis-2-(3-bromo-5-fluorobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (128 mg), phenylboronic acid (72.0 mg), XPhos Pd G3 (12.5 mg), 1M aqueous tripotassium phosphate (0.886 ml) and THF (3 ml) were stirred under argon at 70° C. for 1 hour. The mixture was poured into aqueous sodium hydrogen carbonate and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (107 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.66-2.39 (8H, m), 2.47-3.22 (6H, m), 3.28-3.78 (2H, m), 3.89-4.04(1H, m), 4.23-4.81(2H, m), 6.84-7.10(1H, m), 7.11-7.19(1H, m ), 7.31-7.48(4H, m), 7.50-7.57(2H, m).

Example 300 N-(cis-1-(Cyclobutylcarbonyl)-2-((3',5-difluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

Mixture of N-(cis-2-(3-bromo-5-fluorobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (126 mg), (3-fluorophenyl)boronic acid (81 mg), XPhos Pd G3 (12.3 mg), 1M aqueous tripotassium phosphate (0.872 ml) and THF (2.9 ml) were stirred under argon at 70° C. for 1 hour. The mixture was poured into aqueous sodium hydrogen carbonate and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (118 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67-2.38 (8H, m), 2.43-3.22 (6H, m), 3.28-3.82 (2H, m), 3.89-4.06(1H, m), 4.22-4.66(1H, m), 4.68-4.84(1H, m), 6.88-7.24(4H, m ), 7.27-7.45 (3H, m).

Example 303 N-(cis-1-(Cyclobutylcarbonyl)-2-((6-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

A) tert-Butyl-2-(3-bromo-4-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate.

Pyrrolidine (1.59 g) was added to a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.46 g) and toluene (30 ml) at room temperature. The mixture was stirred at room temperature for 30 minutes, then refluxed for 30 minutes using a Dean Stark trap and then concentrated under reduced pressure. The residue was mixed with CH3CN (30 ml), and 2-bromo-4-(bromomethyl)-1-fluorobenzene (5.00 g) and TBAI (1.38 g) were added to the resulting mixture at room temperature. The mixture is refluxed for 4 hours, then the reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.59 g).

MS: [M+H-Bos] + 271.9.

B) tert-Butyl cis-3-amino-2-(3-bromo-4-fluorobenzyl)pyrrolidine-1-carboxylate.

Mixture of tert-butyl 2-(3-bromo-4-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate (1.59 g), ammonium formate (1.35 g), chloro[N-[4-(dimethylamino) phenyl]-2-pyridinecarboxamidateto](pentamethylcyclopentadienyl)iridium(III) (0.026 g) and MeOH (25 ml) were stirred under argon at 70° C. for 2.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution with cooling ice and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (548 mg).

MS: [M+H(tBu)] ⁺ 317.0.

C) tert-Butyl cis-2-(3-bromo-4-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl cis-3-amino-2-(3-bromo-4-fluorobenzyl)pyrrolidine-1-carboxylate (542 mg), TEA (294 mg) and THF (5.1 ml) was added at room temperature methanesulfonyl chloride (200 mg). The mixture was stirred at room temperature for 1 hour, then poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (482 mg).

MS: [M-N] ^- 448.8.

D) N-(cis-2-(3-Bromo-4-fluorobenzyl)pyrrolidin-3-yl)methanesulfonamide.

TFA was added to a mixture of tert-butyl cis-2-(3-bromo-4-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (477 mg) and toluene (5.3 ml) at room temperature (5.3 ml). The mixture was stirred at room temperature for 1 hour and then poured into a saturated aqueous solution

- 56 039459 sodium bicarbonate with ice cooling. The mixture is adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (323 mg).

MS: [M+H] + 350.9.

E) N-(cis-2-(3-Bromo-4-fluorobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide.

Cyclobutanecarbonyl chloride (108 mg). The mixture was stirred at room temperature for 1 hour, then added to aqueous sodium hydrogen carbonate solution and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (149 mg).

MS: [M+H]+ 433.0.

F) N-(cis-1-(Cyclobutylcarbonyl)-2-((6-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

A mixture of N-(cis-2-(3-bromo-4-fluorobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (72 mg), phenylboronic acid (40.5 mg), XPhos Pd G3 (7, 03 mg), 1M aqueous tripotassium phosphate (0.498 ml) and THF (1.7 ml) were stirred under argon at 70° C. for 1 hour. The mixture was poured into aqueous sodium hydrogen carbonate and extracted with THF-ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (61.3 mg).

1H NMR (300 MHz, CDC13) δ 1.65-2.58 (9H, m), 2.60-3.20 (5H, m), 3.30-3.80 (2H, m), 3, 88-4.04(1H, m), 4.18-4.76(2H, m), 7.06-7.21(2H, m), 7.28-7.54(6H, m).

Example 304 N-(cis-1-(Cyclobutylcarbonyl)-2-((3',6-difluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

A mixture of N-(cis-2-(3-bromo-4-fluorobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (71 mg), (3-fluorophenyl)boronic acid (45.9 mg), XPhos Pd G3 (6.93 mg), 1M aqueous tripotassium phosphate (0.492 ml) and THF (1.7 ml) were stirred under argon at 70° C. for 1 hour. The mixture was poured into aqueous sodium hydrogen carbonate and extracted with THF- ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (59.6 mg).

1H NMR (300 MHz, CDC13) δ 1.68-2.57 (9H, m), 2.65-3.20 (5H, m), 3.28-3.81 (2H, m), 3, 88-4.05(1H, m), 4.19-4.74(2H, m), 7.02-7.26(4H, m), 7.28-7.45(3H, m).

Example 305 N-((2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-1-((1-methylcyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (50 mg), 1-methylcyclobutanecarboxylic acid (17.8 mg), TEA (65.7 mg) and DMF (2 ml) were added at room temperature with HATU (59.3 mg) and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethanol and water to give the title compound (50 mg).

1H NMR (300 MHz, CDC13) δ 1.41 (3H, s), 1.60-2.06 (5H, m), 2.19-2.32 (1H, m), 2.33-2, 49(2H, m), 2.55(3H, s), 2.85-3.02(1H, m), 3.09-3.25(1H, m), 3.26-3.49( 2H, m), 3.86-4.04 (1H, m), 4.35-4.49 (1H, m), 4.60-4.74 (1H, m), 6.92-7, 13 (1H, m), 7.27-7.58 (7H, m).

Example 306 N-((2S,3S)-1-(Bicyclo[1.1.1]pent-1-ylcarbonyl)-2-((3'-fluorobiphenylyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide .

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (50 mg), bicyclo[1.1.1]pentane-1-carboxylic acid (17.5 mg), TEA (65.7 mg) and DMF (2 ml) at room temperature, HATU (59.3 mg) was added and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate and hexane to give the title compound (10 mg).

1H NMR (300 MHz, CDCl ,) δ 1.66-1.94 (2H, m), 2.07-2.34 (6H, m), 2.46-2.60 (3H, m), 2.90-3.23 (2H, m),

3.32-3.82(3H, m), 3.89-4.07(1H, m), 4.30-4.47(1H, m), 4.57-4.70(1H, m ), 6.98-7.10(1H, m), 7.27-7.55(7H, m).

Example 307 N-((2S,3S)-1-(Bicyclo[1.1.1]ient-1-ylcarbonyl)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3- yl)methanesulfonamide.

A) N-((2S,3S)-1-(Bicyclo[1.1.1]ient-1-ylcarbonyl)-2-(3-bromobenzyl)-irrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromobenzyl)-irrolidin-3-yl)methanesulfonamide hydrochloride (240 mg), bicyclo[1.1.1]yentane-1-carboxylic acid (80 mg), TEA ( 328 mg) and DMF (2 ml) at room temperature, add HATU (296 mg) and stir the resulting mixture at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (270 mg).

MS: [M+H]+ 427.2.

B) N-((2S,3S)-1-(Bicyclo[1.1.1]pent-1-ylcarbonyl)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl )methanesulfonamide.

A mixture of N-((2S,3S)-1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide (55 mg), (3.5 -difluorophenyl)boronic acid (61.0 mg), XPhos Pd G3 (5.45 mg), 1 M tripotassium phosphate aqueous solution (0.356 ml) and THF (1 ml) are refluxed for 1 h. The mixture is concentrated under reduced pressure and the residue is diluted with ethyl acetate. The mixture was washed with water and brine, purified by silica gel column chromatography (ethyl acetate/hexane), and the resulting product was crystallized from ethyl acetate and hexane to give the title compound (25 mg).

1H NMR (300 MHz, CDC13) δ 1.68-1.87 (2H, m), 2.08-2.35 (6H, m), 2.44-2.65 (3H, m), 2, 67-3.87(5H, m), 3.88-4.05(1H, m), 4.36-4.51(1H, m), 4.57-4.67(1H, m), 6.73-6.86(1H, m), 7.02-7.12(2H, m), 7.28-7.50(4H, m).

Example 308 N-((2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (49.6 mg), 1-hydroxycyclobutanecarboxylic acid (18.0 mg ) and DMF (1 ml) HATU (73.5 mg) and DIPEA (50.0 mg) are added at room temperature. The mixture is stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (45.5 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 1.28 (1H, dd, J=19.1, 8.5 Hz), 1.55-2.14 (5H, m), 2.36-2 .46 (2H, m), 2.62-2.74 (3H, m), 2.80 (1H, dd, J=13.6, 4.9 Hz), 2.91-3.06 (1H , m), 3.48-3.68 (2H, m), 3.84 (1H, br.s), 4.364.72 (1H, m), 5.63-6.07 (1H, m), 7.12-7.23(1H, m), 7.31-7.42(2H, m), 7.45-7.57(5H, m), 7.64(1H, s).

Example 309 N-((2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-1-((1-(trifluoromethyl)cyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (51.0 mg), 1-(trifluoromethyl)cyclobutanecarboxylic acid (26 .7 mg) and DMF (1 ml) HATU (76 mg) and DIPEA (51.4 mg) are added at room temperature. The mixture is stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (54.5 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 1.40 (1H, d, J=10.6 Hz), 1.74-2.08 (2H, m), 2.11-2.37 (4H , m), 2.53-2.66 (1H, m), 2.68-2.83 (4H, m), 2.98 (1H, dd, J=13.8, 6.6 Hz), 3.32-3.41 (1H, m), 3.45-3.61 (1H, m), 3.86 (1H, d, J=9.8 Hz), 4.53 (1H, d, J=7.3 Hz), 7.12-7.24(1H, m), 7.30-7.41(2H, m), 7.43-7.56(4H, m), 7.59 (1H, s), 7.63 (1H, s).

Example 310 N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin3-yl)methanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (9.5 mg), (3,5-difluorophenyl)boronic acid (28.2 mg), 1M tripotassium phosphate aqueous solution (0.358 ml), XPhos Pd G3 (3.03 mg) and THF (2 ml) were stirred under nitrogen atmosphere at 70° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture and extracted the resulting mixture with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (NH, ethyl acetate/hexane). The resulting solid is crystallized from ethyl acetate/hexane to give the title compound (32.7 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 0.86-2.40 (9H, m), 2.64-3.30 (6H, m), 3.33-3.58 (1H, m) , 3.75-3.98(1H, m), 4.02-4.46(1H, m), 7.13-7.69(8H, m).

Example 311 N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((3'-methylbiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

Mixture of N-((2S,3S)-2-(3-bromobenzyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (51.4mg), (3-methylphenyl)boronic acid (25.2mg) , 1M tripotassium phosphate aqueous solution (0.371 ml), XPhos Pd G3 (3.14 mg) and THF (2 ml) were stirred under nitrogen atmosphere at 70° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture and the resulting mixture was extracted ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (52.0 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 0.91-2.36 (8H, m), 2.37 (3H, s), 2.64-3.07 (5H, m), 3.11 -3.60(3H, m), 3.73-3.97(1H, m), 4.01-4.45(1H, m), 7.09-7.69(9H, m).

Example 312 N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)-1-methoxymethanesulfonamide.

A) tert-Butyl-(2S,3S)-2-(3-bromobenzyl)-3-(((bromomethyl)sulfonyl)amino)pyrrolidine-1-carboxylate.

DIPEA (1.33 ml) was added to a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate (900 mg) and THF (3 ml) at 0°C. and bromomethanesulfonyl chloride (0.392 ml). The mixture was stirred for 30 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.35 g).

MS: [M-H] ⁺ 510.8.

B) tert-Butyl-(2S,3S)-2-(3-bromobenzyl)-3-{((methoxymethyl)sulfonyl)amino)pyrrolidine-1-carboxylate

A mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-(((bromomethyl)sulfonyl)amino)pyrrolidine-1-carboxylate (1.20 g), silver(I) carbonate (3, 23 g) and MeOH (3 ml) are heated in a sealed tube to 100°C. The mixture was stirred for 3 hours and filtered, a saturated aqueous sodium hydrogen carbonate solution was added and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (640 mg).

MS: [M-H] ⁺ 460.9.

C) tert-Butyl-(2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)-3-(((methoxymethyl)sulfonyl)amino)pyrrolidine-1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-(((methoxymethyl)sulfonyl)amino)pyrrolidine-1carboxylate (342mg), (3-fluorophenyl)boronic acid (155mg), XPhos Pd G3 (125 mg), 1M tripotassium phosphate aqueous solution (1 ml) and THF (1 ml) were stirred at 60° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (286 mg).

Navy: [M-N] ⁺ 477.0.

D) N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)-1-methoxymethanesulfonamide.

(58 mg) acid in ethyl acetate (1 ml) and the resulting mixture was stirred for 1 hour. The reaction solution was concentrated, and TEA (0.084 ml) and cyclobutanecarbonyl chloride (17.2 mg) were added to a mixture of the residue and THF (1 ml) at room temperature. The mixture was stirred for 30 minutes, then a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (28 mg).

1H NMR (300 MHz, CDCl ₃ ) δ 1.63-2.01 (4H, m), 2.07-2.67 (5H, m), 3.00-3.23 (2H, m), 3 .26-3.53 (2H, m), 3.55-3.71 (3H, m), 3.92-4.27 (3H, m), 4.50 (2H, s), 6.93 -7.24 (2H, m), 7.29-7.55 (6H, m).

- 59 039459

Example 313 N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (50.2 mg) and THF (2 ml) at 0°C bis(trichloromethyl)carbonate (31.0 mg) and DIPEA (33.7 mg) are added. The mixture is stirred at 0° C. for 10 minutes, and the reaction solution is concentrated. THF (2 ml) and azetidine (22.3 mg) were added to the resulting residue. The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (NH, ethyl acetate/hexane). The resulting solid was crystallized from ethyl acetate/hexane to give the title compound (44.7 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.79-2.02 (3H, m), 2.08 (1H, dt, J=7.5, 4.0 Hz), 2.68- 2.79(1H, m), 2.83(3H, s), 2.86-2.97(1H, m), 3.09-3.22(1H, m), 3.26-3, 38(1H, m), 3.60(2H, q, J=7.6Hz), 3.79(3H, d, J=7.6Hz), 4.28(1H, d, J=6 .7 Hz), 7.12-7.23(1H, m), 7.26-7.32(1H, m), 7.32-7.41(1H, m), 7.44-7, 55 (5H, m), 7.57 (1H, s).

Example 314 N-((2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-1-((1-methoxycyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (50 mg), 1-methoxycyclobutanecarboxylic acid (20.3 mg), TEA (65.7 mg) and DMF (2 ml) were added at room temperature with HATU (59.3 mg) and the resulting mixture was stirred at room temperature for 30 minutes. A saturated sodium hydrogen carbonate aqueous solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (53 mg).

1H NMR (300 MHz, CDCl ₃ ) δ 1.60-2.03 (3H, m), 2.03-2.20 (2H, m), 2.20-2.37 (1H, m), 2 .42-2.61(5H, m), 2.85-2.98(1H, m), 3.08(3H, s), 3.19-3.30(1H, m), 3.52 -3.66(2H, m), 3.91-4.09(1H, m), 4.36-4.48(1H, m), 4.68-4.80(1H, m), 6 .98-7.09(1H, m), 7.26-7.48(6H, m), 7.53-7.58(1H, m).

Example 315 N-(cis-1-(Cyclobutylcarbonyl)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide.

A) tert-Butyl-cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((2-bromo-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (500 mg), TEA (209 mg) and THF ( 5 ml) ethanesulfonyl chloride (213 mg) is added at room temperature. The mixture is stirred at room temperature for 1 hour and then diluted with ethyl acetate. The insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (610 mg).

MS: [M+H]+454.1.

B) tert-Butyl cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate.

tert-Butyl cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1carboxylate mixture (610 mg), (3,5-difluorophenyl )boronic acid (318 mg), (A-taPhos) ₂ PdCl ₂ (90 mg), potassium carbonate (371 mg), DME (4.8 ml) and water (1.6 ml) were stirred under nitrogen at 90° C for 30 min. The mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (595 mg).

MS: [M+H]+ 488.3.

C) N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)ethansulfonamide dihydrochloride.

To a mixture of tert-butyl-cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (595 mg) and MeOH (2 ml), 4M hydrochloric acid in cyclopentyl methyl ether (8 ml) was added at room temperature. The mixture was stirred at room temperature for 30 minutes and then concentrated to give the title compound (560 mg).

MS: [M+H]+ 388.2.

D) N-(cis-1-(Cyclobutylcarbonyl)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)ethanesulfonamide.

To a mixture of N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)ethanesulfonamide dihydrochloride (100 mg), TEA (110 mg) and THF (2 ml) was added at room temperature with cyclobutanecarbonyl chloride (38.6 mg). The mixture is stirred at room temperature for 1 hour and then the reaction mixture is diluted with ethyl acetate. The insoluble matter is removed by filtration and

- 60 039459 the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (73 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 1.16 (3H, s), 1.28-2.23 (8H, m), 2.65-3.47 (7H, m), 3.77 -3.96 (1H, m),

4.15-4.49(1H, m), 7.31-7.74(5H, m).

Example 316 N-(cis-2-((2-(3,5-Difluorophenyl)-1,3-thiazol-4-yl)methyl)-1-((1-methylcyclobutyl)carbonyl)pyrrolidin-3-yl )ethanesulfonamide.

To a mixture of N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)ethanesulfonamide dihydrochloride (100 mg), 1-methylcyclobutanecarboxylic acid (29 .8 mg), TEA (110 mg) and DMF (2 ml) were added at room temperature with HATU (99 mg) and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (68 mg).

1H NMR (300 MHz, DMSO-d6) δ 1.08-1.30 (6H, m), 1.35-1.51 (1H, m), 1.55-1.69 (2H, m), 1.70-1.93(2H, m), 2.04-2.21(2H, m), 2.24-2.39(1H, m), 2.82-3.30(6H, m ), 3.75-3.94(1H, m), 4.39-4.53(1H, m), 7.31-7.44(1H, m), 7.48(1H, s), 7.52-7.69 (3H, m).

Example 317 N-(cis-2-((2-(3,5-Difluorophenyl)-1,3-thiazol-4-yl)methyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl )ethanesulfonamide.

To a mixture of N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)ethanesulfonamide dihydrochloride (100 mg), 1-hydroxycyclobutanecarboxylic acid (30 .3 mg), TEA (110 mg) and DMF (2 ml) were added at room temperature with HATU (99 mg) and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (56 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 1.16 (3H, t, J=7.4 Hz), 1.22-1.49 (1H, m), 1.55-1.82 (2H , m), 1.83-2.17 (3H, m), 2.31-2.47 (2H, m), 2.87-3.28 (4H, m), 3.37-3.52 (1H, m), 3.54-3.71 (1H, m), 3.73-3.94 (1H, m), 4.394.57 (1H, m), 5.73 (1H, s), 7.31-7.43(1H, m), 7.47(1H, s), 7.51-7.58(1H, m), 7.59-7.68(2H, m).

Example 318 N-(cis-1-(Bicyclo[1.1.1]pent-1-ylcarbonyl)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolidin- 3 yl)ethanesulfonamide.

To a mixture of N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)ethanesulfonamide dihydrochloride (100 mg), bicyclo[1.1.1] pentane-1-carboxylic acid (29.2 mg), TEA (110 mg) and DMF (2 ml) were added at room temperature with HATU (99 mg) and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (41 mg). 1H NMR (300 MHz, DMSO-d ₆ ) δ 1.11-1.21 (3H, m), 1.63-2.03 (7H, m), 2.05-2.19 (1H, m) , 2.22-2.42(1H, m), 2.75-3.55(6H, m), 3.75-3.96(1H, m), 4.34-4.60(1H, m), 7.27-7.69 (5H, m).

Example 319 N-(cis-1-(Cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

A) tert-Butyl cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (45.3 mg), TEA (25.5 mg ) and THF (1 ml) at 0° C., methanesulfonic anhydride (28.5 mg) was added, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44.3 mg).

MS: [M+H]+ 438.2.

B) N-(cis-1-(Cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

tert-Butyl cis-3-((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidine 1-carboxylate mixture (44.3 mg), 4M hydrochloric acid solution in cyclopentylmethyl ether (0.506 ml) and MeOH (0.25 ml) was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was suspended in THF (0.8 ml) and TEA (51.2 mg) and cyclobutanecarbonyl chloride (18.0 mg) were added to the mixture at 0°C. The mixture is stirred at room temperature for

- 61 039459 for 1 hour, a saturated salt solution is added to the mixture and the resulting mixture is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (32.9 mg).

¹ H NMR (400 MHz, CDCl ,) δ 1.32-1.51 (1H, m), 1.82-2.03 (2H, m), 2.07-2.59 (5H, m) , 2.96-3.03(3H, m), 3.07-3.41(4H, m), 3.55-3.67(1H, m), 4.02-4.09(1H, m), 4.29-4.58 (1H, m), 6.84-7.04 (1H, m), 7.39-7.53 (3H, m), 7.88-8.00 ( 2H, m), 8.29 (1H, d, J=9.5 Hz).

Example 320 N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((2-(3-fluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

The racemate (123 mg) of N-(cis-1-(cyclobutylcarbonyl)-2-((2-(3-fluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide was separated with HPLC (column: CHIRALPAK OD (IK001), 50 mm IDx500 mm L, manufactured by Daicel Chemical Industries, mobile phase: hexane ethanol=600/400) to obtain a product constituting a fraction with a shorter retention time. The resulting product was triturated in diethyl ether/hexane to give the title compound (43.2 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.35-1.50 (1H, m), 1.82-2.47 (7H, m), 2.95-3.40 (7H, m), 3.61 (1H, dd, J=14.7, 6.0 Hz), 3.88-4.19 (1H, m), 4.30-4.57 (1H, m), 6.89- 7.05(1H, m), 7.10-7.20(1H, m), 7.40-7.50(1H, m), 7.59-7.68(1H, m), 7, 70-7.78 (1H, m), 8.12 (1H, d, J=9.1 Hz).

Example 321 N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)cyclopropanesulfonamide.

The racemate (234 mg) of N-(cis-1-(cyclobutylcarbonyl)-2-((2-phenyl-1,3-thiazol-4-yls)methyl)pyrrolidin3-yl)cyclopropanesulfonamide was separated by HPLC (column: CHIRALPAK AS (CC001), 50 mm IDx500 mm L, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=700/300) to obtain a compound constituting a fraction with a longer retention time. The resulting compound was triturated in diethyl ether/hexane to give the title compound (42.6 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.80-1.44 (5H, m), 1.81-2.50 (8H, m), 3.02-3.39 (4H, m), 3.65 (1H, dd, J=14.8, 5.7 Hz), 4.03-4.21 (1H, m), 4.43-4.57 (1H, m), 6.89- 6.97(1H, m), 7.41-7.57(3H, m), 7.90-7.96(2H, m), 8.11(1H, d, J=9.8Hz) .

Example 322 N-(cis-2-((2-(3,5-Difluorophenyl)-1,3-thiazol-4-yl)methyl)-1-((1-methylcyclobutyl)carbonyl)pyrrolidin-3-yl )methanesulfonamide.

A) tert-Butyl cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

A mixture of tert-butyl-cis-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3 -((methylsulfonyl)amino)pyrrolidine-1 carboxylate (430 mg), (3,5- difluorophenyl)boronic acid (231 mg), (A-taPhos) ₂ PdCl2 (32.8 mg), potassium carbonate (270 mg), DME (4 ml) and water (1 ml) were stirred under nitrogen at 80°C in within 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (379 mg).

MS: [M+H]+ 474.1.

B) N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)methanesulfonamide dihydrochloride.

tert-Butyl cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate mixture (379 mg ), 4M hydrochloric acid in cyclopentylmethyl ether (4 ml) and MeOH (2 ml) were stirred at room temperature for 1 hour and then concentrated under reduced pressure to give the title compound (420 mg).

MS: [M+H]+ 374.0.

C) N-(cis-2-((2-(3,5-Difluorophenyl)-1,3-thiazol-4-yl)methyl)-1-((1-methylcyclobutyl)carbonyl)pyrrolidin-3-yl) methanesulfonamide.

To a mixture of N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)methanesulfonamide dihydrochloride (80 mg) and DMF (1 ml) at room temperature, TEA (0.106 ml), 1-methylcyclobutanecarboxylic acid (20.9 mg) and HATU (69.5 mg) are added. The mixture was stirred for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (60.7 mg).

¹ H NMR (300 MHz, CDCl3) δ 1.33 (3H, s), 1.64-1.85 (4H, m), 1.88-2.00 (1H, m), 2.06-2 .20 (1H, m), 2.22.55 (2H, m), 2.98-3.31 (6H, m), 3.68 (1H, dd, J=14.7, 6.4 Hz), 4.01-4.24(1H, m), 4.51(1H, t, J=6.6Hz), 6.767.00(1H, m), 7.08(1H, s), 7.38 -7.63 (2H, m), 8.21 (1H, d, J=8.7 Hz).

Example 323 N-(cis-2-((2-(3,5-Difluorophenyl)-1,3-thiazol-4-yl)methyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl )methanesulfonamide.

To a mixture of N-(cis-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-62 039459 yl)methanesulfonamide dihydrochloride (80 mg) and DMF ( 1 ml) TEA (0.106 ml), 1-hydroxycyclobutanecarboxylic acid (21.2 mg) and HATU (69.5 mg) are added at room temperature. The mixture was stirred for 1 hour, then a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (65 mg).

1H NMR (300 MHz, CDCl ,) δ 1.41-1.56 (1H, m), 1.63-1.74 (1H, m), 1.88-2.23 (4H, m), 2.35-2.40(1H, m), 2.42-2.58(1H, m), 2.58-2.78(1H, m), 3.02(3H, s), 3, 19 (1H, d, J=14.7 Hz), 3.29-3. 43(1H, m), 3.45-3.74(2H, m), 3.98-4.27(1H, m), 4.53(1H, t, J=6.6 Hz), 6 .79-6.95(1H, m), 7.10(1H, s), 7.41-7.54(2H, m), 8.02(1H, d, J=9.0 Hz).

Example 324 N-((2S,3S)-2-(Biphenyl-3-ylmethyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)-1-methoxymethanesulfonamide.

A) tert-Butyl-(2S,3S)-2-(biphenyl-3-ylmethyl)-3-(((methoxymethyl)sulfonyl)amino)pyrrolidine-1carboxylate.

Mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-(((methoxymethyl)sulfonyl)amino)pyrrolidine-1-carboxylate (200 mg), phenylboronic acid (79 mg), XPhos Pd G3 (73 .2 mg), 1M aqueous tripotassium phosphate (1 ml) and THF (1 ml) were stirred at 60° C. for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (188 mg).

MS: [M-H] ⁺ 459.0.

B) N-((2S,3S)-2-(Biphenyl-3-ylmethyl)-1-(cyclobutylcarbonyl)pyrrolidin-3-yl)-1-methoxymethanesulfonamide.

To tert-butyl-(2S,3S)-2-(biphenyl-3-ylmethyl)-3-(((methoxymethyl)sulfonyl)amino)pyrrolidine-1-carboxylate (70.2 mg) at room temperature was added a 4M solution of hydrochloric acid in ethyl acetate (1 ml). The mixture is stirred for 1.5 h and then concentrated under reduced pressure. THF (1 ml), TEA (0.106 ml) and cyclobutanecarbonyl chloride (21.7 mg) were added to the resulting residue. The mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.3 mg).

1H NMR (300 MHz, CDC13) δ 1.62-2.03 (4H, m), 2.15 (4H, dd, J=8.1, 4.7 Hz), 3.13 (2H, s) , 3.27-3.38(1H, m), 3.41-3.51(1H, m), 3.52-3.72(4H, m), 4.08(2H, s), 4 .19(1H, s), 4.37-4.71(2H, m), 7.32-7.67(9H, m).

Example 328 N-((2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-1-(oxetan-2-ylcarbonyl)pyrrolidin-3yl)methanesulfonamide m.p.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (50 mg), oxetane-2-carboxylic acid (15.9 mg ), TEA (65.7 mg) and DMF (1 ml), HATU (59.3 mg) was added at room temperature and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and crystallized from ethyl acetate, diisopropyl ether and hexane to give the title compound (40 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 1.75-2.44 (4H, m), 2.54-3.10 (6H, m), 3.15-4.04 (3H, m) , 4.15-4.57(3H, m), 7.11-7.69(9H, m).

Example 333 N-(cis-1-(Azetidin-1-ylcarbonyl)-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

A) (6-(3-Fluorophenyl)pyridin-2-yl)methanol.

A mixture of (6-bromopyridin-2-yl)methanol (10.0 g), (3-fluorophenyl)boronic acid (12.0 g), (AtaPhos) ₂ PdCl ₂ (2.10 g), 2M aqueous sodium carbonate solution (100 ml) and DME (300 ml) were stirred under nitrogen at 70° C. for 5 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.8 g).

MS: [M+H] ⁺ 204.2.

C) 2-(Bromomethyl)-6-(3-fluorophenyl)pyridine.

Tribro

- 63 039459 phosphorus mide (43.2 g). The mixture is stirred overnight under nitrogen at room temperature. The reaction mixture was poured into ice water and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.5 g).

MS: [M+H]+ 265.9.

C) tert-Butyl 2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)-3-oxopyrrolidine-1-carboxylate.

A mixture of pyrrolidine (7.74 g), tert-butyl-3-oxopyrrolidine-1-carboxylate (17.5 g) and toluene (200 ml) was refluxed overnight. The mixture is concentrated under reduced pressure. To a mixture of the resulting residue, TBAI (3.75 g) and CH3CN (200 ml) was added a solution of 2-(bromomethyl)-6(3-fluorophenyl)pyridine (13.5 g) in CH3CN (200 ml) at 80°C. The mixture was stirred under nitrogen at 80° C. for 3 hours. The reaction mixture was poured into water at room temperature and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (16.0 g).

MS: [M+H] ⁺ 371.1.

D) tert-Butyl-cis-3-amino-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)pyrrolidin-1-carboxylate.

Ammonium formate mixture (40 g), chloro[N-[4-(dimethylamino)phenyl]-2-pyridinecarboxamidateto](pentamethylcyclopentadienyl)iridium(III) (0.521 g), tert-butyl-2-((6-(3fluorophenyl )pyridin-2-yl)methyl)-3oxopyrrolidine-1-carboxylate (16.0 g) and MeOH (500 ml) are refluxed for 5 hours. The reaction mixture is concentrated, the residue is poured into brine at room temperature and extract the resulting mixture with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (9.00 g).

MS: [M+H] ⁺ 372.1.

E) tert-Butyl cis-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-cis-3-amino-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)pyrrolidin-1-carboxylate (1.10 g), TEA (653 mg) and THF (30 ml) at 0° C. methanesulfonic anhydride (690 mg) is added. The mixture is stirred at room temperature for 30 minutes and the resulting mixture is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.14 g).

MS: [M+H] ⁺ 450.1.

F) N-(cis-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)methanesulfonamide dihydrochloride.

To a mixture of tert-butyl cis-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (1.10 g) and simple cyclopentylmethyl ether (10 ml) at 0°C add 4M hydrochloric acid in methylcyclopentyl ether (10 ml). The mixture was stirred overnight under nitrogen at room temperature, and then the reaction mixture was concentrated to give the title compound (1.00 g).

MS: [M+H] + 350.0.

G) N-(cis-1-(Azetidin-1-ylcarbonyl)-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

To a mixture of bis(trichloromethyl)carbonate (69.5 mg) and THF (7 ml) was added a mixture of N-(cis-2-((6-(3fluorophenyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (120 mg), DIPEA (148 mg) and THF (7 ml) at 0°C. The mixture is stirred at 0° C. for 20 minutes and concentrated under reduced pressure to give an intermediate. Azetidine (85 mg) was added to a mixture of the resulting intermediate and THF (7 ml) at 0°C. The mixture is stirred under nitrogen at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (85 mg).

¹ H NMR (300 MHz, CDCl ,) δ 1.24-1.46 (1H, m), 1.94-2.09 (1H, m), 2.11-2.30 (2H, m) , 2.85(3H, s), 2.973.19(2H, m), 3.23-3.37(1H, m), 3.43-3.60(1H, m), 3.69-3 .84(2H, m), 3.91-4.15(3H, m), 4.44-4.62(1H, m), 7.05-7.25(2H, m), 7.41 -7.86(5H, m), 8.47-8.67(1H, m).

Example 338 N-(cis-2-((6-(3-Fluorophenyl)pyridin-2-yl)methyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-(cis-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)methanesulfonamide dihydrochloride (51.1 mg), 1-hydroxycyclobutanecarboxylic acid (24.3 mg ), TEA (72.6 mg) and DMF (1.0 ml) HATU (54.2 mg) was added at room temperature. The mixture is stirred at room

- 64 039459 temperature for 1 hour, then a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and triturated in diethyl ether and hexane to give the title compound (27.3 mg).

¹ H NMR (300 MHz, CDCl ,) δ 1.29-1.43 (1H, m), 1.58-1.74 (1H, m), 1.86-2.21 (5H, m) , 2.38-2.53(1H, m), 2.61-2.95(4H, m), 3.21-3.37(2H, m), 3.41-3.58(1H, m), 3.72 (1H, dd, J=14.0, 6.4 Hz), 4.05-4.21 (1H, m), 4.62 (1H, t, J=6.6 Hz ), 7.10-7.21 (2H, m), 7.43-7.83 (5H, m), 8.73 (1H, d, J=8.7 Hz).

Example 339 N-((2S,3S)-2-((2-(3,5-Difluorophenyl)-1,3-thiazol-4-yl)methyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidine -3-yl)methanesulfonamide.

A) tert-Butyl-(2S,3S)-3-amino-2-((2-bromo-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate.

Racemate (550 mg) tert-butyl cis-3-amino-2-((2-bromo-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate separated by HPLC (column: CHIRALPAK AD (NF001) , 50 mm IDx500 mm L, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=850/150) to give the title compound (207 mg) (lower retention time fraction).

MS: [M+H]+362.1.

B) tert-Butyl-(2S,3S)-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1 carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-((2-bromo-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (150 mg) and THF (1 ml ) at room temperature, TEA (126 mg) and methanesulfonic anhydride (87 mg) are added. The mixture was stirred for 30 minutes, then a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (184 mg).

MS: [M-H] ⁺ 437.8.

C) tert-Butyl-(2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidin-1 -carboxylate.

A mixture of tert-butyl-(2S,3S)-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (182 mg), (3,5-difluorophenyl)boronic acid (131 mg), potassium carbonate (114 mg), (A-taPhos) ₂ PdCl ₂ (13.9 mg), DME (4 ml) and water (1 ml) were stirred at 60 °C for 30 min. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (172 mg).

MS: [M-N] ^- 471.9.

D) N-((2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)methanesulfonamide dihydrochloride

To a mixture of tert-butyl-(2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1 -carboxylate (172 mg) and MeOH (2 ml) was added 4M hydrochloric acid in cyclopentylmethyl ether (1 ml) at room temperature. The mixture was stirred for 2 hours and concentrated under reduced pressure to give the title compound (173 mg).

MS: [M+H]+ 374.0.

E) N-((2S,3S)-2-((2-(3,5-Difluorophenyl)-1,3-thiazol-4-yl)methyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidine- 3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (72.6 mg) and DMF (1 ml) TEA (82 mg), 1-hydroxycyclobutanecarboxylic acid (22.7 mg) and HATU (74.2 mg) are added at room temperature. The mixture was stirred for 1 hour, then a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (68.5 mg).

% NMR (300 MHz, CDCI3) δ 1.43-1.54 (1H, m), 1.62-1.73 (1H, m), 1.88-2.22 (5H, m), 2, 40-2.57(1H, m), 2.59-2.75(1H, m), 3.02(3H, s), 3.21(1H, s), 3.30-3.45( 1H, m), 3.47-3.60 (1H, m), 3.66 (1H, dd, J=14.9, 6.6 Hz), 4.00-4.21 (1H, m) , 4.53(1H, t, J=6.6Hz), 6.84-6.95(1H, m), 7.10(1H, s), 7.44-7.50(2H, m ), 8.02 (1H, d, J=9.0 Hz).

Example 340 N-((2S,3S)-1-(Azetidinylcarbonyl)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl) methanesulfonamide.

To a mixture of N-((2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (92.6 mg) and THF (1 ml) bis(trichloromethyl) carbonate (30.8 mg) and DIPEA (53.6 mg) at 0°C. Mixture

- 65 039459 stirred for 30 minutes, then add water and extract the mixture with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. THF (1 ml) and azetidine (35.5 mg) were added to the resulting residue. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (56 mg).

¹ H NMR (300 MHz, CDCI3) δ 1.26 (1H, t, J=7.2 Hz), 2.06-2.27 (3H, m), 3.00 (3H, s), 3, 10-3.24 (3H, m), 3.47 (1H, dd, J=14.7, 6.8 Hz), 3.75 (2H, q, J=7.8 Hz), 3.95 -4.15(3H, m), 4.28-4.52(1H, m), 6.79-6.97(1H, m), 7.13(1H, s), 7.49(2H, m), 8.02 (1H, d, J=7.9 Hz).

Example 341 N-((2S,3S)-1-((3-Fluoroazetidin-1-yl)carbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

A) (2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carbonyl chloride.

Bis trichloromethyl) carbonate (62.3 mg) and DIPEA (67.8 mg). The mixture was stirred at 0° C. for 15 minutes, and then the reaction solution was concentrated under reduced pressure to give the title compound (152 mg).

MS: [M+H]+ 411.2.

C) N-((2S,3S)-1-((3-Fluoroazetidin-1-yl)carbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

To a mixture of (2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carbonichloride (50 mg) and THF (1 ml) at room temperature 3-fluoroazetidine hydrochloride (19.3 mg) and DIPEA (33.5 mg) are added. The mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the resulting solid was crystallized from ethyl acetate/hexane to give the title compound (37.8 mg).

% NMR (300 MHz, DMSO-d6) δ 1.80-1.98 (1H, m), 2.02-2.19 (1H, m), 2.70-2.79 (1H, m), 2.82 (3H, s), 2.92 (1H, dd, J=13.8, 6.2 Hz), 3.12-3.25 (1H, m), 3.32-3.39 ( 1H, m), 3.55-3.74(1H, m), 3.75-4.01(3H, m), 4.034.19(1H, m), 4.28(1H, d, J= 6.4 Hz), 5.00-5.37(1H, m), 7.11-7.23(1H, m), 7.25-7.32(1H, m), 7.32-7 .39(1H, m), 7.43-7.55(5H, m), 7.58(1H, s).

Example 342 N-((2S,3S)-1-((3,3-Difluoroazetidin-1-yl)carbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl) methanesulfonamide.

To a mixture of 3,3-difluoroazetidine hydrochloride (22.4 mg), DIPEA (33.5 mg) and THF (0.5 ml) was added at room temperature 3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carbonyl chloride (50 mg) and THF (0.5 ml). The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the resulting solid was crystallized from ethyl acetate/hexane to give the title compound (28.4 mg).

% NMR (300 MHz, DMSO-d6) δ 1.84-2.02 (1H, m), 2.07-2.20 (1H, m), 2.74 (1H, dd, J=13.4 , 7.4 Hz), 2.84 (3H, s), 2.87-2.99 (1H, m), 3.16-3.27 (1H, m), 3.32-3.42 ( 1H, m), 3.76-3.90(1H, m), 3.99(2H, td, J=13.1, 10.6 Hz), 4.20(2H, td, J=13, 3, 10.6 Hz), 4.31 (1H, d, J=6.6 Hz), 7.12-7.23 (1H, m), 7.24-7.31 (1H, m), 7.31-7.38(1H, m), 7.43-7.55(5H, m), 7.58(1H, s).

Example 343 N-((2S,3S)-2-((3'-Fluorobiphenyl-3-yl)methyl)-1-((2-methylazetidin-1-yl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of 2-methylazetidine hydrochloride (46.5 mg), DIPEA (112 mg) and THF (0.5 ml) was added at room temperature a mixture of (2S,3S)-2-((3'-fluorobiphenyl-3-yl) methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carbonyl chloride (50 mg) and THF (0.5 ml). The resulting mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium bicarbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (31.1 mg).

% NMR (300 MHz, DMSO-d6) δ 1.03-1.24 (3H, m), 1.55-1.94 (2H, m), 1.97-2.23 (2H, m), 2.68-2.89 (4H, m), 2.90-3.05 (1H, m), 3.14 (1H, t, J=8.9 Hz), 3.23-3.39 ( 1H, m), 3.40-3.75(1H, m), 3.75-3.91(2H, m), 3.97-4.40(2H, m), 7.13-7, 23(1H, m), 7.23-7.41(2H, m), 7.44-7.63(6H, m).

Example 344 N-((2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-1-((1-hydroxycyclobutyl)carbo- 66 039459 nyl)pyrrolidin-3-yl )methanesulfonamide.

A) Na(DO^)-2-(3-Bromobenzyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (101 mg), 1-hydroxycyclobutanecarboxylic acid (38.1 mg) and DMF (1 ml) at room temperature add HATU (156 mg) and DIPEA (106 mg). The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (105 mg).

MS: [M+H]+ 431.1.

B) N-((2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromobenzyl)-1-((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide (49.5 mg), (3,5-difluorophenyl)boronic acid (27.2 mg), XPhos Pd G3 (2.91 mg), 1 M tripotassium phosphate aqueous solution (0.344 ml) and THF (2 ml) were stirred at 70° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture. and extract the resulting mixture with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the resulting solid was collected by hexane filtration to give the title compound (33.2 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 1.16-1.37 (2H, m), 1.57-1.72 (1H, m), 1.82-1.97 (2H, m) , 2.08 (1H, br. s), 2.35-2.47 (2H, m), 2.63-2.75 (3H, m), 2.75-2.86 (1H, m) , 2.91-3.04(1H, m), 3.45-3.67(2H, m), 3.75-3.93(1H, m), 4.33-4.72(1H, m), 5.71-6.02 (1H, m), 7.20 (1H, tt, J=9.2, 2.3 Hz), 7.37 (1H, d, J=7.2 Hz ), 7.39-7.47(3H, m), 7.48-7.57(2H, m), 7.65(1H, s).

Example 345 N-((2S,3S)-1-(Azetidinylcarbonyl)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin3-yl)methanesulfonamide.

A) N-((2S,3S)-1-(azetidine-1-carbonyl)-2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide.

Bis(trichloromethyl)carbonate (64.9 mg) and DIPEA (70.6 mg). The mixture is stirred at 0° C. for 15 minutes and then concentrated under reduced pressure. THF (2 ml) and azetidine (46.8 mg) were added to the residue, and the resulting mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (78.4 mg).

MS: [M+H]+ 416.2.

B) N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

A mixture of N-((2S,3S)-1-(azetidinylcarbonyl)-2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide (46.8 mg), (3,5-difluorophenyl)boronic acid (26.6 mg), XPhos Pd G3 (2.85 mg), 1M tripotassium phosphate aqueous solution (0.337 ml) and THF (2 ml) were stirred at 70° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. . The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the resulting solid was crystallized from ethyl acetate/hexane to give the title compound (35.8 mg).

1H NMR (300 MHz, DMSO-d ₆ ) δ 1.83-2.14 (4H, m), 2.69-2.80 (1H, m), 2.83 (3H, s), 2.86 -2.97(1H, m), 3.09-3.21(1H, m, J=9.5Hz), 3.34(1H, br.s), 3.61(2H, q, J = 7.6 Hz), 3.79 (3H, d, J=8.0 Hz), 4.28 (1H, d, J=6.4 Hz), 7.15-7.26 (1H, m ), 7.29-7.34 (1H, m), 7.34-7.40 (1H, m), 7.44 (2H, dd, J=9.5, 2.3 Hz), 7, 48 (1H, br s), 7.53 (1H, d, J=7.6 Hz), 7.60 (1H, s).

Example 346 N-((2S,3S)-1-((1-cyanocyclobutyl)carbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (30 mg), 1-cyanocyclobutanecarboxylic acid (11.7 mg) and DMF (1 ml) HATU (44.5 mg) and DIPEA (30.2 mg) are added at room temperature. The mixture is stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the resulting solid was crystallized from ethyl acetate/hexane to give the title compound (28.7 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 1.58-1.75 (1H, m), 1.94-2.11 (2H, m), 2.14-2.25 (1H, m) , 2.37-2.48(3H, m), 2.52-2.59(1H, m), 2.71-2.83(4H, m), 3.01(1H, dd, J= 13.6, 6.4 Hz), 3.37-3.45(1H, m), 3.48-3.61(1H, m), 3.85-4.05(1H, m), 4 .46 (1H, d, J=6.4 Hz), 7.09-7.23 (1H, m), 7.26-7.38 (2H, m), 7.42-7.56 (4H , m), 7.58-7.67 (2H, m).

Example 347 N-((2S,3S)-1-(5-Azaspiro[2.3]hex-5-ylcarbonyl)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide .

To a mixture of N-((2S,3S)-2-((3'-fluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (30.3 mg) and THF (2 ml) at 0°C bis(trichloromethyl)carbonate (18.7 mg) and DIPEA (20.4 mg) are added. The mixture is stirred at 0° C. for 20 minutes and then concentrated under reduced pressure. THF (2 ml), 5-azaspiro[2.3]hexane hydrochloride (37.7 mg) and DIPEA (81 mg) were added to the residue, and the resulting mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the resulting solid was crystallized from ethyl acetate/hexane to give the title compound (27.2 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 0.38-0.52 (4H, m), 1.80-1.97 (1H, m), 2.03-2.20 (1H, m) , 2.68-2.79(1H, m), 2.85(3H, s), 2.88-2.98(1H, m), 3.13-3.25(1H, m), 3 .26-3.38 (1H, m), 3.64 (2H, d, J=8.0 Hz), 3.80 (1H, br.s), 3.86 (2H, d, J=8 .0 Hz), 4.23-4.41(1H, m), 7.11-7.24(1H, m), 7.25-7.31(1H, m), 7.32-7, 39 (1H, m), 7.437.55 (5H, m), 7.55-7.60 (1H, m).

Example 348 N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin- 3-yl)ethanesulfonamide.

A) tert-Butyl-(2S,3S)-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-((2-bromo-1,3-thiazol-4-yl)methyl)pyrrolidine-1-carboxylate (300 mg), TEA (126 mg ) and THF (3 ml), ethanesulfonyl chloride (128 mg) was added at room temperature. The mixture is stirred at room temperature for 1 hour and diluted with ethyl acetate. The insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (240 mg).

MS: [M+H]+ 454.2.

B) tert-Butyl-(2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidin-1 -carboxylate.

A mixture of tert-butyl-(2S,3S)-2-((2-bromo-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine 1-carboxylate (240 mg), (3 ,5-difluorophenyl)boronic acid (125 mg), (A-taPhos) ₂ PdCl2 (35.5 mg), potassium carbonate (146 mg), DME (2.4 ml) and water (0.8 ml) were stirred in nitrogen atmosphere at 90°C for 30 min. The mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (240 mg).

MS: [M+H]+ 488.2.

C) N-((2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide dihydrochloride.

To a mixture of tert-butyl-(2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidin-1 -carboxylate (240 mg) and methanol (1 ml) at room temperature, add a 4M solution of hydrochloric acid in cyclopentylmethyl ether (4 ml). The mixture was stirred at room temperature for 30 minutes and then concentrated to give the title compound (226 mg).

MS: [M+H]+ 388.2.

D) N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3 -yl)ethanesulfonamide.

To a mixture of N-((2S,3S)-2-((2-(3,5-difluorophenyl)-1,3-thiazol-4-yl)methyl)pyrrolidin-3yl)ethanesulfonamide dihydrochloride (70 mg), DIPEA ( 79 mg) and THF (5 ml) at 0° C. a solution of bis(trichloromethyl) carbonate (36.1 mg) in THF (5 ml) was added. The mixture is stirred at 0° C. for 20 minutes and then concentrated. THF (5 ml) and azetidine (43.4 mg) were added to the resulting residue. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (52 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.10-1.22 (3H, m), 1.70-1.89 (1H, m), 1.93-2.16 (3H, m ), 2.83-3.21(5H, m), 3.23-3.30(1H, m), 3.56-3.70(2H, m), 3.76-3.93(3H , m), 4.27-4.40 (1H, m), 7.33-7.44 (1H, m), 7.47-7.55

- 68 039459 (2H, m), 7.57-7.70 (2H, m).

Example 349 N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl)methanesulfonamide.

A) tert-Butyl-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate.

The racemate (848 mg) of tert-butyl cis-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate was separated by HPLC (column: CHTRALPAK AD (AK001), 50 mm ID x 500 mm L , manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=850/150) to give the title compound (352 mg) (lower retention time fraction).

MS: [M+H-tBu]+316.9.

B) tert-Butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (349 mg), TEA (189 mg) and THF (3.3 ml) methanesulfonyl chloride (129 mg) was added at room temperature. The mixture was stirred at room temperature for 1 hour, then poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (386 mg).

MS: [M+H-Bos] + 350.9.

C) tert-Butyl-(2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine 1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (380 mg), (3-fluorophenyl)boronic acid (236 mg), XPhos Pd G3 (35.6 mg), 1 M tripotassium phosphate aqueous solution (2.53 ml) and THF (9 ml) were stirred under argon at 70° C. for 1 hour. The mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (353 mg).

MS: [M-N]' 465.0.

D) N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of tert-butyl-(2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (349 mg) and toluene ( 3.8 ml) TFA (3.8 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour and poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture was adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate-THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (283 mg).

MS: [M+H]+ 367.2.

E) N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (68 mg), TEA (75 mg) and THF (1, 6 ml) 2,2-dimethylpropanoyl chloride (67.1 mg) was added at room temperature. The mixture was stirred at room temperature for 3 hours, then added to aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (68.9 mg).

1H NMR (300 MHz, CDCl ,) δ 1.25 (9H, s), 1.95-2.04 (1H, m), 2.28-2.39 (1H, m), 2.53 ( 3H, s), 2.92-3.08 (2H, m), 3.64-3.71 (2H, m), 3.92-4.05 (1H, m), 4.65-4, 75(2H, m), 7.03-7.11(1H, m), 7.15-7.26(2H, m), 7.277.32(2H, m), 7.36-7.45( 1H, m), 7.53 (1H, td, J=7.1, 1.7 Hz).

Example 350 N-((2S,3S)-1-(Cyclobutylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (66 mg), TEA (54.7 mg) and THF ( 1.6 ml) at room temperature, add cyclobutanecarbonyl chloride (42.7 mg). The mixture was stirred at room temperature for 2 hours, added to aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain crystals. The crystals were collected by filtration and washed with diisopropyl ether-hexane to give the title compound (49.9 mg).

¹ H NMR (300 MHz, CDC13) δ 1.67-2.40 (8H, m), 2.57-3.22 (6H, m), 3.27-3.77 (2H, m), 3 .94-4.08 (1H, m),

4.26-4.64(1H, m), 4.75-4.83(1H, m), 7.03-7.12(1H, m), 7.14-7.24(2H, m ), 7.27-7.34(2H, m), 7.36-7.50(2H, m).

Example 351 N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-((1-methylcyclopropyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide.

To a solution of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (66 mg), 1-methylcyclopropanecarboxylic acid (23.4 mg) , DIPEA (46.6 mg) and DMF (1 ml) HATU (103 mg) was added at room temperature. The mixture was stirred at room temperature for 3 hours, then added to aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (54.5 mg).

1H NMR (300 MHz, CDC13) δ 0.46-0.61 (2H, m), 0.71-0.80 (1H, m), 0.94-1.03 (1H, m), 1, 25 (3H, s), 1.882.02 (1H, m), 2.27-2.39 (1H, m), 2.70 (3H, s), 2.91-2.99 (1H, m) , 3.05 (1H, dd, J=14.2, 7.4 Hz), 3.58-3.76 (2H, m), 3.94-4.06 (1H, m), 4.66 (1H, d, J=6.5 Hz), 4.77 (1H, dd, J=9.3, 4.4 Hz), 7.03-7.11 (1H, m), 7.17 ( 1H, t, J=7.8 Hz), 7.20-7.25(1H, m), 7.27-7.44(4H, m).

Example 352 N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (68 mg), DIPEA (48.0 mg) and THF ( 1.6 ml) bis(trichloromethyl)carbonate (44.1 mg) was added at 0°C. The mixture is stirred at 0° C. for 20 minutes and then concentrated under reduced pressure. The residue was diluted with THF (1.6 ml) and azetidine (63.6 mg) was added to the solution at room temperature. The mixture was stirred at 70° C. for 20 minutes, added to aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate-THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (40.0 mg).

Ή NMR (300 MHz, CDCI3) δ 1.89-2.01 (1H, m), 2.13-2.26 (3H, m), 2.68 (3H, s), 2.90-2, 99(1H, m), 3.023.11(1H, m), 3.24-3.41(2H, m), 3.80-4.06(5H, m), 4.53(1H, d, J=6.8Hz), 4.64(1H, dd, J=9.1, 3.4Hz), 7.037.11(1H, m), 7.16-7.25(2H, m), 7.27-7.33(2H, m), 7.36-7.44(2H, m).

Example 364 N-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)ethanesulfonamide m.p.

A) tert-Butyl-(2S,3S)-2-(3-bromobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate (3.2 g), TEA (1.37 g) and THF (50 ml) at room temperature temperature, ethanesulfonyl chloride (1.39 g) was added. The mixture was stirred at room temperature for 1 hour. The insoluble matter was removed by filtration and washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). The resulting oil is crystallized from ethyl acetate and diluted with hexane. The precipitate was collected by filtration to give the title compound (3.46 g).

MS: [M+H-Bos] + 347.2.

B) tert-Butyl-(2S,3S)-2-(biphenyl-3-ylmethyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (1.0 g), phenylboronic acid (0.409 g), XPhos Pd G3 ( 0.057 g), 1M aqueous tripotassium phosphate (6.71 ml) and THF (20 ml) were stirred at 70° C. for 1.5 hours. The mixture was concentrated. The residue is partitioned between ethyl acetate and water and the resulting mixture is extracted with ethyl acetate. The extract was washed with 1M aqueous sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane and the precipitate was collected by filtration to give the title compound (714 mg).

MS: [M+H-Bos] + 345.3.

C) N-((2S,3S)-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride.

A mixture of tert-butyl-(2S,3S)-2-(biphenyl-3-ylmethyl)-3-((ethylsulfonyl)amine)pyrrolidine-1-carboxylate (714 mg), 4M hydrochloric acid in ethyl acetate (5 ml) and ethyl acetate (10 ml) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, and then the precipitate was collected by filtration to give the title compound (576 mg).

MS: [M+H]+ 345.3.

D) N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)ethanesulfonamide.

A mixture of N-((2S,3S)-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (576 mg), DIPEA (391 mg) and THF (10 ml) was added dropwise to the bis( trichloromethyl) carbonate (359 mg) and THF (10 ml), the resulting mixture was stirred at room temperature for 30 minutes and then

- 70 039459 concentrate. The residue is partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution and the resulting mixture is extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was mixed with THF (10 ml), and azetidine (432 mg) was added to the mixture at room temperature. The mixture was stirred at room temperature for 4 hours. Azetidine (432 mg) was added to the mixture, the resulting mixture was stirred at room temperature for 15 minutes, and then concentrated. The resulting residue is partitioned between ethyl acetate and 1M hydrochloric acid and the resulting mixture is extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl ethyl acetate/hexane to give the title compound (453 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.18 (3H, t, J=7.4 Hz), 1.75-1.92 (1H, m), 2.08-2.24 (3H, m), 2.73-2.97 (3H, m), 3.16 -3.42 (3H, m), 3.80-3.97 (3H, m), 4.02 (2H, sq. J=8.0 Hz), 4.32(1H, d, J=8.3 Hz), 4.46-4.55(1H, m), 7.27-7.49(6H, m), 7.51 (1H, s), 7.55-7.62 (2H, m).

Example 366 (2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-N-dimethyl-3-((methylsulfonyl)amino)pyrrolidine-1-carboxamide

A) tert-Butyl-(2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (1.73 g), (3,5-difluorophenyl)boronic acid (0.947 d), potassium carbonate (1.11 g), (A-taPhos) ₂ PdCl ₂ (0.135 g), DME (20 ml) and water (4 ml) were stirred at 70°C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.74 g).

MS: [M+Na]+ 489.3.

B) N-((2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride.

A mixture of tert-butyl-(2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (1.74 g), A 4M solution of hydrochloric acid in CPME (18.7 ml) and methanol (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to give the title compound (1.47 g).

MS: [M+H] ⁺ 367.2.

C) (2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-N,N-dimethyl-3-((methylsulfonyl)amino)pyrrolidine-1-carboxamide.

To a mixture of N-((2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (1.47 g) and THF (20 ml) at room temperature, TEA (1.29 g) and dimethylcarbamoyl chloride (0.589 g) are added. The mixture was stirred at room temperature for 1 hour, brine was added to the mixture, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.49 g).

% NMR (400 MHz, CDCl3) δ 2.03-2.11 (2H, m), 2.63-2.72 (1H, m), 2.73 (3H, s), 2.85 (6H, s), 3.23-3.38 (2H, m), 3.56-3.65 (1H, m), 3.85-3.93 (1H, m), 4.41-4.50 (1H, m) , 4.69 (1H, d, J=8.6 Hz), 6.73-6.81 (1H, m), 7.06-7.15 (2H, m), 7.32-7.41 (3H, m), 7.49 (1H, s).

Example 373 (2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-N,N-dimethylpyrrolidine-1-carboxamide.

A) tert-Butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (1.20 g), TEA (0.651 g), DMAP (0.118 g) and THF (11.5 ml), ethanesulfonyl chloride (0.620 g) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution, an aqueous sodium hydrogen carbonate solution, and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.43 g).

MS: [M-N] ^- 463.1.

B) tert-Butyl-(2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine 1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (465 mg), (3-fluorophenyl)boronic acid (280 mg), XPhos Pd G3 (42.3 mg), 1 M tripotassium phosphate aqueous solution (3.00 ml) and THF (11 ml) were stirred under argon at 70° C. for 1

- 71 039459

h. The reaction mixture was poured into an aqueous solution of sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (449 mg).

MS: [M-N] - 479.2.

C) N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide.

To a mixture of tert-butyl-(2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (444 mg) and toluene ( 4.8 ml) TFA (4.8 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour and then poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture was adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol-ethyl acetate) to give the title compound (341 mg).

MS: [M+H]+381.2.

D) (2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carbonyl chloride.

To a mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide (215 mg), DIPEA (146 mg) and THF (4, 8 ml) bis(trichloromethyl)carbonate (134 mg) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 10 minutes. The mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), the resulting crystals were collected by filtration and washed with diisopropyl ether/hexane to give the title compound (223 mg).

MS: [M-N]'441.1.

E) (2S,3S)-2-(2,3'-Difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-N,N-dimethylpyrrolidine 1-carboxamide.

To a mixture of (2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1carbonyl chloride (110 mg) and THF (1.9 ml) at room temperature, a 2M solution of dimethylamine in THF (0.373 ml) was added. The mixture was stirred at room temperature for 30 minutes and then at 70° C. for 10 minutes. The mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate/THF. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (97.0 mg).

1H NMR (300 MHz, CDCl ,) δ 1.27 (3H, t, J=7.4 Hz), 2.06-2.20 (2H, m), 2.79 (6H, s), 2 .81-2.95 (3H, m), 3.00-3.10 (1H, m), 3.28 (1H, dd, J=10.3, 8.4, 4.4 Hz), 3 .62 (1H, dt, J=10.3, 7.9 Hz), 3.88-3.98 (1H, m), 4.48-4.59 (2H, m), 7.02-7 .10 (1H, m), 7.16 (1H, t, J=7.6 Hz), 7.20-7.25 (1H, m), 7.26-7.31 (2H, m), 7.32-7.43 (2H, m).

Example 387 N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (60 mg), 2-hydroxy-2-methylpropanoic acid (22 .2 mg), DIPEA (42.3 mg) and DMF (1 ml) HATU (93 mg) was added at room temperature. The mixture was stirred at room temperature for 3 hours, then the reaction mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate/THF. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (63.8 mg).

1H NMR (300 MHz, CDC13) δ 1.41 (3H, s), 1.43 (3H, s), 1.89-2.01 (1H, m), 2.29-2.41 (1H, m), 2.66 (3H, s), 2.91-3.00 (1H, m), 3.06-3.16 (1H, m), 3.68 (2H, br.s), 3 .84 (1H, br.s), 3.97-4.10 (1H, m), 4.74 (2H, br.s), 7.07 (1H, tdd, J=8.4, 2, 6, 1.0 Hz), 7.16-7.25(2H, m), 7.26-7.33(2H, m), 7.36-7.45(2H, m).

Illustrative example 389.

N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3yl)ethanesulfonamide (not within the scope of the present invention ).

To a mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide (59 mg), 2-hydroxy-2-methylpropanoic acid (21 0 mg), DIPEA (40.1 mg) and DMF (1 ml) HATU (88 mg) was added at room temperature. The mixture was stirred at room temperature for 3 hours, then poured into aqueous sodium hydrogen carbonate solution and the resulting mixture was extracted with ethyl acetate/THF. The organic layer was separated, washed with water and brine, dried

- 72 039459 over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (62.4 mg).

¹ H NMR (300 MHz, CDCl ,) δ 1.22 (3H, t, J=7.4 Hz), 1.40 (3H, s), 1.42 (3H, s), 1.85- 1.99(1H, m), 2.282.41(1H, m), 2.86(2H, q, J=7.4Hz), 2.95(1H, dd, J=15.0, 3, 9 Hz), 3.08-3.19 (1H, m), 3.67 (2H, br.s), 3.834.06 (2H, m), 4.56 (1H, br.s), 4, 73 (1H, br.s), 7.07 (1H, tdd, J=8.4, 2.6, 1.0 Hz), 7.15-7.25 (2H, m), 7.27- 7.32(2H, m), 7.36-7.44(2H, m).

Example 395 N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3'5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide .

A) tert-Butyl-(2S,3S)-3-((methylsulfonyl)amino)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-1-carboxylate.

tert-Butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate mixture (450 mg), (3,5-difluorophenyl)boronic acid (315 mg), XPhos Pd G3 (42.2 mg), 1 M tripotassium phosphate aqueous solution (2.99 ml) and THF (11 ml) were stirred under argon at 70° C. for 1 h. The reaction mixture was poured into the aqueous solution sodium bicarbonate and extract the resulting mixture with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (482 mg).

MS: [M-N] ^- 483.2.

B) N-((2S,3S)-2-((2,3',5'-Trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of tert-butyl-(2S,3S)-3-((methylsulfonyl)amino)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-1-carboxylate (477 mg) and toluene (5.2 ml) TFA (5.2 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour and then, under ice-cooling, poured into a saturated aqueous sodium hydrogen carbonate solution. The mixture was adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol-ethyl acetate) to give the title compound (339 mg).

MS: [M+H]+ 385.2.

C) N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide .

To a mixture of N-((2S,3S)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (60 mg), 2-hydroxy-2-methylpropanoic acid (21.1 mg), DIPEA (40.3 mg) and DMF (1 ml) HATU (89 mg) are added at room temperature. The mixture was stirred at room temperature for 3 hours, then poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate/THF. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (63.1 mg).

¹ H NMR (300 MHz, CDC13) δ 1.40 (3H, s), 1.42 (3H, s), 1.91-2.03 (1H, m), 2.30-2.42 (1H , m), 2.70 (3H, s), 2.89-2.97 (1H, m), 3.10 (1H, dd, J=14.0, 8.0 Hz), 3.63- 3.84(3H, m), 3.96-4.07(1H, m), 4.68-4.84(2H, m), 6.82(1H, tt, J=8.9, 2 .3 Hz), 7.02-7.10 (2H, m), 7.19 (1H, t, J=7.6 Hz), 7.26-7.31 (1H, m), 7.44 (1H, t, J=6.7 Hz).

Example 399 (2S,3S)-3-((Ethylsulfonyl)amino)-N,N-dimethyl-2-((2,3',5'-trifluorobiphenyl-3yl)methyl)pyrrolidine-1-carboxamide.

A) (2S,3S)-2-(3-Bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)-N,N-dimethylpyrrolidine-1-carboxamide.

To a mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (340 mg) and MeOH (1 ml) at room temperature add 4M hydrochloric acid in CPME (3.65 ml). The mixture is stirred for 1 hour and then concentrated under reduced pressure. The resulting residue is mixed with THF (4 ml). TEA (739 mg) and dimethylcarbamoyl chloride (393 mg) were added to the mixture at room temperature. The mixture was stirred at 70° C. for 1 hour. Saturated brine was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to give the title compound (327 mg).

MS: [M+H]+ 436.2.

B) (2S,3S)-3-((Ethylsulfonyl)amino)-N,N-dimethyl-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-1-carboxamide.

Mixture of (2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)-N,N-dimethylpyrrolidine-1-carboxamide (70.4 mg), (3,5-difluorophenyl ) boronic acid (38.2 mg), XPhos Pd G3 (4.10 mg), 1M aqueous

A solution of tripotassium phosphate (0.484 ml) and THF (2 ml) was stirred at 70° C. for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (62.0 mg).

¹ H NMR (400 MHz, DMSO-d6) δ 1.20 (3H, t, J=7.3 Hz), 1.82-1.98 (1H, m), 2.02-2.19 (1H , m), 2.58 (6H, s), 2.68 (1H, dd, J=14.1, 9.2 Hz), 2.91 (1H, dd, J=13.4, 5.7 Hz), 2.96-3.06 (2H, m), 3.07-3.18 (1H, m), 3.54-3.65 (1H, m), 3.76 (1H, t, J=6.1 Hz), 4.35-4.47(1H, m), 7.13-7.21(1H, m), 7.23-7.32(3H, m), 7.33 -7.41 (2H, m), 7.51 (1H, d, J=6.8 Hz).

Example 402 N-((2S,3S)-1-Isobutyryl-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide (60 mg), TEA (47.4 mg) and THF (1.4 ml) 2-methylpropanoyl chloride (33.3 mg) was added at room temperature. The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), the resulting solid was collected by filtration and washed with diisopropyl ether/hexane to give the title compound (56.7 mg).

¹ H NMR (300 MHz, CDCl ,) δ 0.56-1.12 (6H, m), 1.86-2.05 (1H, m), 2.31-2.43 (1H, m) , 2.54-3.21(6H, m), 3.42-3.79(2H, m), 3.96-4.10(1H, m), 4.36-4.68(1H, m), 4.72-4.80(1H, m), 6.77-6.86(1H, m), 6.98-7.53(5H, m).

Example 404 N-((2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide.

A) tert-Butyl-(2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine 1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (1.00 g), (3,5-difluorophenyl)boronic acid (0.529 d), XPhos Pd G3 (0.057 g), 1 M tripotassium phosphate aqueous solution (6.71 ml) and THF (20 ml) were stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated aqueous hydrogen carbonate sodium and extract the resulting mixture with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.08 g).

MS: [M+H-Bos]+ 381.3.

B) N-((2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethansulfonamide hydrochloride.

To a mixture of tert-butyl-(2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (1.10 g) and ethyl acetate (5 ml), 4M hydrochloric acid in ethyl acetate (11.2 ml) was added at room temperature. The mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting solid was collected by ethyl acetate filtration and dried to give the title compound (875 mg).

MS: [M+H] ⁺ 381.3.

C) N-((2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin3-yl)ethanesulfonamide.

To a mixture of N-((2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (100 mg), 2-hydroxy-2-methylpropanoic acid (32.5 mg), DIPEA (62.0 mg) and DMF (1 ml) HATU (137 mg) are added at room temperature. The mixture was stirred at room temperature for 3 hours, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (60.0 mg).

¹ H NMR (300 MHz, DMSO-d6) δ 0.99-1.33 (9H, m), 1.80-2.24 (2H, m), 2.61-3.21 (4H, m) , 3.38-3.93(3H, m), 4.31-4.52(1H, m), 4.95-5.37(1H, m), 7.20(1H, tt, J= 9.3, 2.3 Hz), 7.30-7.54 (6H, m), 7.65 (1H, s).

Example 417 N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1 - fluoromethanesulfonamide.

A) tert-Butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-(((fluoromethyl)sulfonyl)amino)pyrrolidine-1carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (1.24 g), DIPEA (0.859 g) and THF (11 ml) at 0° C., fluoromethanesulfonyl chloride (0.484 g) is added. The mixture was stirred at room temperature for 1 hour, then poured into water and extracted with ethyl acetate.

The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.49 g).

MS: [M-N] ^- 466.9.

C) N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide.

To a mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-(((fluoromethyl)sulfonyl)amino)pyrrolidine-1-carboxylate (1.48 g) and toluene (16 ml) TFA (16 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour and then poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture was adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate/THF (3:1). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol-ethyl acetate) to give the title compound (1.09 g).

MS: [M+H]+ 368.9.

C) N-((2S,3S)-2-(3-Bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide (556 mg), 2-hydroxy-2-methylpropanoic acid (204 mg), DIPEA (389 mg) and DMF (10 ml) HATU (859 mg) are added at room temperature. The mixture was stirred at room temperature for 3.5 hours, then the reaction mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (627 mg).

MS: [M+H]+ 455.0.

D) N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3yl)-1-fluoromethanesulfonamide.

N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1fluoromethanesulfonamide mixture (73 mg), (3-fluorophenyl )boronic acid (44.9 mg), XPhos Pd G3 (6.79 mg), 1 M tripotassium phosphate aqueous solution (0.481 ml) and THF (1.6 ml) were stirred under argon at 70° C. for 1 hour. the mixture was poured into an aqueous sodium hydrogen carbonate solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (57.0 mg).

1H NMR (300 MHz, CDCl ,) δ 1.42 (3H, s), 1.43 (3H, s), 1.85-2.02 (1H, m), 2.29-2.40 ( 1H, m), 2.95-3.04 (1H, m), 3.13 (1H, dd, J=14.0, 8.0 Hz), 3.62-3.88 (3H, m) , 4.03-4.12(1H, m), 4.59-4.82(2H, m), 4.85-5.06(2H, m), 7.04-7.12(1H, m), 7.17-7.25 (2H, m), 7.27-7.34 (2H, m), 7.36-7.45 (2H, m).

Example 421 N-((2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1 -fluoromethanesulfonamide.

A) tert-Butyl-(2S,3S)-2-(3-bromobenzyl)-3-(((fluoromethyl)sulfonyl)amino)pyrrolidine-1-carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate (1.22 g), DIPEA (0.888 g) and THF (12 ml) at 0°C add fluoromethanesulfonyl chloride (0.501 g). The mixture is stirred at room temperature for 1.5 hours, poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.46 g).

MS: [M+H-Bos] + 350.9.

C) N-((2S,3S)-2-(3-Bromobenzyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide.

To a mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-(((fluoromethyl)sulfonyl)amine)pyrrolidine-1-carboxylate (1.45 g) and toluene (15.5 ml) TFA (15.5 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour and then poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture was adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol-ethyl acetate) to give the title compound (693 mg).

MS: [M+H] + 350.9.

- 75 039459

C) P-((28.38)-2-(3-Bromobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromobenzyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide (692 mg), 2hydroxy-2-methylpropanoic acid (267 mg), DIPEA (509 mg) and DMF (13 ml) HATU (1.12 g) was added at room temperature. The mixture was stirred at room temperature for 3.5 hours, then poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (788 mg).

MS: [M+H]+ 437.0.

D) N-((2S,3S)-2-((3',5'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin3-yl)-1-fluoromethanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromobenzyl)-1 -(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1-fluoromethanesulfonamide (71 mg), (3.5- difluorophenyl)boronic acid (51.3 mg), XPhos Pd G3 (6.87 mg), 1M tripotassium phosphate aqueous solution (0.487 ml) and THF (1.6 ml) were stirred under argon at 70°C for 1 hour. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (41.4 mg).

1H NMR (300 MHz, CDCI3) δ 1.43 (6H, br. s), 1.83-1.99 (1H, m), 2.26-2.39 (1H, m), 2.98- 3.19 (2H, m), 3.73 (3H, br.s), 4.03-4.13 (1H, m), 4.55-5.04 (4H, m), 6.79 ( 1H, tt, J=8.9, 2.3 Hz), 7.05-7.14(2H, m), 7.31-7.51(4H, m).

Example 423 1-Fluoro-N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3yl)methyl)pyrrolidin-3- yl)methanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1fluoromethanesulfonamide (73 mg), (3.5 -difluorophenyl)boronic acid (50.6 mg), XPhos Pd G3 (6.79 mg), 1M tripotassium phosphate aqueous solution (0.481 ml) and THF (1.6 ml) were stirred under argon at 70° C. for 1 h The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44.4 mg).

1H NMR (300 MHz, CDCl ,) δ 1.41 (3H, s), 1.43 (3H, s), 1.89-2.03 (1H, m), 2.30-2.41 ( 1H, m), 2.93-3.01 (1H, m), 3.12 (1H, dd, J=14.0, 7.6 Hz), 3.63-3.83 (3H, m) , 4.02-4.13(1H, m), 4.65-4.86(2H, m), 4.87-5.08(2H, m), 6.82(1H, tt, J= 8.9, 2.5 Hz), 7.01-7.10(2H, m), 7.21(1H, t, J=7.6 Hz), 7.27-7.32(1H, m ), 7.41-7.48 (1H, m).

Example 424 3 yl)methanesulfonamide.

A) tert-Butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-(((difluoromethyl)sulfonyl)amino)pyrrolidine-1carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (1.33 g), 2,6-di-tert-butylpyridine (1 .50 g) and THF (11 ml) at -78°C, difluoromethanesulfonyl chloride (1.07 g) was added. The mixture was stirred at 0°C for 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (955 mg).

MS: [M-N] ^- 484.9.

B) N-((2S,3S)-2-(3-Bromo-2-fluorobenzyl)pyrrolidin-3-yl)-1,1-difluoromethanesulfonamide.

To a mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-(((difluoromethyl)sulfonyl)amino)pyrrolidine-1-carboxylate (949 mg) and toluene (10.2 ml) TFA (10.2 ml) was added at room temperature. The mixture was stirred at room temperature for 1 hour and then poured into a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture was adjusted to pH 8 with potassium carbonate and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (643 mg).

MS: [M+H]+ 386.9.

C) N-((2S,3S)-2-(3-Bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1,1-difluoromethanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)-1,1-difluoromethanesulfonamide (639

- 76 039459 mg), 2-hydroxy-2-methylpropanoic acid (223 mg), DIPEA (427 mg) and DMF (11 ml) at room temperature, add HATU (941 mg). The mixture was stirred at room temperature for 3.5 hours, then poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate/THF. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (702 mg).

MS: [M+H]+ 473.0.

D) 1,1-Difluoro-N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine -3-yl)methanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1,1 difluoromethanesulfonamide (76 mg), (3,5-difluorophenyl)boronic acid (50.7 mg), XPhos Pd G3 (6.80 mg), 1M tripotassium phosphate aqueous solution (0.482 ml) and THF (1.6 ml) were stirred under argon at 70° C. for 1 hour. The reaction mixture is poured into an aqueous solution of sodium bicarbonate and the resulting mixture is extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (63.6 mg).

1H NMR (300 MHz, CDCI3) δ 1.42 (3H, s), 1.43 (3H, s), 1.88-2.03 (1H, m), 2.36-2.42 (1H, m), 2.94-3.02 (1H, m), 3.13 (1H, dd, J=14.0, 7.8 Hz), 3.64-3.80 (3H, m), 4 .11-4.22 (1H, m), 4.75 (1H, br.s), 5.10 (1H, br.s), 6.04 (1H, t, J=54.0 Hz), 6.83 (1H, tt, J=8.9, 2.3 Hz), 7.01-7.09 (2H, m), 7.21 (1H, t, J=7.6 Hz), 7 .26-7.32 (1H, m), 7.43 (1H, t, J=6.4 Hz).

Example 428 N-((2S,3S)-2-((3'-Chloro-2,5'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3- yl)methanesulfonamide.

A) N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride.

To tert-butyl-(2S,3S)-2-(3-((bromo-2-fluorobenzyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (5 g) was added 4M hydrochloric acid solution at room temperature in ethyl acetate (22.2 ml) The mixture was stirred at room temperature for 10 hours and then concentrated under reduced pressure The resulting solid was washed with diisopropyl ether to give the title compound (4.11 g).

MS: [M+H] ⁺ 351.1.

B) N-((2S,3S)-2-(3-Bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)methanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (4.11 g), 2-hydroxy-2-methylpropanoic acid (1.32 g ) and DMF (40 ml) HATU (4.84 g) and TEA (4.29 g) are added at room temperature. The mixture was stirred overnight at room temperature, then a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.30 g).

MS: [M+H]+ 437.2.

C) N-((2S,3S)-2-((3'-Chloro-2,5'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl )methanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)methanesulfonamide (70 mg), (3 chloro-5 -fluorophenyl)boronic acid (41.9 mg), XPhos Pd G3 (4.06 mg), 1 M tripotassium phosphate aqueous solution (0.480 mil) and THF (2 ml) were stirred at 70° C. for 1 h. The reaction mixture was purified with silica gel column chromatography (NH, ethyl acetate/hexane) and then purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). A saturated aqueous sodium hydrogen carbonate solution was added to the resulting fraction, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (19 mg).

1H NMR (400 MHz, DMSO-d6) δ 1.01-1.27 (6H, m), 1.96-2.06 (1H, m), 2.08-2.25 (1H, m), 2.55-2.73(1H, m), 2.91(3H, s), 2.95-3.12(1H, m), 3.42-3.98(3H, m), 4, 56-4.71(1H, m), 4.92-5.39(1H, m), 7.05-7.20(1H, m), 7.29-7.53(6H, m).

Example 431 N-((2S,3S)-2-((3'-Chloro-2-fluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide .

A) N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride.

To tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (847 mg) was added a 4M solution of hydrochloric acid in ethyl acetate at room temperature (8 ml). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced

- 77 039459 pressure. The resulting solid was washed with ethyl acetate to give the title compound (527 mg).

MS: [M+H]+ 364.9.

B) H-((28.38)-2-(3-Bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (727 mg), 2-hydroxy-2-methylpropanoic acid (227 mg) and DMF ( 5 ml) HATU (1.03 g) and TEA (549 mg) are added at room temperature. The mixture was stirred at room temperature for 2 hours, then a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (569 mg).

MS: [M ⁺ H]+451.0.

C) N-((2S,3S)-2-((3'-Chloro-2-fluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide (60 mg), (3-chlorophenyl )boronic acid (31.2 mg), XPhos Pd G3 (3.38 mg), 1M aqueous tripotassium phosphate solution (0.399 ml) and THF (2 ml) were stirred at 70°C for 1 h. chromatography on silica gel (NH, ethyl acetate/hexane) and then purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). A saturated aqueous sodium hydrogen carbonate solution was added to the resulting fraction, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (38 mg).

1H NMR (400 MHz, DMSO-d6) δ 1.03-1.17 (6H, m), 1.18-1.23 (3H, m), 1.99-2.23 (2H, m), 2.54-2.67(1H, m), 2.95-3.11(3H, m), 3.62-3.83(2H, m), 3.84-3.98(1H, m ), 4.53-4.73(1H, m), 4.89-5.04(1H, m), 7.07-7.17(1H, m), 7.26-7.39(2H , m), 7.41-7.52 (4H, m), 7.54-7.62 (1H, m).

Example 435 N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl) ethanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide (70 mg), (3.5 -difluorophenyl)boronic acid (36.7 mg), XPhos Pd G3 (3.94 mg), 1M tripotassium phosphate aqueous solution (0.465 ml) and THF (3 ml) were stirred at 70° C. for 1.5 h. partition between ethyl acetate and water and extract the resulting mixture with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (NH, methanol/ethyl acetate). The resulting solid was recrystallized from ethyl acetate/hexane/water to give the title compound (65.9 mg).

1H NMR (400 MHz, CDCI3) δ 1.24 (3H, t, J=7.3 Hz), 1.39 (3H, s), 1.41 (3H, s), 1.87-2.01 (1H, m), 2.282.43 (1H, m), 2.79-2.98 (3H, m), 3.05-3.18 (1H, m), 3.68 (2H, br.s ), 3.83 (1H, br.s), 3.90-4.05 (1H, m), 4.504.63 (1H, m), 4.75 (1H, br.s), 6.74- 6.90(1H, m), 6.98-7.11(2H, m), 7.14-7.22(1H, m), 7.24-7.32(1H, m), 7.367, 47 (1H, m).

Example 437 N-((2S,3S)-2-((3'-Chloro-2,5'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3- yl) ethanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide (70 mg), (3-chloro -5-fluorophenyl)boronic acid (40.6 mg), XPhos Pd G3 (3.94 mg), 1M tripotassium phosphate aqueous solution (0.465 ml) and THF (3 ml) were stirred at 70°C for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (NH, methanol/ethyl acetate). The resulting solid was recrystallized from ethyl acetate/hexane/water to give the title compound (10 mg).

1H NMR (400 MHz, CDCI3) δ 1.24 (3H, t, J=6.8 Hz), 1.40 (3H, s), 1.41 (3H, br.s), 1.82-2 .04 (1H, m), 2.25-2.44 (1H, m), 2.77-3.01 (3H, m), 3.05-3.23 (1H, m), 3.68 (2H, br.s), 3.81 (1H, br.s), 3.90-4.08 (1H, m), 4.39-4.58 (1H, m), 4.75 (1H , br.s), 7.04-7.22 (3H, m), 7.23-7.35 (2H, m), 7.37-7.47 (1H, m).

Example 439 N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl) cyclopropanesulfonamide.

A) tert-Butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((cyclopropylsulfonyl)amine)pyrrolidine-1carboxylate

- 78 039459

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (1 g), TEA (0.542 g), DMAP (0.327 g) and THF (10 ml) cyclopropanesulfonyl chloride (0.753 g) was added at room temperature. The mixture was stirred at 50° C. for 3.5 hours, and then ethyl acetate was added to the reaction mixture. The insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.2 g).

MS: [M+H-Bos] + 377.1.

B) N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)cyclopropanesulfonamide hydrochloride.

To tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((cyclopropylsulfonyl)amino)pyrrolidine-1-carboxylate (722 mg) at room temperature was added a 4M solution of hydrochloric acid in ethyl acetate (7 .56 ml). The mixture is stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (617 mg).

MS: [M+H]+ 377.1.

C) N-((2S,3S)-2-(3-Bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)cyclopropanesulfonamide.

To a mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)cyclopropanesulfonamide hydrochloride (607 mg), 2-hydroxy-2-methylpropanoic acid (183 mg) and DMF ( 10 ml) HATU (837 mg) and TEA (445 mg) are added at room temperature. The mixture was stirred at room temperature for 2 hours, then a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (527 mg).

MS: [M+H]+ 463.1.

D) N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)cyclopropanesulfonamide .

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)cyclopropanesulfonamide (73.3 mg), (3, 5-difluorophenyl)boronic acid (37.5 mg), XPhos Pd G3 (4.02 mg), 1M tripotassium phosphate aqueous solution (0.475 ml) and THF (3 ml) were stirred at 70° C. for 1.5 h. the mixture is partitioned between ethyl acetate and water and the resulting mixture is extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (35.8 mg).

1H NMR (400 MHz, CDC13) δ 0.83-0.98 (2H, m), 1.10 (2H, br.s), 1.38 (3H, br.s), 1.40 (3H, br.s), 1.932.14 (2H, m), 2.25-2.45 (1H, m), 2.80-2.99 (1H, m), 3.05-3.23 (1H, m), 3.71 (2H, br.s), 3.86 (1H, br.s), 3.954.06 (1H, m), 4.78 (1H, br.s), 4.96 (1H , d, J=7.1 Hz), 6.81(1H, t, J=8.4 Hz), 6.99-7.11(2H, m), 7.12-7.20(1H, m), 7.22-7.31 (1H, m), 7.40 (1H, br.s).

Example 362 N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide.

A) (2S,3S)-2-((3',5'-Difluoro[biphenyl]-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carbonyl chloride.

To a mixture of N-((2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (1.0 g), DIPEA (0.620 g) and Bis(trichloromethyl)carbonate (0.569 g) in THF (5 ml) was added at 0° C. with THF (30 ml). After stirring at 0° C. for 10 minutes, the mixture is warmed to room temperature and stirred for 3 hours. The mixture is concentrated in vacuo. The residue is triturated with ethyl acetate and the insoluble matter is removed by filtration. The filtrate is concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.06 g).

MS: [M-N] ^- 441.2.

B) N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-(3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3yl)ethanesulfonamide

To a mixture of (2S,3S)-2-((3',5'-difluoro[biphenyl]-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1carbonyl chloride (500 mg), azetidine (129 mg ) and THF (10 ml) at room temperature, add TEA (343 mg). The mixture was stirred at room temperature for 3 hours, then diluted with THF and the insoluble matter was removed by filtration. The filtrate is concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (380 mg).

1H NMR (300 MHz, CDC13) δ 1.18-1.28 (3H, m), 1.75-1.90 (1H, m), 2.08-2.25 (3H, m), 2, 81-2.99 (3H, m), 3.16 (1H, dd, J=14.0, 4.9 Hz), 3.26-3.43 (2H, m), 3.80-4, 08 (5H, m), 4.36 (1H, d, J=8.7 Hz), 4.43-4.53 (1H, m),

- 79 039459

6.78 (1H, tt, J=8.9, 2.3 Hz), 7.07-7.17 (2H, m), 7.31-7.43 (3H, m), 7.46- 7.50 (1H, m).

Example 372 N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide.

Azetidine (244 mg) was added to a stirred mixture of (2S,3S)-2-(2,3'-difluorobiphenyl-3-yl)methyl)3-((ethylsulfonyl)amino)pyrrolidine-1-carbonyl chloride (632 mg) and THF (6 ml) at room temperature. After stirring for 30 minutes, the reaction mixture is concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was crystallized from ethyl acetate/ethanol to give the title compound (416 mg).

1H NMR (400 MHz, CDCl ₃ ) δ 1.23 (3H, t, J=7.4 Hz), 1.82-1.97 (1H, m), 2.08-2.30 (3H, m ), 2.78-2.91 (2H, m), 2.92 -3.06 (2H, m), 3.22-3.40 (2H, m), 3.74-4.02 (5H , m), 4.46-4.61 (2H, m), 7.03-7.11 (1H, m), 7.14-7.25 (2H, m), 7.26-7.44 (4H, m).

Example 377 (2S,3S)-2-((2,3'-Difluorobuphenyl-3-yl)methyl)-3-((dimethylsulfαmoyl)αmino)-N,N-dimethylpyrrolidine-1-carboxamide.

A) tert-Butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((dimethylsulfamoyl)amino)pyrrolidine-1-carboxylate.

Dimethylsulfamoyl chloride (2.31 g) was added at room temperature to a mixture of tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (2.5 g), TEA (1.36 g), DMAP (0.982 g) and THF (25 ml). After stirring at 50° C. for 4 hours, the reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.4 g).

MS: [M+H-Bos] + 380.0.

B) N'-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)-N,N-dimethylsulfuric acid diamide hydrochloride.

A mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((dimethylsulfamoyl)amino)pyrrolidine-1-carboxylate (2.4 g) and 4M hydrochloric acid in ethyl acetate (12, 5 ml) stirred at room temperature in a dry atmosphere (CaCl ₂ tube) overnight. The mixture is concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound (1.78 g).

MS: [M+H]+ 379.9.

C) (2S,3S)-2-(3-Bromo-2-fluorobenzyl)-3-((dimethylsulfamoyl)amino)-N,N-dimethylpyrrolidine-1carboxamide.

To N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)-N,N-dimethylsulfuric acid diamide hydrochloride mixture (1.78 g), TEA (4.32 g ) and THF (20 ml) dimethylcarbamoyl chloride (2.30 g) was added at room temperature. The mixture is refluxed for 3 hours. The mixture is quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.9 g).

MS: [M ⁺ H]+451.0.

D) (2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-3-((dimethylsulfamoyl)amino)-N,N-dimethylpyrrolidine-1-carboxamide.

Mixture of (2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((dimethylsulfamoyl)amino)-N,N-dimethylpyrrolidine1-carboxamide (600 mg), (3-fluorophenyl)boronic acid (242 mg ), XPhos Pd G3 (16.9 mg), 1M aqueous tripotassium phosphate (3.99 ml) and THF (6 ml) were stirred at 70° C. for 1 h. The aqueous phase was removed, the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the resulting solid was crystallized from ethyl acetate/hexane to give the title compound (562 mg).

1H NMR (400 MHz, CDCl ₃ ) δ 2.03-2.23 (2H, m), 2.73 (6H, s), 2.76 (6H, s), 2.85-2.93 (1H , m), 2.94-3.03 (1H, m), 3.20-3.32 (1H, m), 3.53-3.67 (1H, m), 3.81-3.92 (1H, m), 4.48 (1H, d, J=8.1 Hz), 4.54-4.62 (1H, m), 7.01-7.08 (1H, m), 7, 12-7.18(1H, m), 7.20-7.26(2H, m), 7.27-7.43(3H, m).

Example 407 (2S,3S)-2-(Biphenyl-3-ylmethyl)-3-((ethylsulfonyl)amino)-N-methoxy-N-methylpyrrolidin-1-carboxamide

Methoxy(methyl )carbamoyl chloride (143 mg). After 15 minutes the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (302 mg).

1H NMR (400 MHz, CDCL3) δ 1.19 (3H, t, J=7.4 Hz), 1.83-1.94 (1H, m), 2.06-2.23 (1H, m) , 2.72-2.94 (3H,

- 80 039459

m), 2.98(3H, s), 3.17-3.27(1H, m), 3.42-3.52(1H, m), 3.55(3H, s), 3.60 -3.70(1H, m), 3.86-4.02(1H, m), 4.40(1H, d, J=8.8Hz), 4.52-4.68(1H, m ), 7.27-7.62 (9H, m).

Example 441 N-{(2S,3S)-1-(Oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[1,Γ-biphenyl]-3-yl)methyl]irrolidine -3-yl}methanesulfonamide.

A) N-((2S,3S)-2-(3-Bromo-2-fluorobenzyl)-1-(oxetan-2-ylcarbonyl)-irrolidin-3-yl)methanesulfonamide.

HATU (374 mg) was added to a mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3yl)methanesulfonamide hydrochloride (318 mg), oxetane-2-carboxylic acid (100 mg), TEA (415 mg) and DMF (6 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes. The mixture was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (methanol/ethyl acetate). The solid is crystallized from ethyl acetate/diisopropyl ether/hexane to give the title compound (244 mg).

MS: [M+H]+ 435.2.

B) N-{(2S,3S)-1-(Oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[1,1-biphenyl]-3-yl)methyl]pyrrolidin- 3yl} methanesulfonamide.

A mixture of N-((2S,3S)-2-(3-bromo-2-fluorobenzyl)-1-(oxetan-2-ylcarbonyl)pyrrolidin-3-yl)methanesulfonamide (76.5 mg), (3.5- difluorophenyl)boronic acid (41.6 mg), XPhos Pd G3 (4.46 mg), 1M aqueous solution in tripotassium phosphate (0.527 ml) and THF (3 ml) were stirred at 70°C for 1.5 h. ethyl acetate and water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a solid. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (42.4 mg).

¹ H NMR (400 MHz, CDCl ,) δ 1.82-1.98 (1H, m), 2.25-2.63 (2H, m), 2.69-3.03 (5H, m) , 3.06-3.16(1H, m), 3.25-3.81(2H, m), 3.93-4.58(3H, m), 4.62-5.25(3H, m), 6.76-7.55 (6H, m).

Example 450 N-[(2S,3S)-2-[(2,3'-Difluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine -3-yl]-1-fluorocyclopropan-1-sulfonamide.

A) tert-Butyl-(2S,3S)-3-((cyclopropylsulfonyl)amino)-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)pyrrolidine-1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((cyclopropylsulfonyl)amino)pyrrolidine 1-carboxylate (1.17 g), (3-fluorophenyl)boronic acid (0.514 d), XPhos Pd G3 (0.207 g), 1M tripotassium phosphate aqueous solution (7.35 ml) and THF (10 ml) were stirred at 70° C. for 1 hour. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.02 g).

MS: [M+H-Bos]+ 393.1.

B) tert-Butyl-(2S,3S)-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)-3-(((1-fluorocyclopropyl)sulfonyl)amino)pyrrolidine-1- carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-((cyclopropylsulfonyl)amino)-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)pyrrolidin-1-carboxylate (156 mg) and THF (3 ml) at -78° C., a 2.6M solution of nbutyllithium (0.268 ml) was added dropwise. After stirring at -78°C for 1 h, a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (120 mg) in THF (1 ml) was added dropwise to the reaction mixture. The mixture was stirred at 0° C. under nitrogen for 1 hour, then at room temperature for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (81.9 mg).

MS: [M+H-Sun] ⁺ 411.3.

C) N-((2S,3S)-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)pyrrolidin-3-yl)-1-fluorocyclopropanesulfonamide hydrochloride.

To a mixture of tert-butyl-(2S,3S)-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)-3-(((1-fluorocyclopropyl)sulfonyl)amino)pyrrolidine-1- carboxylate (81.9 mg) and ethyl acetate (0.5 ml) were added at room temperature with 4M hydrochloric acid in ethyl acetate (0.802 ml). The mixture is stirred at room temperature overnight. The mixture was concentrated in vacuo to give the title compound (57.0 mg).

MS: [M+H]+ 411.3.

D) N-[(2S,3S)-2-[(2,3'-Difluoro[1,1-biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3 -yl]-1-fluorocyclopropan-1-sulfonamide.

A mixture of N-((2S,3S)-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)pyrrolidin-3-yl)-1-fluoro-81 039459 cyclopropanesulfonamide hydrochloride (447 mg), DIPEA (1.29 g) and THF (5 ml) were stirred at room temperature for 30 minutes. 1-Chloro-2-methyl-1-oxopropan-2ylacetate (198 mg) was added dropwise to the suspension at 0°C, and the resulting mixture was stirred at the same temperature for 1 hour. Water (2 ml) and a 4M aqueous solution were added to the mixture. lithium hydroxide (2.00 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with brine and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) followed by preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). The desired fraction was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid is crystallized from ethanol/water to give the title compound (140 mg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.14-1.52 (10H, m), 1.79-2.03 (1H, m), 2.28-2.42 (1H, m), 2.91-3.04(1H, m), 3.11-3.26(1H, m), 3.52-3.95(3H, m), 4.07-4.24(1H, m ), 4.69-5.06(2H, m), 7.03-7.10(1H, m), 7.15-7.25(2H, m), 7.27-7.44(4H , m).

Example 456 N-{(2S,3S)-1-(Azetudin-1-kαcarbonyl)-2-[(2-fluoro[1,1'-buphenyl]-3-yl)methyl]nirrolidin-3-yl} ethanesulfonamide.

A) N-((2S,3S)-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride.

A mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (0.698 g), phenylboronic acid (0.238 g), XPhos Pd G3 ( 0.019 g), 2M aqueous tripotassium phosphate (2.25 ml) and THF (3 ml) were stirred at 70° C. for 1 h. The aqueous phase was removed and the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give a solid. A 4M solution of hydrochloric acid in ethyl acetate (7.50 ml) was added at room temperature to a stirred mixture of the solid (694 mg) and ethyl acetate (2 ml). After 18 hours, the reaction mixture was concentrated in vacuo and the solid collected by filtration to give the title compound (568 mg).

MS: [M+H]+363.3.

B) N-{(2S,3S)-1-(Azetudin-1-karbonyl)-2-[(2-fluoro[1,1'-buphenyl]-3-yl)methyl]nirroludin-3yl}ethanesulfonamide.

To a stirred mixture of N-((2S,3S)-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3yl)ethanesulfonamide hydrochloride (568 mg), bis(trichloromethyl)carbonate (254 mg) and THF (6 ml) DIPEA (368 mg) was added at 0°C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, and purified by silica gel column chromatography (ethyl acetate/hexane) to give an oil. Azetidine (243 mg) was added to a stirred mixture of the obtained oil (603 mg) and THF (7 ml) at room temperature. The mixture is stirred for 30 minutes and then the reaction mixture is concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was crystallized from hexane/ethanol to give the title compound (516 mg).

1H NMR (400 MHz, CDCl3) δ 1.21 (3H, t, J=7.4 Hz), 1.82-1.96 (1H, m), 2.06-2.28 (3H, m) , 2.76-2.90(2H, m), 2.93-3.08(2H, m), 3.20-3.40(2H, m), 3.82(2H, q, J= 7.8 Hz), 3.88-4.06 (3H, m), 4.52 (1H, d, J=6.6 Hz), 4.584.65 (1H, m), 7.13-7, 20(1H, m), 7.27-7.33(1H, m), 7.33-7.39(2H, m), 7.41-7.48(2H, m), 7.49- 7.56 (2H, m).

Example 457 N-{(2S,3S)-1-(3-Hydroxu-2,2-dimethylpronanoyl)-2-[(2,3',5'-trifluoro[1,1-buphenyl]-3yl)methyl ]pyrrolidin-3-yl}methanesulfonamide.

A) N-((2S,3S)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride.

tert-Butyl-(2S,3S)-3-((methylsulfonyl)amino)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-1-carboxylate mixture (1.67 g ), 4M hydrochloric acid in ethyl acetate (20 ml) and ethyl acetate (20 ml) were stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the precipitate was collected by filtration to give the title compound (1.37 g).

MS: [M+H]+ 385.2.

B) N-{(2S,3S)-1-(3-Hydroxu-2,2-dimethylpronαnoyl)-2-[(2,3',5'-trifluoro[1,1-buphenyl]-3-yl) methyl]pyrrolidin-3-yl]methanesulfonamide.

HATU (67.8 mg) was added to a mixture of N-((2S,3S)-2-((2,3',5'-trifluorobiphenyl-3yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (50 mg), 3-hydroxy-2,2-dimethylpropanoic acid (18.2 mg), DIPEA (77 mg) and DMF (1 ml) at room temperature. After stirring at room temperature for 7 hours, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) to give an oil. The oil was crystallized from ethyl acetate/hexane to give the title compound (24.7 mg).

- 82 039459 ¹ H NMR (300 MHz, CDCl ,) δ 1.18 (3H, s), 1.19 (3H, s), 1.86-2.11 (1H, m), 2.31- 2.47 (1H, m), 2.31-2.47 (1H, m), 2.72 (3H, s), 2.86 (1H, dd, J=13.8, 5.5 Hz) , 3.06 (1H, dd, J=13.4, 7.4 Hz), 3.15-3.25 (1H, m), 3.28-3.39 (1H, m), 3.53 (1H, dd, J=10.8, 6.2 Hz), 3.64-3.73 (2H, m), 3.89-4.08 (1H, m), 4.56-4.68 (1H, m), 4.75-4.84 (1H,

m), 6.77-6.87 (1H, m), 7.01-7.13 (2H, m), 7.15-7.26 (2H, m), 7.38-7.47 ( 1H, m).

Example 459 N-{(2S,3S)-1-(Lzetidine-1-carbonyl)-2-[(3'-fluoro[1,Γ-biphenyl]-3-yl)methyl]irrolidin-3-yl} -1-fluoromethanesulfonamide.

A) Benzyl((2S,3S)-2-(3-bromobenzyl)-irrolidin-3-yl)carbamate hydrochloride.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromobenzyl)iirrolidine-1-carboxylate (10.7 g), 2M aqueous sodium hydroxide solution (19 ml) and THF (100 ml) at 0° C., benzyl chloroformate (5.98 g) is added. The mixture is stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. To a mixture of the resulting residue and ethyl acetate (20 ml) was added a 4M solution of hydrochloric acid in ethyl acetate (75 ml) at room temperature. The mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue was triturated with ethyl acetate and the precipitate was collected by filtration to give the title compound (12.8 g).

MS: [M+H] + 389.0.

B) Benzyl-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-(3-bromobenzyl)pyrrolidin-3-yl)carbamate.

Bis(trichloromethyl) carbonate (2.79 g) was added to a mixture of benzyl ((2S,3S)-2-(3-bromobenzyl)pyrrolidin-3-yl)carbamate (5 g) and THF (100 ml) at 0°C. and DIPEA (3.04 g). After stirring at 0° C. for 20 minutes, the mixture was concentrated in vacuo. THF (100 ml) and azetidine (5.36 g) were added to the residue. The mixture is stirred at room temperature overnight. The mixture was quenched with saturated aqueous sodium hydrogen carbonate at room temperature and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid is crystallized from ethyl acetate/diisopropyl ether to give the title compound (4.74 g).

MS: [M+H]+ 472.1.

C) Benzyl-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3-yl)carbamate.

A mixture of benzyl ((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-(3-bromobenzyl)pyrrolidin-3-yl)carbamate (1.4 g), (3-fluorophenyl)boronic acid (0.539 g ), XPhos Pd G3 (0.038 g), 1 M tripotassium phosphate aqueous solution (8.89 ml) and THF (20 ml) were stirred at 70° C. for 5 hours. After cooling, the insoluble matter was removed by filtration and the filtrate was concentrated in vacuo. The residue is extracted with ethyl acetate/THF. The organic layer is separated, washed with brine, filtered through NH-silica gel and concentrated in vacuo. The resulting solid was washed with ethyl acetate and diisopropyl ether to give the title compound (1.25 g).

MS: [M+H]+ 488.2.

D) ((2S,3S)-3-Λmino-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-yl)(azetidin-1-yl)methanone.

Benzyl((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3yl)carbamate mixture (1.25 g), 10% palladium-carbon (0.12 g), ethanol (20 ml) and THF (20 ml) were hydrogenated under balloon pressure at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (900 mg).

MS: [M+H]+ 354.0.

E) N-{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl} -1fluoromethanesulfonamide.

To a mixture of ((2S,3S)-3-amino-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-yl)(azetidin-1-yl)methanone (100 mg) and THF (2 ml) DIPEA (47.5 mg) and fluoromethanesulfonyl chloride (41.3 mg) are added at room temperature. After stirring for 30 minutes, the mixture was concentrated in vacuo. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). The solid is crystallized from ethyl acetate/hexane to give the title compound (58 mg).

¹ H NMR (400 MHz, DMSO-d6) δ 1.86-2.00 (3H, m), 2.02-2.16 (1H, m), 2.70-2.82 (1H, m) , 2.85-2.95(1H, m), 3.10-3.21(1H, m), 3.32-3.38(1H, m), 3.52-3.64(2H, m), 3.72-3.88 (3H, m), 4.20-4.31 (1H, m), 5.17-5.50 (2H, m), 7.14-7.22 ( 1H, m), 7.26-7.30(1H, m), 7.33-7.39(1H, m), 7.46-7.58(5H, m), 8.22(1H, br.s).

Example 460 N-{(2S,3S)-1-(Λzetidine-1-carbonyl)-2-[([1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}1-fluoromethanesulfonamide .

A) Benzyl-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-([biphenyl]-3-ylmethyl)pyrrolidin-3-yl)carbamate.

Mixture of benzyl ((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-(3-bromobenzyl)pyrrolidin-3-yl)carbamate (1.4 g), phenylboronic acid (0.470 g), XPhos Pd G3 (0.038 g), 1M aqueous tripotassium phosphate (8.89 ml) and THF (20 ml) were stirred at 70° C. for 5 hours. After cooling, the insoluble matter was removed by filtration and the filtrate was concentrated in vacuo. The residue is extracted with ethyl acetate/THF. The organic layer was separated, washed with brine, passed through

NH silica gel and concentrated in vacuo. The resulting solid was washed with ethyl acetate and diisopropyl ether to give the title compound (1.08 g).

MS: [M+H]+ 470.2.

B) ((2S,3S)-3-Amino-2-([biphenyl]-3-ylmethyl)pyrrolidin-1-yl)(azetidin-1-yl)methanone.

Benzyl-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-([biphenyl]-3-ylmethyl)pyrrolidin-3-yl)carbamate mixture (1.08 g), 10% palladium on charcoal (0.10 g), ethanol (20 ml) and THF (20 ml) were hydrogenated with balloon pressure at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (700 mg).

MS: [M+H] ⁺ 336.1.

C) N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[([1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-1-fluoromethanesulfonamide .

To a mixture of ((2S,3S)-3-amino-2-([biphenyl]-3-ylmethyl)pyrrolidin-1-yl)(azetidin-1-yl)methanone (100 mg) in THF (2 ml) at 0 °C, DIPEA (50.1 mg) and fluoromethanesulfonyl chloride (43.5 mg) are added. After stirring for 30 minutes, the mixture was concentrated in vacuo. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). The solid is crystallized from ethyl acetate/hexane to give the title compound (98 mg).

1H NMR (400 MHz, DMSO-d6) δ 1.85-1.99 (3H, m), 2.03-2.14 (1H, m), 2.69-2.79 (1H, m), 2.85-2.95(1H, m), 3.12-3.20(1H, m), 3.31-3.39(1H, m), 3.52-3.67(2H, m ), 3.71-3.87(3H, m), 4.19-4.29(1H, m), 5.18-5.46(2H, m), 7.21-7.29(1H , m), 7.31-7.38 (2H, m), 7.42-7.50 (3H, m), 7.51-7.55 (1H, m), 7.64-7.72 (2H, m), 8.22 (1H, br.s).

Example 462 N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl } cyclopropanesulfonamide.

To a mixture of ((2S,3S)-3-amino-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-yl)(azetidin-1-yl)methanone (200 mg) and THF ( 4 ml) DIPEA (95 mg), DMAP (69.1 mg) and cyclopropanesulfonyl chloride (88 mg) are added at room temperature. After stirring for 10 hours, the mixture was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (methanol/ethyl acetate). The solid is crystallized from ethyl acetate/diisopropyl ether to give the title compound (221 mg).

1H NMR (400 MHz, DMSO-d6) δ 0.77-1.00 (4H, m), 1.88-2.03 (3H, m), 2.03-2.16 (1H, m), 2.37-2.48(1H, m), 2.70-2.81(1H, m), 2.88-2.97(1H, m), 3.13-3.23(1H, m ), 3.33-3.39(1H, m), 3.53-3.65(2H, m), 3.72-3.86(3H, m), 4.21-4.30(1H , m), 7.13-7.23 (1H, m), 7.26-7.39 (2H, m), 7.45-7.61 (6H, m).

Example 463 N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[([1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3yl}cyclopropanesulfonamide.

To a mixture of ((2S,3S)-3-amino-2-([biphenyl]-3-ylmethyl)pyrrolidin-yl)(azetidin-1-yl)methanone (200 mg) and THF (4 ml) was added at room temperature DIPEA (100 mg), DMAP (14.6 mg) and cyclopropanesulfonyl chloride (92 mg). After stirring overnight, the mixture was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (methanol/ethyl acetate). The solid is crystallized from ethyl acetate/diisopropyl ether to give the title compound (228 mg).

1H NMR (400 MHz, DMSO-d6) δ 0.79-0.99 (4H, m), 1.87-2.01 (3H, m), 2.02-2.15 (1H, m), 2.38-2.47(1H, m), 2.69-2.79(1H, m), 2.87-2.98(1H, m), 3.12-3.22(1H, m ), 3.32-3.39 (1H, m), 3.51-3.67 (2H, m), 3.72-3.84 (3H, m), 4.20-4.30 (1H, m), 7.22-7.29(1H, m), 7.30-7.39(2H, m), 7.41-7.49(3H, m), 7.50-7.57(2H, m ), 7.627.71 (2H, m).

Example 466 N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl} -1-fluoromethanesulfonamide.

A) tert-Butyl-(2S,3S)-3-(((benzyloxy)carbonyl)amino)-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1carboxylate.

To a mixture of tert-butyl-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (1.43 g), 2M aqueous sodium hydroxide solution (2.30 ml) and THF (20 ml), benzyl chloroformate (0.719 g) was added at 0°C. The mixture is stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.03 g).

MS: [M+H-Bos] + 407.0.

B) Benzyl((2S,3S)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)carbamate hydrochloride.

Mixture of tert-butyl-(2S,3S)-3-(((benzyloxy)carbonyl)amino)-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (1.94 g) and 4M hydrochloric acid in ethyl acetate (9.58 ml) stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is triturated with ethyl acetate

- 84 039459 and the precipitate is collected by filtration to obtain the title compound (1.54 g).

MS: [M+H]+ 407.0.

C) Benzyl ((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)carbamate.

Bis(trichloromethyl) carbonate (0.824 g) and DIPEA (0.897 g). After stirring at 0° C. for 20 minutes, the mixture was concentrated in vacuo. THF (30 ml) and azetidine (0.991 g) were added to the residue. The mixture is stirred at room temperature overnight. The mixture was quenched with saturated aqueous sodium hydrogen carbonate at room temperature and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid is crystallized from ethyl acetate/diisopropyl ether to give the title compound (1.64 g).

MS: [M ⁺ H]+490.1.

D) Benzyl ((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3yl)carbamate.

Benzyl((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-(3-bromo-2-fluorobenzyl)pyrrolidin-3-yl)carbamate (600mg), phenylboronic acid (194mg), XPhos mixture Pd G3 (15.5 mg), 1 M tripotassium phosphate aqueous solution (3.67 ml) and THF (20 ml) were stirred at 70° C. for 5 hours. After cooling, the insoluble matter was removed by filtration and the filtrate was concentrated in vacuo. The residue is extracted with ethyl acetate/THF. The organic layer is separated, washed with brine, passed through NH silica gel and concentrated in vacuo. The resulting solid was washed with ethyl acetate and diisopropyl ether to give the title compound (500 mg).

MS: [M+H]+ 488.2.

E) ((2S,3S)-3-Amino-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-yl)(azetidin-1-yl)methanone.

Benzyl((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3yl)carbamate mixture (500 mg), 10% palladium per charcoal (50 mg), ethanol (20 ml) and THF (20 ml) were hydrogenated with balloon pressure at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (360 mg).

MS: [M+H]+ 354.0.

F) N-{(2S,3S)-1-(Azetidin-1-carbonyl)-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}- 1fluoromethanesulfonamide.

To a mixture of ((2S,3S)-3-amino-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-yl)(azetidin-1-yl)methanone (100 mg) and THF (2 ml) at 0° C. DIPEA (47.5 mg) and fluoromethanesulfonyl chloride (41.3 mg) are added. After stirring for 30 minutes, the mixture was concentrated in vacuo. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). The solid is crystallized from ethyl acetate/hexane to give the title compound (98 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.90-2.19 (4H, m), 2.60-2.71 (1H, m), 2.86-2.97 (1H, m ), 3.09-3.20(1H, m), 3.32-3.39(1H, m), 3.43-3.53(2H, m), 3.66-3.77(2H , m), 3.80-3.89 (1H, m), 4.34-4.46 (1H, m), 5.22-5.55 (2H, m), 7.13-7.20 (1H, m), 7.25-7.34 (2H, m), 7.35-7.42 (1H, m), 7.44-7.51 (2H, m), 7.52-7 .57 (2H, m), 8.158.34 (1H, m).

Example 467 N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3 -yl} -1-fluoromethanesulfonamide.

A) Benzyl ((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)pyrrolidin-3yl)carbamate.

A mixture of benzyl ((2S,3S) -1- (azetidin-1-ylcarbonyl) -2- (3-bromo-2-fluorobenzyl) pyrrolidin-3-yl) carbamate (600 mg), (3-fluorophenyl) boronic acid ( 223 mg), XPhos Pd G3 (15.5 mg), 1M tripotassium phosphate aqueous solution (3.67 ml) and THF (20 ml) were stirred at 70°C for 5 hours. After cooling, the insoluble matter was removed by filtration and the filtrate was concentrated in vacuum. The residue is extracted with ethyl acetate/THF. The organic layer is separated, washed with brine, passed through NH silica gel and concentrated in vacuo. The resulting solid was washed with ethyl acetate and diisopropyl ether to give the title compound (475 mg).

MS: [M+H]+ 506.2.

B) ((2S,3S)-3-Amino-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)pyrrolidin-yl)(azetidin-1-yl)methanone.

A mixture of benzyl ((2S,3 S)-1 - (azetidin-1 -ylcarbonyl) -2- ((2,3'-difluoro[biphenyl] -3-yl) methyl) pyrrolidin3-yl) carbamate (475 mg), 10% palladium-carbon (0.47 g), ethanol (20 ml) and THF (20 ml) were hydrogenated with balloon pressure at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (330 mg).

MS: [M+H] ⁺ 372.1.

C) N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3yl} -1-fluoromethanesulfonamide.

To a mixture of ((2S,3S)-3-amino-2-((2,3'-difluoro[biphenyl]-3-yl)methyl)pyrrolidin-yl)(azetidin-1-yl)methyl- 85 039459 tanone ( 100 mg) and THF (2 ml) DIPEA (45.2 mg) and fluoromethanesulfonyl chloride (39.3 mg) are added at 0°C. After stirring for 30 minutes, the mixture was concentrated in vacuo. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). The solid is crystallized from ethyl acetate/hexane to give the title compound (80 mg).

¹ H NMR (400 MHz, DMSO-d6) δ 1.85-2.21 (4H, m), 2.60-2.70 (1H, m), 2.88-2.99 (1H, m) , 3.08-3.18(1H, m), 3.32-3.39(1H, m), 3.42-3.52(2H, m), 3.65-3.76(2H, m), 3.78-3.91(1H, m), 4.34-4.45(1H, m), 5.22-5.56(2H, m), 7.15-7.28( 2H, m), 7.29-7.42(4H, m), 7.48-7.57(1H, m), 8.15-8.36(1H, m).

Example 471 N-[(2S,3S)-2-[([1,1'-Biphenyl]-3-yl)methyl]-1-(cyclobutanecarbonyl)pyrrolidin-3yl]ethanesulfonamide.

To a mixture of N-((2S,3S)-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (100 mg), cyclobutanecarboxylic acid (31.5 mg), HATU (120 mg) and DMF ( 1 ml) at 0° C. TEA (80 mg) is added. The mixture is stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (methanol/ethyl acetate). The residue was crystallized from ethyl acetate/diisopropyl ether to give the title compound (75 mg).

¹ H NMR (400 MHz, DMSO-d6) δ 0.91-1.30 (5H, m), 1.38-2.36 (8H, m), 2.63-3.31 (5H, m) , 3.38-3.88(2H, m), 3.99-4.39(1H, m), 7.12-7.68(9H, m).

Example 474 (2S,3S)-3-[(Ethansulfonyl)amino]-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-N-methoxyN-methylpyrrolidin-1 - carboxamide.

A) tert-Butyl-(2S,3S)-3-((ethylsulfonyl)amino)-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidine-1carboxylate.

Mixture of tert-butyl-(2S,3S)-2-(3-bromobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (671mg), (3-fluorophenyl)boronic acid (273mg), XPhos Pd G3 (38.1 mg), 1M aqueous tripotassium phosphate (4.50 ml) and THF (7.5 ml) were stirred at 70° C. for 1 h. The mixture was concentrated in vacuo to remove THF and the residue was extracted with ethyl acetate. The organic layer is concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (690 mg).

MS: [M-N]'461.3.

B) N-((2S,3S)-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride.

A 4M solution of hydrochloric acid in ethyl acetate (7.46 ml) was added at room temperature to a stirred mixture of tert-butyl-(2S,3S)-3-((ethylsulfonyl)amino)-2-((3'-fluoro[biphenyl]- 3-yl)methyl)pyrrolidine-1-carboxylate (0.690 g) and ethyl acetate (3 ml). After 1 hour, the resulting solid was collected by filtration to give the title compound (508 mg).

MS: [M+H]+ 363.2.

C) (2S,3S)-3-((Ethylsulfonyl)amino)-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-1-carbonyl chloride.

To a mixture of N-((2S,3S)-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (508 mg), bis(trichloromethyl)carbonate (302 mg ) and THF (6 ml) at 0° C. DIPEA (329 mg) was added. After stirring at room temperature for 30 minutes, the reaction mixture is concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, and purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (542 mg).

MS: [M-N] ^- 423.2.

D) (2S,3S)-3-[(Ethansulfonyl)amino]-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-N-methoxy-N-methylpyrrolidin-1 -carboxamide.

DIPEA (330 mg) was added at room temperature to a stirred mixture of (2S,3S)-3-((ethylsulfonyl)amino)-2-((3'-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-1-carbonyl chloride (271 mg), N-methoxymethanamine hydrochloride (124 mg) and THF (3 ml).

After stirring at 60°C for 2 h, the reaction mixture is cooled to room temperature, quenched with brine and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the product as a solid. The solid is crystallized from ethyl acetate/hexane to give the title compound (248 mg).

¹ H NMR (400 MHz, CDCl ,) δ 1.23 (3H, t, J=7.4 Hz), 1.80-1.92 (1H, m), 2.09-2.23 (1H , m), 2.86 (2H, q, J=7.3 Hz), 2.90-2.97 (1H, m), 2.98 (3H, s), 3.14-3.22 ( 1H, m), 3.42-3.52(1H, m), 3.56(3H, s), 3.60-3.70(1H, m), 3.89-4.01(1H, m), 4.35 (1H, d, J=8.8 Hz), 4.53-4.66 (1H, m), 6.98-7.07 (1H, m), 7.27-7 .45 (6H, m), 7.50 (1H, s).

Example 475 (2S,3S)-3-[(Dimethylsulfamoyl)amino]-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-N,Ndimethylpyrrolidine-1-carboxamide

A mixture of (2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((dimethylsulfamoyl)amino)-N,N-dimethylpyrrolidine- 86 039459

1-carboxamide (650 mg), phenylboronic acid (228 mg), XPhos Pd G3 (18.3 mg), 1M tripotassium phosphate aqueous solution (4.32 ml) and THF (3.6 ml) were stirred at 70° C. for 1 h. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography (NH, ethyl acetate/hexane). The solid is crystallized from ethyl acetate/hexane to give the title compound (560 mg).

1H NMR (400 MHz, CDCI3) δ 2.05-2.22 (2H, m), 2.71 (6H, s), 2.77 (6H, s), 2.84-2.92 (1H, m), 2.96-3.07 (1H, m), 3.20-3.30 (1H, m), 3.55-3.66 (1H, m), 3.82-3.91 ( 1H, m), 4.31-4.42(1H, m), 4.54-4.63(1H, m), 7.117.19(1H, m), 7.26-7.39(3H, m), 7.40-7.47 (2H, m), 7.48-7.56 (2H, m).

Example 476 (2S,3S)-3-[(Dimethylsulfamoyl)amino]-N,N-dimethyl-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl) methyl]pyrrolidine-1-carboxamide.

A mixture of (2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((dimethylsulfamoyl)amino)-N,N-dimethylpyrrolidine1-carboxamide (650 mg), (3,5-difluorophenyl)boronic acid ( 296 mg), XPhos Pd G3 (18.3 mg), 1 M tripotassium phosphate aqueous solution (4.32 ml) and THF (3.6 ml) were stirred at 70°C for 1 hour. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (NH, ethyl acetate/hexane). The solid is crystallized from ethyl acetate/hexane to give the title compound (600 mg).

1H NMR (400 MHz, CDCI3) δ 2.03-2.21 (2H, m), 2.75 (6H, s), 2.77 (6H, s), 2.83-2.93 (1H, m), 2.94-3.04 (1H, m), 3.20-3.32 (1H, m), 3.54-3.65 (1H, m), 3.81-3.92 ( 1H, m), 4.30-4.40(1H, m), 4.52-4.63(1H, m), 6.766.84(1H, m), 7.02-7.10(2H, m), 7.13-7.20(1H, m), 7.21-7.25(1H, m), 7.34-7.41(1H, m).

Example 477 (2S,3S)-2-[(3',5'-Difluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(ethanesulfonyl)amino]-N-methoxy-M -methylpyrrolidine-1-carboxamide.

To a mixture of N-((2S,3S)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (500 mg), TEA (607 mg) and THF ( 10 ml) N-methoxy-M-methylcarbamoyl chloride (310 mg) was added at room temperature. The mixture is refluxed for 15 minutes. The mixture is diluted with THF and the precipitate is removed by filtration. The filtrate is concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (467 mg).

1H NMR (300 MHz, CDCl ,) δ 1.27 (3H, t, J=7.4 Hz), 1.78-1.93 (1H, m), 2.11-2.27 (1H, m), 2.85-3.00(6H, m), 3.07-3.18(1H, m), 3.41-3.53(1H, m), 3.57(3H, s) , 3.59-3.72 (1H, m), 3.90-4.03 (1H, m), 4.39 (1H, d, J=9.1 Hz), 4.55-4.65 (1H, m), 6.77 (1H, tt, J=8.9, 2.3 Hz), 7.07-7.18 (2H, m), 7.31-7.43 (3H, m ), 7.45-7.52 (1H, m).

Example 479 1-Fluoro-N-[(2S,3S)-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl]cyclopropan-1-sulfonamide.

A) tert-Butyl-(2S,3S)-3-((cyclopropylsulfonyl)amino)-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((cyclopropylsulfonyl)amino)pyrrolidine 1-carboxylate (500 mg), phenylboronic acid (153 mg), XPhos Pd G3 ( 8.87 mg), 1M tripotassium phosphate aqueous solution (3.14 ml) and THF (2 ml) were stirred at 70° C. for 1 hour. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (490 mg).

MS: [M+H-Bos] + 375.1.

B) 1-Fluoro-N-[(2S,3 S)-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl]cyclopropan-1-sulfonamide.

To a mixture of tert-butyl-(2S,3S)-3-((cyclopropylsulfonyl)amino)-2-((2-fluoro[biphenyl]-3-yl)methyl)pyrrolidin-1-carboxylate (490 mg) and THF ( 4 ml), a 2.6M solution of nbutyllithium in hexane (1.39 ml) was added dropwise at -78°C. After stirring at -78°C for 30 min, a mixture of M-fluoro-M-(phenylsulfonyl)benzenesulfonamide (488 mg) and THF (4 ml) was added dropwise to the reaction mixture. The mixture was stirred at 0° C. under nitrogen for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). A mixture of the residue (280 mg) and 4M hydrochloric acid in ethyl acetate (2.84 ml) was stirred at room temperature in a dry atmosphere (CaCl ₂ ) overnight. The mixture is concentrated in vacuo. A mixture of the residue (244 mg), DIPEA (737 mg) and THF (5 ml) was stirred at room temperature for 30 minutes. 1-Chloro-2-methyl-1-oxopropan-2-yl acetate (113 mg) was added dropwise to the suspension at 0°C, and the resulting mixture was stirred at the same temperature for 1 hour. To the resulting solution was added 4M aqueous

- 87 039459 lithium hydroxide solution (1.14 ml) and stir the resulting mixture at room temperature overnight. The mixture was diluted with brine and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (C18, mobile phase: water acetonitrile (containing 0.1% TFA)). The desired fraction was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (20 mg).

¹ H NMR (400 MHz, DMSO-d6) δ 0.97-1.27 (6H, m), 1.35-1.64 (4H, m), 2.03-2.29 (2H, m) , 2.57-2.70(1H, m), 2.98-3.09(1H, m), 3.66-3.96(2H, m), 3.98-4.09(1H, m), 4.58-4.76(1H, m), 4.90-5.06(1H, m), 7.03-7.18(1H, m), 7.21-7.33( 2H, m), 7.34-7.41(1H, m), 7.42-7.48(2H, m), 7.49-7.57(2H, m), 8.35(1H, br.s).

Example 480 yl)methyl]pyrrolidin-3-yl}cyclopropan-1-sulfonamide.

A) tert-Butyl-(2S,3S)-3-((cyclopropylsulfonyl)amino)-2-((2,3',5'-trifluoro[biphenyl]-3-yl)methyl)pyrrolidin-1-carboxylate.

A mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((cyclopropylsulfonyl)amino)pyrrolidine 1-carboxylate (500 mg), (3,5-difluorophenyl)boronic acid (248 mg), XPhos Pd G3 (44.3 mg), 1M tripotassium phosphate aqueous solution (3.14 ml) and THF (2 ml) were stirred at 70° C. for 2 hours. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (488 mg).

MS: [M-N]' 509.2.

C) 1-Fluoro-N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}cyclopropan-1-sulfonamide.

To a mixture of tert-butyl-(2S,3S)-3-((cyclopropylsulfonyl)amino)-2-((2,3',5'-trifluoro[biphenyl]-3yl)methyl)pyrrolidine-1-carboxylate (453 mg ) and THF (6 ml), a 2.6M solution of n-butyllithium in hexane (1.19 ml) was added dropwise at -78°C. After stirring at -78° C. for 30 minutes, a mixture of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (699 mg) and THF (12 ml) was added dropwise to the reaction mixture. The mixture is slowly warmed to room temperature and stirred under nitrogen overnight. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). A mixture of the residue and 4M hydrochloric acid in CPME (5 ml) was stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is triturated with ethyl acetate and the resulting solid is collected by filtration. To a mixture of the residue, DIPEA (143 mg) and THF (5 ml), 1-chloro-2-methyl-1-oxopropan-2-ylacetate (43.8 mg) was added dropwise at room temperature, and the resulting mixture was stirred at the same temperature for for 1 hour. Water (2 ml) and 4M aqueous lithium hydroxide solution (0.443 ml) were added to the mixture, and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with brine and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM NH4HCO ₃ )/acetonitrile). The desired fraction was concentrated in vacuo to give the title compound (8.1 mg).

1H NMR (300 MHz, CDCl ,) δ 1.30-1.54 (10H, m), 1.85-2.12 (1H, m), 2.29-2.48 (1H, m), 2.84-3.03(1H, m), 3.08-3.30(1H, m), 3.59-3.94(3H, m), 4.14(1H, dt, J=11 .7, 7.2 Hz), 4.79 (1H, br. s), 6.82 (1H, tt, J=9.0, 2.4 Hz), 6.99-7.10 (2H, m), 7.11-7.22(2H, m), 7.22-7.31(1H, m), 7.38(1H, t, J=6.2 Hz).

Illustrative Example 482 N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide (not included within the scope of the present invention).

A) N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride.

To a mixture of tert-butyl-(2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (5.69 g) and MeOH (10 ml) at room temperature is added 4M hydrochloric acid in ethyl acetate (35.5 ml). The mixture is stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid was triturated with diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether and dried to give the title compound (4.87 g).

MS: [M+H]+381.3.

B) N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3yl)ethanesulfonamide.

A mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (4.87g), DIPEA (7.55g) and THF (50 ml) was stirred at room temperature for 30

- 88 039459 min. 1-Chloro-2-methyl-1-oxopropan-2-yl acetate (2.31 g) was added dropwise to the suspension at 0°C, and the resulting mixture was stirred at the same temperature for 1 hour. Water (30 ml) was added to the mixture. , 2-propanol (10 ml) and 4M aqueous lithium hydroxide solution (14.6 ml) and the mixture was stirred at room temperature overnight. A 4M aqueous lithium hydroxide solution (4.38 ml) was added to the mixture. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with brine and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (ethyl acetate/hexane). The residue was crystallized from ethanol/water to give the title compound (4.75 g) as its hydrate.

1H NMR (400 MHz, CDC13) δ 1.22 (3H, t, J=7.2 Hz), 1.33-1.47 (6H, m), 1.80-2.03 (1H, m) , 2.27-2.42 (1H, m), 2.78-2.92 (2H, m), 2.96 (1H, dd, J=14.4, 5.5 Hz), 3.13 (1H, dd, J=14.4, 7.6 Hz), 3.66 (2H, br.s), 3.90 (1H, br.s), 3.94-4.06 (1H, m ), 4.55 (1H, br.s), 4.73 (1H, br.s), 7.04-7.11 (1H, m), 7.16-7.21 (1H, m), 7.21-7.25(1H, m), 7.27-7.33(2H, m), 7.35-7.44(2H, m).

elemental analysis. Calculated for C2 ₃ H2 ₈ F2N ₂ 04S-0.3H20: C 58.53; H 6.11; N 5.94. Found: C 58.42; H 6.35; N 6.00.

Example 483 N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl) methanesulfonamide.

N-((2S,3S)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride mixture (8.5 g), DIPEA (13.1 d) and THF (81 ml) were stirred at room temperature for 30 minutes. 1-Chloro-2-methyl-1-oxopropan-2-yl acetate (3.99 g) was added dropwise to the suspension at 0° C. and stirred at the same temperature overnight. Water (53.9 ml) and 4M aqueous lithium hydroxide solution (25.2 ml) were added to the mixture, and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract is washed with brine and passed through a pad of silica gel. The solution is purified by silica gel column chromatography (NH, ethyl acetate/hexane). The resulting product was crystallized from ethanol/water to give the title compound (5.27 g) as a hydrate.

1H NMR (400 MHz, DMSO-d ₆ ) δ 1.04-1.19 (6H, m), 1.90-2.07 (1H, m), 2.11-2.23 (1H, m) , 2.59-2.70(1H, m), 2.85-2.95(3H, m), 2.95-3.10(1H, m), 3.69-3.99(3H, m), 4.50-4.68(1H, m), 5.00(1H, s), 7.08-7.18(1H, m), 7.21-7.51(6H, m) .

elemental analysis. Calculated for C24H2 ₇ F ₃ N ₂ O5S-1.5H2O: C 53.11; H, 5.67; N 5.63. Found: C 53.19; H 5.65; N 5.61.

Example 484 N-((2S,3S)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3yl)methyl)pyrrolidin-3-yl)ethanesulfonamide.

A) N-((2S,3S)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride.

To a mixture of tert-butyl-(2S,3S)-2-(3-bromo-2-fluorobenzyl)-3-((ethylsulfonyl)amino)pyrrolidine-1-carboxylate (10 g), (3,5-difluorophenyl)boronic acid (5.09 g), tripotassium phosphate (13.7 g), THF (50 ml) and water (30 ml) were added XPhos PD G3 (0.273 g) at room temperature. The mixture was stirred at 70° C. for 1 hour. After concentration in vacuo, the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give an oil. To a mixture of the resulting oil and ethyl acetate (10 ml) was added 4M hydrochloric acid in ethyl acetate (53.7 ml) with stirring at room temperature. After 18 hours, the reaction mixture was concentrated in vacuo, the solid was collected by filtration to give the title compound (8.81 g).

MS: [M+H]+ 399.3.

B) N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl) hydrochloride ethanesulfonamide.

Mixture of N-((2S,3S)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide (8.81g), DIPEA (7.85g ) and THF (100 ml) were stirred at room temperature for 30 min. 1-Chloro-2-methyl-1-oxopropan-2-yl acetate (4.00 g) was added dropwise to the resulting suspension at 0°C. After stirring for 1 hour at room temperature, water (10 ml) and 4M aqueous lithium hydroxide solution (25.3 ml) were added to the mixture. After 48 hours, the mixture was quenched with saturated aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from ethyl acetate/hexane to give the title compound (8.71 g).

1H NMR (400 MHz, CDCl ,) δ 1.24 (3H, t, J=7.3 Hz), 1.39 (3H, s), 1.41 (3H, s), 1.83-2 .03 (1H, m), 2.232.43 (1H, m), 2.83-2.97 (3H, m), 3.12 (1H, dd, J=14.0, 7.5 Hz), 3.58-3.76 (2H, m), 3.84 (1H, br.s), 3.91-4.07 (1H, m), 4.45-4.63 (1H, m), 4.67-4.89(1H, m), 6.77-6.87(1H, m), 6.99-7.10(2H, m), 7.16-7.22(1H, m ), 7.267.30 (1H, m), 7.37-7.46 (1H, m).

N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- 89 039459 yl)ethanesulfonamide (550 mg) crystallized from ethyl acetate/hexane to give the title compound (400 mg). m.p. 139°C.

Example 485 N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

A) N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride.

To a mixture of tert-butyl-(2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate (1.77 g) and ethyl acetate (20 ml) at room temperature was added 4M hydrochloric acid in ethyl acetate (28.5 ml). The mixture was stirred at room temperature for 2 hours, then at 60° C. for 1 hour. After evaporation, the solid was collected by filtration with diisopropyl ether to give the title compound (1.44 g).

MS: [M+H]+ 367.0.

B) (2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl chloride)-3-((methylsulfonyl)amino)pyrrolidine-1carbonyl.

To a mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide hydrochloride (492 mg), bis(trichloromethyl)carbonate (217 mg) and THF (6 ml) DIPEA (316 mg) was added at 0°C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, and purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (548 mg).

MS: [M-N] ^- 427.2.

C) N-((2S,3S)-1-(Azetidin-1-ylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide.

Azetidine (209 mg) was added at room temperature to a stirred mixture of (2S,3S)-2-((2,3'difluorobiphenyl-3-yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carbonyl chloride (524 mg) and THF (6 ml). After stirring for 30 minutes, the reaction mixture is concentrated in vacuo. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was crystallized from ethyl acetate/EtOH to give the title compound (404 mg).

1H NMR (400 MHz, CDCl ,) δ 1.87-2.00 (1H, m), 2.09-2.32 (3H, m), 2.69 (3H, s), 2.91- 2.99(1H, m), 3.013.10(1H, m), 3.24-3.41(2H, m), 3.84(2H, q, J=7.8Hz), 3.90 -4.07 (3H, m), 4.53 (1H, d, J=6.5 Hz), 4.68 (1H, d, J=6.6 Hz), 7.01-7.11 ( 1H, m), 7.14-7.25(2H, m), 7.27-7.33(2H, m), 7.35-7.46(2H, m).

Example 486 (2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-N,N-dimethylpyrrolidine-1-carboxamide.

(2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-N,N-dimethylpyrrolidine-1carboxamide (200 mg) recrystallized from ethyl acetate/hexane to give the title compound (152 mg).

1H NMR (300 MHz, CDC13) δ 1.26 (3H, t, J=7.4 Hz), 1.99-2.26 (2H, m), 2.80 (6H, s), 2.81 -2.96 (3H, m), 2.99-3.12 (1H, m), 3.28 (1H, dd, J=10.4, 8.3, 4.4 Hz), 3.61 (1H, dt, J=10.4, 7.7 Hz), 3.87-3.98 (1H, m), 4.44 (1H, d, J=8.3 Hz), 4.50-4, 60(1H, m), 7.01-7.10(1H, m), 7.12-7.19(1H, m), 7.20-7.31(3H, m), 7.32- 7.44 (2H, m).

Example 487 (2S,3S)-3-((Ethylsulfonyl)amino)-N,N-dimethyl-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-1-carboxamide.

(2S,3S)-3-((Ethylsulfonyl)amino)-N,N-dimethyl-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-1-carboxamide (137mg) crystallized from ethyl acetate/hexane to give the title compound (115 mg).

1H NMR (400 MHz, CDC13) δ 1.29 (3H, t, J=7.4 Hz), 1.99-2.10 (1H, m), 2.11-2.24 (1H, m) , 2.79(6H, s), 2.83-3.10(4H, m), 3.23-3.34(1H, m), 3.56-3.66(1H, m), 3 .89-3.98(1H, m), 4.43(1H, d, J=8.6Hz), 4.50-4.59(1H, m), 6.76-6.85(1H , m), 7.00-7.09 (2H, m), 7.12-7.21 (1H, m), 7.22-7.25 (1H, m), 7.35-7.43 (1H, m).

Illustrative example 488.

N-((2S,3S)-2-((2,3'-Difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3yl)ethanesulfonamide (not within the scope of the present invention ).

A mixture of N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide (1.00 d) and diisopropyl ether (15 ml) are stirred at room temperature for 6 days. The precipitate was collected by filtration and dried to give the title compound (0.973 g).

1H NMR (400 MHz, CDCI3) δ 1.22 (3H, t, J=7.2 Hz), 1.36-1.46 (6H, m), 1.80-2.03 (1H, m) , 2.28-2.43 (1H, m), 2.76-2.91 (2H, m), 2.96 (1H, dd, J=14.5, 4.6 Hz), 3.13 (1H, dd, J=14.4, 7.2 Hz), 3.66 (2H, br.s), 3.89 (1H, br.s), 3.94-4.05 (1H, m ), 4.54 (1H, br.s), 4.73 (1H, br.s), 7.04-7.11 (1H, m), 7.16-7.21 (1H, m), 7.21-7.25(1H, m), 7.27-7.33(2H, m), 7.35-7.45(2H, m). m.p. 89°C.

Example compounds are shown in the tables below. MC in the tables means the value actually obtained from the measurement. Example Connections

- 90 039459

2-18, 20-23, 25, 26, 28-63, 65-74, 77-80, 82-87, 90-92, 94-99, 102-15, 118-121, 123-177, 179205, 207 208 211 212 215-226 228-253 257 260 263-265 267 268 270-292 295-298 301 302 325-327 329-332 334- 337 353-361 363 365 367-371 374-376 378-386 388 390-394 396-398 400 401 403 405 406 408-416 418-420 422, 425-427, 429, 430, 432-434, 436, 438, 440, 442-449, 451-455, 458, 461, 464, 465, 468-470, 472, 473, 478 and 481 in the following tables obtained in accordance with the methods described in the above examples, or similar methods.

Table 1-1

EXAMPLE IUPAC NAME Structure Additional component MS one cis-2-(3-Be nz ylbe nz yl) -M-ethyl-3 ((methyl sul f onyl) amino)piperidine-1-carboxamide ίΟΠΟι V n । Ί about 430.3 2 cis-Shetyl-2-(3-(3-methylbenzyl)benzyl)-3((methylsulfonyl)amino)piperidine-1-carboxamide Hue ν H T] O 444.2 3 cis-2-(B iphenyl-3 -ylmethyl)-M-ethyl- 3-((methylsulfonyl)amino)piperidine-1-carboxamide n τη 416.1 4 cis-Shetyl-2-(3-(2methylbenzyl)benzyl)-3((methylsulfonyl)amino)piperidine-1-carboxamide H 11 O 444.2 5 trans-M-ethyl-2-(3-(2methylbenzyl)benzyl)-3((methylsulfonyl)amino)piperidine-1-carboxamide about 442.2 6 trans-2-(B iphenyl-3 -yl methyl)-Methyl-3 -((methylsulfonyl)amino)piperidine-1-carboxamide about 416.1 7 cis-2-(3-(Cyclohexyloxy)benzyl)-M-ethyl-3((methylsulfonyl)amino)piperidine-1-carboxamide O. / No. to / N> \u003d O G ²⁷ ZZ b ' 438.1 eight cis-M-ethyl-2-(3-(4methylbenzyl)benzyl)-3((methylsulfonyl)amino)piperidine-1-carboxamide HGYUHE ν 444.2 nine (28.38)-2-(biphenyl-3-ylmethyl)-X- ethyl-3-((methylsulfonyl)amino)piperidine-1-carboxamide ^5V ΗΤ] 416.1 ten cis-M-ethyl-3((methylsulfonyl)amino)-2(3-phenoxybenzyl)piperidine-1-carboxamide Ο. / j—<°' )- ⁷ τζ ъ ^? 430.1

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Table 1-2

EXAMPLE IU PACK NAME Structure Additional component MS eleven Methyl cis-2-(biphenyl-3 ylmethyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate 'about < G* o '—f / about 403.1 12 trans-M-ethyl-2-((3 ’fluorobiphenyl-3 -yl)methyl)-3 ((methyl sulfonyl)amino) piperidine-1-carboxamide F όν. oh oh MnA ν Ό ϊ 434.1 thirteen cis-M-ethyl-2-((3'-fluorobiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxamide F KN' H T] ο 434.1 fourteen Methyl-cis-2-((3'-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate F. ^γ^ΗΗ ^Γ Η Τ] 421.1 fifteen cis-X-ethyl-2-((2'-fluorobiphenyl- 3-yl)methyl)-3- ((methylsulfonyl)amino) piperidine-1-carboxamide ο ο 0 434.1 sixteen trans-M-ethyl-2-((2'fluorobiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxamide v 0 434.1 17 cis-M-ethyl-3((methylsulfonyl)amino)-2-(3((triisopropylsilyl)oxy)benzyl)piperidine-1 carboxamide Vox 512.3 eighteen Methyl-cis-2-((2'-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate VX 421.1 nineteen tert-Butyl-cis-2-(biphenyl-3 ylmethyl)-3 -((methylsulfonyl)amino)piperidine-1-carboxylate νΧ 443.1 20 Methyl-cis-2-((4'-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate with 421.1

Table 1-3

EXAMPLE IUPAC NAME Structure Additional component MS 21 Methyl-cis-2-((2'-methylbiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate v 417.1

-92039459

22 M-(cis-1-acetyl-2-(biphenyl-3 ylmethyl)piperide in-3yl)methanesulfonamide with 387.1 23 Methyl-cis-2-((3 '-methylbiphenyl-3 yl)methyl)-3 -((methylsulfonyl) amino)piperidine-1-carboxylate o s 417.1 24 Methyl cis-2-(3-iodine benzyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate '% about 452.8 25 Methyl-cis-3 - ((methyl sulfonyl) amino) -2- (3 - (pyridin-3 -yl) benzyl) piperidine-1 -carboxylate 404.0 26 Methyl-cis-2-((4'-methoxybiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 433.0 27 Methyl-cis-3 - ((methyl sulfonyl) amino) -2- (3 - (pyrrolidin-1 yl) benzyl) piperidine-1 carboxylate 396.2 28 Methyl-cis-3 - ((methyl sulfonyl) amino) -2- (3 - (pyridin-2-yl) benzyl) piperidine-1 -carboxylate BUT? about 404.1 29 Ethyl-cis-2-(biphenyl-3 -ylmethyl)-3 ((methyl su l f onyl) amino) piperidine-1 -carboxylate 417.1 thirty cis-M-ethyl-2-((4'-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxamide 434.1

Table 1-4

EXAMPLE IU PACK NAME Structure Additional component MS 31 Methyl-cis-2-((2'-methoxybiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Oh NJ - Tg about 433.0

- 93 039459

32 Methyl-cis-2-((3'-methoxybiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Λ > C J s 'L ³ 433.0 33 cis-M-ethyl-2-((2'methoxybiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxamide 446.1 34 cis-M-ethyl-2-((3 '- methoxybiphenyl-3-yl)methyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxamide db o 446.1 35 cis-M-ethyl-3((methylsulfonyl)amino)-2-((4'(trifluoromethyl)biphenyl-Zyl)methyl)piperidine-1 carboxamide τΓ^ϊ o o H T] 484.0 36 cis-LT-ethyl-2-((2'-methylbiphenyl-3 yl)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxamide v 430.1 37 Methyl-cis-3 -((methylsulfonyl)amino)-2-((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate “F about 404.1 38 Ethyl-cis-3 -((methylsulfonyl)amino)-2-((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate about 418.1 39 cis-M-ethyl-3((methylsulfonyl)amino)-2-((6phenylpyridin-2yl)methyl)piperidine-1 carboxamide -¾ O 417.1 40 Methyl cis-2-((4-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 421.1

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Table 1-5

EXAMPLE IU PACK NAME Structure Additional component MS 41 Methyl cis-2-((6-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate AI ¥ ΔΑ ⁵ O 421.1 42 Ethyl cis-2-((6-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Oh NJ O 435.1 43 M-(cis-2-(biphenyl-2ylmethyl)piperide in-3yl)methanesulfonamide hnJ HCl 345.0 44 Methyl cis-3((methylsulfonyl)amino)-2-(3(trifluoromethyl)benzyl)piperidine-1-carboxylate BUT O 395.1 45 Propyl-cis-2-(biphenyl-3 ylmethyl)-3 -((methylsulfonyl)amino)piperidine-1-carboxylate Ίι M O .C ALn ^:s; > Ύ 431.1 46 Butyl-cis-2-(biphenyl-3 ylmethyl)-3 -((methylsulfonyl)amino)piperidine-1-carboxylate BUT 445.1 47 2-Methoxyethyl-cis-2-(bifenyl-3 ylmethyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate Gw. ¥j ν /BUT 447.0 48 2,2-Difluoroethyl-cis-2-(biphenyl3-ylmethyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate cw Tt A O <5 unc W. 451.1 49 2,2,2-Trifluoroethyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate °.· / About a) CPA' HA *---/IL LL 469.0 fifty Isopropyl-cis-2-(biphenyl-3 ylmethyl)-3 -((methylsulfonyl)amino)piperidine-1-carboxylate Gw Τ μ .° Ύ°ι/θl o 431.1

-95 039459

Table 1-6

EXAMPLE R IU PACK NAME Structure Additional component MS 51 1,1,1-Trifluoropropan-2-yl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 483.0 52 Methyl-cis-2-((4'(difluoromethyl)biphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate F about 453.0 53 Methyl-cis-2-(3-(1-methyl-1Nindazol-5-yl)benzyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxylate one about 457.1 54 Methyl-cis-3((methylsulfonyl)amino)2-(3-vinylbenzyl)piperidine-1-carboxylate O. / and y—, — /— ° 353.0 55 Methyl-cis-3((methylsulfonyl)amino)-2-(3(prop-1-en-2-yl)benzyl)piperidine-1-carboxylate Χό O 367.1 56 Methyl-cis-2-(3-(cyclopent-1-en1-yl)benzyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate oh oh U L 'S· 393.1 57 Methyl cis-2-(3 -(cyclohex-1-επί-yl)benzyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate ¢. / >1 ,—. o z4 ) /—' ° 407.1 58 Methyl cis-2-((2-fluorobiphenyl-3yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Τι O ⁰ l e F ο 421.0 59 Ethyl cis-2-((2-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate ζ Γλ'-Ο /“'0 435.1 60 Methyl cis-2-(3-cyclobenzyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate % 0 381.1

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Table 1-7

EXAMPLE IUPAC NAME Structure Additional component MS 61 Methyl cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate |Ί o 389.1 62 cis-M-ethyl-3((methylsulfonyl)amino)-2-(2phenoxybenzyl)piperidine-1 carboxamide \ -o dm & 432.1 63 cis-M-ethyl-3((methylsulfonyl)amino)-2-(4phenoxybenzyl)piperidine-1 carboxamide with 432.0 64 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((6phenylpyridin-2yl)methyl)piperidine-1 carboxylate ^{0 0} An'. Ύ°Χ' 432.1 65 Ethyl cis-3((methylsulfonyl)amino)-2-((5phenylpyridin-3 yl)methyl)piperidine-1 carboxylate 0/ ϊ - <4 /2^ o o ^; 418.1 66 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((5phenylpyridin-3 yl)methyl)piperidine-1 carboxylate o, / ^W 2--CH O ¢-( ) Y* 432.1 67 Ethyl cis-2-(3-chloro-2fluorobenzyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 0 393.0 68 Methyl cis-2-((6-methylbiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Χή) ν 417.2 69 Methyl cis-2-((5-methylbiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate about 417.2 70 Ethyl cis-3((methylsulfonyl)amino)-2-((2phenylpyridin-4yl)methyl)piperidine-1 carboxylate 418.1

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Table 1-8

EXAMPLE IUPAC NAME Structure Additional component MS 71 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((2phenylpyridin-4yl)methyl)piperidine-1 carboxylate QL N FR qr nN 1 about 432.1 72 cis-M-ethyl-3((methylsulfonyl)amino)-2-((2phenylpyridin-4yl)methyl)piperidine-1 carboxamide p * π o, o μ 11 O 417.2 73 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-(2phenoxybenzyl)piperidine-1 carboxylate O-oUXa' 1 about 445.2 74 Isopropyl-cis-2-(biphenyl-3 ylmethyl)-3 -((methylsulfonyl)amino)pyrrolidine-1 carboxylate 417.1 75 Ethyl cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate ' ' 0 403.1 76 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((6phenylpyridin-2yl)methyl)piperidine-1 carboxylate (optical isomer) I D 432.1 77 Methyl-cis-2-(3-cyclopropylbenzyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate if!) V o 367.1 78 Isopropyl-cis-2-(dibenzo[b, <1]furan4-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate U© Ύθ'/θ Iα 443.2 79 Propyl-cis'2-(biphenyl-3 ylmethyl)-3- ((methylsulfonyl)amino) pyrrolidine-1-carboxylate 'V γΗΝ 417.2 80 trans-2-(Biphenyl-3-ylmethyl)-Methyl-3- ((methylsulfonyl)amino) pyrrolidine-1-carboxylate Si. ⁿ s 7 402.0

Table 1-9

EXAMPLE IUPAC NAME Structure Additional component MS 81 M-(cis-2-(biphenyl-3 ylmethyl) pyrrolide in-3 yl) methanesulfonamide HN-\hn3 331.0

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82 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((6(prop-1-en-2-yl)pyridin-2-yl)methyl)piperidine-1-carboxylate % 396.2 83 Isopropyl-cis-2-((6isopropylpyridin-2-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate '% 398.1 84 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((4phenyl-1 H-pyrazol-1 yl)methyl)piperidine-1 carboxylate 421.1 85 Methyl cis-2-(dibenzo[b, d]furan-4-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate ° I Τ ⁰ o 417.0 86 Methyl-cis-3((methylsulfonyl)amino)-2-( 1 naphthylmethyl)piperidine-1 carboxylate Ji X s ^N 1 ⁰ 377.0 87 Isopropyl-cis-2-(3 isopropylbenzyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate ι o 395.1 88 tert-Butyl-cis-3 ((methylsulfonyl)amino)-2-((2phenyl-1,3-thiazol-4yl)methyl)piperidine-1 carboxylate Q Y" O O Μ™ 452.0 89 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((2phenyl-1,3-thiazol-4yl)methyl)piperidine-1 carboxylate © V ^s , 0.0 Ν Λ S''γ UN ' rb ¹ ο 438.1 90 Ethyl-cis-3- ((methylsulfonyl)amino)-2-((2phenyl-1,3-thiazol-4yl)methyl)piperidine-1 - carboxylate I /G® 0 0 τ HW ο 424.0

- 99 039459

Table 1-10

EXAMPLE IUPAC NAME Structure Additional component MS 91 Methyl cis-2-((4-methylbiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate GA x—ς 417.0 92 M-(cis-2-(biphenyl-3-ylmethyl)1-propionylpiperidin-3-yl) methanesulfonamide ζχ O v χΗΝ A 401.1 93 M-(cis-2-(biphenyl-3-ylmethyl)1-(cyclopropylcarbonyl)piperidin-3-yl)methanesulfonamide Αιχ A 413.2 94 M-(cis-2-(biphenyl-3 -ylmethyl)1-(2,2- difluoropropanoyl)piper idin-3 yl)methanesulfonamide SH XX s 437.1 95 M-(cis-2-(biphenyl-3-ylmethyl)1-isobutyr ylpiper idin-3yl)methanesulfonamide cx xn □ 415.1 96 Isopropyl-cis-2-((6-(3-fluorophenyl)pyridin-2-yl)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate _Ρ Χϊχ ^F ΪΊ O O GL 450.1 97 Isopropyl-cis-2-((6-(2fluorophenyl)pyridin-2yl)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate Сх gХХ Ύ' mm 'h· uX 1 about 450.1 98 Isopropyl-cis-2-((6-(2,3 difluorophenyl)pyridin-2yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate pXX ^F T GN ° ° 468.1 99 Isopropyl-cis-2-((6-(3,5 difluorophenyl)pyridin-2yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Άοχ g# ¹ o 468.2 100 Isopropyl-cis-2-((6-(2,5 difluorophenyl)pyridin-2yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 468.2

- 100 039459

Table 1-11

EXAMPLE IUPAC NAME Structure Additional component MS 101 Ethyl-(28.38)-2-(biphenyl-3ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate (optical isomer) about. / O * _Λ R 403.1 102 Butyl cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate ρ η ^s . ? 431.0 103 2-Methoxyethyl-cis-2-(bifenyl3-ylmethyl)-3- ((methylsulfonyl)amino) pyrrolidine-1-carboxylate * * and Р /ts ₀ S “ 433.0 104 2,2-Difluoroethyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)pyrrolidine-1-carboxylate 437.0 105 2,2,2-Trifluoroethyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)pyrrolidine-1-carboxylate Τί' R ^f f 455.0 106 sec-Butyl-cis-2-(biphenyl-3ylmethyl)-3- ((methylsulfonyl)amino) pyrrolidine-1-carboxylate RR 429.1 107 Isobutyl-cis-2-(biphenyl-3ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate U-J 's' N—/PP 431.0 108 Cyclopropyl-cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate R 415.0 109 Cyclobutyl-cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate _A n-y ci's 429.0 110 3,3-Difluoro cyclobutyl-cis-2 (biphenyl-3 -ylmethyl) -3 ((methylsulfonyl) amino) pyrrolidine-1 -carboxylate CV. Tch o. about p F 465.0

- 101 039459

Table 1-12

EXAMPLE IUPAC NAME Structure Additional component MS 111 Cyclopentyl-cis-2-(biphenyl-3ylmethyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate Ql wD ν О ⁴ 441.0 112 Cyclopropylmethyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)pyrrolidine-1-carboxylate % 429.0 FROM (1-Methylcyclopropyl)methylcis-2-(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)pyrrolidine-1-carboxylate X 441.0 114 (1-Fluorocyclopropyl)methyl-cis2-(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)pyrrolidine-1-carboxylate Η D O. -O Whh-% Cha 445.2 115 Cyclobutylmethyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)pyrrolidine-1-carboxylate ? fAU ί /Ό 441.0 116 Isopropyl-cis-2-((2', 3' difluorobiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate ^F ^TT ^: ii o o F kJ S' 467.2 117 Isopropyl-cis-2-(3-iodine benzyl)3-((methylsulfonyl)amino)piperidine-1-carboxylate 'Ό ν ΥΗΝ '' gD ¹ o 478.9 118 M-(cis-2-(biphenyl-3-ylmethyl)1-(difluoroacetyl)piperidin-3-yl)methanesulfonamide V-food O 423.1 119 Isopropyl-cis-2-(3(d-imethylamino)benzyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate A 398.1 120 M-(cis-2-(biphenyl-3-ylmethyl)1-((1fluorocyclopropyl)carbonyl)piperidin-3-yl)methanesulfonamide OU _oo ts xJ 's' yes o 431.1

- 102 039459

Table 1-13

EXAMPLE IUPAC NAME Structure Additional component MS 121 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-(2naphthylmethyl)piperidine-1 carboxylate Y^Y 1 o 403.1 122 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((3 phenyl-1 H-pyrazol-1 yl)methyl)piperidine-1 carboxylate Va o o K U Υ 'G NN ⁴ γX^ 1 o 421.1 123 sec-Butyl-cis-2-(biphenyl-3ylmethyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate 1 about 443.1 124 3-Methylbutan-2-yl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Se-. In d o. about 1 about mJ 1 about 457.1 125 Isobutyl-cis-2-(biphenyl-3 ylmethyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate 445.0 126 Cyclopropyl-cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate oh oh 429.1 127 Cyclobutyl-cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate YY%? γπΗ - Ο Ν Jrr 443.0 128 3,3-Difluoro cyclobutyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Cy Y %? F 477.0 129 Cyclopentyl-cis-2-(biphenyl-3ylmethyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate Y σγ 455.0 130 Cyclohexyl-cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Y 469.0

- 103 039459

Table 1-14

EXAMPLE IUPAC NAME Structure Additional component MS 131 1-Methylcyclopropyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Si. U'A 441.0 132 Oxetan-3-yl-cis-2-(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate CVs pi Oh NJ 445.0 133 Tetrahydrofuran-3-yl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 459.0 134 T tetrahydro-2H-pyran-4-yl-cis2-(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Ou XYhh ⁵ . O 471.0 135 T tetrahydro-2H-pyran-3 -yl-cis2-(biphenyl-3 -ylmethyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxylate about / rt j—ι C Η ) o b 473.0 136 Cyclopropylmethyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperdine-1-carboxylate Q T D o o 2k O N J α 443.0 137 (1-Methylcyclopropyl)methylcis-2-(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Ux ο 457.0 138 (1-Fluorocyclopropyl)methyl-cis2-(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Ο U tx* .0 '—< tx /ο 459.0 139 (2,2-Difluorocyclopropyl) methyl-cis-2-(biphenyl-3ylmethyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate 0 477.0 140 Cyclobutylmethyl-cis-2(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate qu ^o ' c 455.0

- 104039459

Table 1-15

EXAMPLE IUPAC NAME Structure Additional component MS 141 Cyclopentylmethyl-cis-2(b-iphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate O- / \ O'5 o e d 469.0 142 Oksetan-2-ylmethyl-cis-2(6-phenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Xu 11 D o U 'S''Yunn ¹ o 458.9 143 Oxetan-3-ylmethyl-cis-2(6-phenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 459.0 144 T tetrahydrofuran-2-ylmethylcis-2-(biphenyl-3-ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Г-Λ ° ) 473.0 145 Phenyl-cis-2-(biphenyl-3 ylmethyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate 465.0 146 Benzyl-cis-2-(biphenyl-3 ylmethyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate O. / Ώ )—'o θd 477.0 147 Ethyl cis-2-((4-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate ⁰ about 435.1 148 149 Ethyl cis-2-(3-bromo-4fluorobenzyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate Methyl cis-2-((5-fluorobiphenyl3-yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate yu o SYUL Τι Yu o o about 436.9 421.1 150 T4-(cis-2-((6fluorobiphenyl-3yl)methyl)piperide in-3yl)methanesulfonamide hydrochloride OA ^{0 0} Yu U ^L <i ΗΝ^ HC1 363.0

- 105 039459

Table 1-16

EXAMPLE IUPAC NAME Structure Additional component MS 151 cis-H-ethyl-2-((3 '- methylbiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxamide v and τη about 430.1 152 Methyl cis-3((methylsulfonyl)amino)-2-((4phenylpyridin-2yl)methyl)piperidine-1 carboxylate 'o g-c t>=( \ga -o ⁴ ----' chg. / o 404.1 153 Ethyl cis-3((methylsulfonyl)amino)-2-((4phenylpyridin-2yl)methyl)piperidine-1 carboxylate o o ⁷ 418.1 154 cis-M-ethyl-3((methylsulfonyl)amino)-2-((4phenylpyridin-2yl)methyl)piperidine-1 carboxamide ZX J—( on \ G* ° '--' J' / about 417.1 155 Methyl-cis-2-((4' methylbiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate AC, %? unp- 0 417.1 156 Methyl-cis-3 ((methylsulfonyl) amino) -2 ((2 ' - (trifluoro methyl) biphenyl-3 yl) methyl) piperidine-1 carboxylate FF O, .o U A 'th ^j O Ν J 471.0 157 Methyl-cis-3 ((methylsulfonyl) amino) -2 ((3 ' - (trifluoro methyl) biphenyl-3 yl) methyl) piperidine-1 carboxylate uOw ^F 1 Ίι Ί 0. ο ο 470.9 158 Methyl cis-3((methylsulfonyl)amino)-2-(3(pyridin-4-yl)benzyl)piperidine-1-carboxylate Αξχ .γ 404.0 159 Methyl-cis-3((methylsulfonyl)amino)-2-(3(3-thienyl)benzyl)piperidine-1-carboxylate ⁰ Γ=Λ < Η.ο 407.0 160 Methyl cis-3((methylsulfonyl)amino)-2-(3(2-thienyl)benzyl)piperidine-1-carboxylate :ϊ· 409.1

- 106 039459

Table 1-17

EXAMPLE IUPAC NAME Structure Additional component MS 161 Methyl-cis-2-(3-(1-methyl-1Hpyrazol-3-yl)benzyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxylate about. / /—X ° ιΛ > Ln \=U o V ⁴ ί 407.0 162 Methyl-cis-2-(3-(1-methyl-1Hpyrazol-4-yl)benzyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxylate γ^ΗΝ α ν J 407.1 163 Methyl-cis-2-(3-(1-methyl-1Hpyrazol-5-yl)benzyl)-3 ((methylsulfonyl)amino)piperidine-1-carboxylate 407.1 164 Methyl-cis-2-(3-methylbenzyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate ο. / “/—X ο' ζ-ί) ' /° Y—' o / X 340.9 165 Methyl-cis-2-((3 ’,4’ difluorobiphenyl-3 -yl) methyl)-3 ((methylsulfonyl) amino) piperidine-1-carboxylate Oh..Oh Vhn ^ 0 437.1 166 Methyl-cis-2-((2 ', 4' difluorobiphenyl-3 -yl) methyl) -3 ((methyl sul f onyl) amino) piperidine-1 -carboxylate xxx %? 439.0 167 Methyl-cis-2-((2', 3' difluorobiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate V Q 439.1 168 Methyl-cis-2-((2', 6' difluorobiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate O. / dU U. □ 439.0 169 Methyl-cis-2-((3', 5' difluorobiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate about 439.1 170 Methyl-cis-2-((2', 5' difluorobiphenyl-3 -yl)methyl)-3 ((methylsulfonyl)amino) piperidine-1-carboxylate -η X / e » / C ⁴¹ ° \u003d < / - O / A * ί I-O X - / sv; / 0 439.1

Table 1-18

EXAMPLE IUPAC NAME Structure Additional component MS 171 Methyl-cis-2-((3 ’(difluoromethyl)biphenyl-3 yl)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate about / 453.0

- 107 039459

172 Isopropyl-cis-3 ((ethylsulfonyl)amino)-2-((6phenylpyridin-2yl)methyl)piperidine-1 carboxylate SAL. VO 446.2 173 Isopropyl-cis-2-((6phenylpyridin-2-yl)methyl)-3((propylsulfonyl)amino)piperidine-1-carboxylate I" \__/—Ch O' No. 1 JSC 460.0 174 Isopropyl-cis-3 ((butylsulfonyl)amino)-2-((6phenylpyridin-2yl)methyl)piperidine-1 carboxylate I of 474.0 175 Isopropyl-cis-3 ((isobutylsulfonyl)amino)-2((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate I b=/\5' γ^ 474.0 176 Isopropyl-cis-2-((6phenylpyridin-2-yl)methyl)-3((vinylsulfonyl)amino)piperidine-1-carboxylate l Α"S G 444.2 177 Isopropyl-cis-3 ((allylsulfonyl)amino)-2-((6phenylpyridin-2yl)methyl)piperidine-1 carboxylate u" u L 458.0 178 Isopropyl-cis-3 ((cyclopropylsulfonyl) amino)-2-((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate A oL ¹ V 458.1 179 Isopropyl-cis-3 -((oxetan-3 ylsulfonyl)amino)-2-((6phenylpyridin-2-yl)methyl)piperidine-1-carboxylate O U _ Λ ^ΝΗ JSC Υ 474.1 180 Isopropyl-cis-2-((6phenylpyridin-2-yl)methyl)-3 (((2,2,2-trifluoroethyl)sulfonyl)amino)piperidine-1 carboxylate YAL AO Y 500.1

- 108 039459

Table 1-19

EXAMPLE IUPAC NAME Structure Additional component MS 181 Isopropyl-cis-3 (((chloromethyl)sulfonyl) amino)-2-((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate O = y" ¥ \_y-\o nn 466.1 182 Trifluoroacetic acid salt of isopropyl-cis-3-(((2hydroxyethyl)sulfonyl)amino)-2((6-phenylpyridin-2yl)methyl)piperidine-1-carboxylate is he I'm 4 \ O' NH V'O _CF3COOH 461.9 183 Isopropyl-cis-3 -(((2methoxyethyl)sulfonyl)amino)-2-((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate Q 476.1 184 Isopropyl-cis-3 (((cyanomethyl)sulfonyl) amino)-2-((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate Q Ν γ XT 457.0 185 Isopropyl-cis-3 ((dimethylsulfamoyl)amino)-2((6-phenylpyridin-2yl)methyl)piperidine-1 carboxylate -zO \=) xz O y—u P t/U Ύ 461.2 186 Isopropyl-cis-3 ((ethylsulfonyl) amino) -2- ((6 (prop-1 -en-2-yl) pyridin-2 yl) methyl) piperidine-1 -carboxylate X 410.0 187 Isopropyl-cis-2-((6-(prop-1-en2-yl)pyridin-2-yl)methyl)-3-((propylsulfonyl)amino)piperidine-1-carboxylate X 424.1 188 Isopropyl-cis-3 - ((butylsulfonyl)amino)-2-((6(prop-1-en-2-yl) pyridin-2-yl)methyl)piperidine-1-carboxylate one. Viz o' z^t )—ί 20 Λ 438.0 189 190 Isopropyl-cis-2-((6-(prop-1-en2-yl)pyridin-2-yl)methyl)-3-((vinylsulfonyl)amino)piperidine-1-carboxylate Isopropyl-cis-3 ((allylsulfonyl)amino)-2-((6(prop-1-en-2-yl)pyridin-2-yl)methyl)piperidine-1-carboxylate X ^£ ' 408.0 422.0

- 109 039459

Table 1-20

EXAMPLE R IUPAC NAME Structure Additional component MS 191 Isopropyl-cis-3 ((cyclopropylsulfonyl) amino)-2-((6-(prop-1-en-2yl)pyridin-2-yl)methyl) piperidine-1-carboxylate X 422.0 192 Isopropyl-cis-3 -((oxetan-3 ylsulfonyl)amino)-2-((6-(prop1-en-2-yl)pyridin-2yl)methyl)piperidine-1 carboxylate Xl ^1'X 438.0 193 Isopropyl-cis-2-((6-(prop-1-en2-yl)pyridin-2-yl)methyl)-3-(((2,2,2trifluoroethyl)sulfonyl)amino)piperidine-1-carboxylate X 464.0 194 Isopropyl-cis-3 (((chloromethyl)sulfonyl) amino)-2-((6-(prop-1-en-2yl)pyridin-2yl)methyl)piperidine-1 carboxylate Yo y-Z ω ''•—J o 430.0 195 Isopropyl-cis-3 -(((2methoxyethyl)sulfonyl)amino)-2((6-(prop-1-en-2-yl)pyridin-2yl)methyl)piperidine-1-carboxylate -O Λ /—h ^m ό ζ-/ _ 440.0 196 Isopropyl-cis-3 (((cyanomethyl) su l f onyl) amino) -2- ((6- (prop-1 -en-2yl) pyridin-2-yl) methyl) piperidine-1 -carboxylate χ 421.0 197 198 199 Isopropyl-cis-3 ((dimethylsulfamoyl)amino)-2((6-(prop-1-en-2-yl)pyridin-2yl)methyl) piperidine-1-carboxylate Isopropyl-3((methylsulfonyl)amino)-2 -((1 phenylpyrrolidin-3 yl)methyl)piperidine-1 carboxylate Methyl cis-2-(biphenyl-3 ylmethyl)-3((cyclopropylsulfonyl)amino)piperidine-1-carboxylate X ^J ο Vr ν Ο Μ j Τ' ο 425.1 424.1 429.1 200 Methyl-cis-2-(biphenyl-3 ylmethyl)-3- ((dimethylsulfamoyl)amino)piperidine-1-carboxylate 'θ' 432.1

- 110 039459

Table 1-21

EXAMPLE IUPAC NAME Structure Additional component MS 201 Ethyl-cis-3-(methylsulfonyl)amino)-2-((2-phenyl-1,3-oxazol4-yl)methyl)piperidine-1-carboxylate X-Y ^J 408.1 202 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((2phenyl-1,3-oxazol-4yl)methyl)piperidine-1 carboxylate oh oh 1 about 422.1 203 Isopropyl-cis-2-(3-(1-methyl1 H-indazol-5-yl)benzyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate χ., Y# 485.2 204 cis-2-(Biphenyl-3-ylmethyl)-H N-dimethyl-3- ((methylsulfonyl)amino)piperidine-1-carboxamide cx o ν γ HN- ό X 416.1 205 M-(cis-2-(biphenyl-3-ylmethyl)1-propionylpyrrolidin-3 yl)methanesulfonamide Q 387.1 206 M-(cis-2-(biphenyl-3-ylmethyl)1-(cyclopropylcarbonyl)pyrrolidin-3-yl)methanesulfonamide οα. A 399.1 207 M-(cis-1-acetyl-2-(biphenyl-3 ylmethyl) pyrrolide in-3 yl) methanesulfonamide Οχ x© ν Υ HH'\ Ν V 373.1 208 cis-2-(Biphenyl-3-ylmethyl)-Methyl-M-methyl-3((methylsulfonyl)amino)piperidine-1-carboxamide x0 430.1 209 M- (cis-2- (biphenyl-3 -ylmethyl) 1 -isobutyr ylpyrrolidin-3 -yl) methanesulfonamide Cx Λ 401.1 210 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((2phenyl-1,3-thiazol-4yl)methyl)piperidine-1 carboxylate (optical isomer) ο V ^s ο ο 1 ο 438.1

- 111 039459

Table 1-22

EXAMPLE IUPAC NAME Structure Additional component MS 211 Ethyl-cis-3 -((methylsulfonyl)amino)-2-((4-phenyl-1,3-thiazol-2yl)methyl)piperidine-1 carboxylate X V a 424.0 212 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((4phenyl-1,3-thiazol-2 yl)methyl)piperidine-1 carboxylate h. w; one & 438.1 213 Isopropyl-cis-3 ((methylsulfonyl)amino)-2(pyride in-3-ylmethyl)piperidine-1-carboxylate O ν A । about 356.0 214 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((1phenylpiper idin-3 yl)methyl)piperidine-1 carboxylate > about a 438.1 215 Isopropyl-cis-3 - ((methylsulfonyl)amino)-2-(3(pyrimidin-2yl)benzyl)piperidine-1 - carboxylate + P o /g / ° ¹ nO (/ ° ^h - '. W O X 433.2 216 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((1phenyl-1 H-pyrazol-3 yl)methyl)piperidine-1 carboxylate 1 a 421.2 217 Methyl cis-3((methylsulfonyl)amino)-2-((1phenylpiper idin-3 yl)methyl)piperidine-1 carboxylate > o o Χό o 410.3 218 Isopropyl-cis-3 - ((methylsulfonyl)amino)-2-((1(pyrimidin-2-yl)piperidin-3yl)methyl) piperidine-1-carboxylate o o rU 440.2 219 Isopropyl-cis-3 ((methylsulfonyl)amino)-2-((2phenyl-1,3-thiazol-4yl)methyl)pyrrolidine-1 carboxylate h. XYf 424.0 220 M-(cis-2-((2-(2,3-difluorophenyl)1,3-thiazol-4-yl)methyl)-1isobutyrylpyrrolidin-3yl)methanesulfonamide 444.1

- 112039459

Table 1-23

EXAMPLE IUPAC NAME Structure Additional component MS M-(cis-2-(biphenyl-3 -ylmethyl)-1 - 221 (cyclobutylcarbonyl) pyrrolidin-3 yl) methanesulfonamide 413.2 M-(cis-2-(biphenyl-3 -ylmethyl)-1 - yes>, 222 (cyclopropylacetyl)pyrrolidine Yes 413.2 -3-yl)methanesulfonamide V about M-(cis-2-(biphenyl-3 -ylmethyl)-1 - Hae-o 223 butyrylpyrrolidin-3 yl)methanesulfonamide Yes 401.1 M-(cis-2-(biphenyl-3 -ylmethyl)-1 - 224 (3-methylbutanoyl) pyrrolide in-3 - 415.1 yl)methanesulfonamide M-(cis~2-(biphenyl-3 -ylmethyl)-1 - 225 (cyclopentylcarbonyl)pyrrolide A < 427.1 in-3-yl)methanesulfonamide M-(cis-2-(biphenyl-3 -ylmethyl)-1 - 226 (2-methylbutanoyl) pyrrolide in-3 - 415.1 yl)methanesulfonamide Yes Yes M-(cis-2-(biphenyl-3 -ylmethyl)-1 - Yes 227 (2,2- dimethylpropanoyl)pyrrolidin3-yl)methanesulfonamide U 415.2 228 M-(cis-2-(biphenyl-3 -ylmethyl)-1 ((2S)-2- 415.1 methylbutanoyl)pyrrolide in-3 yl)methanesulfonamide Yes' M-(cis-2-(biphenyl-3 -ylmethyl)-1 - Oh yeah 229 isobutyrylpyrrolidine-3 - Yes Yes 427.3 yl)cyclopropanesulfonamide Yes X-(cis-2-(bifenyl-3 -ylmethyl)-1 - Yes 230 (cyclopropylcarbonyl) pyrrolidin-3 -yl)-1 methoxymethanesulfonamide food yes 429.1

- 113 039459

Table 1-24

EXAMPLE IU PACK NAME Structure Additional component MS 231 M-(cis-2-(biphenyl-3-ylmethyl)-1 isobutyrylpyrrolidin-3-yl)-1 chloromethanesulfonamide 1 K ° K 435.1 232 M-(cis-2-(biphenyl-3-ylmethyl)-1 isobutyr ylpyrrolidin-3-yl)-1 fluoromethanesulfonamide X O 419.1 233 M-(cis-2-(biphenyl-3-ylmethyl)-1isobutyr ylpyrrolidin-3-yl)-1,1difluoromethanesulfonamide ΟυαΥ 437.1 234 N-(cis-2-((3',5'-difluorobiphenyl3-yl)methyl)-1isobutyrylpyrrolidin-3 yl)methanesulfonamide 437.1 235 T4-(cis-2-((2’,5’-difluorobiphenyl3-yl)methyl)-1isobutyrylpyrrolidin-3 yl)methanesulfonamide Υ°° ' ΛΑ ώ 437.1 236 N- (ljhc- 1 -isobutyr yl-2- ((2 ’ (trifluoromethyl) biphenyl-Zyl) methyl) pyrrolide in-3 yl) methanesulfonamide Α' 469.0 237 bcis-2-((2'-chlorobiphenyl-3 yl)methyl)-1isobutyrylpyrrolidin-3 yl)methanesulfonamide ig η A 435.1 238 M-(cis-2-((2’,3’-difluorobiphenyl3-yl)methyl)-1isobutyrylpyrrolidin-3 yl)methanesulfonamide Y 437.1 239 240 M-(cis-2-((2',6'-difluorobiphenyl3-yl)methyl)-1- isobutyrylpyrrolidin-3 yl)methanesulfonamide M-(cis-2-((2'-fluorobiphenyl-3- yl)methyl)-1- isobutyr ylpyrrolidin-3-yl) methanesulfonamide γό OK F Tj 0 HM-S Oj o o 437.1 419.1

- 114 039459

Table 1-25

EXAMPLE IU PACK NAME Structure Additional component MS 241 M-(cis-2-((3'-fluorobiphenyl-3 yl)methyl)-1 isobutyrylpyrrolidin-3 yl)methanesulfonamide (JUJU o C. 419.1 242 M- (cis-1 - isobutyr yl-2- ((2 ', 3 ', 5 ' trifluorobiphenyl-3 yl) methyl) pyrrolide in-3 yl) methanesulfonamide Fύ 455.1 243 N- (ljhc- 1 -isobutyr yl-2- ((2 ', 3 ', 5 ', 6 ' tetrafluorobiphenyl-3 -yl) methyl) pyrrolidin-3 yl) methanesulfonamide F f C. j Q 4 lj about 473.1 244 CG-(cis-1-isobutyr yl-2-(3(pyrrolidin-1-yl)benzyl) pyrrolidin-3-yl) methanesulfonamide V 394.2 245 M- (cis-2- (3 - (2,3 -dihydro-1Nindol-1 -yl) benzyl) -1 isobutyrylpyrrolidin-3 yl) methanesulfonamide v 442.0 246 ChG-(cis-1-isobutyr yl-2-((2-phenyl1,3-thiazol-4yl)methyl)pyrrolide in-3yl)methanesulfonamide 408.1 247 248 249 N-(ljhc- 1 -(cyclopropylcarbonyl)2-((6-phenylpyridin-2yl)methyl)pyrrolide in-3yl)methanesulfonamide Ethyl-cis-3- ((methylsulfonyl)amino)-2-((6phenylpyridin-2-yl)methyl) pyrrolidine-1-carboxylate Methyl-cis-2-(biphenyl-3-ylmethyl)3 -((ethyl su l f onyl) amino) piperidine-1-carboxylate u u 400.1 404.0 417.0 250 Methyl cis-2-(biphenyl-3-ylmethyl)3-((isopropylsulfonyl))amino)piperidine-1-carboxylate θΌ V 431.0

- 115 039459

Table 1-26

EXAMPLE IUPAC NAME Structure Additional component MS 251 cis-2-(Biphenyl-3-ylmethyl)-Methyl-3-((methylsulfonyl)amino)azetidine-1-carboxamide Cm from 388.0 252 N-(uhc-1-(2,2- dimethylpropanoyl)-2-((2-phenyl- 1,3-thiazole-4- yl)methyl)pyrrolide in-3 yl)methanesulfonamide % , y 422.2 253 1-Fluoro-M-(cis-1-isobutyr yl-2((2-phenyl-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)methanesulfonamide '%; m 426.2 254 T4-(cis-1-(cyclobutylcarbonyl)2-((2-(3-fluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)methanesulfonamide about. _g X 11- 438.1 255 M-(cis-1-(cyclobutylcarbonyl)2-((2-(2-fluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)methanesulfonamide % m 438.2 256 M-(cis-1-(cyclobutylcarbonyl)2-((2-(2,3-difluorophenyl)-1,3thiazol-4-yl)methyl)pyrrolidin-3-yl)methanesulfonamide from X D J hmm -Lb 456.1 257 M-(cis~1-(cyclobutylcarbonyl)2-((2-(4-fluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)methanesulfonamide h. oh eight 438.1 258 M-(cis-1-(cyclobutylcarbonyl)2-((2-(3,5-difluorophenyl)-1,3thiazol-4-yl)methyl)pyrrolidin-3yl)methanesulfonamide F about 456.1 259 M-(cis-1-(cyclobutylcarbonyl)2-((2-phenyl-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)cyclopropanesulfonamide X 446.2 260 M-(cis-1-isobutyr yl-2-((2-phenyl1,3-thiazol-4yl)methyl)pyrrolide in-3yl)cyclopropanesulfonamide %VX 434.2

- 116 039459

Table 1-27

EXAMPLE IUPAC NAME Structure Additional component MS 261 M-((28.38)-2-(biphenyl-3-ylmethyl)1-(cyclobutylcarbonyl)pyrrolidin-3yl)methanesulfonamide 413.3 262 N-((2S,3S)-1- (cyclobutylcarbonyl)-2-((3’ fluorobiphenyl-3- yl) methyl) pyrrolide in-3 -yl) methanesulfonamide τι Α ΥχΜ ^u K ϊ Ύ 431.2 263 N-((28.38)-2-(biphenyl-3-ylmethyl)1-((3,3difluorocyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide 447.1 264 N-((2S,38)-1-((3,3- difluorocyclobutyl) carbonyl) -2 ((3 '-fluorobiphenyl-3 -yl) methyl) pyrrolidine-3 - yl)methanesulfonamide 465.0 265 N-((28.38)-2-(biphenyl-3-ylmethyl)1 -((1-fluorocyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide Cl 431.2 266 N-((2S,3 8)-2-((3'-fluorobiphenyl -3 -yl)methyl)-1-((1fluorocyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide v 447.1 267 N-((28.38)-2-(biphenyl-3-ylmethyl)1-(cyclobutylcarbonyl)pyrrolidin-3-yl)-1 fluoromethanesulfonamide oh oh 431.2 268 N-((2S,3S)-1- (cyclobutylcarbonyl) -2- ((3 'fluorobiphenyl-3 -yl) methyl) pyrrolidin-3 -yl) -1 - fluoromethanesulfonamide X ^hn 'Vf 449.1 269 X-(cis-1-(cyclobutylcarbonyl)-2((2-phenyl-1,3-thiazol-4yl)methyl)pyrrolide in-3-yl)-1 fluoromethanesulfonamide ( V s Az g n 438.0 270 K- (cis-1 - isobutyr yl-2- ((3 'methylbiphenyl-3 yl) methyl) pyrrolide in-3 yl) methanesulfonamide 0 415.2

- 117039459

Table 1-28

EXAMPLE IUPAC NAME Structure Additional component MS 271 M-(cis-2-((3'-chlorobiphenyl-3 yl)methyl)-1isobutyrylpyrrolidin-3 yl)methanesulfonamide “Ha... G 435.2 272 CG-(cis-1 - isobutyr yl-2-((3' methoxybiphenyl-3 yl)methyl) pyrrolide in-3 yl) methanesulfonamide V 431.0 273 M-(cis-2-((3 '-(difluoromethyl) biphenyl-3 -yl)methyl)-1 isobutyrylpyrrolidin-3 yl)methanesulfonamide 451.2 274 M-(cis-2-(biphenyl-3-ylmethyl)-1((1-methylcyclopropyl)carbonyl)pyrrole idin-3yl)methanesulfonamide % v 413.3 275 M-(cis-2-(biphenyl-3-ylmethyl)-1((2,2-dimethylcyclopropyl)carbonyl)pyrrole idin-3yl)methanesulfonamide ^y ό 427.0 276 M-(cis-1 -(bicyclo[ 1.1.1 ]pent-1 ylcarbonyl)-2-(biphenyl-3ylmethyl)pyrrolide in-3 yl)methanesulfonamide ^.ο y H"-\ 425.0 277 M-(cis-2-(biphenyl-3-ylmethyl)-1(2,2-difluoropropanoyl)pyrrolidin-3yl)methanesulfonamide CV 423.0 278 M-(cis-2-(biphenyl-3-ylmethyl)-1-(2fluoro-2-methylpropanoyl)pyrrolidin-3yl)methanesulfonamide 'V 417.2 279 M-(cis-2-(biphenyl-3-ylmethyl)-1(3,3,3-trifluoro-2methylpropanoyl)pyrrolidin-3yl)methanesulfonamide V, 'V 454.9 280 M-(cis-2-(biphenyl-3-ylmethyl)-1((1-fluorocyclopropyl)carbonyl)pyrrolidin-3yl)methanesulfonamide T MN-\V 417.0

- 118039459

Table 1-29

EXAMPLE IUPAC NAME Structure Additional component MS 281 M-(cis-2-(biphenyl-3-ylmethyl)-1((trans-2-fluorocyclopropyl)carbonyl)pyrrolidin-3yl)methanesulfonamide Λ 417.0 282 M-(cis-2-(biphenyl-3-ylmethyl)-1((cis-2-fluorocyclopropyl)carbonyl)pyrrolidin-3yl)methanesulfonamide BUT 417.0 283 M-(cis-2-(biphenyl-3-ylmethyl)-1((2,2-difluorocyclopropyl)carbonyl)pyrrolidin-3yl)methanesulfonamide R 435.0 284 M-(cis-2-(biphenyl-3-ylmethyl)-1(oxetan-3-ylcarbonyl)pyrrolidin-3yl)methanesulfonamide Wed At ΗΑίγ eight 415.0 285 M-(cis-1-(cyclopropylcarbonyl)-2((2-phenyl-1,3-thiazol-4-yl)methyl) pyrrolidin-3 yl)methanesulfonamide %ϊ 406.0 286 Ethyl-cis-3 -((methylsulfonyl)amino)-2-((2-phenyl-1,3-thiazol-4yl)methyl)pyrrolidine-1 carboxylate ^Ή0 410.1 287 Isopropyl-cis-2-(biphenyl-3 yl(difluoro)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate 465.1 288 M-(cis-2-(biphenyl-3 yl(difluoro)methyl)-1(cyclopropylcarbonyl)piperidin3-yl)methanesulfonamide ο 449.2 289 290 M-(cis-1-acetyl-2-(biphenyl-3 yl(difluoro)methyl)piperide in-3yl)methanesulfonamide Ethyl cis-2-(biphenyl-3 yl(difluoro)methyl)-3((methylsulfonyl)amino)piperidine-1-carboxylate K J a Y hn ^j 0 η O Ρ Υ'ην®' ο 423.0 451.0

- 119 039459

Table 1-30

EXAMPLE IUPAC NAME Structure Additional component MS 291 Ethyl cis-2-((2-fluorobiphenyl-3 yl)methyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate YuE ν y ΗΝ\ 421.0 292 Ethyl-cis-2-((2,3'-difluorobiphenyl3-yl)methyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate 439.2 293 M-(cis-2-((2-fluorobiphenyl-3yl)methyl)-1isobutyrylpyrrolidin-3yl)methanesulfonamide Qi 'ECHE o _n ^F γ ⁷ ni-®; 419.2 294 M-(cis-2-((2,3'-difluorobiphenyl-3 yl)methyl)-1isobutyrylpyrrolidin-3 yl)methanesulfonamide YES O 437.2 295 Ethyl cis-2-((5-fluorobiphenyl-3 yl)methyl)-3-((methylsulfonyl)amino)pyrrolidine-1-carboxylate %.· 421.0 296 Ethyl-cis-2-((3', 5-difluorobiphenyl3-yl)methyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate LT o „ 438.9 297 M-(cis-2-((5-fluorobiphenyl-3yl)methyl)-1 - isobutyrylpyrrolidin-3 yl)methanesulfonamide la o 419.2 298 M-(cis-2-((3',5-difluorobiphenyl-Zyl)methyl)-1isobutyrylpyrrolidin-3 yl)methanesulfonamide .-Sc, L T o „ D'nm 437.2 299 M-(cis-1-(cyclobutylcarbonyl)-2-((5-fluorobiphenyl-3yl)methyl)pyrrolide in-3yl)methanesulfonamide 431.2 300 M- (cis-1 - (cyclobutylcarbonyl) -2- ((3 5 -difluorobiphenyl-3 yl) methyl) pyrrolide in-3 yl) methanesulfonamide 449.2

- 120 039459

Table 1-31

EXAMPLE IUPAC NAME Structure Additional component MS 301 Ethyl cis-2-((6-fluorobiphenyl-3 yl)methyl)-3 -((methylsulfonyl)amino)pyrrolidine-1-carboxylate AH W 421.0 302 Ethyl-cis-2-((3',6-difluorobiphenyl3-yl)methyl)-3((methylsulfonyl)amino) pyrrolidine-1-carboxylate BUT 439.0 303 M- (cis-1 - (cyclobutylcarbonyl) -2- ((6-fluorobiphenyl-3 yl) methyl) pyrrolide in-3 yl) methanesulfonamide BUT 431.2 304 M- (cis-1 - (cyclobutylcarbonyl) -2- ((3 ', 6-difluorobiphenyl-3 yl) methyl) pyrrolide in-3 yl) methanesulfonamide A A 449.2 305 N-((2S,3 S)-2-((3'-fluorobiphenyl-3 yl)methyl)-1-((1-methylcyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide Ή y o 445.3 306 N-((2S,3S)-1 -(bicyclo [1.1.1 ] pent-1 -ylcarbonyl)-2-((3' fluorobiphenyl-3 -yl)methyl) pyrrolidin-3 - yl)methanesulfonamide v 443.3 307 N-((2S,3S)-1 -(bicyclo [1.1.1] pent-1-ylcarbonyl)-2-((3’, 5’ difluorobiphenyl-3 yl)methyl)pyrrolide in-3-yl)methanesulfonamide F ^1A V 460.9 308 N-((2S,3 S)-2-((3'-fluorobiphenyl-3 yl)methyl)-1-((1hydroxycyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide MO 447.0 309 N-((2S,3 S)-2-((3'-fluorobiphenyl-3 yl)methyl)-1 -((1(trifluoromethyl)cyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide lQ) V 'Υ' HN = ₄ 498.9 310 N-((2S,3S)-1- (cyclobutylcarbonyl)-2-((3', 5' difluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)methanesulfonamide F 448.9

- 121 039459

Table 1-32

EXAMPLE IUPAC NAME Structure Additional component MS 311 N-((2S,3 S)-1 -(cyclobutylcarbonyl)2-((3 '-methylbiphenyl-3 -yl)methyl) pyrrolidin-3 -yl) methanesulfonamide Hhi-° _h 427.0 312 N-((2S,3 S)-1 -(cyclobutylcarbonyl)2-((3 '-fluorobiphenyl-3 -yl)methyl) pyrrolidin-3 -yl)-1 methoxymethanesulfonamide ⁰ X LL 461.0 313 N-((2S,3 S)-l-(azetidin-1ylcarbonyl)-2-((3'-fluorobiphenyl-3 yl)methyl) pyrrolidin-3 yl)methanesulfonamide Yhn ³ _h o# o 432.2 314 N-((2S,3 S)-2-((3'-fluorobiphenyl-3 yl)methyl)-1- ((1-methoxycyclobutyl)carbonyl)pyrrolidin-3 yl)methanesulfonamide Al# οξύ 461.1 315 M-(cis~1-(cyclobutylcarbonyl)-2((2-(3,5-difluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)ethanesulfonamide 470.1 316 N-(cis-2-((2-(3,5-difluorophenyl)-1,3thiazol-4-yl)methyl)-1-((1methylcyclobutyl)carbonyl)pyrrolidin-3-yl)ethanesulfonamide 484.1 317 N-(cis-2-((2-(3,5-difluorophenyl)-1,3thiazol-4-yl)methyl)-1-((1hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl)ethanesulfonamide 486.1 318 N-(hhc- 1 -(bicyclo[ 1.1.1 ]pent-1 ylcarbonyl)-2-((2-(3,5 difluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)ethanesulfonamide about/ 0^ * γΧ b- 482.1 319 M-(cis-1-(cyclobutylcarbonyl)-2((2-phenyl-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)methanesulfonamide 420.2 320 N-((2 S, 3 S)-1 -(cyclobutylcarbonyl)2-((2-(3-fluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)methanesulfonamide / about 438.2

Table 1-33

EXAMPLE IUPAC NAME Structure Additional component MS 321 N-((2S,3S)-1- (cyclobutylcarbonyl)-2-((2phenyl-1,3-thiazol-4yl)methyl)pyrrolidine-3 - A™ V 446.1

- 122039459

yl)cyclopropanesulfonamide (optical isomer) 322 N-(pnc-2-((2-(3,5-d ifluorophenyl)1,3-thiazol-4-yl)methyl)-1-((1methylcyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide F V*0.0 468.0 323 N-(phc-2-((2-(3,5-d-ifluorophenyl)1,3-thiazol-4-yl)methyl)-1-((1hydroxycyclobutyl)carbonyl)pyrrolide in-3yl)methanesulfonamide h.. "to 469.9 324 X-((28.38)-2-(biphenyl-3ylmethyl)-1 cyclobutylcarbonyl) pyrrolidin-3 -yl)-1 methoxymethanesulfonamide V <' ^ΰ 0 / 443.1 325 X-(cis-1- (cyclobutylcarbonyl)-2-((5 methyl-2-phenyl-1,3-thiazol-4yl)methyl)pyrrolidin-3yl)methanesulfonamide well and 434.1 326 N-(pnc-1-((1 hydroxycyclobutyl)carbonyl)-2-((5-methyl-2-phenyl1,3-thiazol-4-yl)methyl)pyrrolide in-3yl)methanesulfonamide //ν 0¾ 450.1 327 X-(cis-1-(azetidin-1 ylcarbonyl)-2-((5-methyl-2-phenyl-1,3-thiazol-4yl)methyl)pyrrolidin-3-yl)methanesulfonamide 0. < 0 4 f 435.2 328 N-((2S,3 8)-2-((3'-fluorobiphenyl3 -yl)methyl)-1 -(oxetan-2ylcarbonyl)pyrrolidin-3yl)methanesulfonamide with 433.1 329 18[-(cis'2-((6-(3-fluorophenyl) pyridin-2-yl)methyl)-1isobutyrylpyrrolidin-3yl)methanesulfonamide Chnn-=° V 420.2 330 X-(cis-1-(2,2- dimethylpropanoyl)-2-((6-(3 fluorophenyl)pyridine-2- yl)methyl)pyrrolidin-3 yl)methanesulfonamide J'. True Λ 0 434.2

- 123 039459

Table 1-34

EXAMPLE IUPAC NAME Structure Additional component MS 331 X-(cis-1-(cyclopentylcarbonyl)-2((6-(3-fluorophenyl)pyridin-2yl)methyl)pyrrolide in-3yl)methanesulfonamide J j) o o 446.2 332 M-(cis-1-(cyclopropylcarbonyl)-2((6-(3-fluorophenyl)pyridin-2yl)methyl)pyrrolide in-3yl)methanesulfonamide nine. Yes 418.2 333 M-(cis-1 -(azetidin-1 -ylcarbonyl)-2((6-(3-fluorophenyl) pyridin-2-yl)methyl)pyrrolidin-3yl)methanesulfonamide No. J p hh-s; Yes 433.2 334 M-(cis-1-(cyclobutylcarbonyl)-2-((6-(3-fluorophenyl)pyridin-2yl)methyl)pyrrolide in-3yl)methanesulfonamide £ HM S o 432.2 335 M-(cis-2-((6-(3-fluorophenyl)pyridin2-yl)methyl) -1-((1-methyl cyclobutyl) carbonyl) pyrrolidin-3 yl) methanesulfonamide ' *0 v £ HM' x Yes about 446.2 336 M-(cis-1 -(bicyclo[ 1.1.1 ]pent-1 ylcarbonyl)-2-((6-(3 fluorophenyl)pyridin-2yl)methyl)pyrrolide in-3yl)methanesulfonamide ^Uz 'o 444.2 337 M-(cis-2-((6-(3-fluorophenyl) pyridin-2-yl)methyl)-1-((1 methylcyclopropyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide nJ nn Ch Yes 432.2 338 339 M-(cis~2-((6-(3-fluorophenyl) pyridin-2-yl)methyl)-1-((1hydroxycyclobutyl)carbonyl) pyrrolidin-3-yl) methanesulfonamide M-((28.38)-2-((2-(3,5-difluorophenyl)1,3-thiazol-4-yl)methyl)-1-((1- hydroxycyclobutyl)carbonyl)pyrrolidin-3-yl)methanesulfonamide Ρ ^ΗΝ χ 'S ^: 448.2 469.9 340 N-((2 S, 3 S)-1 -(azetidin-1 ylcarbonyl)-2-((2-(3,5-d ifluorophenyl)1,3-thiazol-4-yl)methyl)pyrrolidin-3 yl )methanesulfonamide 0 454.9

- 124 039459

Table 1-35

EXAMPLE IUPAC NAME Structure Additional component MS 341 N-((2S,3 S)-1 -((3-fluoroazetidin-1 yl)carbonyl)-2-((3'-fluorobiphenyl-3 yl)methyl)pyrrolide in-3 yl)methanesulfonamide ^F QV HN \ V 450.2 342 N-((2S,3 S)-1 -((3,3-difluoroazetide in1 -yl)carbonyl)-2-((3'-fluorobiphenyl3 -yl)methyl)pyrrolidin-3yl)methanesulfonamide // 468.1 343 N-((2S,3 8)-2-((3'-fluorobiphenyl-3 yl)methyl)-1 -((2-methylazetidin-1 yl)carbonyl)pyrrolide in-3yl)methanesulfonamide ,jOa 446.2 344 N-((2S,3S)-2-((3',5'- difluorobiphenyl-3 -yl)methyl)-1-((1hydroxycyclobutyl)carbonyl)pyrrolidine-3 - yl)methanesulfonamide X ns 17 465.1 345 N-((2S,3 S)-l-(azetidin-1ylcarbonyl)-2-((3’, 5’ difluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)methanesulfonamide F v or 450.2 346 N-((2S,38)-1-((1- cyanocyclobutyl)carbonyl)-2-((3 ’- fluorobiphenyl-3- yl)methyl)pyrrolide in-3 yl)methanesulfonamide N L J X 456.3 347 M-((28.38)-1-(5-azaspiro[2.3]hex-5ylcarbonyl)-2-((3'-fluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)methanesulfonamide nV 9 458.3 348 N-((2S,3S)-l-(azetidin-1ylcarbonyl)-2-((2-(3,5 difluorophenyl)-1,3-thiazol-4yl)methyl)pyrrolide in-3yl)ethanesulfonamide O.) Ik 471.2 349 N-((2S,3 8)-2-((2,3'-difluorobiphenyl3 -yl)methyl)-1-(2,2dimethylpropanoyl)pyrrolidin-3yl)methanesulfonamide V 451.1 350 N-((2 S, 3 S)-1 - (cyclobutylcarbonyl) 2- ((2,3 '-difluorobiphenyl-3 yl) methyl) pyrrolide in-3 yl) methanesulfonamide JO V UN ³ ,. 449.1

- 125 039459

Table 1-36

EXAMPLE IUPAC NAME Structure Additional component MS 351 N-((2S,3 8)-2-((2,3'-difluorobiphenyl3 -yl)methyl)-1-((1methylcyclopropyl)carbonyl)pyrrolidin-3yl)methanesulfonamide 449.1 352 N-((2S,3 S)-1 -(azetidin-1 ylcarbonyl)-2-((2,3 ' difluorobiphenyl-3 -yl) methyl) pyrrolidin-3 yl) methanesulfonamide ^F 0^5 450.1

Table 1-37

EXAMPLE IUPAC NAME Structure Additional component MS 353 N-((2 S, 3 S)-1 -(azetidin-1 ylcarbonyl)-2-(biphenyl-3 ylmethyl) pyrrolide in-3 yl) methanesulfonamide about. / e>4 414.2 354 (2S,3 8)-2-((3'-fluorobiphenyl-3yl)methyl)-M, N-dimethyl-3- ((methylsulfonyl)amino) pyrrolidine-1-carboxamide _f j0u MN A 420.2 355 N-((2S,3S)-1- (cyclobutylcarbonyl)-2-((2,3', 5 trifluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)methanesulfonamide 467.2 356 N-((2 S, 3 S)-1 -(azetidin-1 ylcarbonyl)-2-((2,3 ', 5 trifluorobiphenyl-3 yl) methyl) pyrrolide in-3 yl) methanesulfonamide about 468.2 357 N-((2S,3S)-1- (cyclobutylcarbonyl) -2- ((2,3 ', 5 trifluorobiphenyl-3 yl) methyl) pyrrolide in-3 - yl) ethanesulfonamide Xj v O 481.2 358 N-((2 S, 3 S)-1 -(azetidin-1 ylcarbonyl)-2-((2,3', 5 trifluorobiphenyl-3 -yl)methyl) pyrrolidin-3 -yl)ethanesulfonamide F'U HN a 482.2 359 Diamid N'-((2S,3S)-1- (cyclobutylcarbonyl)-2-((2,3 ', 5 trifluorobiphenyl-3 - yl)methyl)pyrrolidin-3-yl)-N-dimethylsulfuric acid 'Hd G 496.2 360 Diamid N '-((2 S, 3 S) -1 - (azetidin-1 ylcarbonyl) -2- ((2,3 ', 5 trifluorobiphenyl-3 - yl)methyl)pyrrolidin-3-yl)-N-dimethylsulfuric acid A·?u_ 497.1 361 (2S,3S)-N-3thh-2-((3'fluorobiphenyl-3-yl)methyl)-Mmethyl-3 -((methylsulfonyl)amino)pyrrole idine-1-carboxamide HN'\ 434.2

- 126039459

362 N-((2S,3 S)-1 -(azetidin-1 ylcarbonyl)-2-((3’, 5’ difluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)ethanesulfonamide 464.2

Table 1-38

EXAMPLE IUPAC NAME Structure Additional component MS 363 N-((2S,3 S)-1 -(azetidin-1 ylcarbonyl)-2-((3'-fluorobiphenyl3 -yl)methyl)pyrrolidin-3yl)ethanesulfonamide %V 446.2 364 N-((2S,3 S)-1 -(azetidin-1 ylcarbonyl)-2-(biphenyl-3 ylmethyl) pyrrolide in-3 yl) ethanesulfonamide oX 0 428.3 365 (28.38)-3-((ethylsulfonyl)amino)-2-((3'-fluorobiphenyl-3 yl)methyl)-A,Adimethylpyrrolidine-1 carboxamide 434.2 366 (2S,3 8)-2-((3', 5'-difluorobiphenyl3 -yl)methyl)-N, N-d and methyl-3((methylsulfonyl)amino)pyrrolidine-1-carboxamide 438.2 367 (2S,3 8)-2-((3', 5'-difluorobiphenyl3-yl)methyl)-3- ((ethylsulfonyl)amino)-A,Adimethylpyrrolidine-1 carboxamide V- 452.1 368 (2S,3 8)-2-((3'-fluorobiphenyl-3yl)methyl)-N-isopropyl-N-methyl- 3 -((methyl sulfonyl) amino)pyrrolidine-1-carboxamide $5 448.2 369 (2S,3 8)-2-((3', 5'-difluorobiphenyl3 -yl) methyl)-M-ethyl-3 ((ethylsulfonyl) amino)-M-methyl pyrrole ide in-1 carboxamide Yr 466.2 370 (2S,3 8)-2-((2,3'-difluorobiphenyl-3yl)methyl)-H N-dimethyl-3- ((methylsulfonyl)amino) pyrrolidine-1-carboxamide 'yao v R^G HH \ 438.2 371 (2S,3 8)-2-((2,3 '-difluorobiphenyl-3 - yl)methyl)-X-ethyl-X-methyl-3- ((methylsulfonyl)amino) pyrrolidine-1-carboxamide BUT 452.2 372 N-((2S,3 S)-1 -(azetidin-1 ylcarbonyl)-2-((2,3' difluorobiphenyl-3 yl)methyl) pyrrolide in-3 yl) ethanesulfonamide 'Yahch. 464.2

- 127039459

Table 1-39

EXAMPLE IUPAC NAME Structure Additional component MS (2S,3 8)-2-((2,3 '-difluorobiphenyl-3- yl)methyl)-3- ^F cO % ° 373 ((ethylsulfonyl)ημπηο)-Ν,Ν- nm ^s ;__ 452.2 dimethylpyrrolidine-1 - γ carboxamide O N-((2S,3 S)-1 -(azetidine-1 - ylcarbonyl)-2-((2,3 '- JO 374 difluorobiphenyl-3 -yl)methyl) SL x 476.1 pyrrolidin-3-yl) O/ cyclopropanesulfonamide (2S,3S)-3- ((cyclopropylsulfonyl)amino)- 375 2-((2,3 '-difluorobiphenyl-3 - JO 464.2 yl)methyl)-M,M- dimethylpyrrolidine-1 carboxamide about Diamide M'-((28.38)-1-(azetidin-1ylcarbonyl)-2-((2.3'- 376 difluorobiphenyl-3 - 'U 479.2 yl)methyl)pyrrolidin-3-yl)-HMdimethylsulfuric acid γ' (2S,3 8)-2-((2,3 '-difluorobiphenyl-3 - yl)methyl)-3- G 1] ° o 377 ((dimethylsulfamoyl)amino)-H N- ~ .Up to X ¹ ι НН 467.2 dimethylpyrrolidine-1 carboxamide 'f N-((2 S, 3 S)-1 -(azetidine-1 - F ylcarbonyl)-2-((2,3 ',5 '- ⁰ a 378 trifluorobiphenyl-3 -yl)methyl) 468.2 pyrrolidine-3 - C/R yl)methanesulfonamide & (2S,3S)-N, N-dimethyl-3- ((methylsulfonyl)amino)-2- ^g P o 379 ((2,3 ', 5 '-trifluorobiphenyl-3 - '0-° 456.2 yl)methyl)pyrrolidine-1 - carboxamide N-((2S,3 S)-l-(azetidine-1- ylcarbonyl)-2-((3 '-chloro-2- %." 380 fluorobiphenyl-3 -yl)methyl) F MI 466.1 pyrrolidine-3 - yl)methanesulfonamide with (2S,3 8)-2-((3'-chloro-2- 381 fluorobiphenyl-3-yl)methyl)-^H- 454.1 dimethyl-3 -((methylsulfonyl) \ |u*_y amino)pyrrolidine-1-carboxamide 'ί (2S,3 8)-2-((3 ', 5 '-difluorobiphenyl-3 - F Ο 382 yl)methyl)-H-methoxy^-methyl-3- 454.2 ((methylsulfonyl)amino) '° pyrrolidine-1-carboxamide

- 128 039459

Table 1-40

EXAMPLE IUPAC NAME Structure Additional component MS 383 (28.38)-2-((2-fluorobiphenyl-3yl)methyl)-H N-dimethyl-3((methylsulfonyl)amino)pyrrolidine-1-carboxamide X 420.2 384 N-((2S,3 S)-1 -(azetidin-1 ylcarbonyl)-2-((2fluorobiphenyl-3 -yl)methyl) pyrrolidin-3 yl)methanesulfonamide cm With 432.1 385 (28.38)-2-(biphenyl-3ylmethyl)-3- ((ethylsulfonyl)amino)-U Ndimethylpyrrolidine-1 carboxamide cm MH°M 416.2 386 N-((2S,3 8)-2-((2,3 difluorobiphenyl-3 -yl)methyl)1 -((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide 465.2 387 N-((2S,3 8)-2-((2,3'difluorobiphenyl-3 -yl)methyl)1 -(2-hydroxy-2methylpropanoyl)pyrrolidin3 -yl)methanesulfonamide Μ V НН ^s _s 453.2 388 N-((2S,3 8)-2-((2,3'difluorobiphenyl-3 -yl)methyl)1 -((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3yl)ethanesulfonamide 479.2 389 N-((2S,3 8)-2-((2,3'difluorobiphenyl-3 -yl)methyl)1-(2-hydroxy-2methylpropanoyl)pyrrolidin-3yl)ethanesulfonamide 'Mind 465.1 390 N-((2S, 38)-2-((2,3'difluorobiphenyl-3-yl)methyl)1 -((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3yl)cyclopropanesulfonamide _f j0m XV ^h Y HN Μ ν Όέ 491.2 391 N-((2S,3 8)-2-((2,3difluorobiphenyl-3 -yl)methyl)1 -(2-hydroxy-2methylpropanoyl)pyrrolidin-3yl)cyclopropanesulfonamide Cha 477.2 392 Diamid N'-((2S, 38)-2-((2,3'- difluorobiphenyl-3 -yl)methyl)1 -((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3 -yl)N, N-dimethylsulfuric acid 494.2

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Table 1-41

EXAMPLE IU PACK NAME Structure Additional component MS 393 N'-((2S,3S)-2-((2 _r 3'difluorobiphenyl-3 -yl)methyl)1 -(2-hydroxy-2methylpropanoyl)pyrrolidin3 -yl)-X,X-dimethylsulfuric acid diamide Ύρ ν Υ' 482.2 394 N-((2S,38)-1-((1hydroxycyclobutyl)carbonyl)-2-((2,3’, 5’ trifluorobiphenyl-3-yl)methyl) pyrrolidin-3-yl)methanesulfonamide Υ ν ΗΝ-»ς γ 481.1 395 N-((2S,3S)-l-(2-rHflpoKCH-2methylpropanoyl)-2-((2,3’, 5’ trifluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)methanesulfonamide ώγ χο ν Υ 469.1 396 N-((2S,3 8)-2-((3'-chloro-2fluorobiphenyl-3 -yl)methyl)-1 ((1-hydroxycyclobutyl)carbonyl)pyrrolidin-3yl)methanesulfonamide Ύ ο to and AY ""Ο 481.1 397 N-((2S,3 8)-2-((3'-chloro-2fluorobiphenyl-3 -yl)methyl)-1 (2-hydroxy-2methylpropanoyl)pyrrolidin3 -yl)methanesulfonamide οΥΥ ΥΥγ 469.2 398 (28.38)-3-((ethylsulfonyl)amino)-2-((2-fluorobiphenyl-3 yl)methyl)^^dimethylpyrrolidine-1 carboxamide ©Υ YV Α 434.2 399 (28.38)-3-((ethylsulfonyl) βμηηο)-Ν, M-dimethyl-2- ((2,3', 5'-trifluorobiphenyl-3 yl)methyl)pyrrolidine-1 carboxamide Y.. 470.2 400 (28.38)-2-(biphenyl-3- yl methyl l) -N, N -dimethyl-3 - ((methylsulfonyl)amino) pyrrolidine-1-carboxamide Y' 402.2 401 (2S,3 8) -2- ((2,3 'difluorobiphenyl-3 -yl) methyl) -3 - ((ethylsulfonyl) amino) -Ν-Μετοκοπ-Νmethylpyrrolidine-1 carboxamide γ 468.1 402 1H-((28.38)-1-isobutyryl-2((2,3',5'-trifluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)methanesulfonamide Α V Υ ο 455.2

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Table 1-42

EXAMPLE IUPAC NAME Structure Additional component MS 403 (28.38)-M-methoxy-M-methyl-3((methylsulfonyl)amino)-2((2,3', 5'-trifluorobiphenyl-3 yl)methyl)pyrrolidine-1 carboxamide F Ά 472.2 404 N-((2S,3 8)-2-((3',5'- difluorobiphenyl-3 -yl)methyl)-1 -(2- hydroxy-2-methylpropanoyl) pyrrolidin-3 -yl) ethanesulfonamide F 465.1 405 N-((2S,3S)-2-((3',5'difluorobiphenyl-3 -yl)methyl)-1(oxetan-2ylcarbonyl)pyrrolide in-3yl)ethanesulfonamide γ^ 463.1 406 (2S,38)-2-((3'-fluorobiphenyl-3yl)methyl)^-methoxy^-methyl-3((methylsulfonyl)amino) pyrrolidine-1-carboxamide _F CX y V γ# ΐ> Ό ¹ Ίί Ο 436.2 407 (28.38)-2-(biphenyl-3-ylmethyl)-3- ((ethylsulfonyl) amino)-M-methoxy-M- methylpyrrolidine-1-carboxamide Οχ'° 432.2 408 (28.38)-2-((2-fluorobiphenyl-3yl)methyl)-18F-methoxy-18F-methyl-3((methylsulfonyl)amino)pyrrolidine-1-carboxamide Οχ g ⁴ #™ γ -Ό- Ίΐ 436.2 409 (28.38)-2-(biphenyl-3-ylmethyl)-Mmethoxy-M-methyl-3((methylsulfonyl)amino)pyrrolidin-1-carboxamide A 418.2 410 411 Ν-((28.38)-2-((2-φτορ-3'methylbiphenyl-3 -yl)methyl)-1 -(2hydroxy-2-methylpropanoyl)pyrrolidin-3yl)methanesulfonamide N-((2S, 38)-2-((2,3'-difluoro-5'methylbiphenyl-3 -yl)methyl)-1 -(2hydroxy-2methylpropanoyl)pyrrolidin-3yl)methanesulfonamide αγγΛ Ο F ax? χ 449.2 467.2 412 N-((2S,3 8)-2-((3'-fluorobiphenyl-3 yl)methyl)-1 -(2-methoxy-2methylpropanoyl)pyrrolidin-3yl)methanesulfonamide nm \ 449.2

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Table 1-43

EXAMPLE IUPAC NAME Structure Additional component MS 413 M-((28.38)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,2’, 3’ trifluorobiphenyl-3-yl)methyl) pyrrolidin-3-yl)methanesulfonamide m/© v F 471.2 414 N-((2S, 38)-2-((2,2'-difluorobiphenyl3 -yl)methyl)-1 -(2-hydroxy-2methylpropanoyl)pyrrolidin-3yl)methanesulfonamide W© v 453.2 415 1-Φτορ-Ν-((28.38)-2-((3’fluorobiphenyl-3-yl)methyl)-1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3yl)methanesulfonamide ( O And 451.0 416 1,1-Difluoro-X-((28.3 8)-2-((3 'fluorobiphenyl-3 -yl)methyl)-1 -(2hydroxy-2- methylpropanoyl)pyrrolidin-3 yl)methanesulfonamide '4- 468.9 417 N-((2S,3 8)-2-((2,3'-difluorobiphenyl3 -yl)methyl)-1 -(2-hydroxy-2methylpropanoyl)pyrrolidin-3 -yl)-1 fluoromethanesulfonamide F V 469.1 418 N-((2S,3 8)-2-((2,3'-difluorobiphenyl3 -yl)methyl)-1 -(2-hydroxy-2methylpropanoyl)pyrrolidin-3 -yl)-1,1difluoromethanesulfonamide 'H· 487.0 419 N-((2S,3 8)-2-((2,3'-difluorobiphenyl3 -yl)methyl)-1 -(2-hydroxy-2methylpropanoyl)pyrrolidin-3 -yl)-1 methoxymethanesulfonamide 483.2 420 M-((28.38)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3’,5’trifluorobiphenyl-3-yl)methyl) pyrrolidin-3-yl)-1 methoxymethanesulfonamide F V 499.1 421 N-((2S,3 8)-2-((3',5'difluorobiphenyl-3 -yl)methyl)-1 -(2hydroxy-2-methylpropanoyl)pyrrolidin-3 -yl)-1 fluoromethanesulfonamide F MN 469.1 422 N-((2S,3 8)-2-((3',5'difluorobiphenyl-3 -yl)methyl)-1 -(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-1,1difluoromethanesulfonamide 487.0

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Table 1-44

EXAMPLE 423 424 425 IUPAC NAME 1 -Φτορ-Ν-((28.3 S)-1 -(2-hydroxy-2methylpropanoyl)-2-((2.3', 5' trifluorobiphenyl-3 yl)methyl)pyrrolide in-3-yl)methanesulf onamid 1,1-Difluoro-X-((28.3 S)-1 -(2hydroxy-2-methylpropanoyl)-2((2,3', 5'-trifluorobiphenyl-3 yl)methyl) pyrrolide in-3 yl) methanesulfonamide N-((2 S, 3 8)-2-((2 ',3 '-d iftorbiphenyl3 -yl)methyl)-1 -(2-hydroxy-2methylpropanoyl) pyrrolidin-3-yl)ethanesulfonamide Structure F ^F ν Ύ ύ Additional component MS 487.1 505.1 467.2 426 N-((2S,3 8)-2-((3 '-chlorobiphenyl-3 yl)methyl)-1 -(2-hydroxy-2methylpropanoyl) pyrrolidin-3-yl)ethanesulfonamide “Ya. 465.2 427 M-((28.38)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,2', 5' trifluorobiphenyl-3-yl)methyl) pyrrolidin-3-yl)methanesulfonamide F-% 471.2 428 N-((2S,3 8)-2-((3'-chloro-2,5'difluorobiphenyl-3 -yl)methyl)-1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3yl)methanesulfonamide o, / Wx A*s ΰ 484.9 429 N-((2S,3 8)-2-((3 '-fluorobiphenyl-3 yl)methyl)-1 -(2-hydroxy-2methylpropanoyl) pyrrolidin-3-yl)ethanesulfonamide v 447.0 430 M-((28.38)-2-((2-fluorobiphenyl-3yl)methyl)-1-(2-hydroxy-2methylpropanoyl)pyrrolidin-3yl)ethanesulfonamide 449.2 431 N-((2S,3 8)-2-((3'-chloro-2fluorobiphenyl-3 -yl)methyl)-1 -(2hydroxy-2-methylpropanoyl)pyrrolidin-3 -yl)ethanesulfonamide W 483.1 432 Ν-((28.38)-2-((2-φτορ-3'methylbiphenyl-3 -yl)methyl)-1 -(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide 463.2

Table 1-45

EXAMPLE IUPAC NAME Structure Additional component MS 433 M-((28.38)-2-((2-fluorobiphenyl-3yl)methyl)-1-(2-hydroxy-2methylpropanoyl)pyrrolidin-3yl)methanesulfonamide Oh 435.2

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434 M-((28.38)-1-(2-hydroxy-2-methylpropanoyl)-2-((2.2' 5' trifluorobiphenyl-3 -yl)methyl) pyrrolidin-3 -yl)ethanesulfonamide v 485.2 435 M-((28.38)-1-(2-hydroxy-2-methylpropanoyl)-2-((2.3', 5' trifluorobiphenyl-3-yl)methyl) pyrrolidin-3-yl)ethanesulfonamide F Λ YU 483.1 436 M-((28.38)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,2’, 3’ trifluorobiphenyl-3-yl)methyl) pyrrolidin-3-yl)ethanesulfonamide 485.2 437 N-((2S,3 8)-2-((3'-chloro-2,5'difluorobiphenyl-3-yl)methyl)-1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide F A ^α το 499.0 438 N-((2S,38)-2-((2,3'-difluoro-5'methylbiphenyl-3 -yl)methyl)-1 -(2hydroxy-2methylpropanoyl)pyrrolidin-3yl)ethanesulfonamide 481.2 439 M-((28.38)-1-(2-hydroxy-2-methylpropanoyl)-2-((2.3’, 5’ trifluorobiphenyl-3-yl)methyl) pyrrolidin-3-yl) cyclopropanesulfonamide G v v _\M—/ 495.1 440 M-((28.38)-2-((2-fluorobiphenyl-3yl)methyl)-1-(2-hydroxy-2methylpropanoyl)pyrrolidin-3yl)cyclopropanesulfonamide 461.2

Table 1-46

EXAMPLE IUPAC NAME Structure Additional component MS 441 М-{(28,38)-1-(oxetane-2-carbonyl)2-[(2,3’,5’-trifluoro [ 1, G -biphenyl]-3 -yl)methyl] pyrrolidin-3yl } methanesulfonamide %... 469.1

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442 M-[(28.38)-2-[(2-fluoro[1,G-biphenyl]3-yl)methyl]-1-(oxetan-2carbonyl)pyrrolidin-3yl]methanesulfonamide Sda And' '4 yes 433.2 443 N-{(2S,3S)-1-(azetidine-1-carbonyl)2-[(3-benzylphenyl)methyl]pyrrolidin-3yl } ethanesulfonamide O 442.3 444 N-{cis-1-(azetidine-1-carbonyl)-2[(dibenzo[b,<1]furan-2-yl)methyl]pyrrolidin-3yl}methanesulfonamide HZ °··? Yes 428.3 445 N-{cis-1-(azetidine-1-carbonyl)-2[(3-phenoxyphenyl)methyl]pyrrolidin-3yl}ethanesulfonamide yes oh 444.2 446 N-{cis-1-(cyclobutanecarbonyl)-2[(3-phenoxyphenyl)methyl]pyrrolidin-3-yl}ethanesulfonamide d) yes 443.2 447 M-[cis-1 -(azetidine-1 carbonyl)-2{[3 -(propan-2-yl)-1-benzofuran-5 yl] methyl } pyrrolidin-3 yl] methanesulfonamide give ν op 420.2 448 N-{cis-1-(azetidine-1-carbonyl)-2[(4-phenoxyphenyl)methyl]pyrrolidin-3yl }methanesulfonamide A V yes o 430.2 449 1,1,1 -Trifluoro-N- { (2S,3 S) -1 - (2hydroxy-2-methylpropanoyl) -2 [(2,3 ', 5' -trifluoro [ 1, G-biphenyl] -3 yl )methyl]pyrrolidin-3 yl }methanesulfonamide F _oh yeah 523.0 450 N-[(2S,3 S)-2-[(2,3 '-difluoro [ 1, G-biphenyl] -3 -yl)methyl] -1- (2hydroxy-2-methylpropanoyl) pyrrolidin-3 -yl] -1 - fluorine cyclopropane-1-sulfonamide Yes 497.2

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Table 1-47

EXAMPLE IUPAC NAME Structure Additional component MS (2S,3 S)-N-3thh-2-[(3 '-fluorine 451 [ 1, G-biphenyl] -3 -yl)methyl] -3 - about a 420 1 [(methanesulfonyl)amino] V pyrrolidine-1-carboxamide -4 N-[(2S,3 S)-2-[(2,3 '-difluoro [ 1, G-biphenyl] -3 -yl)methyl] -1-(2- T Ί V 452 hydroxy-2-methylpropanoyl) F'Y UN ^s y. 485.2 pyrrolidin-3 -yl]-1 -fluoroethane-1 - V' sulfonamide Diamide N'-{(2S,ЗS)-l-(azetidine-l- carbonyl)-2- [(3-bromo-2- 453 fluorophenyl)methyl] 463.1 pyrrolidin-3 -yl } -Ν,Ν- dimethylsulfuric acid Q M-[(28.38)-2-[(3',5'-difluoro[1,G- F biphenyl]-3 -yl)methyl]-1 -(1 -methyl- 454 1Н-pyrazole-3- 489.2 carbonyl)pyrrolidine-3 - yl]ethanesulfonamide $ N-[(2S,3S)-2-[(3',5'-difluoro BUT. 4SS [ 1, G-biphenyl] -3 -yl)methyl] -1 - ' YH - 47S9 TJ J (furan-2-carbonyl) pyrrolidine-3 - m / -',Z. yl]ethanesulfonamide N-{(2S,3 S)-l -(azetidine-1-carbonyl)- 456 2-[(2-fluoro[ 1,1 '-biphenyl]-3 - -o hn ®^ 446 0 yl)methyl]pyrrolidin-3 -yl } ethanesulfonamide N-{ (2S,3 S)-1 -(3-hydroxy-2,2- dimethylpropanoyl)-2-[(2.3', 5'- 457 trifluoro [ 1, G-biphenyl] -3 -yl)methyl] o o 484.9 pyrrolidine-3 - yl] methanesulfonamide M-[(28.38)-2-[(3',5'-difluoro[1,G- BUT- 458 biphenyl]-3 -yl)methyl] -1 -(1H- ^g w 447 2 imidazol-2-yl) pyrrolidine-3 - yl]ethanesulfonamide N-{ (2S,3 S) -1 - (azetidine-1 -carbonyl) - -- ⁰ % about 45Q 2-((3 '-fluoro[ 1,1 '-biphenyl]-3 - 450 9 At yl)methyl] pyrrolidin-3 -yl] -1 - fluoromethanesulfonamide N-((2S,3 S)-1 -(azetidine-1 -carbonyl)- 460 2-[([ 1, G-biphenyl] -3 - O 432 2 yl)methyl] pyrrolidin-3 -yl)-1 - fluoromethanesulfonamide O

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Table 1-48

EXAMPLE IUPAC NAME Structure Additional component MS 461 N-[(2S,3S)-2-[(3',5'-difluoro [ 1, G-biphenyl] -3 -yl)methyl] -1 - (1 methyl-1 H-imide azol-2 yl) pyrrolidin-3 yl] ethanesulfonamide 461.2 462 N-((2S,3 S)-1 -(azetidine-1-carbonyl)2-[(3’-fluoro[1,1’-biphenyl]-3 yl)methyl] pyrrolidin-3-yl] cyclopropanesulfonamide O'S Ha 458.2 463 N-((2S,3 S)-1 -(azetidine-1-carbonyl)2-[([ 1,1-biphenyl]-3 yl)methyl] pyrrolidin-3 -yl } cyclopropanesulfonamide Cha O 440.2 464 N-((2S,3S)-1-[1- (hydroxymethyl) cyclopropan-1 carbonyl] -2- [(2,3 ', 5 '-trifluoro [ 1, G biphenyl]-3-yl) methyl] pyrrolidin3 -yl } methanesulfonamide g A. 483.1 465 T4-((28.38)-1-(1H-imidazol-2-yl)-2[(2,3', 5'-trifluoro [ 1, G-biphenyl] -3 yl)methyl] pyrrolidin-3 yl } ethanesulf onamide 'H-A .A 465.2 466 N-((2S,3 S)-1 -(azetidine-1-carbonyl)2-[(2-fluoro[1,1 '-biphenyl]-3 yl)methyl] pyrrolidin-3 -yl)-1 fluoromethanesulfonamide $ Ύ ζ-Γ '—' С° ΊΙ 450.2 467 N-((2S,3 S)-1 -(azetidine-1-carbonyl)2-[(2,3'-difluoro[1,G-biphenyl]-3yl)methyl] pyrrolidin-3 -yl] -1 fluoromethanesulfonamide οΥ ο·” _Λ ίΌ AZn $ U. 468.2 468 M-[(28.38)-2-[(3',5'-difluoro[1,Hbiphenyl]-3-yl)methyl]-1-(1-ethyl-1nimidazol-2-yl)pyrrolidin-3yl ]ethanesulfonamide 4 475.3 469 N-((2S,3S)-1-[1- (hydroxymethyl) cyclobutan-1 carbonyl] -2- [(2,3 ', 5 ' - trifluoro [ 1, G biphenyl] -3 -yl) methyl] pyrrolide in3 -yl } methanesulfonamide %,. O H-/HoASf 497.2 470 M-((28.38)-1-(6-chloropyridazin-3yl)-2-[(3’, 5’-difluoro [1, G-biphenyl] 3-yl)methyl] pyrrolidin-3-yl} ethanesulfonamide f at 493.1

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Table 1-49

EXAMPLE IU PACK NAME Structure Additional component MS 471 N-[(2S,3 S)-2-[([ 1, G-biphenyl]-3yl)methyl]-1-(cyclobutanecarbonyl)pyrrolidin-3-yl]ethanesulfonamide He ν M O 427.3 472 X-[(28.38)-2-[(3',5'-difluoro[1,G- biphenyl]-3-yl)methyl]-1-(6- methyl pyride azin-3-yl) pyrrolidine- 3-yl]ethanesulfonamide 473.2 473 N-[(2S,3S)-2-[(3',5'-difluoro [ 1, G-biphenyl] -3 -yl)methyl] -1 (pyride azin-3 -yl) pyrrolide in-3 yl] ethanesulfonamide Ό 459.1 474 (28.38)-3-[(ethanesulfonyl)amino]-2-[(3'-fluoro[1,G-biphenyl]-3yl)methyl]-M-methoxy-Mmethylpyrrolidine-1-carboxamide nJ v HN ³ ^ 450.2 475 (2S,3S)-3- [(dimethylsulfamoyl)amino]-2-[(2fluoro[ 1, G-biphenyl]-3 -yl)methyl]-N, N-dimethylpyrrolidine-1 carboxamide cm t N 449.2 476 477 478 479 (2S,3S)-3- [(dimethylsulfamoyl)amino] -N, M-dimethyl-2-[(2,3',5'trifluoro [ 1, G-biphenyl] -3 yl)methyl] pyrrolidine-1 carboxamide (28.38)-2-[(3',5'-difluoro [ 1, G-biphenyl] -3 -yl)methyl] -3 [(ethanesulfonyl)amino]-M-methoxyN-methylpyrrolidine-1-carboxamide N-[(2S,3 S)-2-[(3',5'-difluoro [ 1, G-biphenyl] -3 -yl)methyl] -1-(1,2oxazolidin-2-carbonyl) pyrrolidin-3 -yl] ethanesulfonamide 1-Φτορ-Ν-[(28.38)-2-[( 2-φτορ [ 1, G-biphenyl] -3 -yl)methyl] -1-(2hydroxy-2-methylpropanoyl) pyrrolidin-3 -yl]cyclopropan-1 sulfonamide -Aov MO V 485.2 468.1 480.2 479.2 480 1 -Φτορ-Ν- { (2S,3 S) -1 - (2-hydroxy-2methylpropanoyl) -2- [(2,3 ', 5' trifluoro [ 1, G-biphenyl] -3 -yl) methyl] pyrrolidin-3-yl } cyclopropan-1 sulfonamide mJ v Sa 515.1

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Table 1-50

EXAMPLE 481 482 483 IUPAC NAME M-[(28.38)-2-[(3’,5’-difluoro[1,Hbiphenyl]-3-yl)methyl]-1 (trimethylhydrazinecarbonyl)pyrrolidin-3yl]ethanesulfonamide N-((2S,3 8)-2-((2,3 difluorobiphenyl-3 -yl)methyl)-1 (2-hydroxy-2methylpropanoyl)pyrrolidin-3 yl)ethanesulfonamide M-((28.38)-1-(2-hydroxy-2methylpropanoyl)-2-((2,3', 5' trifluorobiphenyl-3 -yl)methyl) pyrrolidin-3 yl)methanesulfonamide Structure f ά. Y-A .„Υ 1 O F hee iD N E Υ Additional component MS 481.2 467.1 469.1 484 M-((28.38)-1-(2-hydroxy-2methylpropanoyl)-2-((2,3’, 5’ trifluorobiphenyl-3 yl)methyl)pyrrolide in-3yl)ethanesulfonamide F Y 485.2 485 N-((2S,3 S)-1 -(azetidin-1 ylcarbonyl)-2-((2,3' difluorobiphenyl-3 yl)methyl) pyrrolide in-3 yl) methanesulfonamide F UN ⁵ ,, Y 450.1 486 (2S,3 8)-2-((2,3'-difluorobiphenyl3-yl)methyl)-3- ((ethylsulfopil)amipo)-NMdimethylpyrrolidine-1 carboxamide XjY 452.1 487 (28.38)-3-((ethylsulfonyl) βμηηο)-N, M-dimethyl-2-((2,3',5'trifluorobiphenyl-3 yl)methyl)pyrrolidine-1 carboxamide F Υβ ν Y 470.2 488 N-((2S,3 8)-2-((2,3 difluorobiphenyl-3 -yl)methyl)-1 (2-hydroxy-2methylpropanoyl)pyrrolidin-3yl)ethanesulfonamide Av Y=Y 467.2

Experimental Example 1 Generation of cells stably expressing the human orexin type 2 receptor (hOX2R).

To obtain a cell clone stably expressing the human orexin type 2 receptor, the human orexin type 2 receptor cDNA was inserted into the plasmid vector pcDNA3.1(+) (Invitrogen) and the plasmid DNA was cloned to express the human orexin type 2 receptor (pcDNA3.1)(+ )/hOX2R). Plasmid DNA was introduced into the CHO-dhfr cell by electroporation, and cell clones expressing the human orexin type 2 receptor were obtained by limited dilution using drug resistance G418 as a selection marker.

Experimental Example 2 Measurement of orexin type 2 receptor agonist activity.

CHO cells coercively expressing the human OX2 receptor were plated in each well of a 384-well black clear bottom plate (BD Falcon) at a density of 7500 cells/well and cultured for one day in a 5% CO2 incubator at 37°C. After removing the medium, Buffer A containing calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Wako Pure Chemical Industries, Ltd. or SigmaAldrich) 2.5 µl is added to the cell plate /ml Fluo-4 AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical), 1.25 mm probenecid (DOJINDO Chemical)), at 30 μl/well. The plate is incubated for 30 minutes in a 5% CO ₂ incubator at 37° C. and further incubated at room temperature for 30 minutes. Test compound diluted in assay buffer B (HBSS, 20 mM HEPES, 0.1%

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BSA) was added at 10 µl/well and fluorescence was measured with FDSSpCELL (Hamamatsu Photonics KK) every second for 1 min and then every two seconds for 1 min 40 s. The activity (%) of the test compound is calculated assuming that the change in fluorescence value when DMSO is added instead of the test compound is 0%, and the change in fluorescence value when added with orexin A (human) (PEPTIDE INSTITUTE, INC.) at a final concentration of 10 nM is 100%. The activities of the compounds at a concentration of 3 μM are presented in table. 2. As can be seen from the results, the compound of the present invention has agonist activity at the human orexin type 2 receptor.

Table 2-1

Example No. OX2R agonist activity (3 μM, %) one 81 2 90 3 101 7 62 ten 91 And 80 fourteen 82 17 29 22 60 27 66 29 98 35 41 38 75 41 67 fifty 97 53 72 55 84 60 26 61 74 62 93 63 24 64 96 74 104 76 106 78 35 89 96 93 101 95 97 100 107 101 96 108 69 116 106 122 82 126 90 145 24 159 65 173 68 178 99 181 100 185 99

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Table 2-2

Example No. OX2R agonist activity (3 µM, %) 191 79 204 95 206 94 209 106 210 102 214 70 227 99 254 101 255 101 256 97 258 95 259 95 261 97 262 101 266 107 269 111 293 102 294 104 299 100 300 99 303 95 304 94 305 105 306 100 307 102 308 107 309 101 310 102 311 103 312 103 313 100 314 107 315 105 316 104 317 103 318 102 319 101 320 103 321 104 322 104

Table 2-3

Example No. OX2R agonist activity (3 µM, %) 323 109 324 103 328 104 333 101 338 103 339 102 340 103 341 98 342 109

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343 107 344 99 345 93 346 107 347 87 348 109 349 99 350 99 351 106 352 102

Table 2-4

Example No. OX2R agonist activity (3 μM,%) 364 104 366 100 373 96 387 106 389 102 395 104 399 107 402 107 404 100 417 110 421 106 423 109 424 101 428 102 431 101 435 107 437 99 439 98

Table 2-5

Example No. OX2R agonist activity (3 μM,%) 362 103 372 98 377 103

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407 107 441 99 450 107 456 104 457 103 459 93 460 92 462 112 463 105 466 108 467 101 471 116 474 109 475 104 476 103 477 106 479 103 480 FROM 482 110 483 103 484 112 485 104 486 102 487 104 488 101

Experimental Example 3 Evaluation of human microsome stability.

Human liver microsomes were obtained from Xenotech, LLC (Lenexa, KS). The incubation mixture consists of microsomes in 50 mmol/l KH ₂ PO ₄ - K ₂ HPO ₄ phosphate buffer (pH 7.4) and 1 µmol/l test compound. The concentration of microsomal protein is 0.2 mg/ml. NADPH-generating system (5 mmol/l MgCl ₂ , 5 mmol/l glucose-6-phosphate, 0.5 mmol/l β-ΝΑϋΡ+ and 1.5 U/ml glucose-6-phosphate dehydrogenase) is added to the incubation mixture and a half the volume of the reaction mixture to initiate the enzymatic reaction. The reaction is stopped 15 and 30 minutes after the start of the reaction by mixing the reaction mixture with acetonitrile, followed by centrifugation at 2500 rpm. within 10 min. The supernatant is subjected to LC/MS/MS analysis. The metabolic rate is calculated as the slope of the concentration-time graph. In vitro internal metabolic clearance is calculated by dividing the initial metabolic rate by the concentration of the test compound in the incubation mixture. The results are presented in table. 3.

Table 3

Compound Clearance (µl/min./mg) Example 450 78 Example 482 26 Example 483 6 Example 484 23

The results presented show that the internal metabolic clearance of the test compounds of the present invention is low. Those. these compounds have been shown to have good metabolic stability.

Experimental Example 4 Evaluation of wakefulness-enhancing effects in cynomolgus monkeys.

The wakefulness effects of cynomolgus monkeys are assessed using electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG). Under anesthesia with isoflurane (1-5%, Pfizer Japan Inc., Tokyo, Japan), male cynomolgus monkeys (3-5 years old, Hamri Co., Ltd., Ibaraki, Japan) are surgically implanted with radio telemetry transmitters (TL10M3-D70-EEE, Data Sciences International Inc., MN, USA). EEG leads are stereotaxically placed in the parietal region and attached to the skull with stainless steel screws in contact with the dura mater. Unilateral EOG leads are placed on the superior orbital margin of one eye and secured with stainless steel screws. Bilateral EMG leads are implanted in the cervical muscles of the back. After surgery, each monkey is given penicillin (100,000 U/individual, i.m., Meiji Seika Pharma Co., Ltd., Tokyo, Japan), buprenorphine (0.02 mg/kg, i.m., Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) and prednisolone (1 mg/kg, s.c, Kyoritsu Seiyaku Co., Ltd., Tokyo, Japan) daily for one week. After a recovery period of at least one month in the home cages, the monkeys are accustomed to the recording cage (acrylic cage 60W x55Dx75H (cm)) located in isolation.

- 143 039459 soundproof and electrically isolated room. After confirming that the monkeys had slept for a sufficient period of time in the experimental room, EEG, EMG and EOG cortical signals were recorded using Dataquest ART software (Data Sciences International Inc., MN, USA). Signals are semi-automatically assessed at 20 second periods using a sleep scoring system (SleepSign, Kissei Comtec Co., Ltd., Nagano, Japan). This preliminary estimate is visually checked and corrected if necessary. Test compound (10 mg/kg, Table 4-1) suspended in 0.5% aqueous methylcellulose or diluent (i.e., 0.5% aqueous methylcellulose) was administered orally (po) to monkeys in target time 12 (ZT12) in a volume of 5 ml/kg body weight in a crossover design. Recording of EEG, EMG and EOG is carried out within 4 hours after administration of the compound/treatment. The time spent awake within 4 hours after administration (% of the value at the introduction of the vehicle), calculated using SleepSign. Test compound (1 mg/kg, Table 4-2) dissolved in a mixed solution containing 5% DMSO, 5% Cremophor EL, 20% PEG400 and 70% soluplus (1 w/v%), or vehicle ( i.e., a mixed solution containing 5% DMSO, 5% Cremophor EL, 20% PEG400 and 70% soluplus (1 w/v%), is administered subcutaneously (s.c.) to monkeys in ZT12 in a volume of 0.5 ml/ kg of body weight in pre-post design. Recording of EEG, EMG and EOG is carried out within 4 hours after administration of the compound. Time spent awake within 4 hours after administration (% of vehicle exposure) was calculated using SleepSign. The results are presented in table. 4.

Table 4-1

Test compound (10 mg/kg, po) Wake time (% of diluent value) (mean, n=4-8) Example 482 280.82 Example 483 359.35 Example 484 492.32

Table 4-2

Test compound (1 mg/kg, S.C.) Wake time (% of diluent value) (mean, n=1-2) Example 362 270.87 Example 364 375.40 Example 372 327.78 Example 377 343.49 Example 407 391.30 Example 450 242.72 Example 456 445.67 Example 474 329.00 Example 475 410.04 Example 476 392.22 Example 477 382.61 Example 485 449.21 Example 486 328.47 Example 487 354.86

The results show that in cynomolgus monkeys, the test compounds of the invention increase wake time relative to the vehicle treated group. Those. the results indicate that the compounds are effective in the treatment of narcolepsy.

Formulation Example 1 (Preparation of Capsules).

1) Compound of example 1-30 mg;

2) crystalline cellulose - 10 mg;

3) lactose - 19 mg;

4) magnesium stearate - 1 mg, total - 60 mg.

Components 1), 2), 3) and 4) are mixed and filled into a gelatin capsule with the resulting mixture.

Preparation example 2 (tablet preparation).

1) Example compound 1-30 g;

2) lactose - 50 g;

3) corn starch - 15 g;

4) calcium carboxymethylcellulose - 44 g;

5) magnesium stearate - 1 g,

1000 tablets - 140 g total.

The total amount of components 1), 2), 3) and 30 g 4) is mixed with water, dried in vacuum and sieved. The sieved powder is mixed with 14 g 4) and 1 g 5) and the mixture is perforated on a tablet machine.

- 144 039459

In this way, 1000 tablets are obtained containing 30 mg of the compound of example 1 per tablet.

Industrial Applicability

The compound of the invention has an orexin type 2 receptor agonist activity and can be used as an agent for the prevention or treatment of narcolepsy.

This application is based on Japanese Patent Applications No. 2017150685, filed August 3, 2017, and No. 2017248495, filed December 25, 2017, the contents of which are incorporated herein in their entirety.

CLAIM

Claims (11)

CLAIM 1. The compound represented by the formula where R ¹ is: (1) C _1-6 alkyl group optionally substituted with 1-3 substituents selected from: (a) a halogen atom, (b) a C _1-6 alkoxy group, (2) a C _3-6 cycloalkyl group optionally substituted with 1-3 halogen atoms, or (3) a mono- or di-C _1-6 alkylamino group; R ² represents a hydrogen atom; ^R3 is: (1) C _1-6 alkoxycarbonyl group, (2) C _1-6 alkylcarbonyl group optionally substituted with 1-3 hydroxyl groups, (3) mono- or di-C _1-6 alkylcarbamoyl group, (4) NC _1-6 alkyl-N-C _1-6 alkoxycarbamoyl group, (5) C _3-6 cycloalkylcarbonyl group (wherein C _3-6 cycloalkyl in C _3-6 cycloalkylcarbonyl group may be a ring bridging group) optionally substituted with 1-3 substituents selected from: (a) a halogen atom, (b) a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms, (c) a hydroxyl group, (d) a C _1-6 alkoxy group, and (e) a cyano group, (6) an oxetanecarbonyl group , (7) an azetidinylcarbonyl group optionally substituted with 1-3 substituents selected from: (a) a halogen atom, and (b) a C _1-6 alkyl group, or (8) a 5-azaspiro[2.3]hexylcarbonyl group; each of R ⁴ and R ⁵ represents a hydrogen atom; Ring A is: (1) a pyrrolidine ring, or (2) a piperidine ring; and ring B is: (1) a benzene ring further substituted with one phenyl group optionally substituted with 1-3 substituents selected from: (i) a halogen atom, (ii) a C _1-6 alkyl group and optionally further substituted with one halogen atom, (2) a pyridine ring further substituted with one phenyl group, optionally substituted with 1-3 halogen atoms, (3) a thiazole ring, optionally substituted with one phenyl group, or a pharmacologically acceptable salt thereof, provided that N-((2S,3S)-2-((2,3'-difluorobiphenyl-3yl)methyl)-1-(2-hydroxy-2-methylpropanoyl) pyrrolidin-3-yl)ethanesulfonamide and its pharmacologically acceptable salt are excluded. 2. The compound or pharmacologically acceptable salt thereof according to claim 1, where R ¹ is: (1) a C _1-6 alkyl group, (2) a C _3-6 cycloalkyl group optionally substituted with 1-3 halogen atoms, or (3) a mono- or di-C _1-6 alkylamino group; R ² represents a hydrogen atom; - 145 039459 ^R3 is: (1) Cie alkylcarbonyl group optionally substituted with 1-3 hydroxyl groups, (2) mono- or di-C1.b alkylcarbamoyl group, (3) N-Ci-b alkyl-I-C1.b alkoxycarbamoyl group, or (4 ) an azetidinylcarbonyl group; R ⁴ and R ⁵ are both hydrogen atoms; ring A is a pyrrolidine ring; and ring B is a benzene ring further substituted with one phenyl group optionally substituted with 1-3 halogen atoms and optionally further substituted with one halogen atom. 3. N-((28.38)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide or a pharmacologically acceptable salt thereof. 4. N-((28.38)-1-(2-Hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide or a pharmacologically acceptable salt thereof. 5. Connection selected from: (1) N-((2S,3S)-1-(azetidin-1-ylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide, (2 ) N-((28.38)-1-(azetidin-1-ylcarbonyl)-2-((3',5'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide, (3) N -((2S,3S)-1 -(azetidin-1-ylcarbonyl)-2-(biphenyl-3-ylmethyl)pyrrolidin-3-yl)ethanesulfonamide, (4) R-((28.38)-1 -(azetidin-1-ylcarbonyl)-2-((2,3'-difluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide, (5) (2S,3 8)-2-((2, 3'-difluorobiphenyl-3-yl)methyl)-3-((ethylsulfonyl)amino)-K,K-dimethylpyrrolidine-1-carboxamide, (6) (2S,3 8)-2-((2,3 '-difluorobiphenyl-3-yl)methyl)-3-((dimethylsulfamoyl)amino)-K,K-dimethylpyrrolidine-1-carboxamide, (7) (28.38)-3-((ethylsulfonyl)amino)- K,K-dimethyl-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-1-carboxamide, (8) (28.38)-2-(biphenyl-3-ylmethyl) -3-((ethylsulfonyl)amino)-N-methoxy-N-methylpyrrolidine-1-carboxamide, (9) N-[(2S, 3S)-2-[(2,3'-difluoro[1, G-biphenyl ]-3-yl)methyl]-1 -(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl] -1 - fluorocyclopropane-1-sulfonamide, (10) N-{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(2-fluoro[1,1'-biphenyl]-3-yl) methyl]pyrrolidin-3-yl}ethanesulfonamide, (11)(28.38)-3-[(ethanesulfonyl)amino]-2-[(3'-fluoro[1,G-biphenyl]-3-yl)methyl] -N-methoxy-N-methylpyrrolidine-1-carboxamide, (12) (28.38)-3-[(dimethylsulfamoyl)amino]-2-[(2-fluoro[1,G-biphenyl]-3-yl) methyl]-K,K-dimethylpyrrolidine-1-carboxamide, (13) (28.38)-3-[(dimethylsulfamoyl)amino]-K,K-dimethyl-2-[(2,3',5'-trifluoro [1,G-biphenyl]-3-yl)methyl] pyrrolidine-1-carboxamide and (14) (28.38)-2-[(3',5'-difluoro[1,G-biphenyl]-3- yl)methyl]-3-[(ethanesulfonyl)amino]-M-methoxy-N-methylpyrrolidine-1-carboxamide, or a pharmacologically acceptable salt thereof. 6. A drug that is an orexin type 2 receptor agonist containing a compound or a pharmacologically acceptable salt thereof at π. one. 7. The drug according to claim 6 for the prevention or treatment of narcolepsy. 8. The use of a compound or a pharmacologically acceptable salt thereof according to claim 1 for the prevention or treatment of narcolepsy. 9. A method of activating a type 2 orexin receptor in a mammal, which comprises administering to the mammal an effective amount of a compound or a pharmacologically acceptable salt thereof at π. one. 10. A method for preventing or treating narcolepsy in a mammal, which comprises administering to the mammal an effective amount of a compound or a pharmacologically acceptable salt thereof according to claim 1. 11. Use of a compound or a pharmacologically acceptable salt thereof at π. 1 for the manufacture of a medicament for the prevention or treatment of narcolepsy.