PHENYL UREA DERIVATIVE

Abstract

The present invention relates to a medicament for treating or preventing a disease related to orexin receptor, especially orexin receptor type 2, comprising a new compound having a urea structure or a pharmaceutically acceptable salt thereof as an active ingredient. In more detail, the present invention relates to a medicament for treating or preventing a disease such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome.

Description

TECHNICAL FIELD

The present invention relates to a medicament for treating or preventing a disease associated with orexin receptor, especially orexin receptor type 2, comprising a new compound having a urea structure or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the present invention relates to a medicament for treating or preventing a disease such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome.

BACKGROUND ART

Orexin is a neuropeptide which is specifically produced in a specific neuron spreading across lateral hypothalamus and its adjacent region. Orexin is an endogenous ligand of orexin receptor that is a G-protein-coupled receptor existing mainly in brain, which binds to orexin receptor. It is known that orexin receptor has two subtypes, type 1 and type 2 (Non-Patent Document 1).

It was reported that a narcolepsy-like symptom in a transgenic mouse whose orexin neuron was denatured could be improved by intraventricular injection of an orexin peptide (Non-Patent Document 2), and a narcolepsy-like symptom could be initiated by knocking out (KO) prepro-orexin which is a precursor protein of orexin (Non-patent Reference 3), furthermore the orexin concentration in cerebrospinal fluid of narcolepsy patients was markedly lowered (Non-Patent Document 4). Thus, it is suggested that narcolepsy can be initiated due to lack of orexin.

In addition, it was reported that there was a mutation of orexin receptor type 2 in a dog suffering from hereditary narcolepsy (Non-Patent Document 5), which suggests that orexin receptor type 2 is involved in sleep-wake function. Furthermore, it was revealed that narcolepsy-like symptom was initiated in a KO mouse of orexin receptor type 2 (Non-Patent Document 6), which strongly suggests that the stimulation on orexin receptor type 2 is involved in sleep-wake function. Thus, an orexin receptor type 2 agonist is expected to be a hopeful therapy for a patient presenting with hypersomnia-like symptom such as narcolepsy.

Recently, a compound with orexin receptor type 2 agonistic effect was reported (Patent Document 1).

PRIOR ART DOCUMENTS

Patent Documents

• • Patent Document 1: WO 2017/135306

Non-Patent Documents

• • Non-Patent Document 1: Cell, Vol. 92, 573-585, 1998
  • Non-Patent Document 2: Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004
  • Non-Patent Document 3: Cell, Vol. 98, 437-451, 1999
  • Non-Patent Document 4: THE LANCET, Vol. 355, 39-40, 2000
  • Non-Patent Document 5: Cell, Vol. 98, 365-376, 1999
  • Non-Patent Document 6: Neuron, Vol. 38, 715-730, 2003
  • Non-Patent Document 7: Brain, Vol. 130, 1577-1585, 2007
  • Non-Patent Document 8: Neuroscience Letters, Vol. 569, 68-73, 2014

SUMMARY OF INVENTION

Problem to be Solved by the Invention

An object of the present invention is to provide a medicament for treating or preventing a disease associated with orexin receptor type 2, specifically a disease such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome.

Means for Solving the Problems

The present inventors have extensively studied to reach the above object, and then have found that a compound of the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, it may be referred to as “the present compound”) has therapeutic and prophylactic effect for a disease associated with orexin receptor type 2, specifically, a disease such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome. Based on the new findings, the present invention has been completed.

The present invention can show as follows.

[Item 1]

A compound of formula (1):

or a pharmaceutically acceptable salt thereof,wherein

• • R¹ is optionally-substituted C_6-10 aromatic carbocyclyl group, optionally-substituted 5- to 10-membered aromatic heterocyclyl group, optionally-substituted C_3-6 saturated carbocyclyl group, optionally-substituted 4- to 10-membered saturated heterocyclyl group, or cyano;
  • L¹ and L² are each independently single bond, methylene (which may be optionally substituted with the same or different one or more C_1-6 alkyl groups), —NR⁶—, —C(═O)—, —OC(═O)—, —SO—, —SO₂—, —S—, or oxygen atom;
  • R² is hydrogen atom, hydroxy group, halogen atom, cyano, optionally-substituted C_1-6 alkyl, optionally-substituted C_1-6 alkoxy, C(═O)NR³R⁴ or C(═O)O—R⁵;
  • R³, R⁴, R⁵ and R⁶ are each independently hydrogen atom or optionally-substituted C_1-6 alkyl;
  • ring E is optionally-substituted 5- to 10-membered aromatic heterocyclyl group or optionally-substituted 4- to 10-membered saturated heterocyclyl group;
  • ring G is optionally-substituted C_6-10 aromatic carbocyclyl group, optionally-substituted 5- to 10-membered aromatic heterocyclyl group, optionally-substituted C₃-6 saturated carbocyclyl group, or optionally-substituted 4- to 10-membered saturated heterocyclyl group; and
  • A is oxygen atom or sulfur atom.

[Item 2]

The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein in R² to R⁶, the optional substituent of “optionally-substituted C_1-6 alkyl” is each independently the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkoxy, or C_3-7 cycloalkyl, and the optional substituent of “optionally-substituted C_1-6 alkoxy” is each independently the same or different one or more substituents selected from halogen atom, hydroxy group, or C_3-7 cycloalkyl,

• • in R¹, the optional substituent of C_6-10 aromatic carbocyclyl group, 5- to 10-membered aromatic heterocyclyl group, C_3-6 saturated carbocyclyl group, and 4- to 10-membered saturated heterocyclyl group is each independently one or more substituents selected from the group consisting of halogen atom, hydroxy group, C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl, C_1-6 alkoxy or C_3-7 cycloalkyl), C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkoxy or C_3-7 cycloalkyl), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl, C_1-6 alkoxy or C_3-7 cycloalkyl), C_1-6 alkylamino (the alkyl group of which may be optionally substituted with halogen atom, hydroxy group or C_3-7 cycloalkyl), C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl, C_1-6 alkoxy or C_3-7 cycloalkyl), cyano, C_1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_3-7 cycloalkyl), and 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl, C_1-6 alkoxy or C_3-7 cycloalkyl), and
  • in ring E and ring G, the optional substituent of C_6-10 aromatic carbocyclyl group, 5- to 10-membered aromatic heterocyclyl group, C_3-6 saturated carbocyclyl group, and 4- to 10-membered saturated heterocyclyl group is each independently one or more substituents selected from the group consisting of halogen atom, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkoxy or C_3-7 cycloalkyl), C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl, C_1-6 alkoxy or C_3-7 cycloalkyl), C_1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_3-7 cycloalkyl), C_1-6 alkylamino (the alkyl group of which may be optionally substituted with halogen atom, hydroxy group or C_3-7 cycloalkyl), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl, C_1-6 alkoxy or C_3-7 cycloalkyl), and C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl, C_1-4 alkoxy or C_3-7 cycloalkyl), or when there are plural optional substituents, two of them may be taken together via C_1-6 alkylene to form a chemically-possible bicyclic structure selected from a fused ring, a spiro ring, or bridged ring.

[Item 3]

The compound according to Item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the formula is represented by formula (2):

wherein

• • R² is hydroxy group, halogen atom, cyano, optionally-substituted C_1-4 alkyl, optionally-substituted C_1-4 alkoxy, C(═O)NR³R⁴ or C(═O)OR⁵; and
  • R¹, L¹, L², R³, R⁴, R⁵, ring E, ring G, and A are as defined in Item 1.

[Item 4]

The compound according to any one of Items 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from cyano or the following formulae (1a-1) to (1a-6):

wherein

• • X¹ to X⁶ are each independently nitrogen atom or CR^a4;
  • Q¹ and Q² are oxygen atom, —NR^a5— or sulfur atom;
  • Q³ is CH or nitrogen atom; and
  • R^a1 to R^a5 are each independently (if there are plural
  • CR^a4, each R^a4 is also independently) hydrogen atom, halogen atom, C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-4 alkoxy or C_3-7 cycloalkyl), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl which may be optionally substituted with the same or different one or more halogen atoms, or C_1-6 alkoxy), cyano, C_1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_1-6 alkoxy), C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), or 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy).

[Item 5]

The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof, wherein ring G is selected from the following formulae (1b-1) to (1b-7):

wherein

• • W¹ and W² are each independently NR^b7, oxygen atom or CR^b8R^b9;
  • W³, W⁴, W⁵ and W⁶ are each independently nitrogen atom or CR^b10;
  • R^b1 to R^b10 are each independently hydrogen atom, halogen atom, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-4 alkoxy), C_1-6 alkoxy (which may be optionally substituted with the same or different one or more halogen atoms), C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), or C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), and R^b2 and R^b3 may bind to the same carbon atom if chemically possible;
  • wherein R^b2 and R^b3 may be taken together via C_1-6 alkylene to form a fused ring or a bridged ring; and
  • n, m and p are each independently an integer of 1 or 2.

[Item 6A]

The compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein ring E is selected from the following formulae (1c-1) to (1c-4):

wherein

• • R^c1, R^c2, R^c3 and R^c4 are each independently hydrogen atom, halogen atom, cyano, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-6 alkoxy), C_1-6 alkoxy (which may be optionally substituted with the same or different one or more halogen atoms), C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), or C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), and R^c1 and R^c2 may bind to the same carbon atom if chemically possible; and
  • wherein R^c1 and R^c2 may be taken together via C_1-6 alkylene to form a fused ring or a bridged ring.

[Item 6]

The compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein ring E is selected from the following formulae (1c-1) to (1c-3):

wherein

• • R^c1, R^c2 and R^c3 are each independently hydrogen atom, halogen atom, cyano, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-6 alkoxy), C_1-6 alkoxy (which may be optionally substituted with the same or different one or more halogen atoms), C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), or C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), and R^c1 and R^c2 may bind to the same carbon atom if chemically possible; and
  • wherein R^c1 and R^c2 may be taken together via C_1-6 alkylene to form a fused ring or a bridged ring.

[Item 7A]

The compound according to any one of Items 1 to 6A and Item 6 or a pharmaceutically acceptable salt thereof, wherein ring E is selected from the following formulae (1c-11) to (1c-41):

wherein

• • R^c4 is each independently halogen atom, cyano, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-6 alkoxy), C_1-6 alkoxy (which may be optionally substituted with the same or different one or more halogen atoms), C_6-10 aromatic carbocyclyl group (which may be optionally substituted with one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), or C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy).

[Item 7]

The compound according to any one of Items 1 to 6A and Item 6 or a pharmaceutically acceptable salt thereof, wherein ring E is selected from the following formulae (1c-11) to (1c-31):

wherein

• • R^c4 is each independently halogen atom, cyano, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-6 alkoxy), C_1-6 alkoxy (which may be optionally with the same or different one or more halogen atoms), C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6, alkoxy), or C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy).

[Item 8]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Item 7 or a pharmaceutically acceptable salt thereof, wherein the formula is represented by formula (3):

wherein

• • R² is C_1-6 alkoxy which may be optionally substituted with halogen atom; and
  • R¹, A, L¹ and ring G are as defined in Item 1.

[Item 9]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A, Item 7 and Item 8 or a pharmaceutically acceptable salt thereof, wherein L¹ is single bond, —CH₂— or oxygen atom.

[Item 10]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 9 or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the following formulae (1a-1) to (1a-3):

wherein

• • X¹ to X⁵ are each independently nitrogen atom or CR^a4;
  • Q¹ and Q² are each independently oxygen atom or sulfur atom;
  • R^a1 is hydrogen atom, halogen atom, cyano, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_1-6 alkoxy), or C_1-4 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_1-6 alkoxy); and
  • R^a4 is each independently (if there are plural CR^a4, each R^a4 is independently) hydrogen atom, halogen atom, C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkoxy or C_3-7 cycloalkyl), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), C_1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_1-6 alkoxy), C_3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), or 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy).

[Item 11]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 10 or a pharmaceutically acceptable salt thereof, wherein ring G is selected from the following formulae (1b-1) to (1b-3):

wherein

• • R^b1 to R^b3 are each independently hydrogen atom, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-6 alkoxy), C_1-6 alkoxy (which may be optionally substituted with the same or different one or more halogen atoms), 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), or C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy).

[Item 12]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 11 or a pharmaceutically acceptable salt thereof, wherein R² is halogen atom selected from F, Cl or Br, and A is oxygen atom.

[Item 13]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 12 or a pharmaceutically acceptable salt thereof, wherein R¹ is the following formula

wherein

• • R^a1 is hydrogen atom, halogen atom, cyano, C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_1-6 alkoxy), or C_1-4 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_1-6 alkoxy).

[Item 14]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 12 or a pharmaceutically acceptable salt thereof, wherein R¹ is the following formula

wherein

• • X¹ to X³ are each independently nitrogen atom or CR^a4;
  • Q¹ is oxygen atom or sulfur atom;
  • R^a4 is as defined in Item 10; and
    • L¹ is single bond.

[Item 15]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 12 or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the following formulae (1a-21) to (1a-25):

wherein R^a4 is as defined in Item 10; and

• • L¹ is single bond.

[Item 16]

The compound according to Item 15 or a pharmaceutically acceptable salt thereof, wherein R^a4 is (if there are plural CR^a4, each R^a4 is independently) C_6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkoxy or C_3-7 cycloalkyl), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), or 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy)

[Item 17]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 12 or a pharmaceutically acceptable salt thereof, wherein R¹ is the following formula (1a-3):

wherein X⁴ and X⁵ are as defined in Item 10; and

• • L¹ is single bond.

[Item 18]

The compound according to Item 17 or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the following formulae (1a-31) to (1a-34):

wherein R^a4 is as defined in Item 10.

[Item 19]

The compound according to Item 17 or 18 or a pharmaceutically acceptable salt thereof, wherein R^a4 is (if there are plural CR^a4, each R^a4 is independently) C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkoxy or C_3-7 cycloalkyl), C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C_1-6 alkyl or C_1-6 alkoxy), or C_1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C_1-6 alkoxy).

[Item 20]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 19 or a pharmaceutically acceptable salt thereof, wherein ring G is the following formula (1b-2):

wherein R^b2 is as defined in Item 11.

[Item 21]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 19 or a pharmaceutically acceptable salt thereof, wherein ring G is the following formula (1b-1):

wherein

• • R^b1 is C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-6 alkoxy), 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), or C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy).

[Item 22]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 19 or a pharmaceutically acceptable salt thereof, wherein ring G is the following formula (1b-3):

wherein

R^b3 is C_1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom or C_1-6 alkoxy), 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy), or C_3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, C_1-6 alkyl or C_1-6 alkoxy).

[Item 23]

The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

• Example 20: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 22: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide
• Example 44: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 45: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 53: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 54: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 55: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 61: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 67: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 77: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

[Item 24]

The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

• Example 87: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 89: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine-1-carboxamide
• Example 101: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine-1-carboxamide
• Example 115: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide
• Example 116: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide
• Example 117: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide
• Example 118: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide
• Example 130: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 144: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 147: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

[Item 25]

A pharmaceutical composition comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 26]

A medicament for treating a disease associated with orexin receptor type 2, comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 27]

A medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (for example, Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (for example, malignant mast cell, extrinsic obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophysial obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer, impaired consciousness such as coma, side effect or complication caused by anesthesia, sleep disturbance, sleep problem, insomnia, intermittent sleep, night myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of shift workers, dyssomnia, sleep terror, depression, major depression, sleepwalking, enuresis, sleep disorder, Alzheimer's sundown syndrome, disease associated with circadian rhythm, fibromyalgia, condition resulting from decrease in sleeping quality, bulimia, obsessive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin level/insulin resistance, hyperlipemia, hyperlipidaemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstone, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, decrease of fecundability, infertility, hypogonadism in men, sexual/reproductive-function dysfunction such as hirsutism in women, fetal defect associated with maternity obesity, gastrointestinal motility disorder such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory disease such as respiratory distress, inflammation such as vascular systemic inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, secondary risk of obesity such as risk of left ventricle hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweat, disease in genitalium/urinary system, disease associated with sexual function or fecundability, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorder such as cerebral deficiency developed after heart bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, periparturient hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorder associated with muscle spasm, delirium, amnestic disorder, age-associated cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorder, chronic fatigue syndrome, fatigue, medication-induced parkinsonian syndrome, Gilles de 1a Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptom, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, or traumatic brain injury, comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 28]

A medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body, comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 29]

A medicament for treating narcolepsy, comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 30]

A medicament for treating idiopathic hypersomnia, comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 31]

A medicament for treating hypersomnia associated with Parkinson's disease, comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 32]

A medicament for treating hypersomnia associated with dementia with Lewy body, comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof.

[Item 33]

A method of treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body, which comprises administering a therapeutically effective amount of the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[Item 34]

Use of the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body.

[Item 35]

A pharmaceutical composition comprising the compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof for use in the treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body.

[Item 36]

The compound according to any one of Items 1 to 6A, Item 6, Item 7A and Items 7 to 24 or a pharmaceutically acceptable salt thereof for use in the treatment and/or prophylaxis of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention is explained in more detail. The number of carbon atoms in the definition of “substituent group” as used herein may be expressed as, for example, “C_1-6”. Specifically, the expression “C_1-6 alkyl” means an alkyl group having 1 to 6 carbon atoms. As used herein, a substituent group which is not accompanied with the term “optionally-substituted” or “substituted” means an “unsubstituted” substituent group. For example, “C_1-6 alkyl” means “unsubstituted C_1-6 alkyl”.

The substituent group as used herein may be expressed without the term “group”. In case that “optionally-substituted” is used in the definition of substituent group, the number of the substituting group is not limited as long as the substitution is available, i.e., it is one or more. It means that the possible number of substituting groups is the substitution-available number on carbon atoms or carbon/nitrogen atoms in a substituent group which are acceptable for substitution. Unless otherwise specified, the definition of each substituent group also extends over the case that the substituent group is partially included in another substituent group or the case that the substituent group is attached to another substituent group.

Unless otherwise specified, the binding site of substituent groups is not limited as long as the site is chemically available to be bound. Also, in the structural formula as used herein, wedge solid and dashed bonds mean absolute configuration, and thick solid and dashed bonds mean relative configuration.

The “halogen” includes, for example, fluorine, chlorine, bromine, iodine, and the like. Preferably, it is fluorine or chlorine.

The “C_1-4 alkyl” means straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, and the “C_1-6 alkyl” means straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Specific examples of the “C_1-4 alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, and specific examples of the “C_1-6 alkyl” include pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and a structural isomer thereof, besides the above C_1-4 alkyl. The “C_1-6 alkyl” or “C_1-4 alkyl” is preferably methyl, ethyl, propyl and isopropyl, more preferably methyl and isopropyl.

The “C_1-6 alkylene” means divalent straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. The “C_1-6 alkylene” includes preferably “C_1-4 alkylene”, more preferably “C_1-3 alkylene”. Specific examples of the “C_1-3 alkylene” include methylene, ethylene, propylene, trimethylene, and the like. Specific examples of the “C_1-4 alkylene” include butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, and the like, besides the specific examples listed in the above “C_1-3 alkylene”. Specific examples of the “C_1-6 alkylene” include pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene, and the like, besides the specific examples listed in the above “C_1-4 alkylene”.

The “C_3-7 cycloalkyl” means a non-aromatic cyclic hydrocarbon group (i.e., saturated hydrocarbon group and partially-unsaturated hydrocarbon group) having 3 to 7 carbon atoms. Preferably, it is “C_3-6 cycloalkyl”. The “C_3-7 cycloalkyl” also includes a bridged one. Specific examples of the “C_3-7 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, and the like.

The “C_3-7 cycloalkyl” also includes a bi-cyclic condensed ring in which the “C_3-7 cycloalkyl” is fused with benzene ring or a 5- or 6-membered ring having one heteroatom selected from nitrogen, sulfur, or oxygen atom, or the same or different two or more (for example, 2 to 4) heteroatoms thereof (for example, “5- or 6-membered monocyclic aromatic heterocycle” mentioned below, and 5- or 6-membered ring in “4- to 10-membered saturated heterocycle” mentioned below).

The “C_1-4 alkoxy” means oxy group substituted with the above “C_1-4 alkyl”, and the “C_1-6 alkoxy” means oxy group substituted with the above “C_1-6 alkyl”. Specific examples of the “C_1-4 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like, and specific examples of the “C_1-6 alkoxy” include pentyloxy, hexyloxy, and the like. Preferably, the “C_1-4 alkoxy” includes methoxy, ethoxy and isopropoxy.

The “C_3-7 cycloalkoxy” means oxy group substituted with the above “C_3-7 cycloalkyl”. Preferably, it is “C_3-6 cycloalkoxy”. Specific examples of the “C_3-7 cycloalkoxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Preferably, the “C_3-7 cycloalkoxy” is cyclohexyloxy.

The “C_6-10 aromatic carbocyclyl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms, which is also referred to as “C_6-10 aryl”. More preferably, it is phenyl. Specific examples of the “C_6-10 aromatic carbocyclyl group” includes phenyl, 1-naphthyl, 2-naphthyl, and the like.

The “C_6-10 aromatic carbocyclyl group” also includes a condensed ring in which “phenyl” is fused with a 5- or 6-membered ring having one heteroatom selected from nitrogen, sulfur or oxygen atom, or the same or different two or more (for example, 2 to 4) heteroatoms thereof (for example, “5- or 6-membered monocyclic aromatic heterocycle” mentioned below, and 5- or 6-membered ring in “4- to 10-membered saturated heterocycle” mentioned below), or a 5- to 7-membered cycloalkyl ring (for example, cyclopentane, cyclohexane or cycloheptane).

The “5- to 10-membered aromatic heterocyclyl group” means a mono- or poly-cyclic 5- to 10-membered aromatic heterocyclyl group having one heteroatom selected from nitrogen, sulfur or oxygen atom, or the same or different two or more (for example, 2 to 4) heteroatoms thereof, besides carbon atoms as the ring atoms. Preferably, it is “5- or 6-membered monocyclic aromatic heterocyclyl group”. The “5- or 6-membered monocyclic aromatic heterocyclyl group” means a monocyclic 5- or 6-membered aromatic heterocyclyl group within the “5- to 10-membered aromatic heterocyclyl group”.

The polycyclic aromatic heterocyclyl group in the above “5- to 10-membered aromatic heterocyclyl group” includes, for example, a condensed ring in which the same or different two monocyclic aromatic heterocycles are fused, and a condensed ring in which a monocyclic aromatic heterocycle and an aromatic ring (for example, benzene) or a non-aromatic ring (for example, cyclohexane) are fused.

Specific examples of the “5- to 10-membered aromatic heterocyclyl group” include pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. In another embodiment, it preferably includes benzofuranyl in which the binding site is on the heteroaryl (furan) ring, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.

The “C_3-6 saturated carbocyclic ring” means a monocyclic saturated or partially-unsaturated hydrocarbon ring having 3 to 6 carbon atoms. Specific examples of the “C_3-6 saturated carbocyclic ring” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene, and the like. Preferably, it includes cyclopropane and cyclobutane.

The “4- to 10-membered saturated heterocycle” means a monocyclic or bicyclic saturated heterocycle composed of 4 to 10 atoms, which has the same or different one or more (for example, 2 to 4, preferably 2 to 3, more preferably 2) heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom, besides carbon atoms as the ring atoms. The heterocycle includes a partially-unsaturated heterocycle, a partially-bridged heterocycle and a partially-spiro heterocycle. Preferably, the heterocycle is 5- or 6-membered saturated heterocycle. The bicyclic saturated heterocycle also includes a condensed ring in which a monocyclic saturated heterocycle and benzene or a monocyclic 5- to 6-membered aromatic heterocycle are fused. Also, the saturated heterocycle may further comprise one or two carbonyl, thiocarbonyl, sulfinyl or sulfonyl, that is, the saturated heterocycle includes, for example, a cyclic group such as lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate, and cyclic thiocarbamate, which the number of atoms composing 4- to 10-membered ring (i.e., ring size) or the number of heteroatoms composing heterocycle does not count the oxygen atom in carbonyl, sulfinyl and sulfonyl, and the sulfur atom in thiocarbonyl. The “4- to 10-membered saturated heterocycle” includes preferably monocyclic or bicyclic “4- to 8-membered saturated heterocycle”, more preferably monocyclic “4- to 6-membered saturated heterocycle”, and furthermore preferably monocyclic “5- or 6-membered saturated heterocycle”. Specific examples of the “4- to 10-membered saturated heterocycle” include piperazine, oxetane, azetidine, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, homopiperidine, oxetane, thiomorpholine, dioxothiomorpholine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, oxoimidazolidine, dioxoimidazolidine, oxooxazolidine, dioxooxazolidine, dioxothiazolidine, tetrahydrofuran, tetrahydropyran, and tetrahydropyridine, and the like. Preferably, the 4- to 10-membered saturated heterocycle is pyrrolidine, piperidine, piperazine, and morpholine. Specific examples of the bicyclic saturated heterocycle include indoline, isoindoline, dihydropurine, dihydrothiazolopyrimidine, dihydrobenzodioxane, dihydroindazole, dihydropyrrolopyridine, tetrahydroquinoline, decahydroquinoline, tetrahydroisoquinoline, decahydroisoquinoline, tetrahydronapthyridine and tetrahydropyridoazepine, and the like.

The “4- to 10-membered saturated heterocyclyl group” means a monovalent substituent derived from the above “4- to 10-membered saturated heterocycle”, and the “4- to 6-membered saturated heterocyclyl group” means a monovalent substituent derived from “4- to 6-membered saturated heterocycle” which belongs to the above “4- to 10-membered saturated heterocycle”. Preferably, it includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

The compound of the present invention includes various hydrate, solvate, and crystal polymorph thereof.

The compound of the present invention may include one or more isotope atoms such as D, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵, ³⁵S, ¹⁸F and ¹²⁵I by substitution, and such isotope-substituted compound is also included in the compound of the present invention.

The “pharmaceutically acceptable salt” as used herein means a pharmaceutically usable acid addition salt and a pharmaceutically usable base addition salt. Examples of the “pharmaceutically acceptable salt” include an acid addition salt such as acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), laurylsulfate, malate, ascorbate, mandelate, saccharate, xinafoate, pamoate, cinnamate, adipate, cysteine, N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, polyacrylate and carboxy vinyl polymer; an inorganic base addition salt such as lithium salt, sodium salt, potassium salt and calcium salt; an organic base addition salt such as morpholine and piperidine; and an amino acid addition salt such as aspartate and glutamate, but are not limited thereto.

The compound of the present invention may be orally or parenterally administered directly or as a suitable formulation such as drug product, medicament, and pharmaceutical composition. Specific examples of the formulation thereof may include tablet, capsule, powder, granule, liquid, suspension, injection, patch and gel patch, but are not limited thereto. The formulation can be prepared with pharmaceutically acceptable additive agents in known means.

The additive agents may be chosen for any purpose, including an excipient, a disintegrant, a binder, a fluidizer, a lubricant, a coating agent, a solubilizer, a solubilizing agent, a thickener, dispersant, a stabilizing agent, a sweetening agent, a flavor, and the like. Specific examples thereof include lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially-pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like.

The dose of the compound of the present invention should be suitably determined depending on subject animal for administration, administration route, target disease, and age, body weight, and condition of patients. For example, in the case of oral administration, about 0.01 mg as minimum to 10000 mg as maximum may be administered a day for an adult in one to several portions.

The compound of the present invention is a compound with agonist activity on orexin receptor type 2. Hence, the compound of the present invention may be a medicament useful for preventing or treating a disease associated with orexin receptor. Specific examples of the disease include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (for example, Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (for example, malignant mast cell, extrinsic obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophysial obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer, impaired consciousness such as coma, side effect or complication caused by anesthesia, sleep disturbance, sleep problem, insomnia, intermittent sleep, night myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of shift workers, dyssomnia, sleep terror, depression, major depression, sleepwalking, enuresis, sleep disorder, Alzheimer's sundown syndrome, disease associated with circadian rhythm, fibromyalgia, condition resulting from decrease in sleeping quality, bulimia, obsessive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin level/insulin resistance, hyperlipemia, hyperlipidaemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstone, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, decrease of fecundability, infertility, hypogonadism in men, sexual/reproductive-function dysfunction such as hirsutism in women, fetal defect associated with maternity obesity, gastrointestinal motility disorder such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory disease such as respiratory distress, inflammation such as vascular systemic inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, secondary risk of obesity such as risk of left ventricle hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweat, disease in genitalium/urinary system, disease associated with sexual function or fecundability, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorder such as cerebral deficiency developed after heart bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, periparturient hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorder associated with muscle spasm, delirium, amnestic disorder, age-associated cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorder, chronic fatigue syndrome, fatigue, medication-induced parkinsonian syndrome, Gilles de 1a Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptom, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, or traumatic brain injury. Preferably, the disease includes narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body.

The “prophylaxis” as used herein means the administration of the present compound to a healthy subject who does not develop a disease. For example, the prophylaxis is intended to prevent the development of a disease. The “treatment” as used herein means the administration of the present compound to a person diagnosed with the development of a disease by a doctor (i.e., a patient). For example, the treatment is intended to alleviate a disease or symptom thereof or improve the condition of a patient to the previous condition before a disease is developed. Also, even if the present compound is administered for the purpose of preventing the worsening of a disease or symptom thereof, the administration is referred to as “treatment” when the subject to be administered is a patient.

Hereinafter, the processes for preparing the compound of formula (1) of the present invention are exemplified along with examples, but the processes of the present invention should not be limited to the examples.

Preparation Process

The present compound may be synthesized according to each Preparation Process shown below or its combination with a known synthetic process.

Each compound in the following schemes may exist as a salt thereof, wherein the salt includes, for example, the “pharmaceutically acceptable salt” mentioned above. The following schemes are disclosed as just examples, thus it is also possible to optionally prepare the present compound by a different process based on the knowledge of a skilled person in synthetic organic chemistry field.

In each Preparation Process described below, protecting groups can be used as necessary, even if the use of protecting groups is not explicitly stated. And, the protecting groups can be deprotected after a reaction is completed or a series of reactions have been carried out to obtain the desired compound.

As such protecting groups, for example, general protecting groups described in T. W. Greene, and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^rd Ed., John Wiley & Sons, Inc., New York (1999), and the like may be used. Examples of amino-protecting group include tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, tetrahydropyranyl, and the like; examples of hydroxy-protecting group include trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, methoxymethyl, and the like; examples of aldehyde-protecting group include dialkylacetal, cyclic alkylacetal, and the like; and examples of carboxyl-protecting group include tert-butyl ester, orthoester, amide, and the like.

The introduction and elimination of protecting groups can be carried out by a method commonly used in synthetic organic chemistry (for example, see T. W. Greene, and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^rd Ed., John Wiley & Sons, Inc., New York (1999)), or a similar method.

Preparation Process 1:

In a compound of formula (1) or a pharmaceutically acceptable salt thereof, a compound of formula (1′) can be prepared, for example, by the following process.

wherein R¹, R², L¹, L², ring G, and A are as defined in Item 1.

Step (1):

Compound (1′) can be prepared by reacting compound (s-1) and compound (s-2) in a suitable inert solvent under a reaction condition of urea-binding formulation. The present reaction condition includes, for example, using triphosgene, 4-nitrophenyl chloroformate or thiophosgene. A base is used in the present reaction, and the base used herein includes triethylamine and diisopropylethylamine. The solvent includes a halogenated carbon solvent such as chloroform and dichloromethane; an ether solvent such as diethyl ether, THE and 1,4-dioxane; an aromatic hydrocarbon solvent such as benzene, toluene and xylene; and an ester solvent such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is −20° C. to boiling point of a solvent used herein.

Preparation Process 2:

In a compound of formula (1) or a pharmaceutically acceptable salt thereof, a compound of formula (s-5) can be prepared, for example, by the following process.

wherein R¹, R², L¹, L², and A are as defined in Item 1, R^b1 is as defined in Item 5, X is an amino-protecting group. Compound (s-3) is a compound wherein ring G in Preparation Process 1 is a protected nitrogen-containing ring, and can be synthesized in the same manner as Step (1) in Preparation Process 1.

Step (2):

Compound (s-4) can be prepared by reacting compound (s-3) in a suitable inert solvent under a commonly-used deprotection condition. For example, when X is Boc group, deprotection can be carried out by using an acid in the present reaction condition. Examples of the acid include hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and the like. The solvent includes a halogenated carbon solvent such as chloroform and dichloromethane; an ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane; and an ester solvent such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is −20° C. to boiling point of a solvent used herein. When X is Cbz group or Bn group, deprotection can be carried out, for example, by catalytic reduction under hydrogenation condition. A heterogeneous catalyst such as palladium-carbon is used as the catalyst. The “under hydrogenation condition” means under hydrogen atmosphere or in the presence of formic acid, ammonium formate, and the like. The solvent includes methanol, ethanol, THF, ethyl acetate, and the like. The reaction time is 30 minutes to 24 hours, and the reaction temperature is 0° C. to boiling point of a solvent used herein.

Step (3):

Compound (s-5) can be prepared by reacting compound (s-4) in a suitable inert solvent under a commonly-used reductive amination condition. The present reaction condition includes, for example, using sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, and the like. An acid is used in the present reaction, and the acid used herein includes acetic acid. The solvent includes a halogenated carbon solvent such as chloroform and dichloromethane; an ether solvent such as diethyl ether, THE and 1,4-dioxane; and an ester solvent such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is −20° C. to boiling point of a solvent used herein.

EXAMPLES

The present invention is explained in more detail in the following by referring to Reference Examples, Examples and Test Examples, but is not limited thereto. It should be understood that the names of compounds used in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

In the present specification, the abbreviations shown below may be used.

• • CDCl₃: deuterochloroform
  • DMSO-d₆: deuterodimethylsulfoxide
  • Rt: retention time
  • min: minute
  • HATU: O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • THF: tetrahydrofuran
  • TFA: trifluoroacetic acid
  • DMF: N,N-dimethylformamide
  • Boc: tert-butoxycarbonyl
  • Ns: 2-nitrobenzenesulfonyl group
  • Tf: trifluoromethanesulfonyl group
  • Abs: Absolute Configuration; each chemical structure of compounds described along with Abs mark surrounded with a square flame is shown in absolute configuration with a wedged bond. However, not all compounds without Abs mark are shown in non-absolute configuration, i.e., the configuration should be properly judged based on the disclosure about the subject compound in the present specification and its context, and a skilled person's technical knowledge, with or without Abs mark.
  • Rac: Racemic compound; It represents a compound in a state in which two types of enantiomers are present in equal amounts and no longer exhibit optical rotation.

In the column chromatography and amino chromatography used in Reference Examples and Examples, silica gel column and amino column made by YAMAZEN CORPORATION were used. The TLC (silica gel plate) used in the TLC purification was Silica gel 60F254 (Merck), and the TLC (NH silica gel plate) used therein was TLC plate NH (FujiSilysia).

In Reference Examples and Examples, the reactors shown below were used. The physicochemical data described in Reference Examples and Examples were obtained with the apparatuses below.

Microwave reactor: Biotage AB Initiator

¹H-NMR: JEOL JNM-AL400; JEOL JNM-ECS400; Brucker AVANCE 400 Spectrometer

The symbols used in NMR are defined as follows, s: singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doublets of doublets, dddd: doublet of doublets of doublets of doublets, t: triplet, td: triplet of doublets, q: quartet, m: multiplet, br: broad singlet or multiplet, and J: coupling constant.

The LC/MS data of each compound in Examples and Reference Examples were obtained with any one of the apparatuses below.

Method A

• • Detection apparatus: ACQUITY™ SQ detector (Waters Corporation)
  • HPLC: ACQUITY™ UPLC SYSTEM
  • Column: Waters ACQUITY™ UPLC BEH C18 (1.7 μm, 2.1 mm×30 mm)

Method B

• • Detection apparatus: Shimadzu LCMS-2020
  • Column: Phenomenex Kinetex (C18, 1.7 μm, 2.1 mm×50 mm)

Method C

• • Detection apparatus: ACQUITY™ SQ detector (Waters Corporation)
  • HPLC: ACQUITY™ UPLC SYSTEM
  • Column: Waters ACQUITY™ UPLC BEH C18 (1.7 μm, 2.1 mm×30 mm)

Method D

• • Detection apparatus: Shimadzu LCMS-2020
  • Column: Waters ACQUITY UPLC™ C18 (1.8 μm, 2.1 mm×50 mm)

High-performance liquid chromatograph mass spectrometer; the measurement conditions of LC/MS are as follows, wherein the observed value [MS (m/z)] is denoted by [M+H]⁺ and the retention time is denoted by Rt (min). Each measured MS value shown below is accompanied by any one of A to D which were measurement methods used in the actual measurements.

Method A

• • Solvent: A solution; 0.06% formic acid/H₂O, B solution; 0.06% formic acid/acetonitrile
  • Gradient condition: 0.0-1.3 min (linear gradient from B 2% to B 96%)
  • Flow rate: 0.8 mL/min; Detective UV: 220 nm and 254 nm;
  • Temperature: 40° C.

Hereinafter, the LC-MS data shown below were measured by Method A, unless otherwise indicated.

Method B

• • Solvent: A solution; 0.05% TFA/H₂O, B solution; acetonitrile
  • Gradient condition: 0.0-1.7 min (linear gradient from B 10% to B 99%)
  • Flow rate: 0.5 mL/min; Detective UV: 220 nm; Temperature: 40° C.

Method C

• • Solvent: A solution; 0.05% formic acid/H₂O, B solution; acetonitrile
  • Gradient condition: 0.0-1.3 min (linear gradient from B 10% to B 95%) 1.3-1.5 min (B 10%)
  • Flow rate: 0.8 mL/min; Detective UV: 220 nm and 254 nm;
  • Temperature: 40° C.

Method D

• • Solvent: A solution; 0.1% formic acid/H₂O, B solution; 0.1% formic acid/acetonitrile
  • Gradient condition: 0.01-4.0 min (linear gradient from B 5% to B 99%) 4.0-5.0 min (B 95%)
  • Flow rate: 0.5 mL/min; Detective UV: 220 nm; Temperature: 25° C.

Hereinafter, the data were measured by Method A, unless otherwise indicated.

Reference Example 1

tert-Butyl 4-(2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperazine-1-carboxylate

Step (i)

To a mixture of compound 1 (0.100 g), diisopropylethylamine (0.047 g) and chloroform (1.8 mL) was added 4-nitrophenylchloroformate (0.073 g) at 0° C. and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 4-(4-methylphenyl)piperidine (0.070 g) at 0° C. and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 2 (0.152 g).

LCMS: [M+H]⁺/Rt(min): 479/1.27

Reference Example 2

2-[4-(Propan-2-yl)piperazin-1-yl]aniline

Step (i):

A mixture of compound 3 (1.41 g), potassium carbonate (5.52 g), isopropylpiperazine (1.28 g) and THE (25 mL) was stirred at 50° C. for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then used directly in the next step.

Step (ii):

A mixture of the compound 4 mixture, 10% palladium carbon (1.06 g) and methanol (25 mL) was stirred at room temperature under hydrogen gas atmosphere. The reaction mixture was filtrated with Celite, and the filtrate was concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: chloroform/methanol) to give the title compound 5 (1.50 g). LCMS: [M+H]⁺/Rt(min): 220/0.35

Reference Example 3

4-Fluoro-2-[4-(propan-2-yl)piperazin-1-yl]aniline

Step (i):

The title compound 7 mixture was prepared from compound 6 (0.159 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 8 (0.144 g) was prepared from the compound 7 mixture in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 238/0.39

Reference Example 4

2-Metoxy-6-[4-(propan-2-yl)piperazin-1-yl]aniline

Step (i):

The title compound 10 mixture was prepared from compound 9 (0.020 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 11 (0.019 g) was prepared from the compound 10 mixture in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 250/0.60

Reference Example 5

2-Fluoro-6-[4-(propan-2-yl)piperazin-1-yl]aniline

Step (i)

The title compound 13 mixture was prepared from compound 12 (0.159 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 14 (0.190 g) was prepared from the compound 13 mixture in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 238/1.16 (Method B)

Reference Example 6

3-Fluoro-2-[4-(propan-2-yl)piperazin-1-yl]aniline

Step (i)

The title compound 16 mixture was prepared from compound 15 (0.477 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 17 (0.443 g) was prepared from the compound 16 mixture in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 238/0.46

Reference Example 7

2-Methyl-6-[4-(propan-2-yl)piperazin-1-yl]aniline

Step (i):

The title compound 19 mixture was prepared from compound 18 (0.310 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 20 (0.410 g) was prepared from the compound 19 mixture in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 234/0.61

Reference Example 8

2-[4-(Propan-2-yl)piperazin-1-yl]-6-(trifluoromethyl) aniline

Step (i):

The title compound 22 mixture was prepared from compound 21 (0.209 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 23 (0.220 g) was prepared from the compound 22 mixture in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 288/1.50 (Method B)

Reference Example 9

2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]aniline

Step (i):

The title compound 25 mixture was prepared from compound 24 (4.00 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

To a mixture of the compound 25 mixture, reduced iron (3.82g) and methanol (57 mL) was added 4N aqueous ammonium chloride solution (28.5 mL) at 90° C. and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled to room temperature and filtrated with Celite, and the filtrate was concentrated in vacuo. The resulting residue was then dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: chloroform/methanol) to give the title compound 26 (4.10 g).

LCMS: [M+H]⁺/Rt(min): 254/1.33 (Method B)

Reference Example 10

2-Chloro-6-(4-cyclopropylpiperazin-1-yl)aniline

According to the process in the above Reference Example 9, compound 27 was synthesized by using cyclopropylpiperazine instead of isopropylpiperazine at Step (i) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 252/0.60

Reference Example 11

2-Bromo-6-[4-(propan-2-yl)piperazin-1-yl]aniline

Step (i)

The title compound 29 mixture was prepared from compound 28 (1.50 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 30 (1.64 g) was prepared from the compound 29 mixture in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 298,300/0.58

Reference Example 12

2-Amino-N,N-dimethyl-3-[4-(propan-2-yl)piperazin-1-yl]benzamide

Step (i)

The title compound 32 mixture was prepared from compound 31 (0.212 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 33 (0.201 g) was prepared from the compound 32 mixture in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 291/1.07 (Method B)

Reference Example 13

tert-Butyl (2R,5S)-2-(2-aminophenyl)-5-(propan-2-yl) morpholine-4-carboxylate

Step (i)

A mixture of compound 34 (1.00 g), sodium azide (0.533 g), water (10 mL) and ethanol (20 mL) was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then used directly in the next step.

Step (ii):

A mixture of the crude product of compound 35, sodium borohydride (0.127 g) and methanol was stirred at 0° C. for 1 hour. To reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 36 (0.488 g).

Step (iii):

A mixture of compound 36 (0.289 g), 1-bromo-3-methyl-2-butanone (0.641 g), caesium carbonate (1.176 g) and DMF (3 mL) was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 37 (0.402 g).

LCMS: [M+H]⁺/Rt(min): 293/1.05

Step (iv):

A mixture of compound 37 (0.82 g), triphenylphosphine (0.184 g) and THE (2 mL) was stirred at room temperature for 10 hours. The reaction mixture was concentrated in vacuo and then the resulting residue was purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 38 (0.058 g).

LCMS: [M+H]⁺/Rt(min): 249/0.54

Step (v):

A mixture of compound 38 (0.059 g), sodium triacetoxyborohydride (0.100 g) and dichloromethane (2 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by amino silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 39 (0.049 g).

LCMS: [M+H]⁺/Rt(min): 251/0.63

Step (vi):

A mixture of compound 39 (0.038 g), di-tert-butyl dicarbonate (0.040 g), N,N-dimethyl-4-aminopyridine (0.001 g) and acetonitrile (2 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then used directly in the next step.

LCMS: [M+H]⁺/Rt(min): 325/1.24

Step (vii):

The title compound 41 (0.036 g) was prepared from the compound 40 mixture in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 321/1.13

Reference Example 14

Rac-2-[3-methyl-4-(propan-2-yl)piperazin-1-yl]aniline

Step (i)

The crude product of the title compound 43 was prepared from compound 42 (0.282 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

A mixture of the crude product of compound 43, trifluoroacetic acid (1.80 g) and chloroform (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and then the resulting residue was purified by amino silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 44 (0.370 g).

LCMS: [M+H]⁺/Rt(min): 222/1.29 (Method B)

Step (iii)

A mixture of compound 44 (0.221 g), sodium triacetoxyborohydride (0.635 g), acetic acid (0.060 g), acetone (0.058 g) and THE (5 mL) was stirred at room temperature for 3 hour. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then used directly in the next step.

Step (iv):

The title compound 46 (0.170 g) was prepared from the crude product of compound 45 in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 234/0.48 (Method B)

Reference Example 15

Rac-2-[2-methyl-4-(propan-2-yl)piperazin-1-yl]aniline

Step (i)

The crude product of the title compound 48 was prepared from compound 47 (0.221 g) in the same manner as Step (iii) in Reference Example 14.

Step (ii):

The title compound 49 (0.098 g) was prepared from the crude product of compound 48 in the same manner as Step (ii) in Reference Example 14.

LCMS: [M+H]⁺/Rt(min): 143/0.30

Step (iii):

The crude product of the title compound 50 was prepared from compound 49 (0.071 g) in the same manner as Step (i) in Reference Example 2.

Step (iv):

The title compound 51 (0.060 g) was prepared from the crude product of compound 50 in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 234/0.54

Reference Example 16

Methyl 2-amino-3-[4-(propan-2-yl)piperazin-1-yl]benzoate

Step (i):

The title compound 53 mixture was prepared from compound 52 (0.150 g) in the same manner as Step (i) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 308/0.55

Step (ii):

The title compound 54 (0.132 g) was prepared from the compound 53 mixture in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 278/0.58

Reference Example 17

tert-Butyl 4-(2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-1,4-diazepane-1-carboxylate

Step (i):

The title compound 56 (2.40 g) was prepared from compound 55 (1.06 g) in the same manner as Step (i) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 322/1.08

Step (ii):

The title compound 57 (1.77 g) was prepared from compound 56 (2.40 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 292/0.96

Step (iii):

The title compound 58 (0.153 g) was prepared from compound 57 (0.095 g) in the same manner as Step (i) in Reference Example 1.

LCMS: [M+H]⁺/Rt(min): 493/1.12

Reference Example 18

tert-Butyl 4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)-1,4-diazepane-1-carboxylate

Step (i):

The title compound 59 (0.154 g) was prepared from compound 57 (0.104 g) in the same manner as Step (i) in Reference Example 1.

Reference Example 19

2-(4-tert-Butylpiperazin-1-yl)-6-chloroaniline

Step (i):

The crude product of the title compound 60 was prepared from compound 24 (0.300 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 61 (0.315 g) was prepared from the crude product of compound 60 in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 268/0.56

Reference Example 20

2-[1-(Propan-2-yl)piperidin-4-yl]aniline

Step (i)

A mixture of compound 62 (5.00 g), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (7.60 g), Pd(dppf)Cl₂CH₂Cl₂ (2.02 g), sodium carbonate (5.25 g), water (25 mL) and 1,4-dioxane (50 mL) was stirred at 110° C. for 16 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 63 (7.51 g).

LCMS: [M+H]⁺/Rt(min): 305/4.24 (Method D)

Step (ii):

A mixture of compound 63 (7.51 g), 4N dioxane hydrochloride solution (31 mL) and methanol (150 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound 64 (5.13 g).

LCMS: [M+H]⁺/Rt(min): 205/2.15 (Method D)

Step (iii):

A mixture of compound 64 (2.50 g), sodium triacetoxyborohydride (6.60 g), acetone (0.058 g) and dichloromethane (75 mL) was stirred at room temperature for 12 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: chloroform/methanol) to give the title compound 65 (1.60 g).

LCMS: [M+H]⁺/Rt(min): 247/2.17 (Method D)

Step (iv):

The title compound 66 (0.675 g) was prepared from compound 65 (1.60 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 219/1.85 (Method D)

Reference Example 21

2-Fluoro-6-[1-(propan-2-yl)piperidin-4-yl]aniline

Step (i):

The title compound 67 (0.234 g) was prepared from compound 28 (0.220 g) in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 323/2.12 (Method B)

Step (ii):

A mixture of compound 67 (0.230 g), trifluoroacetic acid (1.80 g) and chloroform (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product of the title compound 68.

Step (iii):

A mixture of the crude product of compound 68, sodium triacetoxyborohydride (0.454 g), acetic acid (0.064 g), acetone (0.166 g) and THE (3 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by amino silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 69 (0.150 g).

LCMS: [M+H]⁺/Rt(min): 265/0.60 (Method B)

Step (iv):

The title compound 70 (0.050 g) was prepared from compound 69 (0.100 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 237/0.53 (Method B)

Reference Example 22

2-Fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]aniline

Step (i)

The title compound 71 (0.077 g) was prepared from compound 69 (0.100 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 235/0.55 (Method B)

Reference Example 23

tert-Butyl 4-(3-ethoxy-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

Step (i)

A mixture of compound 72 (0.654 g), ethyl iodide (0.702 g), potassium carbonate (1.66 g) and THE (10 mL) was stirred at 50° C. for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 73 (0.621 g).

Step (ii):

The title compound 74 (0.558 g) was prepared from compound 73 (0.500 g) in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 349/2.24 (Method B)

Step (iii):

The crude product of the title compound 75 (0.558 g) was prepared from compound 74 (0.300 g) in the same manner as Step (ii) in Reference Example 2.

Step (iv):

To a mixture of the crude product of compound 75, diisopropylethylamine (0.278 g) and chloroform (4 mL) was added triphosgene (0.064 g) at 0° C. and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 4-(4-methylphenyl)piperidine (0.084 g) at 0° C. and the mixture was stirred for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 76 (0.180 g).

LCMS: [M+H]⁺/Rt(min): 522/2.35 (Method B)

Reference Example 24

tert-Butyl 4-(2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}-3-[(propan-2-yl)oxy]phenyl)piperidine-1-carboxylate

Step (i):

The title compound 77 (0.522 g) was prepared from compound 72 (0.654 g) in the same manner as Step (i) in Reference Example 23.

Step (ii):

The title compound 78 (0.611 g) was prepared from compound 77 (0.520 g) in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 363/2.30 (Method B)

Step (iii)

The crude product of the title compound 79 was prepared from compound 78 (0.300 g) in the same manner as Step (ii) in Reference Example 2.

Step (iv):

The title compound 80 (0.299 g) was prepared from the crude product of compound 79 in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 536/2.40 (Method B)

Reference Example 25

tert-Butyl 4-(3-chloro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Step (i)

The title compound 82 (0.502 g) was prepared from compound 81 (0.709 g) in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 339/2.26 (Method B)

Step (ii):

The title compound 83 (0.070 g) was prepared from compound 82 (0.100 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 309/2.22 (Method B)

Step (iii):

The title compound 84 (0.082 g) was prepared from compound 83 (0.070 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 511/2.27 (Method B)

Reference Examples 26-29

According to the process in the above Reference Example 25, the compounds of Reference Examples 26-29 were synthesized by using each corresponding starting compound instead of 4-(4-methylphenyl)piperidine at Step (iii) in Reference Example 25.

TABLE 1
Reference	Chemical Structural	Instrumental Analysis
Example	Formula	Data
26		LCMS: [M + H]+/Rt (min): 542/0.98
27		LCMS: [M + H]+/Rt (min): 542/1.68 (Method B)
28		LCMS: [M + H]+/Rt (min): 525/2.30 (Method B)
29		LCMS: [M + H]+/Rt (min): 459/0.94 (Method C)

• Reference Example 26: tert-butyl 4-(3-chloro-2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate
• Reference Example 27: tert-butyl 4-(3-chloro-2-{[4-(5-cyclopropyl-1,2-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate
• Reference Example 28: tert-butyl 4-(3-chloro-2-{[4-methyl-4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate
• Reference Example 29: tert-butyl 4-{3-chloro-2-[(4-cyano-4-methylpiperidine-1-carbonyl)amino]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

Reference Example 30

tert-Butyl 4-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Step (i):

The title compound 89 (0.750 g) was prepared from compound 67 (0.900 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 293/2.10 (Method B)

Step (ii):

The title compound 90 (0.130 g) was prepared from compound 89 (0.100 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 494/2.27 (Method B)

Reference Example 31

tert-Butyl 4-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

Step (i):

The crude product of the title compound 91 was prepared from compound 67 (0.100 g) in the same manner as Step (ii) in Reference Example 2.

Step (ii):

The title compound 92 (0.120 g) was prepared from the crude product of compound 91 in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 496/1.22

Reference Example 32

2-Methoxy-6-[1-(propan-2-yl)piperidin-4-yl]aniline

Step (i):

The title compound 94 (3.78 g) was prepared from compound 93 (3.00 g) in the same manner as Step (i) in Reference Example 20.

Step (ii):

The title compound 95 (2.80 g) was prepared from compound 94 (3.78 g) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 235/2.31 (Method D)

Step (iii):

The title compound 96 (2.80 g) was prepared from compound 95 (2.80 g) in the same manner as Step (iii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 277/2.42 (Method D)

Step (iv):

The title compound 97 (1.45 g) was prepared from compound 96 (2.00 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 249/3.57 (Method C)

Reference Example 33

2-Methoxy-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]aniline

Step (i):

The title compound 98 (0.237 g) was prepared from compound 96 (0.350 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 247/5.02 (Method D)

Reference Example 34

tert-Butyl 3-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

Step (i):

The title compound 99 (0.113 g) was prepared from compound 28 (0.100 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 4.20-4.34 (2H, m), 4.35-4.50 (2H, m), 5.90-6.04 (1H, m), 7.08-7.17 (1H, m), 7.17-7.25 (1H, m), 7.42-7.51 (1H, m).

Step (ii):

The title compound 100 (0.065 g) was prepared from compound 99 (0.111 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 279/0.99 (Method B)

Step(iii):

The title compound 101 (0.030 g) was prepared from compound 100 (0.030 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 480/2.21(shi) (Method C)

Reference Example 35

2-(3,6-Dihydro-2H-pyran-4-yl)-6-fluoroaniline

Step (i):

The title compound 102 (0.056 g) was prepared from compound 28 (0.100 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

¹H-NMR (CDCl₃) δ: 2.34-2.42 (2H, m), 3.86-3.92 (2H, m), 4.21-4.27 (2H, m), 5.79-5.86 (1H, m), 7.07-7.13 (1H, m), 7.13-7.21 (1H, m), 7.40-7.50 (1H, m).

Step (ii):

The title compound 103 (0.032 g) was prepared from compound 102 (0.054 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 194/0.70 (Method C)

Reference Example 36

2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-fluoroaniline

Step (i):

The title compound 105 (0.007 g) was prepared from compound 104 (0.100 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 218/0.72 (Method C)

Reference Example 37

2-Fluoro-6-[6-(propan-2-yl)pyridin-3-yl]aniline

Step (i):

The title compound 106 (0.110 g) was prepared from compound 28 (0.165 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 261/0.98

Step (ii):

The title compound 107 (0.084 g) was prepared from compound 106 (0.110 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 231/0.64

Reference Example 38

2-Fluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}aniline

Step (i)

A mixture of compound 108 (0.157 g), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.201 g), diisopropyl azodicarboxylate (0.242 g), triphenylphosphine (0.524 g) and THE (10 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 109 (0.233 g).

LCMS: [M+H]⁺/Rt(min): 341/2.17 (Method B)

Step (ii):

The crude product of the title compound 110 was prepared from compound 109 (0.100 g) in the same manner as Step (ii) in Reference Example 21.

Step (iii):

The title compound 111 (0.060 g) was prepared from the crude product of compound 110 in the same manner as Step (iii) in Reference Example 20.

Step (iv):

The title compound 112 (0.030 g) was prepared from compound 111 (0.060 g) in the same manner as Step (ii) in Reference Example 2.

Reference Example 39

Rac-2-chloro-6-{[1-(propan-2-yl)pyrrolidin-3-yl]oxy}aniline

According to the process in the above Reference Example 38, the compound shown below was synthesized by using each corresponding starting compound instead of compound 108 and tert-butyl 4-hydroxypiperidine-1-carboxylate at Step (i) in Reference Example 38.

TABLE 2
Reference	Chemical Structural	Instrumental Analysis
Example	Formula	Data
39		LCMS: [M + H]+/Rt (min): 255/0.57 (Method C)

Reference Example 40

tert-Butyl 3-(3-chloro-2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenoxy)azetidine-1-carboxylate

Step (i):

A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.30 g), sodium hydride (0.41 g) and THE (21 mL) was stirred at 0° C. for 30 minutes, and then compound 24 was added thereto and the mixture was stirred at room temperature for 3 hours. To the reaction was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purifiled by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 114 (2.06 g).

LCMS: [M+H]⁺/Rt(min): 329/1.11

Step (ii):

The title compound 115 (0.77 g) was prepared from compound 114 (1.00 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 299/1.06

Step (iii)

The title compound 116 (0.110 g) was prepared from compound 115 (0.060 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 533/1.08

Reference Example 41

2-Methoxy-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}aniline

Step (i):

The title compound 118 (0.231 g) was prepared from compound 117 (0.181 g) and isopropylpiperazine (0.128 g) in the same manner as Step (iii) in Reference Example 20.

Step (ii):

The title compound 119 (0.140 g) was prepared from compound 118 (0.230 g) in the same manner as Step (ii) in Reference Example 2.

Reference Example 42

3-Fluoro-4′-(propan-2-yl) [1,1′-biphenyl]-2-amine

Step (i)

The title compound 20 (0.231 g) was prepared from compound 28 (0.220 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

Step (ii):

The title compound 121 (0.165 g) was prepared from compound 120 (0.230 g) in the same manner as Step (ii) in Reference Example 2.

Reference Example 43

tert-Butyl 4-(3-chloro-2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

Step (i)

The title compound 122 (0.502 g) was prepared from compound 81 (0.709 g) in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 339/2.26 (Method B)

Step (ii):

The title compound 123 (0.039 g) was prepared from compound 122 (0.10 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 311/2.21 (Method B)

Step (iii):

The title compound 124 (0.084 g) was prepared from compound 123 (0.070 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 545/1.12 (Method C)

Reference Examples 44-45

According to the process in the above Reference Example 43, the compounds shown below were synthesized by using each corresponding starting compound instead of 4-(4-methylphenyl)piperidine at Step (iii) in Reference Example 43.

TABLE 3
Reference	Chemical Structural	Instrumental Analysis
Example	Formula	Data
44		LCMS: [M + H]+/Rt (min): 527/2.06 (Method B)
45		LCMS: [M + H]+/Rt (min): 512/2.30 (Method B)

Reference Example 44: tert-butyl 4-(3-chloro-2-{[4-methyl-4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate Reference Example 45: tert-butyl 4-(3-chloro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

Reference Example 46

2-Fluoro-6-(6-methylpyridin-3-yl)aniline

Step (i):

The title compound 127 (0.198 g) was prepared from compound 28 (0.178 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 261/0.98

Step (ii):

The title compound 128 (0.148 g) was prepared from compound 127 (0.184 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 231/0.64

Reference Example 47

2-Chloro-6-[6-(propan-2-yl)pyridin-3-yl]aniline

Step(i):

The title compound 129 (0.147 g) was prepared from compound 81 (0.247 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 277/1.07

Step (ii):

The title compound 130 (0.130 g) was prepared from compound 129 (0.142 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 247/0.75

Reference Example 48

2-Fluoro-6-(5-methylpyridin-3-yl)aniline

Step (i)

The title compound 131 (0.104 g) was prepared from compound 28 (0.143 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 233/0.80

Step (ii):

The title compound 132 (0.072 g) was prepared from compound 131 (0.091 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 203/0.53

Reference Example 49

2-Fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]aniline

Step (i):

The title compound 133 (0.054 g) was prepared from compound 104 (0.248 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 257/0.90 (Method C)

Reference Example 50

2-Fluoro-6-[2-(propan-2-yl)pyrimidin-5-yl]aniline

Step (i):

The title compound 134 (0.038 g) was prepared from compound 28 (0.100 g) and corresponding boronic acid in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 262/0.90 (Method C)

Step (ii):

The title compound 135 (0.004 g) was prepared from compound 34 (0.036 g) in the same manner as Step (ii) in Reference Example 9.

¹H-NMR (CDCl₃) δ: 1.41 (6H, d, J=6.8 Hz), 3.22-3.37 (1H, m), 3.79 (2H, br), 6.72-6.84 (1H, m), 6.84-6.94 (1H, m), 7.00-7.12 (1H, m), 8.81 (2H, s).

Reference Example 51

tert-Butyl (1S,4S)-5-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Step (i):

The title compound 136 (0.530 g) was prepared from compound 12 (0.324 g) in the same manner as Step (i) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 338/1.08

Step (ii):

The title compound 137 (0.385 g) was prepared from compound 136 (0.530 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 308/1.01

Step (iii):

The title compound 138 (0.080 g) was prepared from compound 137 (0.044 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 509/1.15

Reference Example 52

tert-Butyl (1S,4S)-5-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}-3-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Step (i):

The title compound 139 (0.189 g) was prepared from compound 137 (0.124 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 541/1.01

Reference Example 53

tert-Butyl (1R,4R)-5-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Step (i)

The title compound 140 (0.410 g) was prepared from compound 12 (0.252 g) in the same manner as Step (i) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 338/1.08

Step (ii):

The title compound 141 (0.224 g) was prepared from compound 140 (0.404 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 308/1.01

Step (iii):

The title compound 142 (0.080 g) was prepared from compound 141 (0.037 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 509/1.15

Reference Example 54

tert-Butyl (1R,4R)-5-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}-3-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Step (i):

The title compound 143 (0.088 g) was prepared from compound 141 (0.055 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 541/1.01

Reference Example 55

tert-Butyl 3-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step (i):

The title compound 144 (0.575 g) was prepared from compound 12 (0.382 g) in the same manner as Step (i) in Reference Example 2.

Step (ii):

The title compound 145 (0.451 g) was prepared from compound 144 (0.563 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 322/1.11

Step (iii):

The title compound 146 (0.161 g) was prepared from compound 145 (0.111 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 523/1.23

Reference Example 56

tert-Butyl 3-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step (i):

The title compound 147 (0.189 g) was prepared from compound 145 (0.107 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 556/1.12

Reference Example 57

Benzyl 8-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Step (i):

The title compound 148 (0.338 g) was prepared from compound 12 (0.204 g) in the same manner as Step (i) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 386/1.15

Step (ii):

The title compound 149 (0.220 g) was prepared from compound 148 (0.307 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 356/1.10

Step (iii)

The title compound 150 (0.080 g) was prepared from compound 149 (0.073 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 557/1.20

Reference Example 58

Rac-tert-butyl (2R,5S)-2-(2-amino-3-chlorophenyl)-5-(propan-2-yl)morpholine-4-carboxylate

Step (i):

A mixture of compound 151 (3.03 g), manganese dioxide (11.56 g) and chloroform (160 mL) was stirred with heating under reflux for 12 hours. The mixture was cooled, filtrated with Celite, and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 152 (2.59 g).

LCMS: [M+H]⁺/Rt(min): 186/0.81

Step (ii):

To a mixture of methyltriphenylphosphonium bromide (3.25 g) and THE (21 mL) was added n-butyllithium hexane solution (1.57M, 5.35 mL) at 0° C. and the mixture was stirred at the same temperature for 1 hour. To the mixture was added dropwise a solution of compound 152 (1.30 g) in THE (7 mL) and the mixture was stirred at room temperature for 3 hours. To reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 153 (0.756 g).

Step (iii):

A mixture of compound 153 (0.333 g), m-chloroperoxybenzoic acid (0.542 g) and methylene chloride (9 mL) was stirred at room temperature for 4 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: chloroform/methanol) to give the title compound 154 (0.141 g).

Step (iv):

A mixture of compound 154 (0.141 g), sodium azide (0.046 g) and acetonitrile (3 mL) was stirred at 40° C. for 3 hours. Water was further added thereto and the mixture was stirred with heating under reflux for 10 hours. The reaction mixture was concentrated in vacuo and then the resulting residue was purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 155 (0.084 g).

Step (v):

A mixture of compound 155 (0.100 g), 1-bromo-3-methylbutan-2-one (0.086 g), caesium carbonate (0.226 g) and acetonitrile (3.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and then the resulting residue was purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 156 (0.100 g).

LCMS: [M+H]⁺/Rt(min): 327/1.10

Step (vi):

A mixture of compound 156 (0.100 g), triphenylphosphine (0.097 g) and THE (6 mL) was stirred at room temperature for 4 hours. To the reaction mixture was added sodium triacetoxyborohydride (0.098 g) and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then used directly in the next step.

LCMS: [M+H]⁺/Rt(min): 285/0.69, 285/0.74 (Method C)

Step (vii):

A mixture of the crude product of compound 157, Boc₂O (0.067 g) and THE (6 mL) was stirred at room temperature for 16 hours. The title compound mixture (0.55 g) was prepared in the same manner as Step (ii) in Reference Example 2. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 158 (0.031 g) and the title compound 159 (0.018).

Step (vii):

The title compound 160 (0.029 g) was prepared from compound 158 (0.031 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 355/1.29

Reference Example 59

Rac-tert-butyl (2R,5R)-2-(2-amino-3-chlorophenyl)-5-(propan-2-yl)morpholine-4-carboxylate

Step (i):

The title compound 161 (0.011 g) was prepared from compound 159 (0.018 g) in the same manner as Step (ii) in Reference Example 9.

LCMS: [M+H]⁺/Rt(min): 355/1.29

Reference Example 60

Rac-6-(4-methylphenyl)-3-azabicyclo [4.1.0]heptane

Step (i):

A mixture of compound 162 (1.42 g), p-tolylmagnesium bromide (1M, 8.52 mL) and THE (20 mL) was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 163 (1.62 g).

LCMS: [M+H]⁺/Rt(min): 326/1.01

Step (ii):

A mixture of compound 163 (0.742 g), p-toluenesulfonic acid monohydrate (0.217 g) and toluene was stirred at 50° C. for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 164 (0.561 g).

LCMS: [M+H]⁺/Rt(min): 308/2.23 (Method B)

Step (iii):

To a mixture of diethylzinc (1M, 2.12 mL), diiodomethane (0.566 g) and dichloromethane (2 mL) was added dropwise a solution of compound 164 (0.130 g) in dichloromethane (0.8 mL) at 0° C. and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and then the resulting residue was dissolved in THE (2.8 mL) and water (2.8 mL). To the mixture were added N-methylmorphoine N-oxide (0.114 g) and osmium (VIII) oxide and the mixture was stirred at room temperature for 12 hours. To the reaction mixture were added THE (3 mL) and saturated aqueous sodium thiosulfate solution and the mixture was stirred at 0° C. for 30 minutes. The mixture was extracted with ethyl acetate, and then the obtained organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 165 (0.018 g).

LCMS: [M+H]⁺/Rt(min): 322/2.27 (Method B)

Step (iv):

The title compound 166 (0.010 g) was prepared from compound 165 (0.017 g) in the same manner as Step (ii) in Reference Example 2.

LCMS: [M+H]⁺/Rt(min): 188/1.37 (Method B)

Reference Example 61

4-(2-Fluoro-4-methylphenyl)piperidine

Step (i):

The title compound 168 (0.100 g) was prepared from compound 167 (0.095 g) in the same manner as Step (i) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 292/2.26 (Method B)

Step (ii):

The crude product of the title compound 169 was prepared from compound 168 (0.100 g) in the same manner as Step (ii) in Reference Example 2.

Step (iii):

The title compound 170 (0.050 g) was prepared from the crude product of compound 169 in the same manner as Step (ii) in Reference Example 14.

LCMS: [M+H]⁺/Rt(min): 194/0.58

Reference Example 62

4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride

Step (i)

To a solution of compound 171 (50.0 g) in ethanol (446 mL) was added aqueous 50% hydroxylamine solution (132 mL) and the mixture was stirred at 70° C. for 8 hours. The mixture was cooled to room temperature, and then water (892 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The precipitated white crystal was collected on a filter, and then the obtained crystal was suspended in water (344 mL) and stirred at room temperature for 30 minutes again. The precipitated white solid was collected on a filter and dried to give the title compound 172 (52.3 g).

LCMS: [M+H]⁺/Rt(min): 258/0.52 (Method C)

Step (ii):

To a mixture of compound 172 (52.3 g), cyclopropanecarboxylic acid (18.4 g), HATU (85 g) and THE (406 mL) was added slowly dropwise triethylamine (142 mL) in ice bath and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added ethyl acetate (406 mL) and the mixture was washed with water (406 mL) and brine (406 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 173 (59.1 g).

LCMS: [M+H]⁺/Rt(min): 326/0.77 (Method C)

Step (iii):

A mixture of compound 173 (59.1 g), DBU (54.2 mL) and toluene (727 mL) was stirred with heating under reflux for 1 hour. The reaction mixture was cooled to room temperature and then washed with water (727 mL). The organic layer was concentrated in vacuo and then the resulting residue was purified by silica gel column chromatography (eluate: hexane/ethyl acetate) to give the title compound 174 (54.5 g).

LCMS: [M+H]⁺/Rt(min): 308/1.11 (Method C)

Step (iv):

The title compound 175 (35.3 g) was prepared from compound 174 (54.5 g) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 208/0.30 (Method C)

Reference Examples 63-87

According to the process in the above Reference Example 62, the compounds of Reference Examples 63-87 shown the table below were synthesized by using each corresponding starting compound instead of Compound 171 at Step (i) and cyclopropanecarboxylic acid at Step (ii) in Reference Example 62.

TABLE 4
Reference	Chemical Structural	Instrumental Analysis
Example	Formula	Data
63		LCMS: [M + H]+/Rt (min): 182/0.20 (Method C)
64		LCMS: [M + H]+/Rt (min): 196/0.32 (Method C)
65		LCMS: [M + H]+/Rt (min): 210/0.37 (Method C)
66		LCMS: [M + H]+/Rt (min): 222/0.42 (Method C)
67		LCMS: [M + H]+/Rt (min): 236/0.53 (Method C)
68		LCMS: [M + H]+/Rt (min): 236/0.45 (Method C)
69		LCMS: [M + H]+/Rt (min): 250/0.43 (Method C)
70		LCMS: [M + H]+/Rt (min): 258/0.24 (Method C)
71		LCMS: [M + H]+/Rt (min): 222/0.42 (Method C)
72		LCMS: [M + H]+/Rt (min): 222/0.48 (Method C)
73		LCMS: [M + H]+/Rt (min): 212/0.28 (Method C)
74		LCMS: [M + H]+/Rt (min): 200/0.23 (Method C)
75		LCMS: [M + H]+/Rt (min): 222/0.57 (Method C)
76		LCMS: [M + H]+/Rt (min): 222/0.54 (Method C)
77		LCMS: [M + H]+/Rt (min): 236/0.65 (Method C)
78		LCMS: [M + H]+/Rt (min): 276/0.64 (Method C)
79		LCMS: [M + H]+/Rt (min): 238/0.49 (Method C)
80		LCMS: [M + H]+/Rt (min): 226/0.37 (Method C)
81		LCMS: [M + H]+/Rt (min): 244/0.50 (Method C)
82		LCMS: [M + H]+/Rt (min): 226/0.32 (Method C)
83		LCMS: [M + H]+/Rt (min): 226/0.36 (Method C)
84		LCMS: [M + H]+/Rt (min): 226/0.29 (Method C)
85		LCMS: [M + H]+/Rt (min): 226/0.31 (Method C)
86		LCMS: [M + H]+/Rt (min): 222/0.44 (Method C)
87		LCMS: [M + H]+/Rt (min): 222/0.45 (Method C)

Reference Example 63: 4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine hydrochloride

Reference Example 64: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride

Reference Example 65: 4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride

Reference Example 66: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride

Reference Example 67: 4-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride

Reference Example 68: 4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride

Reference Example 69: 4-methyl-4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride

Reference Example 70: 4-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride

Reference Example 71: 4-methyl-4-[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride

Reference Example 72: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine hydrochloride

Reference Example 73: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine hydrochloride

Reference Example 74: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine hydrochloride

Reference Example 75: rac-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine hydrochloride

Reference Example 76: 4-[5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride

Reference Example 77: 4-[5-(2,2-dimethylcyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride

Reference Example 78: 4-methyl-4-{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine hydrochloride

Reference Example 79: 4-[5-(1-methoxycyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride

Reference Example 80: 4-[5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride

Reference Example 81: 4-[5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride

Reference Example 82: rac-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride

Reference Example 83: rac-4-{5-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride

Reference Example 84: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride

Reference Example 85: 4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride

Reference Example 86: 4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride

Reference Example 87: 4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride

Reference Example 88

3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octane

Step (i):

To a solution of compound 201 (0.100 g) in toluene (0.01 mL) was added CDI (0.070 g) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added N′-hydroxycyclopropanecarboximidamide hydrochloride (0.059 mg) and the mixture was stirred heating under reflux for 2 hours with. The reaction mixture was purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 202 (0.123 g).

LCMS: [M+H]⁺/Rt(min): 320/1.01 (Method C)

Step (ii):

The title compound 203 (0.091 g) was prepared from compound 202 (0.121 g) in the same manner as Step (ii) in Reference Example 14.

LCMS: [M+H]⁺/Rt(min): 220/0.30 (Method C)

Reference Example 89

4-(5-Cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine hydrochloride

Step (i):

To a mixture of compound 204 (900 mg), sodium acetate (650 mg) and methanol (5 mL) was added hydroxylamine hydrochloride (550 mg) and the mixture was stirred at room temperature for 24 hours. The reaction solution was cooled to 0° C., water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 205 (1.23 g).

Step (ii):

To a mixture of compound 205 (416 mg) and DMF (4 mL) was added N-chlorosuccinimide (252 mg) and the mixture was stirred for 3 hours. The reaction solution was cooled to 0° C., water (6 mL) was added thereto, and the precipitated solid was filtrated and dried to give the title compound 206 (326 mg).

Step (iii):

To a mixture of ethynylcyclopropane (117 mg) and toluene (5 mL) were added compound 206 (326 mg) and sodium hydrogen carbonate (198 mg) and the mixture was stirred at room temperature. After the reaction was terminated as judged by the consumption of the starting material, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 207 (348 mg).

LCMS: [M+H]⁺/Rt(min): 307/1.13

Step (iv):

The title compound 208 (307 mg) was prepared from compound 207 (337 mg) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 207/0.49

Reference Examples 90-91

According to the process in the above Reference Example 89, the compounds of Reference Examples 90-91 shown the table below were synthesized by using each corresponding starting compound instead of ethynylcyclopropane at Step (iii) in Reference Example 89.

TABLE 5
Reference	Chemical Structural	Instrumental
Example	Formula	Analysis Data
90		LCMS: [M + H]+/Rt (min): 209/0.53
91		LCMS: [M + H]+/Rt (min): 181/0.44

Reference Example 90: 4-methyl-4-[5-(propan-2-yl)-1,2-oxazol-3-yl]piperidine

Reference Example 91: 4-methyl-4-(5-methyl-1,2-oxazol-3-yl)piperidine

Reference Example 92

2-(4-Methylpiperidin-4-yl)-1,3-benzoxazole

Step (i):

To a solution of compound 211 (1.46 g) in THE (30 mL) were added isobutyl chloroformate (819 mg) and diisopropylethylamine (3.88 g) under ice temperature and the mixture was stirred for 1 hour. To the mixture was then added 2-aminophenol (655 mg) under ice temperature and the mixture was heated and stirred at 70° C. for 6 hours. The reation solution was directly purifed by amino silica gel column chromatography (Eluate: ethyl acetate/hexane) to give the title compound 212 (710 mg).

LCMS: [M+H]⁺/Rt(min): 335/2.28 (Method B)

Step (ii):

A mixture of compound 212 (204 mg) and acetic acid (1.10 mL) was stirred at 90° C. with heating for 2 hours and concetnrated in vacuo. The resulting residue was dissolved in chloroform (2 mL), trifluoromethanesulfonic acid (2.1 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo, ethyl acetate and aqueous sodium hydrogen carbonate solution were added thereto, and then the mixture was extraced with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purfied by amino silica gel chromatography (Eluate: ethyl acetate/hexane) to give the title compound 213 (99 mg).

LCMS: [M+H]⁺/Rt(min): 217/1.36 (Method B)

Reference Example 93

4-(4-Chloro-5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine hydrochloride

Step (i)

A solution of compound 207 (500 mg) and N-chlorosuccinimide (240 mg) in DMF (3.3 mL) was stirred at room temperature for 3 days. Water was added to the reaction solution and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 214 (434 mg).

Step (ii):

The title compound 215 (120.1 mg) was prepared from compound 214 (200 mg) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 241/0.65

Reference Example 94

4-(4-Chloro-5-methyl-1,2-oxazol-3-yl)-4-methylpiperidine hydrochloride

According to the process in the above Reference Example 93, compound 126 was synthesized by using compound 210 in Reference Example 91 instead of compound 207 at Step (i) in Reference Example 93.

LCMS: [M+H]⁺/Rt(min): 215/0.51

Reference Example 95

4-Cyclopentyl-4-methylpiperidine hydrochloride

Step (i):

To a mixture of compound 217 (700 mg) and THE (14 mL) was added lithium diisopropylamide (2M, 5.18 mL) at −78° C. and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture were then added bromocyclopentane (1.23 mL) and potassium iodide (478 mg), the mixture was warmed to room temperature and stirred overnight, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: ethyl acetate/hexane) to give the title compound 218 (468 mg).

LCMS: [M+H]⁺/Rt(min): 312/1.26

Step (ii)

To a mixture of lithium aluminium hydride (104 mg) and THE (3 mL) was added a mixture of compound 218 (371 mg) and THE (6 mL) under ice temperature and the mixture was stirred for 4 hours. After the reaction was terminated as judged by the consumption of the starting material, water (0.104 mL), 15% aqueous sodium hydroxide solution (0.104 ml), and then water (0.312 mL) were added to the reaction mixture at 0° C., and the mixture was stirred. The reaction solution was filtrated and the filtrate was concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: ethyl acetate/hexane) to give the title compound 219 (320 mg).

LCMS: [M+H]⁺/Rt(min): 284/1.06

Step (iii):

To a mixture of compound 219 (314 mg), triethylamine (0.309 mL) and THE (5 mL) was added methanesulfonyl chloride (0.104 mL) and the mixture was stirred at room temperature. After the reaction was terminated as judged by the consumption of the starting material, water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: ethyl acetate/hexane) to give the title compound 220 (290 mg).

LCMS: [M+H]⁺/Rt(min): 362/1.15

Step (iv):

To a mixture of compound 220 (278 mg) and THE (3 mL) was added lithium triethylborohydride (0.99 M, 1.55 mL) and the mixture was stirred at room temperature. The reaction solution was then heated to 70° C. After the reaction was terminated as judged by the consumption of the starting material, the reaction solution was cooled to 0° C. and aqueous ammonium chloride solution was added thereto. The mixture was extracted with chloroform, the obtained organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purifed by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 221 (100 mg).

LCMS: [M+H]⁺/Rt(min): 268/1.42

Step (v)

The title compound 222 (58.5 mg) was prepared from compound 221 (90 mg) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 168/0.62

Reference Example 96

4-Methyl-4-(2-methyl-1,3-oxazol-5-yl)piperidine

Step (i):

To a solution of compound 223 (1.00 g) in THE (10 mL) cooled to −78° C. was added dropwise a solution of LHMDS in toluene (1M, 4.35 mL) and the mixture was stirred for 1 hour. Trimethylchlorosilane (0.495 g) was added thereto and the mixture was warmed to 0° C. and minutes. The mixture was cooled to −78° C. again, and then bromine (0.662 g) was added thereto and the mixture was gradually warmed to room temperature. The reaction mixture was added to a mixture of 10% aqueous sodium hypochlorite solution (7.5 mL) and saturated aqueous ammonium chloride solution (7.5 mL) and the mixture was extracted with ethyl acetate. The obtained organic layer was concentrated in vacuo to give the title compound 224 (1.16 g).

LCMS: [M+H]⁺/Rt(min): 321/0.94

Step (ii):

A mixture of compound 224 (0.10 g) and acetamide (0.020 g) was stirred at 130° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 225 (0.007 g).

LCMS: [M+H]⁺/Rt(min): 281/0.97

Step (iii):

The title compound 226 (0.005 g) was prepared from compound 225 (0.007 g) in the same manner as Step (ii) in Reference Example 14.

LCMS: [M+H]⁺/Rt(min): 181/0.22

Reference Example 97

4-Methyl-4-[2-(propan-2-yl)-1,3-oxazol-5-yl]piperidine

Step (i)

The title compound 227 (0.012 g) was prepared from compound 224 (0.10 g) in the same manner as Step (ii) in Reference Example 96.

LCMS: [M+H]⁺/Rt(min): 309/1.18

Step (ii):

The title compound 228 (0.009 g) was prepared from compound 227 (0.011 g) in the same manner as Step (ii) in Reference Example 14.

LCMS: [M+H]⁺/Rt(min): 209/0.38

Reference Example 98

4-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methylpiperidine

Step (i)

To a mixture of compound 211 (399 mg), cyclopropanecarbohydrazide hydrochloride (269 mg) and DMF (5 mL) were added HATU (686 mg) and diisopropylethylamine (1.15 mL) and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 229 (520 mg).

LCMS: [M+H]⁺/Rt(min): 326/0.74

Step (ii):

To a mixture of compound 229 (255 mg) and toluene (6 mL) was added Lawesson's reagent (349 mg) and the mixture was stirred with heating under reflux for 1 hour. The reaction solution was cooled to 0° C., and then aqueous sodium hydrogen carbonate solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by silica gel column chromatography (Eluate: hexane/ethyl acetate) followed by amino silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 230 (102 mg).

LCMS: [M+H]⁺/Rt(min): 324/1.08

Step (iii):

The title compound 231 (78 mg) was prepared from compound 230 (92 mg) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 224/0.45

Reference Example 99

4-(5-Cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine hydrochloride

Step (i):

The title compound 232 (796 mg) was prepared from compound 211 (718 mg) and 2-amino-1-cyclopropylethan-1-one hydrochloride (400 mg) in the same manner as Step (i) in Reference Example 98.

LCMS: [M+H]⁺/Rt(min): 325/0.83

Step (ii):

To a mixture of compound 232 (127 mg), pyridine (0.063 mL) and toluene (3 mL) was added Lawesson's reagent (205 mg) and the mixture was stirred with heating under reflux for 14 hours. The reaction solution was cooled to room temperature, and then aqueous sodium hydrogen carbonate solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by amino silica column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 233 (76.3 mg).

LCMS: [M+H]⁺/Rt(min): 323/1.43

Step (iii):

The title compound 234 (66.5 mg) was prepared from compound 233 (77 mg) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 223/0.67

Reference Example 100

4-(2-Cyclopropyl-1,3-thiazol-4-yl)-4-methylpiperidine hydrochloride

Step (i)

A solution of compound 224 (531.6 mg) and cyclopropanecarbothioamide (168 mg) in methanol (6 mL) was stirred with heating under reflux for 2 and a half hours. The resulting mixture was cooled to room temperature, and then saturated aqueous sodium hydrogen carbonate solution was added thereto and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting residue was then purifed by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 235 (119 mg).

Step (ii)

The title compound 236 (136.8 mg) was prepared from compound 235 (119 mg) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 223/0.57

Reference Example 101

Ethyl 4-methyl-1-({2-[4-(propan-2-yl)piperazin-1-yl]phenyl}carbamoyl)piperidine-4-carboxylate

Step (i):

The title compound 237 (0.357 g) was prepared from compound 5 (0.237 g) in the same manner as Step (i) in Reference Example 1.

LCMS: [M+H]⁺/Rt(min): 417/1.61 (Method B)

Reference Example 102

Ethyl 4-fluoro-1-({2-[4-(propan-2-yl)piperazin-1-yl]phenyl}carbamoyl)piperidine-4-carboxylate

Step (i):

The title compound 238 (0.040 g) was prepared from compound 5 (0.179 g) in the same manner as Step (i) in Reference Example 1.

LCMS: [M+H]⁺/Rt(min): 421/1.57 (Method B)

Reference Example 103

tert-Butyl (3aR,5s,6aS)-5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound A-2) and tert-butyl (3aR,5r,6aS)-5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound A-3)

To a solution of compound A-1 (331 mg) in 1,2-dimethoxyethane (6.7 mL)/ethanol (0.67 mL) were added p-toluenesulfonylmethyl isocyanide (373 mg) and potassium t-butoxide (396 mg) at 0° C. and the mixture was stirred at 40° C. for 4 hours. The mixture was cooled to room temperature, and then the reaction solution was filtrated and the filtrate was concentrated in vacuo. The resulting residue was then purfiled by silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compounds A-2 (80 mg) and A-3 (59.4 mg).

• • Compound A-2: LCMS: [M+H]⁺/Rt(min): 237/0.89
  • Compound A-3: LCMS: [M+H]⁺/Rt(min): 237/0.88

Reference Examples 104-105

According to the process in the above Reference Example 62, the compounds of Reference Examples 104-105 shown in the table below were synthesized by using compound A-2 or A-3 in Reference Example 103 instead of compound 171 at Step (i) in Reference Example 62.

TABLE 6
Reference	Chemical Structural	Instrumental
Example	Formula	Analysis Data
104		LCMS: [M + H]+/Rt (min): 220/0.39
105		LCMS: [M + H]+/Rt (min): 220/0.48

Reference Example 104: (3aR,5s,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)octahydrocyclopenta[c]pyrrole

Reference Example 105: (3aR,5r,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)octahydrocyclopenta[c]pyrrole

Example 1

N-[2-(4-Ethylpiperazin-1-yl)phenyl]-4-(4-methoxyphenyl)piperidine-1-carboxamide

The title compound (0.031 g) was prepared from compound 239 (0.025 g) and compound 240 (0.021 g) in the same manner as Step (iv) in Reference Example 23.

¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J=7.2 Hz), 1.59-1.76 (3H, m), 1.94 (2H, d, J=12.4 Hz), 2.48-2.75 (6H, m), 2.95-3.05 (6H, m), 3.80 (3H, s), 4.28 (2H, d, J=13.2 Hz), 6.87 (2H, d, J=7.2 Hz), 6.96 (1H, dt, J=7.6, 5.6 Hz), 7.12-7.18 (4H, m), 8.22 (1H, dd, J=8.4, 1.6 Hz), 8.26 (1H, s).

Examples 2-120

The compounds of Examples 2-120 shown in the table below were synthesized in the same manner as Example 1 by using each corresponding commercial compound or compound of Reference Example.

TABLE 7
	Strucural Formula	Material A	Material B
Example	Spectral Data
2		Commercial Product	Commercial Product
	1H-NMR (CDCl3) δ: 1.20 (3H, t, J = 6.4 Hz), 1.61 (2H, brs), 2.08 (1H, dd, J = 10.4, 4.0 Hz), 2.12
	(1H, dd, J = 10.4, 4.0 Hz), 2.30 (2H, dd, J = 13.2, 4.0 Hz), 2.56-2.69 (4H, m), 3.00 (4H, brs), 3.27
	(3H, dt, J = 11.2, 2.8 Hz), 4.18 (2H, dt, J = 14.0, 3.6 Hz), 7.00 (1H, dt, J = 7.6, 1.2 Hz), 7.15-7.22
	(2H, m), 7.34-7.38 (2H, m), 7.54 (1H, dd, J = 3.6, 2.4 Hz), 7.73 (1H, dd, J = 3.6, 2.4 Hz), 8.23 (1H, dd, J = 8.4, 0.8 Hz), 8.29 (1H, brs)
3		Commercial Product	Commercial Product
	1H-NMR (CDCl3) δ: 1.22 (3H, m), 1.73 (1H, dd, J = 12.4, 4.0 Hz), 1.78 (1H, dd, J = 12.4, 4.0 Hz),
	1.97 (2H, d, J = 11.6 Hz), 2.76-2.58 (4H, m), 3.07-3.01 (5H, m), 3.82 (6H, s), 4.30 (2H, d, J = 13.2
	Hz), 6.37 (1H, d, J = 2.4 Hz), 6.41 (2H, d, J = 2.4 Hz), 7.00 (1H, dt, J = 8.2, 1.0 Hz), 7.22-7.16 (2H, m), 8.23 (1H, d, J = 8.2 Hz)
4		Commercial Product	Commercial Product
	1H-NMR (CDCl3) δ: 1.35 (3H, s), 1.53 (3H, t, J = 7.2 Hz), 2.13 (2H, t, J = 10.2 Hz), 2.47-2.43 (2H,
	m), 3.24-3.22 (2H, m), 3.40-3.78 (2H, m), 3.54-3.49 (4H, m), 3.69-3.65 (2H, m), 4.19 (4H, dd, J =
	5.8, 1.0 Hz), 7.30-7.26 (2H, m), 7.41-7.34 (5H, m), 7.49 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 7.6 Hz), 9.85 (1H, brs)
5		Reference Example 2	Commercial Product
	1H-NMR (CDCl3) δ: 1.04 (6H, d, J = 6.1 Hz), 1.25 (3H, s), 1.70-1.76 (2H, m), 2.09-2.15 (2H, m),
	2.55-2.68 (4H, m), 2.83 (4H, m), 3.41-3.59 (4H, m), 6.87 (1H, m), 7.03-7.09 (2H, m), 7.15-7.19
	(3H, m), 7.29 (2H, m), 8.10 (1H, m), 8.17 (1H, brs)
6		Reference Example 2	Commercial Product
	1H-NMR (CDCl3) δ: 1.58 (6H, m), 2.26-2.20 (4H, m), 3.51-3.49 (2H, m), 3.64-3.63 (3H, m), 3.89-3.86
	(2H, m), 4.59-4.45 (4H, m), 4.86-4.85 (2H, m), 7.41-7.37 (2H, m), 7.45 (2H, d, J = 8.4 Hz), 7.60-
	7.52 (4H, m), 7.64 (1H, d, J = 8.4 Hz), 9.14 (1H, brs)
7		Reference Example 2	Commercial Product
	1H-NMR (CDCl3) δ: 1.00 (6H, d, J = 6.1 Hz), 1.63-1.72 (2H, m), 1.87 (2H, m), 2.57-2.71 (6H, m),
	2.84 (4H, m), 2.96 (2H, m), 4.23 (2H, m), 6.88 (1H, m), 7.05-7.10 (2H, m), 7.14-7.18 (3H, m),
	7.24-7.28 (2H, m), 8.15 (1H, m), 8.27 (1H, brs)
8		Reference Example 4	Commercial Product
	1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.7 Hz), 1.60-1.72 (2H, m), 1.83 (2H, m), 2.26 (3H, s), 2.57-
	2.69 (6H, m), 2.85-2.96 (6H, m), 3.79 (3H, s), 4.25 (2H, m), 6.12 (1H, s), 6.65 (2H, m), 7.00-7.08 (5H, m)
9		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.06 (6H, d, J = 6.7 Hz), 1.65-1.73 (2H, m), 1.91 (2H, m), 2.32 (3H, s), 2.57-
	2.69 (6H, m), 2.90 (4H, m), 3.01 (2H, m), 4.30 (2H, m), 6.35 (1H, s), 6.83-6.89 (2H, m), 7.01-7.14 (5H, m)
10		Reference Example 3	Commercial Product
	1H-NMR (CDCl3) δ: 1.00 (6H, d, J = 6.7 Hz), 1.64-1.71 (2H, m), 1.85 (2H, m), 2.26 (3H, s), 2.58-
	2.69 (6H, m), 2.81 (4H, m), 2.95 (2H, m), 4.20 (2H, m), 6.74-6.83 (2H, m), 7.05 (4H, m), 7.89 (1H, s), 8.08 (1H, m)
11		Reference Example 6	Commercial Product
	1H-NMR (CDCl3) δ: 0.98 (6H, d, J = 6.7 Hz), 1.59-1.70 (2H, m), 1.85 (2H, m), 2.20-2.26 (5H, m),
	2.60-2.75 (4H, m), 2.83-2.98 (4H, m), 3.33 (2H, m), 4.22 (2H, m), 6.55 (1H, m), 7.00-7.08 (5H, m), 7.97 (1H, m), 8.73 (1H, brs)
12		Reference Example 2	Commercial Product
	1H-NMR (CDCl3) δ: 1.38 (6H, d, J = 6.8 Hz), 1.82 (2H, ddd, J = 14.0, 10.8, 3.2 Hz), 2.45 (2H, d, J =
	13.6 Hz), 2.73-2.70 (4H, m), 2.80 (3H, s), 2.96-2.88 (4H, m), 3.27 (2H, ddd, J = 14.0, 10.8, 3.2
	Hz), 3.96 (2H, dt, J = 14.0, 3.6 Hz), 6.96 (1H, dt, J = 8.0, 1.2 Hz), 7.24-7.11 (2H, m), 7.53-7.48
	(3H, m), 8.11 (2H, dd, J = 7.2, 1.6 Hz), 8.17 (1H, dd, J = 7.2, 0.8 Hz), 8.27 (1H, brs)
13		Reference Example 2	Commercial Product
	1H-NMR (CDCl3) δ: 1.13 (6H, d, J = 6.4 Hz), 1.52 (3H, s), 1.84 (2H, ddd, J = 14.4, 10.0, 4.0 Hz),
	2.46 (2H, dd, J = 11.2, 3.2 Hz), 2.77-2.66 (5H, m), 3.27 (2H, ddd, J = 14.4, 10.0, 4.0 Hz), 3.95
	(2H, dt, J = 14.0, 4.0 Hz), 6.96 (1H, dt, J = 7.6, 1.2 Hz), 7.25-7.11 (3H, m), 7.44 (1H, ddd, J =
	8.0, 4.8, 0.8 Hz), 8.17 (1H, dd, J = 8.0, 1.2 Hz), 8.28 (1H, brs), 8.37 (1H, dt, J = 8.0, 1.6 Hz),
	8.76 (1H, dd, J = 4.8, 1.6 Hz), 9.33 (1H, dd, J = 2.0, 0.8 Hz)
14		Reference Example 2	Reference Example 60
	1H-NMR (CDCl3) δ: 0.99 (1H, dd, J = 9.8, 5.2 Hz), 1.07 (1H, dd, J = 9.8, 5.2 Hz), 1.14 (6H, brs),
	1.55-1.49 (2H, m), 2.21-2.17 (1H, m), 2.34-2.22 (1H, m), 2.36 (3H, s), 2.78-2.68 (4H, m), 2.95-
	2.94 (4H, m), 3.44-3.37 (1H, m), 3.66-3.62 (1H, m), 3.91 (1H, dd, J = 12.8, 2.4 Hz), 4.01 (1H, dd,
	J = 12.8, 4.8 Hz), 6.98 (1H, t, J = 8.0 Hz), 7.27-7.14 (6H, m), 8.25 (1H, dd, J = 8.0, 1.2 Hz)
15		Reference Example 4	Commercial Product
	1H-NMR (CDCl3) δ: 1.05 (6H, d, J = 6.7 Hz), 1.70-1.78 (2H, m), 1.90 (2H, m), 2.60-2.69 (5H, m),
	2.75-2.95 (5H, m), 3.00 (2H, m), 3.85 (3H, s), 4.34 (2H, m), 6.18 (1H, s), 6.71 (2H, m), 7.08 (1H, m), 7.32 (2H, m), 7.56 (2H, m)
16		Reference Example 4	Commercial Product
	1H-NMR (CDCl3) δ: 1.05 (6H, d, J = 6.1 Hz), 1.65-1.75 (2H, m), 1.90 (2H, m), 2.60-2.79 (6H, m),
	2.90 (4H, m), 2.99 (2H, m), 3.85 (3H, s), 4.32 (2H, m), 6.18 (1H, s), 6.71 (2H, m), 7.08 (1H, m), 7.14 (2H, m), 7.22 (2H, m)
17		Reference Example 7	Commercial Product
	1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.7 Hz), 1.60-1.70 (2H, m), 1.85 (2H, m), 2.20 (3H, s), 2.26
	(3H, s), 2.55-2.66 (6H, m), 2.82 (4H, m), 2.94 (2H, m), 4.25 (2H, m), 6.68 (1H, s), 6.85-6.99 (3H, m), 7.01-7.08 (4H, m)
18		Reference Example 2	Reference Example 61
	1H-NMR (CDCl3) δ: 1.05 (6H, d, J = 6.7 Hz), 1.68-1.77 (2H, m), 1.87 (2H, m), 2.30 (3H, s), 2.56-
	2.69 (5H, m), 2.89 (4H, m), 3.02 (3H, m), 4.27 (2H, m), 6.82-6.95 (3H, m), 7.04-7.15 (3H, m), 8.19 (1H, m), 8.30 (1H, brs)
19		Reference Example 2	Reference Example 65
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.7 Hz), 1.75 (2H, ddd, J = 25.4, 12.5, 4.0 Hz), 1.88-1.95 (2H,
	m), 2.33 (3H, s), 2.61-2.78 (6H, m), 2.87-2.94 (4H, m), 2.98-3.07 (2H, m), 3.87 (3H, s), 4.30-
	4.38 (2H, m), 7.05 (1H, dd, J = 7.9, 7.9 Hz), 7.14 (4H, s), 7.28 (1H, dd, J = 7.9, 1.5 Hz), 7.53 (1H, dd, J = 7.9, 1.5 Hz), 7.97 (1H, s).
20		Reference Example 5	Reference Example 65
	1H-NMR (CDCl3) δ: 0.88-0.99 (2H, m), 0.99-1.07 (2H, m), 1.09 (6H, d, J = 6.7 Hz), 1.61-1.90 (6H, m),
	1.96-2.07 (3H, m), 2.18-2.31 (2H, m), 2.68-2.85 (2H, m), 2.90-3.15 (5H, m), 4.09-4.16 (2H, m),
	5.79 (1H, s), 5.85 (1H, s), 6.94 (1H, ddd, J = 9.6, 7.8, 1.4 Hz), 7.10-7.21 (2H, m).
21		Reference Example 4	Reference Example 65
	1H-NMR (CDCl3) δ: 0.91-0.99 (2H, m), 1.00-1.07 (2H, m), 1.09 (6H, d, J = 6.1 Hz), 1.75 (2H, ddd, J =
	25.1, 11.6, 4.3 Hz), 1.96-2.06 (3H, m), 2.61-2.79 (5H, m), 2.88-3.00 (5H, m), 3.09 (2H, ddd, J =
	13.9, 11.6, 2.3 Hz), 4.16-4.26 (2H, m), 5.78 (1H, s), 6.35 (1H, s), 6.83-6.91 (2H, m), 7.05 (1H, ddd, J = 8.3, 8.3, 5.9 Hz).
22		Reference Example 5	Reference Example 63
	1H-NMR (CDCl3) δ: 0.93-1.00 (2H, m), 1.00-1.08 (2H, m), 1.24 (3H, s), 1.32 (6H, d, J = 6.7 Hz), 1.51
	(2H, ddd, J = 14.1, 10.4, 3.7 Hz), 1.96-2.05 (3H, m), 3.04-3.17 (3H, m), 3.60-3.68 (2H, m), 5.76
	(1H, s), 5.78 (1H, s), 7.07-7.17 (2H, m), 7.21-7.26 (2H, m), 7.69 (1H, dd, J = 7.9, 2.1 Hz), 8.55 (1H, d, J = 2.1 Hz).
23		Reference Example 4	Reference Example 63
	1H-NMR (CDCl3) δ: 0.92-1.00 (2H, m), 1.00-1.09 (2H, m), 1.13 (3H, d, J = 6.7 Hz), 1.29 (3H, s), 1.61-
	1.73 (2H, m), 1.97-2.06 (1H, m), 2.06-2.18 (2H, m), 2.37-2.48 (2H, m), 2.72-2.83 (2H, m), 2.93-
	3.07 (1H, m), 3.20-3.35 (4H, m), 3.69-3.82 (2H, m), 4.33-4.62 (2H, m), 5.67 (1H, s), 5.79 (1H, s),
	6.05 (1H, s), 7.04-7.11 (2H, m), 7.29 (1H, dd, J = 6.7, 2.4 Hz).
24		Reference Example 5	Reference Example 68
	1H-NMR (CDCl3) δ: 0.94-1.00 (2H, m), 1.00-1.08 (2H, m), 1.25 (3H, s), 1.51 (2H, ddd, J = 13.9, 10.2,
	3.8 Hz), 1.96-2.05 (3H, m), 2.56 (3H, s), 3.13 (2H, ddd, J = 13.9, 10.9, 2.9 Hz), 3.61-3.69 (2H,
	m), 5.77 (1H, s), 5.84 (1H, s), 7.06-7.10 (1H, m), 7.13 (1H, ddd, J = 9.6, 8.4, 1.4 Hz), 7.17-7.27
	(2H, m), 7.64 (1H, dd, J = 7.9, 2.1 Hz), 8.48 (1H, d, J = 2.1 Hz).
25		Reference Example 4	Reference Example 68
	1H-NMR (CDCl3) δ: 0.92-0.99 (2H, m), 0.99-1.07 (2H, m), 1.23 (3H, s), 1.30 (6H, d, J = 6.7 Hz), 1.47
	(2H, ddd, J = 14.0, 10.4, 3.7 Hz), 1.94-2.04 (3H, m), 3.00-3.16 (3H, m), 3.59-3.68 (2H, m), 5.75
	(1H, s), 6.02 (1H, s), 7.17-7.24 (3H, m), 7.43 (1H, dd, J = 6.7, 3.0 Hz), 7.68 (1H, dd, J = 7.9, 2.4 Hz), 8.52 (1H, d, J = 2.4 Hz).
26		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 0.93-1.00 (2H, m), 1.00-1.09 (2H, m), 1.24 (3H, s), 1.50 (2H, ddd, J = 14.1, 10.7,
	3.7 Hz), 1.94-2.06 (3H, m), 2.36 (3H, s), 3.12 (2H, ddd, J = 13.8, 10.7, 2.8 Hz), 3.60-3.69 (2H,
	m), 5.76 (1H, s), 5.78 (1H, s), 7.06-7.11 (1H, m), 7.11-7.18 (1H, m), 7.21-7.29 (1H, m), 7.54 (1H, s), 8.40 (1H, d, J = 1.8 Hz), 8.44 (1H, d, J = 1.8 Hz).
27		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.04 (3H, t, J = 7.0 Hz), 1.18-1.24 (4H, m), 1.33 (3H, s), 1.66 (2H, ddd, J =
	14.1, 10.4, 3.7 Hz), 1.80 (1H, d, J = 9.8 Hz), 1.88 (1H, d, J = 9.8 Hz), 2.15-2.21 (1H, m), 2.22-
	2.30 (2H, m), 2.44-2.63 (2H, m), 2.71 (1H, d, J = 9.8 Hz), 2.92 (1H, dd, J = 9.8, 2.4 Hz), 3.13-3.23
	(2H, m), 3.31 (1H, dd, J = 9.5, 2.4 Hz), 3.40 (1H, d, J = 9.5 Hz), 3.48-3.52 (1H, m), 3.74-3.84 (2H,
	m), 4.01-4.06 (1H, m), 5.66 (1H, s), 6.49 (1H, d, J = 8.6 Hz), 6.56 (1H, dd, J = 8.6, 8.6 Hz), 6.96-7.04 (1H, m).
28		Reference Example 14	Commercial Product
	1H-NMR (CDCl3) δ: 1.05 (6H, dd, J = 6.1, 1.2 Hz), 1.66-1.77 (2H, m), 1.82-1.95 (4H, m), 2.33 (3H,
	s), 2.54-2.76 (3H, m), 2.95-3.06 (2H, m), 3.13 (1H, dd, J = 9.2, 2.4 Hz), 3.33 (1H, dd, J = 9.8,
	2.4 Hz), 3.46 (1H, d, J = 9.8 Hz), 3.70-3.74 (1H, m), 4.05-4.09 (1H, m), 4.18-4.28 (2H, m), 5.70
	(1H, s), 6.51 (1H, d, J = 8.3 Hz), 6.60 (1H, ddd, J = 9.5, 8.3, 1.2 Hz), 6.99-7.06 (1H, m), 7.11 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz).
29		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.03 (6H, t, J = 6.1 Hz), 1.18-1.25 (4H, m), 1.33 (3H, s), 1.66-1.72 (2H, m),
	1.83 (1H, d, J = 9.2 Hz), 1.91 (1H, d, J = 9.2 Hz), 2.14-2.22 (1H, m), 2.24-2.31 (2H, m), 2.53-
	2.60 (1H, m), 2.62 (1H, dd, J = 9.8, 1.2 Hz), 3.11 (1H, dd, J = 9.8, 2.4 Hz), 3.14-3.25 (2H, m), 3.29
	(1H, dd, J = 9.8, 2.1 Hz), 3.41 (1H, d, J = 9.8 Hz), 3.67-3.72 (1H, m), 3.75-3.85 (2H, m), 4.02-
	4.06 (1H, m), 5.63 (1H, s), 6.49 (1H, d, J = 9.0 Hz), 6.57 (1H, ddd, J = 9.0, 7.9, 1.2 Hz), 6.98-7.05 (1H, m).
30		Reference Example 15	Commercial Product
	1H-NMR (CDCl3) δ: 1.13 (6H, brs), 1.48-1.68 (2H, m), 1.76 (2H, ddd, J = 25.4, 12.8, 4.0 Hz), 1.81-
	2.04 (6H, m), 2.34 (3H, s), 2.57-2.77 (3H, m), 2.98-3.23 (3H, m), 3.53-3.67 (2H, m), 4.28-4.34
	(2H, m), 6.38 (1H, s), 6.88 (1H, dd, J = 8.6, 8.6 Hz), 6.94 (1H, d, J = 8.6 Hz), 7.00-7.08 (1H, m),
	7.12 (2H, d, J = 8.0 Hz), 7.15 (2H, d, J = 8.0 Hz).
31		Reference Example 20	Commercial Product
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.1 Hz), 1.19-1.25 (4H, m), 1.34 (3H, s), 1.66-1.81 (4H, m),
	1.89-1.97 (2H, m), 2.15-2.24 (1H, m), 2.26-2.33 (2H, m), 2.55-2.65 (2H, m), 2.67 (2H, dd, J = 11.3,
	2.8 Hz), 3.04 (2H, d, J = 11.3 Hz), 3.23 (2H, ddd, J = 13.6, 10.9, 2.6 Hz), 3.47-3.57 (1H, m), 3.85-
	3.93 (2H, m), 6.34 (1H, s), 6.84 (1H, dd, J = 8.0, 1.5 Hz), 6.89 (1H, t, J = 8.0 Hz), 6.99-7.06 (1H, m).
32		Reference Example 5	Reference Example 88
	1H-NMR (CDCl3) δ: 0.96-1.05 (4H, m), 1.07 (6H, d, J = 6.8 Hz), 1.81-1.90 (2H, m), 1.95-2.10 (3H, m),
	2.12-2.25 (4H, m), 2.56-2.76 (5H, m), 2.88-3.00 (4H, m), 3.42-3.55 (1H, m), 4.44-4.55 (2H, m), 6.31 (1H, bs), 6.83-6.93 (2H, m), 7.03-7.12 (1H, m).
33		Reference Example 12	Commercial Product
	1H-NMR (CDCl3) δ: 1.07 (6H, d, J = 6.7 Hz), 1.72-1.88 (4H, m), 2.33 (3H, s), 2.63-2.73 (6H, m),
	2.91-3.02 (6H, m), 3.05 (3H, s), 3.09 (3H, s), 4.24 (2H, m), 6.99-7.05 (2H, m), 7.11-7.17 (5H, m), 7.48 (1H, brs)
34		Reference Example 8	Commercial Product
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.7 Hz), 1.68-1.75 (2H, m), 1.90 (2H, m), 2.34 (3H, s), 2.65-
	2.75 (6H, m), 2.91-3.04 (6H, m), 4.30 (2H, m), 6.55 (1H, s), 7.11-7.16 (4H, m), 7.21-7.31 (2H, m), 7.40 (1H, m)
35		Reference Example 9	Commercial Product
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.7 Hz), 1.70-1.80 (2H, m), 1.92 (2H, m), 2.34 (3H, s), 2.63-
	2.77 (6H, m), 2.92 (4H, m), 3.04 (2H, m), 4.34 (2H, m), 6.43 (1H, s), 6.98 (1H, m), 7.06 (1H, m), 7.11-7.18 (5H, m)
36		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.07 (6H, d, J = 6.7 Hz), 1.79-1.90 (2H, m), 2.03 (2H, m), 2.63-2.72 (5H, m),
	2.88-3.01 (5H, m), 3.07 (2H, m), 4.32 (2H, m), 6.38 (1H, s), 6.84-6.89 (2H, m), 7.01-7.07 (1H, m), 7.12-7.18 (2H, m), 7.64 (1H, m), 8.53 (1H, m)
37		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.1 Hz), 1.70-1.81 (2H, m), 1.86 (2H, m), 2.39 (3H, s), 2.65-
	2.75 (5H, m), 2.90-3.08 (7H, m), 4.35 (2H, m), 6.38 (1H, s), 6.86-6.91 (2H, m), 7.04-7.09 (1H, m), 7.11-7.21 (4H, m)
38		Reference Example 16	Commercial Product
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.7 Hz), 1.75 (2H, ddd, J = 25.4, 12.5, 4.0 Hz), 1.88-1.95 (2H,
	m), 2.33 (3H, s), 2.61-2.78 (6H, m), 2.87-2.94 (4H, m), 2.98-3.07 (2H, m), 3.87 (3H, s), 4.30-
	4.38 (2H, m), 7.05 (1H, dd, J = 7.9, 7.9 Hz), 7.14 (4H, s), 7.28 (1H, dd, J = 7.9, 1.5 Hz), 7.53 (1H, dd, J = 7.9, 1.5 Hz), 7.97 (1H, s).
39		Reference Example 21	Commercial Product
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.7 Hz), 1.69-1.81 (4H, m), 1.89 (4H, m), 2.25 (2H, m), 2.34
	(3H, s), 2.69-2.78 (3H, m), 3.04 (4H, m), 4.22 (2H, m), 5.84 (1H, s), 6.93-6.97 (1H, m), 7.10-7.21 (6H, m)
40		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.15 (6H, m), 1.25 (6H, d, J = 7.3 Hz), 1.56 (2H, m), 1.69-1.79 (2H, m), 1.93
	(2H, m), 2.69-2.77 (4H, m), 2.90 (3H, m), 3.03 (4H, m), 4.30 (2H, m), 6.30 (1H, brs), 6.90 (2H, m), 7.04-7.11 (1H, m), 7.14-7.21 (4H, m)
41		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.07 (6H, m), 1.60 (3H, m), 1.73 (2H, m), 2.15 (2H, m), 2.31 (3H, m), 2.56-2.77
	(7H, m), 3.00 (4H, m), 4.44 (2H, m), 6.30 (1H, s), 6.87-6.92 (2H, m), 7.06-7.15 (5H, m)
42		Reference Example 22	Commercial Product
	1H-NMR (CDCl3) δ: 1.10 (6H, d, J = 6.1 Hz), 1.66-1.76 (2H, m), 1.88 (2H, m), 2.33 (3H, s), 2.46
	(2H, m), 2.67-2.82 (4H, m), 2.99 (2H, m), 3.22 (2H, m), 4.22 (2H, m), 5.75 (1H, m), 5.96 (1H, s), 6.97-7.03 (2H, m), 7.07-7.15 (5H, m)
43		Reference Example 21	Reference Example 62
	1H-NMR (CDCl3) δ: 1.07 (6H, d, J = 6.8 Hz), 1.18-1.27 (4H, m), 1.35 (3H, s), 1.53-1.87 (6H, m),
	2.15-2.25 (3H, m), 2.30 (2H, d, J = 14.0 Hz), 2.62-2.80 (2H, m), 2.93-3.06 (2H, m), 3.14-3.32 (2H,
	m), 3.76-3.88 (2H, m), 5.73-5.85 (1H, m), 6.88-6.99 (1H, m), 7.08-7.21 (2H, m).
44		Reference Example 22	Reference Example 62
	1H-NMR (CDCl3) δ: 1.07-1.15 (6H, m), 1.16-1.25 (4H, m), 1.36 (3H, s), 1.62-1.74 (2H, m), 2.14-2.23
	(1H, m), 2.23-2.31 (2H, m), 2.38-2.47 (2H, m), 2.67-2.74 (2H, m), 2.76-2.87 (1H, m), 3.12-3.26
	(4H, m), 3.76-3.85 (2H, m), 5.69-5.75 (1H, m), 5.89-6.06 (1H, m), 6.93-7.04 (2H, m), 7.05-7.13 (1H, m).
45		Reference Example 5	Reference Example 62
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.17-1.29 (4H, m), 1.34 (3H, s), 1.70 (2H, ddd, J =
	14.0, 10.8, 4.0 Hz), 2.15-2.24 (1H, m), 2.29 (2H, d, J = 13.2 Hz), 2.55-2.78 (5H, m), 2.84-2.96 (4H,
	m), 3.23 (2H, ddd, J = 13.2, 10.8, 2.8 Hz), 3.88 (2H, dt, J = 14.0, 4.0 Hz), 6.32 (1H, bs), 6.81-6.91 (2H, m), 7.00-7.09 (1H, m).
46		Reference Example 5	Commercial Product
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.7 Hz), 1.77-1.88 (2H, m), 2.02 (2H, m), 2.31 (3H, s), 2.63-
	2.78 (5H, m), 2.88-2.96 (5H, m), 3.06 (2H, m), 4.32 (2H, m), 6.37 (1H, s), 6.85-6.90 (2H, m), 7.02-7.08 (2H, m), 7.45 (1H, m), 8.37 (1H, m)
47		Reference Example 33	Commercial Product
	1H-NMR (CDCl3) δ: 1.06 (6H, d, J = 6.7 Hz), 1.58-1.68 (2H, m), 1.80 (2H, m), 2.26 (3H, s), 2.47
	(2H, m), 2.60-2.80 (4H, m), 2.89 (2H, m), 3.18 (2H, m), 3.77 (3H, s), 4.16 (2H, m), 5.64 (1H, m), 5.95 (1H, s), 6.72-6.78 (2H, m), 7.00-7.09 (5H, m)
48		Reference Example 32	Commercial Product
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.7 Hz), 1.69-1.92 (8H, m), 2.26 (2H, m), 2.32 (3H, s), 2.68-
	2.82 (3H, m), 3.01 (4H, m), 3.79 (3H, s), 4.22 (2H, m), 5.94 (1H, s), 6.72 (1H, m), 6.97 (1H, m), 7.12-7.17 (5H, m)
49		Reference Example 21	Reference Example 92
	1H-NMR (CDCl3) δ: 1.03 (6H, d, J = 6.7 Hz), 1.42 (3H, s), 1.72-1.79 (6H, m), 2.20 (2H, m), 2.43
	(2H, m), 2.68 (2H, m), 2.97 (2H, m), 3.20 (2H, m), 3.83 (2H, m), 5.78 (1H, s), 6.84-6.89 (1H, m),
	7.05-7.12 (2H, m), 7.25-7.30 (2H, m), 7.45-7.48 (1H, m), 7.64-7.66 (1H, m)
50		Reference Example 22	Reference Example 92
	1H-NMR (CDCl3) δ: 1.07 (6H, d, J = 6.1 Hz), 1.41 (3H, s), 1.70-1.77 (3H, m), 2.40 (3H, m), 2.70
	(3H, m), 3.19 (4H, m), 3.85 (2H, m), 5.66 (1H, m), 6.08 (1H, brs), 6.86-7.04 (3H, m), 7.23-7.28 (2H, m), 7.43-7.46 (1H, m), 7.62-7.65 (1H, m)
51		Reference Example 21	Reference Example 89
	1H-NMR (CDCl3) δ: 0.88-0.99 (2H, m), 0.99-1.07 (2H, m), 1.09 (6H, d, J = 6.7 Hz), 1.61-1.90 (6H, m),
	1.96-2.07 (3H, m), 2.18-2.31 (2H, m), 2.68-2.85 (2H, m), 2.90-3.15 (5H, m), 4.09-4.16 (2H, m),
	5.79 (1H, s), 5.85 (1H, s), 6.94 (1H, ddd, J = 9.6, 7.8, 1.4 Hz), 7.10-7.21 (2H, m).
52		Reference Example 5	Reference Example 89
	1H-NMR (CDCl3) δ: 0.91-0.99 (2H, m), 1.00-1.07 (2H, m), 1.09 (6H, d, J = 6.1 Hz), 1.75 (2H, ddd, J =
	25.1, 11.6, 4.3 Hz), 1.96-2.06 (3H, m), 2.61-2.79 (5H, m), 2.88-3.00 (5H, m), 3.09 (2H, ddd, J =
	13.9, 11.6, 2.3 Hz), 4.16-4.26 (2H, m), 5.78 (1H, s), 6.35 (1H, s), 6.83-6.91 (2H, m), 7.05 (1H, ddd, J = 8.3, 8.3, 5.9 Hz).
53		Reference Example 21	Reference Example 89
	1H-NMR (CDCl3) δ: 0.94-1.01 (2H, m), 1.01-1.08 (2H, m), 1.09 (6H, d, J = 6.7 Hz), 1.31 (3H, s), 1.70
	(2H, ddd, J = 14.0, 10.4, 4.0 Hz), 1.77-1.89 (3H, m), 1.97-2.06 (1H, m), 2.10-2.19 (2H, m), 2.19-
	2.31 (2H, m), 2.66-2.84 (2H, m), 2.97-3.06 (2H, m), 3.28 (2H, ddd, J = 13.8, 10.4, 2.8 Hz), 3.72-
	3.82 (2H, m), 5.80 (1H, s), 5.80 (1H, s), 6.93 (1H, ddd, J = 9.5, 7.6, 1.8 Hz), 7.09-7.20 (2H, m).
54		Reference Example 5	Reference Example 89
	1H-NMR (CDCl3) δ: 0.94-1.01 (2H, m), 1.01-1.09 (2H, m), 1.10 (6H, d, J = 6.4 Hz), 1.30 (3H, s), 1.70
	(2H, ddd, J = 14.0, 10.4, 5.4 Hz), 1.98-2.06 (1H, m), 2.10-2.18 (2H, m), 2.53-2.82 (5H, m), 2.82-
	3.00 (4H, m), 3.31 (2H, ddd, J = 13.8, 10.7, 2.8 Hz), 3.81-3.89 (2H, m), 5.80 (1H, s), 6.30 (1H, s), 6.83-6.90 (2H, m), 7.01-7.08 (1H, m).
55		Reference Example 22	Reference Example 89
	1H-NMR (CDCl3) δ: 0.93-1.06 (4H, m), 1.07 (6H, d, J = 6.7 Hz), 1.27 (3H, s), 1.62-1.69 (2H, m), 2.00
	(1H, m), 2.09 (2H, m), 2.40 (2H, m), 2.70 (2H, m), 2.77 (1H, m), 3.17-3.26 (4H, m), 3.74 (2H, m),
	5.70 (1H, m), 5.77 (1H, s), 5.86 (1H, brs), 6.93-6.99 (2H, m), 7.04-7.09 (1H, m)
56		Reference Example 35	Reference Example 62
	1H-NMR (CDCl3) δ: 1.17-1.29 (4H, m), 1.34 (3H, s), 1.61-1.73 (2H, m), 2.15-2.24 (1H, m), 2.24-2.33
	(2H, m), 2.35-2.42 (2H, m), 3.14-3.24 (2H, m), 3.74-3.84 (2H, m), 3.85-3.91 (2H, m), 4.23-4.30
	(2H, m), 5.73-5.78 (1H, m), 5.83 (1H, bs), 6.93-6.98 (1H, m), 6.98-7.06 (1H, m), 7.09-7.16 (1H, m).
57		Reference Example 5	Reference Example 62
	1H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.8 Hz), 1.36 (3H, s), 1.41-1.70 (4H, m), 1.70-1.83 (2H, m),
	2.14-2.24 (1H, m), 2.24-2.39 (2H, m), 2.51-3.56 (11H, m), 4.23-4.47 (2H, m), 6.76 (1H, bs), 6.82-6.93 (2H, m), 7.10-7.20 (1H, m).
58		Reference Example 36	Commercial Product
	1H-NMR (CDCl3) δ: 1.00-1.08 (2H, m), 1.11-1.19 (2H, m), 1.62-1.76 (2H, m), 1.84-1.95 (2H, m), 2.34
	(3H, s), 2.63-2.76 (1H, m), 2.91-3.07 (2H, m), 3.56-3.66 (1H, m), 4.14-4.26 (2H, m), 5.87 (1H, bs), 6.97-7.08 (1H, m), 7.09-7.22 (6H, m), 7.65 (2H, s).
59		Reference Example 37	Reference Example 89
	1H-NMR (CDCl3) δ: 0.93-1.00 (2H, m), 1.00-1.08 (2H, m), 1.24 (3H, s), 1.32 (6H, d, J = 6.7 Hz), 1.51
	(2H, ddd, J = 14.1, 10.4, 3.7 Hz), 1.96-2.05 (3H, m), 3.04-3.17 (3H, m), 3.60-3.68 (2H, m), 5.76
	(1H, s), 5.78 (1H, s), 7.07-7.17 (2H, m), 7.21-7.26 (2H, m), 7.69 (1H, dd, J = 7.9, 2.1 Hz), 8.55 (1H, d, J = 2.1 Hz).
60		Reference Example 37	Reference Example 62
	1H-NMR (CDCl3) δ: 1.19-1.23 (4H, m), 1.28 (3H, s), 1.32 (6H, d, J = 6.7 Hz) , 1.51 (2H, ddd, J = 14.2,
	10.5, 3.5 Hz), 2.12-2.21 (3H, m), 2.99-3.14 (3H, m), 3.63-3.72 (2H, m), 5.81 (1H, s), 7.07-7.10
	(1H, m), 7.13 (1H, ddd, J = 9.9, 8.1, 1.4 Hz), 7.21-7.26 (2H, m), 7.69 (1H, dd, J = 7.9, 2.1 Hz), 8.53 (1H, d, J = 2.1 Hz).
61		Reference Example 9	Reference Example 89
	1H-NMR (CDCl3) δ: 0.90-1.38 (7H, m), 0.92-1.00 (2H, m), 1.03-1.10 (2H, m), 1.31 (3H, s), 1.71 (2H,
	ddd, J = 14.0, 10.4, 3.6 Hz), 2.02 (1H, tt, J = 8.8, 5.2 Hz), 2.08-2.19 (2H, m), 2,51-3.18 (8H,
	m), 3.27-3.38 (2H, m), 3.77-3.91 (2H, m), 5.80 (1H, s), 6.11-6.45 (1H, brs), 6.98-7.10 (2H, m), 7.14-7.20 (1H, m).
62		Reference Example 38	Commercial Product
	1H-NMR (CDCl3) δ: 1.15 (6H, m), 1.64-1.75 (6H, m), 1.88 (3H, m), 2.32 (4H, s), 2.68 (1H, m), 2.77-
	2.99 (5H, m), 4.22 (2H, m), 4.44 (1H, m), 5.97 (1H, brs), 6.65-6.77 (2H, m), 7.01-7.14 (5H, m)
63		Reference Example 38	Commercial Product
	1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.67-1.77 (2H, m), 1.86 (2H, m), 2.32 (3H, s), 2.29-
	2.70 (9H, m), 2.96 (2H, m), 3.87 (3H, s), 4.30 (2H, m), 6.72-6.80 (1H, m), 6.86-6.92 (1H, m), 7.01-7.14 (5H, m), 8.62 (1H, brs)
64		Reference Example 5	Commercial Product
	1H-NMR (CD3OD) δ: 1.09-1.14 (2H, m), 1.38 (6H, d, J = 6.8 Hz), 1.67-1.81 (2H, m), 1.90-2.00 (2H, m),
	2.30 (3H, s), 2.84-2.97 (1H, m), 3.15-3.30 (4H, m), 3.49-3.76 (6H, m), 4.90-5.01 (2H, m), 6.87-6.99 (2H, m), 7.08-7.35 (5H, m).
65		Reference Example 42	Reference Example 62
	1H-NMR (CDCl3) δ: 1.18-1.26 (13H, m), 1.47-1.53 (2H, m), 2.12-2.17 (3H, m), 2.92 (1H, m), 3.03
	(2H, m), 3.64 (2H, m), 5.72 (1H, brs), 7.05-7.09 (2H, m), 7.15-7.19 (1H, m), 7.26-7.30 (4H, m)
66		Reference Example 9	Reference Example 92
	1H-NMR (CDCl3) δ: 1.05 (6H, d, J = 6.7 Hz), 1.47 (3H, s), 1.81 (2H, m), 2.48 (2H, m), 2.58-2.76
	(5H, m), 2.91 (4H, m), 3.27 (2H, m), 3.97 (2H, m), 6.34 (1H, brs), 6.96-7.06 (2H, m), 7.15 (1H, m),
	7.31-7.33 (2H, m), 7.49-7.51 (1H, m), 7.68-7.70 (1H, m)
67		Reference Example 9	Reference Example 62
	1H-NMR (CDCl3) δ: 1.10 (6H, d, J = 6.1 Hz), 1.19-1.21 (3H, m), 1.33 (3H, s), 1.65-1.72 (3H, m),
	2.17 (1H, m), 2.26 (2H, m), 2.60-2.82 (5H, m), 2.93 (4H, m), 3.22 (2H, m), 3.86 (2H, m), 6.31 (1H, brs), 6.96-7.05 (2H, m), 7.13 (1H, m)
68		Reference Example 46	Reference Example 89
	1H-NMR (CDCl3) δ: 0.94-1.00 (2H, m), 1.00-1.08 (2H, m), 1.25 (3H, s), 1.51 (2H, ddd, J = 13.9, 10.2,
	3.8 Hz), 1.96-2.05 (3H, m), 2.56 (3H, s), 3.13 (2H, ddd, J = 13.9, 10.9, 2.9 Hz), 3.61-3.69 (2H,
	m), 5.77 (1H, s), 5.84 (1H, s), 7.06-7.10 (1H, m), 7.13 (1H, ddd, J = 9.6, 8.4, 1.4 Hz), 7.17-7.27
	(2H, m), 7.64 (1H, dd, J = 7.9, 2.1 Hz), 8.48 (1H, d, J = 2.1 Hz).
69		Reference Example 47	Reference Example 89
	1H-NMR (CDCl3) δ: 0.92-0.99 (2H, m), 0.99-1.07 (2H, m), 1.23 (3H, s), 1.30 (6H, d, J = 6.7 Hz), 1.47
	(2H, ddd, J = 14.0, 10.4, 3.7 Hz), 1.94-2.04 (3H, m), 3.00-3.16 (3H, m), 3.59-3.68 (2H, m), 5.75
	(1H, s), 6.02 (1H, s), 7.17-7.24 (3H, m), 7.43 (1H, dd, J = 6.7, 3.0 Hz), 7.68 (1H, dd, J = 7.9, 2.4 Hz), 8.52 (1H, d, J = 2.4 Hz).
70		Reference Example 48	Reference Example 89
	1H-NMR (CDCl3) δ: 0.93-1.00 (2H, m), 1.00-1.09 (2H, m), 1.24 (3H, s), 1.50 (2H, ddd, J = 14.1, 10.7,
	3.7 Hz), 1.94-2.06 (3H, m), 2.36 (3H, s), 3.12 (2H, ddd, J = 13.8, 10.7, 2.8 Hz), 3.60-3.69 (2H,
	m), 5.76 (1H, s), 5.78 (1H, s), 7.06-7.11 (1H, m), 7.11-7.18 (1H, m), 7.21-7.29 (1H, m), 7.54 (1H,
	s), 8.40 (1H, d, J = 1.8 Hz), 8.44 (1H, d, J = 1.8 Hz).
71		Reference Example 49	Reference Example 89
	1H-NMR (CD3OD) δ: 0.86-0.96 (2H, m), 1.02-1.11 (2H, m), 1.22 (3H, s), 1.35-1.49 (2H, m), 1.92-
	2.02 (2H, m), 2.02-2.13 (1H, m), 3.00-3.17 (2H, m), 3.68 (2H, d, J = 14.0 Hz), 6.04 (1H, s), 7.21-
	7.32 (2H, m), 7.37-7.46 (1H, m), 7.87 (1H, d, J = 8.0 Hz), 8.05 (1H, d, J = 8.0 Hz), 8.74 (1H, s).
72		Reference Example 50	Reference Example 62
	1H-NMR (CDCl3) δ: 1.15-1.25 (4H, m), 1.30 (3H, s), 1.39 (6H, d, J = 7.6 Hz) , 1.44-1.57 (2H, m), 2.12-
	2.24 (3H, m), 2.96-3.10 (2H, m), 3.24-3.38 (1H, m), 3.70 (2H, d, J = 14.0 Hz), 5.92 (1H, bs), 7.11
	(1H, d, J = 8.0 Hz), 7.19 (1H, t, J = 8.0 Hz), 7.23-7.34 (3H, m).
73		Reference Example 5	Reference Example 67
	1H-NMR (CDCl3) δ: 1.10 (6H, d, J = 6.0 Hz), 1.37 (3H, s), 1.66-1.77 (4H, m), 1.77-1.99 (4H, m),
	2.07-2.19 (2H, m), 2.32 (2H, d, J = 14.0 Hz), 2.56-2.82 (5H, m), 2.82-3.02 (4H, m), 3.18-3.39 (3H,
	m), 3.88 (2H, d, J = 14.0 Hz), 6.32 (1H, bs), 6.81-6.92 (2H, m), 7.00-7.10 (1H, m).
74		Reference Example 9	Reference Example 67
	1H-NMR (CDCl3) δ: 1.10 (6H, d, J = 6.4 Hz), 1.37 (3H, s), 1.66-1.78 (4H, m), 1.78-1.86 (2H, m),
	1.86-1.99 (2H, m), 2.07-2.19 (2H, m), 2.32 (2H, d, J = 14.0 Hz), 2.55-2.81 (5H, m), 2.81-3.03 (4H,
	m), 3.19-3.39 (3H, m), 3.90 (2H, d, J = 14.0 Hz), 6.36 (1H, bs), 6.98 (1H, d, J = 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz).
75		Reference Example 5	Reference Example 70
	1H-NMR (CDCl3) δ: 1.10 (6H, d, J = 8.4 Hz), 1.38 (3H, s), 1.74 (2H, ddd, J = 14.0, 10.8, 4.0 Hz),
	2.32 (2H, d, J = 14.0 Hz), 2.58-2.83 (5H, m), 2.83-2.99 (4H, m), 2.99-3.16 (4H, m), 3.25 (2H, ddd, J =
	14.0, 10.8, 4.0 Hz), 3.54-3.66 (1H, m), 3.88 (2H, dt, J = 14.0, 4.0 Hz), 6.32 (1H, bs), 6.82-6.93 (2H, m), 7.01-7.11 (1H, m).
76		Reference Example 9	Reference Example 70
	1H-NMR (CDCl3) δ: 1.10 (6H, bs), 1.39 (3H, s), 1.75 (2H, ddd, J = 14.0, 10.8, 4.0 Hz), 2.32 (2H, d, J =
	14.0 Hz), 2.56-2.81 (5H, m), 2.81-3.00 (4H, m), 3.00-3.16 (4H, m), 3.26 (2H, ddd, J = 14.0, 10.8,
	4.0 Hz), 3.54-3.67 (1H, m), 3.90 (2H, dt, J = 14.0, 4.0 Hz), 6.36 (1H, bs), 6.99 (1H, dd, J = 8.0, 1.2
	Hz), 7.06 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
77		Reference Example 9	Commercial Product
	1H-NMR (CDCl3) δ: 1.03 (6H, d, J = 6.7 Hz), 1.28 (3H, s), 1.74-1.80 (2H, m), 2.14-2.18 (2H, m),
	2.32 (3H, s), 2.56-2.70 (5H, m), 2.87 (4H, m), 3.46-3.52 (2H, m), 3.62-3.68 (2H, m), 6.34 (1H,
	s), 6.94-7.05 (2H, m), 7.12-7.16 (3H, m), 7.23 (2H, m)
78		Reference Example 9	Reference Example 66
	1H-NMR (CDCl3) δ: 1.11 (6H, bs), 1.38 (3H, s), 1.74 (2H, ddd, J = 14.0, 10.8, 4.0 Hz), 1.99-2.21 (2H,
	m), 2.33 (2H, d, J = 13.6 Hz), 2.40-2.52 (4H, m), 2.55-2.82 (5H, m), 2.82-3.04 (4H, m), 3.26 (2H,
	ddd, J = 14.0, 10.8, 4.0 Hz), 3.69-3.81 (1H, m), 3.91 (2H, dt, J = 14.0, 4.0 Hz), 6.36 (1H, bs),
	6.99 (1H, dd, J = 8.0, 1.2 Hz), 7.06 (1H, t, J = 8.0 Hz), 7.17 (1H, dd, J = 8.0, 1.2 Hz).
79		Reference Example 5	Reference Example 71
	1H-NMR (CDCl3) δ: 0.96-1.04 (2H, m), 1.12 (6H, bs), 1.35 (3H, s), 1.37-1.44 (2H, m), 1.45-1.76 (7H,
	m), 2.30 (2H, d, J = 14.0 Hz), 2.52-3.13 (7H, m), 3.18-3.32 (2H, m), 3.81-3.94 (2H, m), 6.30 (1H, bs), 6.81-6.94 (2H, m), 7.01-7.12 (1H, m).
80		Reference Example 9	Reference Example 71
	1H-NMR (CDCl3) δ: 0.97-1.03 (2H, m), 1.12 (6H, bs), 1.35 (3H, s), 1.37-1.44 (2H, m), 1.48-1.76 (7H,
	m), 2.29 (2H, d, J = 14.0 Hz), 2.51-3.11 (7H, m), 3.19-3.32 (2H, m), 3.81-3.97 (2H, m), 6.34 (1H, bs), 6.95-7.10 (2H, m), 7.13-7.19 (1H, m)
81		Reference Example 9	Reference Example 63
	1H-NMR (CDCl3) δ: 1.10 (6H, bs), 1.37 (3H, s), 1.74 (2H, ddd, J = 14.0, 10.4, 4.4 Hz), 2.31 (2H, d, J =
	14.0 Hz), 2.60 (3H, s), 2.52-2.82 (5H, m), 2.82-3.02 (4H, m), 3.25 (2H, ddd, J = 14.0, 10.4, 3.6
	Hz), 3.91 (2H, dt, J = 14.0, 3.6 Hz), 6.35 (1H, bs), 6.99 (1H, dd, J = 8.0, 1.2 Hz), 7.06 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
82		Reference Example 5	Reference Example 64
	1H-NMR (CDCl3) δ: 1.12 (6H, bs), 1.38 (3H, s), 1.40 (3H, t, J = 8.0 Hz), 1.73 (2H, ddd, J = 14.0, 10.4,
	4.4 Hz), 2.32 (2H, d, J = 13.6 Hz), 2.56-2.81 (5H, m), 2.81-3.05 (4H, m), 2.92 (2H, q, J = 8.0 Hz),
	3.25 (2H, ddd, J = 14.0, 10.4, 3.6 Hz), 3.88 (2H, dt, J = 14.0, 3.6 Hz), 6.30 (1H, bs), 6.83-6.92 (2H, m), 7.01-7.10 (1H, m).
83		Reference Example 9	Reference Example 64
	1H-NMR (CDCl3) δ: 1.11 (6H, bs), 1.38 (3H, s), 1.40 (3H, t, J = 8.0 Hz), 1.74 (2H, ddd, J = 14.0, 10.4,
	4.4 Hz), 2.32 (2H, d, J = 13.2 Hz), 2.56-2.82 (5H, m), 2.82-3.03 (4H, m), 2.92 (2H, q, J = 8.0 Hz),
	3.26 (2H, ddd, J = 13.2, 10.4, 3.6 Hz), 3.91 (2H, dt, J = 14.0, 3.6 Hz), 6.35 (1H, bs), 6.99 (1H,
	dd, J = 8.0, 1.2 Hz), 7.06 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
84		Reference Example 9	Reference Example 91
	1H-NMR (CDCl3) δ: 1.33 (3H, s), 1,41-1.59 (6H, m), 1.67-1.75 (2H, m), 1.81-1.89 (1H, m), 2.07-2.20
	(2H, m), 2.42 (3H, s), 2,86-3.09 (2H, m), 3.10-3.29 (2H, m), 3.29-3.50 (4H, m), 3.67-3.85 (4H,
	m), 5.88 (1H, s), 5.97-6.05 (1H, brs), 7.09-7.16 (1H, m), 7.20-7.30 (2H, m).
85		Reference Example 5	Reference Example 91
	1H-NMR (CDCl3) δ: 1.33 (3H, s), 1,43-1.58 (6H, m), 1.66-1.76 (2H, m), 1.81-1.89 (1H, m), 2.09-2.19
	(2H, m), 2.42 (3H, s), 2,88-3.09 (2H, m), 3.11-3.25 (2H, m), 3.26-3.54 (4H, m), 3.68-3.85 (4H,
	m), 5.88 (1H, s), 5.92-6.00 (1H, brs), 6.87-7.02 (2H, m), 7.06-7.17 (1H, m).
86		Reference Example 9	Reference Example 68
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.8 Hz), 1.45 (3H, s), 1.82 (2H, ddd, J = 14.4, 10.4, 4.4 Hz),
	2.34 (2H, dt, J = 9.6, 3.6 Hz), 2.55-2.80 (5H, m), 2.84-3.00 (4H, m), 3.29 (2H, ddd, J = 13.6, 10.4,
	3.2 Hz), 3.91 (2H, dt, J = 13.6, 4.4 Hz), 6.38 (1H, bs), 6.99 (1H, dd, J = 8.0, 1.2 Hz), 7.06 (1H, t, J = 8.0 Hz), 7.17 (1H, dd, J = 8.0, 1.2 Hz).
87		Reference Example 5	Reference Example 72
	1H-NMR (CDCl3) δ: 0.74 (3H, t, J = 7.2 Hz), 1.13 (6H, bs), 1.19-1.23 (1H, m), 1.24 (3H, s), 1.62-
	1.74 (4H, m), 2.15-2.25 (1H, m), 2.27-2.37 (2H, m), 2.57-2.86 (5H, m), 2.86-3.03 (4H, m), 3.03-
	3.15 (2H, m), 3.97 (2H, dt, J = 13.6, 4.0 Hz), 6.27 (1H, bs), 6.82-6.92 (2H, m), 7.00-7.09 (1H, m).
88		Reference Example 11	Reference Example 62
	1H-NMR (CDCl3) δ: 1.05 (6H, d, J = 6.1 Hz), 1.18-1.22 (4H, m), 1.33 (3H, s), 1.67-1.74 (2H, m),
	2.14-2.19 (1H, m), 2.27 (2H, m), 2.60-2.70 (5H, m), 2.87 (4H, m), 3.22 (2H, m), 3.88 (2H, m), 6.38 (1H, brs), 6.94-7.01 (2H, m), 7.30-7.32 (1H, m)
89		Reference Example 9	Reference Example 72
	1H-NMR (CDCl3) δ: 0.74 (3H, t, J = 7.6 Hz), 1.09 (6H, d, J = 6.4 Hz), 1.20-1.26 (4H, m), 1.64-1.74
	(4H, m), 2.16-2.25 (1H, m), 2.27-2.38 (2H, m), 2.53-2.79 (5H, m), 2.83-2.99 (4H, m), 3.02-3.16
	(2H, m), 4.00 (2H, dt, J = 13.6, 4.0 Hz), 6.36 (1H, bs), 6.98 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
90		Reference Example 9	Reference Example 94
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.4 Hz), 1.43 (3H, s), 1.70-1.77 (2H, m), 2.41 (3H, s), 2.43-
	2.51 (2H, m), 2.58-2.66 (4H, m), 2.66-2.76 (1H, m), 2.85-2.94 (4H, m), 3.29-3.41 (2H, m), 3.84-
	3.94 (2H, m), 6.38 (1H, s), 6.97 (1H, dd, J = 8.0, 1.6 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.6 Hz)
91		Reference Example 5	Reference Example 95
	1H-NMR (CDCl3) δ: 0.94 (3H, s), 1.09 (6H, d, J = 6.1 Hz), 1.20-1.34 (2H, m), 1.35-1.45 (2H, m),
	1.46-1.63 (8H, m), 1.72-1.84 (1H, m), 2.60-2.68 (4H, m), 2.68-2.77 (1H, m), 2.86-2.94 (4H, m),
	3.24 (2H, ddd, J = 13.6, 10.9, 2.9 Hz), 3.79-3.88 (2H, m), 6.31 (1H, s), 6.82-6.90 (2H, m), 7.00-7.07 (1H, m).
92		Reference Example 9	Reference Example 96
	1H-NMR (CDCl3) δ: 1.14 (6H, bs), 1.30 (3H, s), 1.63-1.75 (2H, m), 2.02-2.12 (2H, m), 2.45 (3H,
	s), 2.60-2.82 (5H, m), 2.87-3.11 (4H, m), 3.38-3.48 (2H, m), 3.66-3.82 (2H, m), 6.31 (1H, bs),
	6.99 (1H, dd, J = 8.0, 1.2 Hz), 7.06 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz), 7.21 (1H, s).
93		Reference Example 9	Reference Example 97
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.4 Hz), 1.30 (3H, s), 1.32 (3H, s), 1.34 (3H, s), 1.63-1.74
	(2H, m), 2.03-2.13 (2H, m), 2.58-2.82 (5H, m), 2.87-3.00 (4H, m), 3.02-3.13 (1H, m), 3.39-3.49
	(2H, m), 3.66-3.76 (2H, m), 6.36 (1H, bs), 6.98 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz), 7.27 (1H, s).
94		Reference Example 9	Reference Example 73
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.8 Hz), 1.20-1.36 (5H, m), 2.17-2.35 (5H, m), 2.57-2.79 (4H,
	m), 2.87-2.98 (4H, m), 3.47-3.58 (2H, m), 4.03 (2H, dt, J = 13.6, 4.0 Hz), 6.43 (1H, bs), 6.99
	(1H, dd, J = 8.0, 1.2 Hz), 7.07 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
95		Reference Example 9	Reference Example 74
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.4 Hz), 1.42 (3H, t, J = 8.0 Hz), 2.16-2.40 (4H, m), 2.60-2.69
	(4H, m), 2.69-2.79 (1H, m), 2.87-2.96 (4H, m), 2.95 (2H, q, J = 8.0 Hz), 3.49-3.59 (2H, m), 4.05
	(2H, dt, J = 13.2, 4.0 Hz), 6.44 (1H, bs), 7.00 (1H, dd, J = 8.0, 1.2 Hz), 7.07 (1H, t, J = 8.0 Hz), 7.17 (1H, dd, J = 8.0, 1.2 Hz).
96		Reference Example 9	Reference Example 100
	1H-NMR (CDCl3) δ: 0.97-1.03 (2H, m), 1.04-1.15 (8H, m), 1.32 (3H, s), 1.74 (2H, ddd, J = 13.2, 8.8,
	4.4 Hz), 2.19-2.34 (3H, m), 2.57-2.81 (5H, m), 2.85-3.00 (4H, m), 3.43 (2H, ddd, J = 13.2, 8.8,
	4.0 Hz), 3.65-3.76 (2H, m), 6.35 (1H, s), 6.68 (1H, s), 6.98 (1H, dd, J = 8.0, 1.6 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.6 Hz).
97		Reference Example 9	Commercial Product
	1H-NMR (CDCl3) δ: 1.04 (6H, d, J = 6.8 Hz), 2.58-2.72 (5H, m), 2.89-2.96 (4H, m), 3.04-3.10 (4H,
	m), 3.71-3.77 (4H, m), 6.51 (1H, s), 7.01 (1H, dd, J = 8.0, 1.6 Hz), 7.07 (1H, t, J = 8.0 Hz), 7.15-7.20 (5H, m).
98		Reference Example 9	Commercial Product
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.4 Hz), 1.95 (2H, ddd, J = 24.8, 12.0, 4.0 Hz), 2.06-2.16 (2H,
	m), 2.30 (3H, s), 2.59-2.77 (5H, m), 2.87-2.98 (4H, m), 3.04-3.18 (3H, m), 4.25-4.36 (2H, m),
	6.42 (1H, s), 6.98 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz), 8.51 (2H, s).
99		Reference Example 9	Commercial Product
	1H-NMR (CDCl3) δ: 0.99-1.15 (6H, m), 2.10-2.22 (2H, m), 2.25 (3H, s), 2.50-2.74 (5H, m), 2.82-2.96
	(4H, m), 3.42-3.49 (2H, m), 3.62-3.81 (6H, m), 6.33-6.45 (1H, m), 6.67 (2H, d, J = 8.8 Hz), 6.96-7.10 (4H, m), 7.14-7.19 (1H, m).
100		Reference Example 19	Reference Example 62
	1H-NMR (CDCl3) δ: 1.07 (9H, s), 1.18-1.22 (4H, m), 1.33 (3H, s), 1.67-1.73 (2H, m), 2.17 (1H, m),
	2.27 (2H, m), 2.66 (4H, m), 2.86 (4H, m), 3.22 (2H, m), 3.88 (2H, m), 6.36 (1H, brs), 6.94-6.96 (1H, m), 7.00-7.04 (1H, m), 7.12-7.14 (1H, m)
101		Reference Example 9	Reference Example 99
	1H-NMR (CDCl3) δ: 0.69-0.75 (2H, m), 0.99-1.05 (2H, m), 1.07 (6H, d, J = 6.8 Hz), 1.40 (3H, s), 1.82
	(2H, ddd, J = 14.0, 9.6, 3.6 Hz), 1.98-2.08 (1H, m), 2.23-2.32 (2H, m), 2.54-2.66 (4H, m), 2.67-
	2.73 (1H, m), 2.85-2.92 (4H, m), 3.40 (2H, ddd, J = 13.2, 10.0, 3.2 Hz), 3.83 (2H, dt, J = 9.2, 4.4
	Hz), 6.34-6.42 (1H, br), 6.97 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.13-7.18 (1H, m), 7.34 (1H, s).
102		Reference Example 9	Reference Example 98
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.0 Hz), 1.10-1.16 (2H, m), 1.18-1.29 (2H, m), 1.44 (3H, s),
	1.88 (2H, ddd, J = 14.4, 9.6, 3.6 Hz), 2.24-2.33 (2H, m), 2.39 (1H, tt, J = 8.0, 4.8 Hz), 2.66-2.76
	(5H, m), 2.85-2.92 (4H, m), 3.37 (2H, ddd, J = 14.0, 10.4, 3.2 Hz), 3.91 (2H, dt, J = 14.0, 4.4
	Hz), 6.35-6.42 (1H, br), 6.98 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 2.0 Hz).
103		Reference Example 9	Reference Example 93
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.09-1.14 (2H, m), 1.14-1.20 (2H, m), 1.43 (3H, s),
	1.73 (2H, ddd, J = 14.0, 10.4, 3.6 Hz), 2.02-2.13 (1H, m), 2.42-2.50 (2H, m), 2.58-2.76 (5H, m),
	2.85-2.92 (4H, m), 3.35 (2H, ddd, J = 13.6, 10.4, 2.8 Hz), 3.88 (2H, dt, J = 9.2, 4.8 Hz), 6.35-6.40
	(1H, br), 6.97 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
104		Reference Example 9	Reference Example 75
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), , 1.10-1.18 (4H, m), 1.31-1.41 (4H, m), 1.46-1.60 (1H,
	m), 1.67-1.78 (2H, m), 2.24 (1H, td, J = 8.4, 5.2 Hz), 2.28-2.37 (2H, m), 2.57-2.77 (5H, m), 2.85-
	2.93 (4H, m), 3.17-3.30 (2H, m), 3.87-3.97 (2H, m), 6.35-6.41 (1H, br), 6.97 (1H, dd, J = 8.0, 1.2
	Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.6 Hz).
105		Reference Example 9	Reference Example 76
	1H-NMR (CDCl3) δ: 0.27-0.34 (2H, m), 0.60-0.67 (2H, m), 1.08 (6H, d, J = 6.8 Hz), 1.12-1.24 (1H, m),
	1.39 (3H, s), 1.75 (2H, ddd, J = 14.4, 10.8, 4.0 Hz), 2.29-2.38 (2H, m), 2.57-2.77 (5H, m), 2.81
	(2H, d, J = 6.8 Hz), 2.86-2.92 (4H, m), 3.26 (2H, ddd, J = 13.6, 10.4, 2.4 Hz), 3.92 (2H, dt, J =
	13.2, 4.0 Hz), 6.37-6.41 (1H, br), 6.98 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 2.0 Hz).
106		Reference Example 9	Reference Example 77
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.15-1.21 (4H, m), 1.27 (3H, s), 1.34 (1H, t, J = 5.2
	Hz), 1.36 (3H, s), 1.67-1.77 (2H, m), 2.03 (1H, dd, J = 8,4, 5.6 Hz), 2.27-2.36 (2H, m), 2.57-2.75
	(5H, m), 2.86-2.92 (4H, m), 3.16-3.28 (2H, m), 3.88-3.97 (2H, m), 6.36-6.40 (1H, br), 6.97 (1H,
	dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
107		Reference Example 9	Reference Example 78
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.37 (3H, s), 1.63-1.79 (6H, m), 2.26-2.34 (2H, m),
	2.57-2.76 (5H, m), 2.86-2.92 (4H, m), 3.26 (2H, ddd, J = 13.6, 10.4, 3.2 Hz), 3.90 (2H, dt, J =
	14.8, 3.6 Hz), 6.37-6.40 (1H, br), 6.98 (1H, dd, J = 8.0, 1.6 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
108		Reference Example 9	Reference Example 79
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.38 (3H, s), 1.42-1.47 (4H, m), 1.74 (2H, ddd, J =
	14.0, 10.4, 3.6 Hz), 2.29-2.37 (2H, m), 2.57-2.76 (5H, m), 2.86-2.92 (4H, m), 3.26 (2H, ddd, J =
	14.0, 10.8, 3.2 Hz), 3.54 (3H, s), 3.91 (2H, dt, J = 14.0, 4.0 Hz), 6.37-6.40 (1H, br), 6.98 (1H,
	dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.6 Hz).
109		Reference Example 9	Reference Example 80
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.39 (3H, s), 1.48-1.60 (2H, m), 1.65-1.82 (4H, m),
	2.27-2.37 (2H, m), 2.57-2.77 (5H, m), 2.85-2.93 (4H, m), 3.26 (2H, ddd, J = 13.6, 10.4, 2.4 Hz),
	3.92 (2H, dt, J = 13.2, 4.0 Hz), 6.37-6.41 (1H, br), 6.98 (1H, dd, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
110		Reference Example 39	Reference Example 62
	1H-NMR (CDCl3) δ: 1.09 (3H, d, J = 8.0 Hz), 1.10 (3H, d, J = 8.0 Hz), 1.19-1.24 (4H, m), 1.33 (3H,
	s), 1.70 (2H, ddd, J = 14.0, 10.6, 3.7 Hz), 1.95-2.04 (1H, m), 2.15-2.22 (1H, m), 2.22-2.33 (3H,
	m), 2.37-2.43 (1H, m), 2.44-2.52 (1H, m), 2.79 (1H, dd, J = 10.6, 6.1 Hz), 2.84-2.93 (2H, m),
	3.16-3.24 (2H, m), 3.87 (2H, ddd, J = 14.0, 4.6, 4.0 Hz), 4.76-4.82 (1H, m), 6.43 (1H, s), 6.70 (1H, dd, J = 6.1, 3.7 Hz), 6.99-7.05 (2H, m).
111		Reference Example 9	Reference Example 75
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.4 Hz), 1.38 (3H, s), 1.44-1.55 (1H, m), 1.74 (2H, ddd, J =
	14.0, 11.2, 4.4 Hz), 1.93-2.05 (1H, m), 2.27-2.43 (3H, m), 2.56-2.67 (4H, m), 2.67-2.76 (1H, m),
	2.85-2.92 (4H, m), 3.24 (2H, ddd, J = 14.0, 11.2, 3.2 Hz), 3.87-3.98 (2H, m), 4.85 (0.5H, ddd, J =
	6.0, 6.0, 3.6 Hz), 5.01 (0.5H, ddd, J = 6.0, 6.0, 3.6 Hz), 6.38 (1H, brs), 6.97 (1H, d, J = 8.0, 1.2
	Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
112		Reference Example 9	Reference Example 83
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.34 (3H, s), 1.50-1.58 (1H, m), 1.72 (2H, ddd, J =
	14.0, 10.4, 3.6 Hz), 1.81 (1H, dddd, J = 21.6, 11.2, 7.6, 3.6 Hz), 2.28 (2H, dt, J = 14.0, 3.6
	Hz), 2.57-2.76 (6H, m), 2.85-2.93 (4H, m), 3.23 (2H, ddd, J = 14.0, 10.4, 3.2 Hz), 3.90 (2H, dt,
	J = 14.0, 3.6 Hz), 4.91 (0.5H, ddd, J = 6.0, 3.6, 1.60 Hz), 5.07 (0.5H, ddd, J = 6.0, 3.6, 1.6 Hz),
	6.38 (1H, brs), 6.98 (1H, d, J = 8.0, 1.2 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.2 Hz).
113		Reference Example 10	Reference Example 62
	1H-NMR (CDCl3) δ: 0.40-0.52 (4H, m), 1.19-1.27 (4H, m), 1.36 (3H, s), 1.62-1.78 (3H, m), 2.14-2.25
	(1H, m), 2.26-2.36 (2H, m), 2.65-2.79 (4H, m), 2.80-2.88 (4H, m), 3.25 (2H, ddd, J = 13.6, 10.4,
	2.4 Hz), 3.92 (2H, dt, J = 9.2, 4.4 Hz), 6.37-6.42 (1H, br), 6.95 (1H, dd, J = 8.0, 1.2 Hz), 7.04 (1H, t, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 1.6 Hz).
114		Reference Example 9	Reference Example 81
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.4 Hz), 1.38 (3H, s), 1.69-1.81 (2H, m), 2.05-2.18 (1H, m),
	2.23-2.36 (3H, m), 2.53-2.79 (5H, m), 2.82-2.96 (4H, m), 2.96-3.07 (1H, m), 3.17-3.30 (2H, m),
	3.85-3.97 (2H, m), 6.38 (1H, s), 6.98 (1H, d, J = 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz).
115		Reference Example 9	Reference Example 84
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.4 Hz), 1.38 (3H, s), 1.44-1.54 (1H, m), 1.68-1.80 (2H, m),
	1.92-2.05 (1H, m), 2.27-2.43 (3H, m), 2.54-2.77 (5H, m), 2.83-2.94 (4H, m), 3.18-3.29 (2H, m),
	3.87-3.98 (2H, m), 4.82-4.88 (0.5H, m), 4.97-5.04 (0.5H, m), 6.38 (1H, s), 6.97 (1H, d, J = 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz).
116		Reference Example 9	Reference Example 85
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.4 Hz), 1.38 (3H, s), 1.44-1.54 (1H, m), 1.68-1.80 (2H, m),
	1.92-2.05 (1H, m), 2.27-2.43 (3H, m), 2.54-2.77 (5H, m), 2.83-2.94 (4H, m), 3.18-3.29 (2H, m),
	3.87-3.98 (2H, m), 4.82-4.88 (0.5H, m), 4.97-5.04 (0.5H, m), 6.38 (1H, s), 6.97 (1H, d, J = 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz).
117		Reference Example 9	Reference Example 87
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.4 Hz), 1.08-1.16 (1H, m), 1.16 (3H, d, J = 6.4 Hz), 1.31-1.39
	(1H, m), 1.37 (3H, s), 1.45-1.60 (1H, m), 1.66-1.79 (2H, m), 2.20-2.28 (1H, m), 2.28-2.37 (2H,
	m), 2.56-2.67 (4H, m), 2.67-2.76 (1H, m), 2.82-2.95 (4H, m), 3.16-3.30 (2H, m), 3.86-3.99 (2H,
	m), 6.38 (1H, s), 6.97 (1H, d, J = 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz).
118		Reference Example 9	Reference Example 86
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.8 Hz), 1.08-1.16 (1H, m), 1.16 (3H, d, J = 6.0 Hz), 1.31-1.39
	(1H, m), 1.37 (3H, s), 1.45-1.60 (1H, m), 1.66-1.79 (2H, m), 2.20-2.28 (1H, m), 2.28-2.37 (2H,
	m), 2.56-2.67 (4H, m), 2.67-2.76 (1H, m), 2.82-2.95 (4H, m), 3.16-3.30 (2H, m), 3.86-3.99 (2H,
	m), 6.38 (1H, s), 6.97 (1H, d, J = 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz).
119		Reference Example 9	Reference Example 69
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.0 Hz), 1.41 (3H, s), 1.72-1.91 (2H, m), 2.27-2.44 (2H, m),
	2.58-2.83 (5H, m), 2.86-3.00 (4H, m), 3.22-3.42 (2H, m), 3.71-4.02 (4H, m), 6.33-6.47 (1H, m), 6.97-7.24 (3H, m).
120		Reference Example 2	Reference Example 63
	1H-NMR (CDCl3) δ: 1.12 (6H, d, J = 6.4 Hz), 1.36 (3H, s), 1.49-1.66 (2H, m), 1.71 (2H, ddd, J =
	14.0, 10.8, 4.0 Hz), 2.32 (2H, d, J = 14.0 Hz), 2.60 (3H, s), 2.62-2.82 (4H, m), 2.84-2.99 (3H,
	m), 3.22 (2H, ddd, J = 14.0, 10.8, 2.8 Hz), 3.87 (2H, dt, J = 13.6, 4.0 Hz), 6.94 (1H, dt, J = 8.0,
	1.2 Hz), 7.08-7.20 (2H, m), 8.19 (1H, dd, J = 8.0, 1.2 Hz), 8.25 (1H, bs).

• Example 2: 4-(1,3-benzoxazol-2-yl)-N-[2-(4-ethylpiperazin-1-yl)phenyl]piperidine-1-carboxamide
• Example 3: 4-(3,5-dimethoxyphenyl)-N-[2-(4-ethylpiperazin-1-yl)phenyl]piperidine-1-carboxamide
• Example 4: N-[2-(4-ethylpiperazin-1-yl)phenyl]-4-methyl-4-phenylpiperidine-1-carboxamide hydrochloride
• Example 5: 4-methyl-4-phenyl-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 6: 4-cyano-4-phenyl-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 7: 4-phenyl-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 8: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 9: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 10: N-{4-fluoro-2-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 11: N-{3-fluoro-2-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 12: 4-methyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 13: 4-methyl-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxamide
• Example 14: 6-(4-methylphenyl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-azabicyclo[4.1.0]heptane-3-carboxamide
• Example 15: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[4-(trifluoromethyl)phenyl]piperidine-1-carboxamide
• Example 16: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide
• Example 17: 4-(4-methylphenyl)-N-{2-methyl-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 18: 4-(2-fluoro-4-methylphenyl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 19: 4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 20: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 21: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 22: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide
• Example 23: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide
• Example 24: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 25: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 26: Rac-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-methyl-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 27: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-phenoxypiperidine-1-carboxamide
• Example 28: Rac-4-(4-methylphenyl)-N-{2-[3-methyl-4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 29: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(3-methylphenyl)piperidine-1-carboxamide
• Example 30: Rac-4-(4-methylphenyl)-N-{2-[2-methyl-4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 31: 4-(4-methylphenyl)-N-{2-[1-(propan-2-yl)piperidin-4-yl]phenyl}piperidine-1-carboxamide hydrochloride Example 32: 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-8-carboxamide
• Example 33: N-{2-(dimethylcarbamoyl)-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 34: 4-(4-methylphenyl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]-6-(trifluoromethyl)phenyl}piperidine-1-carboxamide
• Example 35: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 36: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(pyridin-2-yl)piperidine-1-carboxamide
• Example 37: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(2-methylphenyl)piperidine-1-carboxamide
• Example 38: methyl 2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}-3-[4-(propan-2-yl)piperazin-1-yl]benzoate
• Example 39: N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 40: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[4-(propan-2-yl)phenyl]piperidine-1-carboxamide
• Example 41: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-8-carboxamide
• Example 42: N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 43: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 44: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 45: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 46: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-methylpyridin-2-yl)piperidine-1-carboxamide
• Example 47: N-{2-methoxy-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 48: N-{2-methoxy-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 49: 4-(1,3-benzoxazol-2-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 50: 4-(1,3-benzoxazol-2-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 51: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}piperidine-1-carboxamide
• Example 52: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 53: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 54: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 55: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 56: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[2-(3,6-dihydro-2H-pyran-4-yl)-6-fluorophenyl]-4-methylpiperidine-1-carboxamide
• Example 57: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carbothioamide
• Example 58: N-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluoro-phenyl]-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 59: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[6-(propan-2-yl)pyridin-3-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 60: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[6-(propan-2-yl)pyridin-3-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 61: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 62: N-(2-fluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}phenyl)-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 63: N-(2-methoxy-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}phenyl)-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 64: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carbothioamide
• Example 65: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[3-fluoro-4′-(propan-2-yl) [1,1′-biphenyl]-2-yl]-4-methylpiperidine-1-carboxamide
• Example 66: 4-(1,3-benzoxazol-2-yl)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 67: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 68: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-[2-fluoro-6-(6-methylpyridin-3-yl)phenyl]-4-methylpiperidine-1-carboxamide
• Example 69: N-{2-chloro-6-[6-(propan-2-yl)pyridin-3-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 70: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-[2-fluoro-6-(5-methylpiperidin-3-yl)phenyl]-4-methylpiperidine-1-carboxamide
• Example 71: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-4-mehylpiperidine-1-carboxamide hydrochloride
• Example 72: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[2-(propan-2-yl)pyrimidin-5-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 73: 4-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 74: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 75: 4-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 76: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide
• Example 77: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 78: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 79: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 80: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 81: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide
• Example 82: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 83: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 84: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2-oxazol-3-yl)piperidine-1-carboxamide
• Example 85: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2-oxazol-3-yl)piperidine-1-carboxamide
• Example 86: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 87: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 88: N-{2-bromo-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 89: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine-1-carboxamide
• Example 90: 4-(4-chloro-5-methyl-1,2-oxazol-3-yl)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 91: 4-cyclopentyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 92: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(2-methyl-1,3-oxazol-5-yl)piperidine-1-carboxamide
• Example 93: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[2-(propan-2-yl)-1,3-oxazol-5-yl]piperidine-1-carboxamide
• Example 94: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine-1-carboxamide
• Example 95: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine-1-carboxamide
• Example 96: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(2-cyclopropyl-1,3-thiazol-4-yl)-4-methylpiperidine-1-carboxamide
• Example 97: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide
• Example 98: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-methylpyrimidin-2-yl)piperidine-1-carboxamide
• Example 99: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)-1,4-diazepane-1-carboxamide
• Example 100: N-[2-(4-tert-butylpiperazin-1-yl)-6-chlorophenyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 101: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine-1-carboxamide
• Example 102: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methylpiperidine-1-carboxamide
• Example 103: 4-(4-chloro-5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 104: Rac-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide
• Example 105: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide
• Example 106: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(2,2-dimethylcyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide
• Example 107: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide
• Example 108: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(1-methoxycyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide
• Example 109: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide
• Example 110: Rac-N-(2-chloro-6-{[1-(propan-2-yl)pyrrolidin-3-yl]oxy}phenyl)-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 111: Rac-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide
• Example 112: Rac-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide
• Example 113: N-[2-chloro-6-(4-cyclopropylpiperazin-1-yl)phenyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 114: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide
• Example 115: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide
• Example 116: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide
• Example 117: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide
• Example 118: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide
• Example 119: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide
• Example 120: 4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide

Example 121

4-(4-Methylphenyl)-N-[2-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide

Step (i):

The crude product of the title compound 242 was prepared from compound 2 (0.152 g) in the same manner as Step (ii) in Reference Example 20.

LCMS: [M+H]⁺/Rt(min): 208/0.30

Step (ii):

The title compound 243 (0.202 g) was prepared from the crude product of compound 242 in the same manner as Step (iii) in Reference Example 20.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.1 Hz), 1.62-1.71 (2H, m), 1.84 (2H, m), 2.26 (3H, s), 2.55-2.69 (6H, m), 2.85 (4H, m), 2.95 (2H, m), 4.22 (2H, m), 6.88 (1H, m), 7.03-7.11 (6H, m), 8.14 (1H, m), 8.25 (1H, brs)

Examples 122-160

The compounds of Examples 122-160 shown in the table below were prepared in the same manner as Example 121 by using each corresponding commerial compound or compound of Reference Example.

TABLE 8
	Spectral Data
Example	Structural Formula	Material
122
	1H-NMR (CDCl3) δ: 1.16 (3H, t, J = 6.6 Hz), 1.58 (1H, brs), 1.69 (1H, dd, J = 12.4, 4.2 Hz), 1.76 (1H, dd, J = 12.4, 4.2 Hz), 1.93 (1H,
	dd, J = 12.4, 1.6 Hz), 2.33 (3H, s), 2.49-2.52 (3H, m), 2.69-2.76 (3H, m), 2.97-3.06 (6H, m), 4.28 (2H, d, J = 13.2 Hz), 6.96 (1H, dt,
	J = 8.0, 1.6 Hz), 7.19-7.10 (6H, m), 8.22 (2H, dd, J = 8.2, 1.4 Hz)
123
	1H-NMR (CDCl3) δ: 1.01 (6H, d, ), 1.64-1.68 (2H, m), 1.86 (2H, m), 2.26 (3H, s), 2.27 (3H, s),
	2.49 (2H, m), 2.66 (1H, m), 2.84 (4H, m), 2.95 (2H, m), 4.21 (2H, m), 6.88 (1H, m), 7.04-7.10
	(6H, m), 8.16 (2H, m)
124
	1H-NMR (CDCl3) δ: 1.72 (2H, m), 1.91 (3H, m), 2.05 (1H, m), 2.31 (3H, s), 2.51-2.73 (4H, m), 2.89-3.05 (5H, m), 3.65
	(1H, m), 3.78 (1H, m), 3.86-3.95 (2H, m), 4.25 (2H, m), 6.96 (1H, m), 7.08-7.15 (6H, m), 8.17 (1H, m), 8.24 (1H, brs
125
	1H-NMR (CDCl3) δ: 1.54-1.68 (2H, m), 1.85 (2H, m), 2.26 (3H, s), 2.53-2.66 (4H, m), 2.86 (4H, m), 2.94 (2H, m), 3.29
	(3H, s), 3.46 (2H, m), 4.20 (2H, m), 6.87 (1H, m), 7.03-7.09 (6H, m), 8.15( 1H, m), 8.21 (1H, brs)
126
	1H-NMR (CDCl3) δ: 0.98 (3H, J = 6.7 Hz), 1.60-1.71 (2H, m), 1.85 (2H, m), 2.26 (3H, s), 2.60-2.85 (9H, m), 2.95 (2H, m),
	3.24-3.28 (4H, m), 3.40 (1H, m), 4.22 (2H, m), 6.88 (1H, m), 7.03-7.09 (6H, m), 8.14 (1H, m), 8.26 (1H, brs)
127
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.7 Hz), 1.38 (3H, t, J = 7.0 Hz), 1.70-1.92 (8H, m), 2.20-2.32 (5H, m), 2.69-2.82
	(3H, m), 3.00 (4H, m), 4.00 (2H, q, J = 7.0 Hz), 4.24 (2H, m), 6.00 (1H, s), 6.69 (1H, m), 6.96 (1H, m), 7.09-7.13 (5H, m)
128
	1H-NMR (CDCl3) δ: 0.94 (3H, m), 1.37 (5H, m), 1.56 (5H, m), 1.68-1.77 (3H, m), 1.85-1.99 (5H, m), 2.31 (3H, s), 2.68-
	2.92 (3H, m), 3.01 (4H, m), 3.99 (2H, q, J = 6.9 Hz), 4.23 (2H, m), 6.05 (1H,brs), 6.70 (1H, m), 7.05-7.13 (6H, m)
129
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.7 Hz), 1.25 (6H, d, J = 6.1 Hz), 1.61-1.85 (8H, m), 2.15-2.28 (5H, m), 2.62-2.79 (3H, m),
	2.95 (4H, m), 4.18 (2H, m), 4.44 (1H, m), 5.98 (1H, s), 6.66 (1H, m), 6.90 (1H, m), 7.02-7.07 (5H, m)
130
	1H-NMR (CDCl3) δ: 1.10 (6H, d, J = 6.8 Hz), 1.17-1.29 (3H, m), 1.34 (3H, s), 1.56-1.84 (6H, m), 2.14-2.23 (1H, m), 2.27
	(2H, d, J = 14.0 Hz), 2.37-2.49 (2H, m), 2.63-2.74 (2H, m), 2.74-2.87 (1H, m), 3.12-3.27 (4H, m), 3.80 (2H, dt, J = 14.0, 4.0 Hz),
	5.65-5.73 (1H, m), 6.04 (1H, bs), 7.04-7.13 (2H, m), 7.29 (1H, dd, J = 7.6, 2.4 Hz).
131
	1H-NMR (CDCl3) δ: 1.15-1.38 (5H, m), 1.34 (3H, s), 1.53-2.00 (5H, m), 2.01-2.12 (2H, m), 2.12-2.35 (3H, m), 2.37-2.46 (2H, m),
	2.46-2.56 (2H, m), 2.76-2.88 (1H, m), 2.92-3.03 (2H, m), 3.19 (2H, ddd, J = 14.0, 10.8, 2.8 Hz), 3.79 (2H, dt, J = 14.0, 4.4 Hz),
	5.64-5.72 (1H, m), 6.03 (1H, bs), 7.04-7.15 (2H, m), 7.29 (1H, dd, J = 7.2, 2.8 Hz)
132
	1H-NMR (CDCl3) δ: 1.12 (6H, d, J = 6.1 Hz), 1.66-1.76 (2H, m), 1.86 (2H, m), 2.31 (3H, s), 2.50 (2H, m), 2.66-2.85 (4H, m),
	2.98 (2H, m), 3.24 (2H, m), 4.22 (2H, m), 5.71 (1H, m), 6.15 (1H, brs), 7.04-7.13 (6H, m), 7.28-7.31 (1H, m)
133
	1H-NMR (CDCl3) δ: 1.09 (6H, d, J = 6.1 Hz), 1.70-1.91 (8H, m), 2.27 (2H, m), 2.32 (3H, s), 2.69-
	2.79 (3H, m), 3.03 (4H, m), 4.22 (2H, m), 6.04 (1H, s), 7.01-7.17 (5H, m), 7.23-7.29 (2H, m)
134
	1H-NMR (CDCl3) δ: 1.14 (3H, d, J = 6.7 Hz), 1.64-1.75 (3H, m), 1.86 (3H, m), 2.31 (3H, s), 2.46 (2H, m), 2.67 (1H, m),
	2.84 (2H, m), 2.97 (3H, m), 3.34 (2H, m), 4.45 (1H, m), 4.56 (1H, m), 5.71 (1H, m), 6.00 (1H, brs), 6.93-7.13 (7H, m)
135
	1H-NMR (CDCl3) δ: 1.17 (3H, d, J = 6.7 Hz), 1.64-1.75 (3H, m), 1.87 (2H, m), 2.31 (3H, s), 2.42 (2H, m), 2.69 (1H, m),
	2.85-3.02 (5H, m), 3.34 (2H, m), 4.21 (2H, m), 5.70 (1H, m), 5.89 (1H, brs), 6.92-7.13 (7H, m)
136
	1H-NMR (CDCl3) δ: 1.64-1.74 (3H, m), 1.87 (2H, m), 2.31 (3H, s), 2.44 (2H, m), 2.69 (1H, m), 2.90-3.01 (4H, m), 3.43 (2H, m),
	4.20 (2H, m), 4.61-4.73 (4H, m), 5.70 (1H, m), 5.90 (1H, brs), 6.92-7.13 (7H, m)
137
	1H-NMR (CDCl3) δ: 1.14 (3H, m), 1.68-1.79 (4H, m), 1.89 (4H, m), 2.32 (3H, s), 2.47 (2H, m), 2.69-2.75 (3H, m), 3.04 (4H, m),
	4.20 (2H, m), 4.44 (1H, m), 4.56 (1H, m), 5.84 (1H, brs), 6.91-6.97 (1H, m), 7.10-7.19 (6H, m)
138
	1H-NMR (CDCl3) δ: 1.07 (3H, m), 1.64-1.87 (8H, m), 2.27 (3H, s), 2.46 (2H, m), 2.67 (3H, m), 2.88-3.01 (5H, m), 4.15 (2H, m),
	5.76 (1H, brs), 6.89 (1H, m), 7.02-7.15 (6H, m)
139
	1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 6.1 Hz), 1.64-1.75 (3H, m), 1.89 (2H, m), 2.31 (3H, s), 2.69 (1H, m), 3.02 (3H, m), 3.90 (2H,
	m), 4.05 (2H, m), 4.26 (1H, m), 5.98 (1H, m), 6.35 (1H, brs), 6.98-7.15 (7H, m)
140
	1H-NMR (CDCl3) δ: 1.63-1.75 (2H, m), 1.89 (2H, m), 2.31 (3H, s), 2.63 (3H, s), 2.69 (1H, m), 2.99 (2H, m), 3.72-3.93 (4H, m),
	4.22 (2H, m), 5.98 (1H, m), 6.06 (1H, brs), 6.99-7.13 (7H, m)
141
	1H-NMR (CDCl3) δ: 0.92-1.00 (2H, m), 1.00-1.09 (2H, m), 1.13 (3H, d, J = 6.7 Hz), 1.29 (3H, s), 1.61-1.73 (2H, m), 1.97-2.06
	(1H, m), 2.06-2.18 (2H, m), 2.37-2.48 (2H, m), 2.72-2.83 (2H, m), 2.93-3.07 (1H, m), 3.20-3.35 (4H, m), 3.69-3.82 (2H, m), 4.33-
	4.62 (2H, m), 5.67 (1H, s), 5.79 (1H, s), 6.05 (1H, s), 7.04-7.11 (2H, m), 7.29 (1H, dd, J = 6.7, 2.4 Hz)
142
	1H-NMR (CDCl3) δ: 1.16-1.24 (7H, m), 1.32 (3H, s), 1.63-1.70 (3H, m), 2.14-2.26 (3H, m), 2.46 (2H, m), 2.83 (2H, m), 3.20 (3H,
	m), 3.33 (1H, m), 3.79 (2H, m), 4.46 (1H, m), 4.58 (1H, m), 5.66 (1H, m), 6.09 (1H, brs), 7.03-7.08 (2H, m), 7.27-7.29 (1H, m)
143
	1H-NMR (CDCl3) δ: 1.02-1.25 (7H, m), 1.36 (3H, s), 1,43-1.93 (4H, m), 1.72 (2H, ddd, J = 13.6, 11.2, 4.4 Hz), 2.20 (1H, tt, J =
	7.6, 3.6 Hz), 2.25-2.35 (2H, m), 2.35-2.55 (2H, m), 2,69-3.13 (4H, m), 3.18-3.29 (2H, m), 3.83 (2H, ddd, J = 14.0, 4.4, 3.6),
	4.24-4.65 (2H, m), 5.92-6.07 (1H, brs), 7.11-7.19 (1H, m), 7.20-7.30 (2H, m).
144
	1H-NMR (CDCl3) δ: 0.88-1.01 (4H, m), 1.06 (6H, d, J = 6.1 Hz), 1.22 (3H, s), 1.58-1.65 (2H, m), 1.91-2.07 (3H, m), 2.41 (2H, m),
	2.66 (2H, m), 2.79 (1H, m), 3.13-3.24 (4H, m), 3.70 (2H, m), 5.62 (1H, m), 5.72 (1H, s), 6.07 (1H, brs), 6.98-7.03 (2H, m), 7.21-
	7.24 (1H, m)
145
	1H-NMR (CDCl3) δ: 0.99-1.42 (10H, m), 1.36 (3H, s), 1.43-1.80 (5H, m), 1.82-2.07 (3H, m), 2.13-2.55 (4H, m), 2.72-3.33
	(5H, m), 3.83 (2H, d, J = 14.0 Hz), 6.03 (1H, bs), 7.10-7.21 (1H, m), 7.21-7.29 (1H, m), 7.29-7.41 (1H, m).
146
	1H-NMR (CDCl3) δ: 1.17-1.28 (5H, m), 1.37 (3H, s), 1.65-1.77 (3H, m), 1.79-2.09 (4H, m), 2.11-2.36 (4H, m), 3.17-3.35 (2H, m),
	3.73-3.87 (2H, m), 4.52-4.61 (2H, m), 4.63-4.74 (2H, m), 4.78-4.85 (2H, m), 4.85-4.94 (1H, m), 6.04 (1H, bs), 7.14-
	7.22 (1H, m), 7.23-7.36 (2H, m).
147
	1H-NMR (CDCl3) δ: 1.05 (6H, d, J = 6.1 Hz), 1.26 (3H, s), 1.72-1.77 (2H, m), 2.10-2.16 (2H, m), 2.32 (3H, s), 2.41 (2H,
	m), 2.62-2.75 (3H, m), 3.12 (2H, m), 3.40-3.44(2H, m), 3.55-3.60 (2H, m), 5.66 (1H, m), 5.97 (1H, s), 7.03-7.09 (2H,
	m), 7.14 (2H, m), 7.21-7.28 (3H, m)
148
	1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.28 (3H, s), 1.62-1.84 (6H, m), 2.11-2.19 (4H, m), 2.33 (3H, s), 2.66-2.74 (2H, m),
	2.95 (2H, m), 3.43-3.49 (2H, m), 3.58-3.64 (2H, m), 5.95 (1H, s), 7.10-7.17 (3H, m), 7.21-7.25 (4H, m)
149
	1H-NMR (CDCl3) δ: 1.04 (3H, t, J = 7.0 Hz), 1.18-1.24 (4H, m), 1.33 (3H, s), 1.66 (2H, ddd, J = 14.1, 10.4, 3.7 Hz), 1.80 (1H, d, J =
	9.8 Hz), 1.88 (1H, d, J = 9.8 Hz), 2.15-2.21 (1H, m), 2.22-2.30 (2H, m), 2.44-2.63 (2H, m), 2.71 (1H, d, J = 9.8 Hz), 2.92 (1H, dd,
	J = 9.8, 2.4 Hz), 3.13-3.23 (2H, m), 3.31 (1H, dd, J = 9.5, 2.4 Hz), 3.40 (1H, d, J = 9.5 Hz), 3.48-3.52 (1H, m), 3.74-3.84 (2H, m),
	4.01-4.06 (1H, m), 5.66 (1H, s), 6.49 (1H, d, J = 8.6 Hz), 6.56 (1H, dd, J = 8.6, 8.6 Hz), 6.96-7.04 (1H, m).
150
	1H-NMR (CDCl3) δ: 1.05 (6H, dd, J = 6.1, 1.2 Hz), 1.66-1.77 (2H, m), 1.82-1.95 (4H, m), 2.33 (3H, s), 2.54-2.76 (3H, m), 2.95-3.06
	(2H, m), 3.13 (1H, dd, J = 9.2, 2.4 Hz), 3.33 (1H, dd, J = 9.8, 2.4 Hz), 3.46 (1H, d, J = 9.8 Hz), 3.70-3.74 (1H, m), 4.05-4.09
	(1H, m), 4.18-4.28 (2H, m), 5.70 (1H, s), 6.51 (1H, d, J = 8.3 Hz), 6.60 (1H, ddd, J = 9.5, 8.3, 1.2 Hz), 6.99-7.06 (1H, m), 7.11
	(2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz).
151
	1H-NMR (CDCl3) δ: 1.05 (6H, dd, J = 6.1, 1.2 Hz), 1.66-1.77 (2H, m), 1.82-1.95 (4H, m), 2.33 (3H,
	s), 2.54-2.76 (3H, m), 2.95-3.06 (2H, m), 3.13 (1H, dd, J = 9.2, 2.4 Hz), 3.33 (1H, dd, J = 9.8,
	2.4 Hz), 3.46 (1H, d, J = 9.8 Hz), 3.70-3.74 (1H, m), 4.05-4.09 (1H, m), 4.18-4.28 (2H, m), 5.70
	(1H, s), 6.51 (1H, d, J = 8.3 Hz), 6.60 (1H, ddd, J = 9.5, 8.3, 1.2 Hz), 6.99-7.06 (1H, m), 7.11
	(2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz).
152
	1H-NMR (CDCl3) δ: 1.03 (6H, t, J = 6.1 Hz), 1.18-1.25 (4H, m), 1.33 (3H, s), 1.66-1.72 (2H, m), 1.83 (1H, d, J = 9.2 Hz),
	1.91 (1H, d, J = 9.2 Hz), 2.14-2.22 (1H, m), 2.24-2.31 (2H, m), 2.53-2.60 (1H, m), 2.62 (1H, dd, J = 9.8, 1.2 Hz), 3.11 (1H, dd,
	J = 9.8, 2.4 Hz), 3.14-3.25 (2H, m), 3.29 (1H, dd, J = 9.8, 2.1 Hz), 3.41 (1H, d, J = 9.8 Hz), 3.67-3.72 (1H, m), 3.75-3.85 (2H,
	m), 4.02-4.06 (1H, m), 5.63 (1H, s), 6.49 (1H, d, J = 9.0 Hz), 6.57 (1H, ddd, J = 9.0, 7.9, 1.2 Hz), 6.98-7.05 (1H, m).
153
	1H-NMR (CDCl3) δ: 1.38-1.52 (3H, m), 1,52-1.76 (2H, m), 1.76-2.01 (4H, m), 2.32 (3H, s), 2.44-2.56 (1H, m), 2.65-2.85 (4H, m),
	2.96-3.33 (4H, m), 3.40-3.47 (1H, m), 3.53 (1H, t, J = 6.4 Hz), 3.66-3.72 (1H, m), 3.77-4.17 (3H, m), 4.48-4.80 (1H, m), 7.04 (1H, d,
	J = 7.2 Hz), 7.07-7.22 (6H, m), 7.37 (1H, d, J = 6.8 Hz).
154
	1H-NMR (CDCl3) δ: 1.13 (6H, brs), 1.48-1.68 (2H, m), 1.76 (2H, ddd, J = 25.4, 12.8, 4.0 Hz), 1.81-
	2.04 (6H, m), 2.34 (3H, s), 2.57-2.77 (3H, m), 2.98-3.23 (3H, m), 3.53-3.67 (2H, m), 4.28-4.34
	(2H, m), 6.38 (1H, s), 6.88 (1H, dd, J = 8.6, 8.6 Hz), 6.94 (1H, d, J = 8.6 Hz), 7.00-7.08 (1H, m),
	7.12 (2H, d, J = 8.0 Hz), 7.15 (2H, d, J = 8.0 Hz).
155
	1H-NMR (CDCl3) δ: 1.08 (6H, d, J = 6.1 Hz), 1.19-1.25 (4H, m), 1.34 (3H, s), 1.66-1.81 (4H, m),
	1.89-1.97 (2H, m), 2.15-2.24 (1H, m), 2.26-2.33 (2H, m), 2.55-2.65 (2H, m), 2.67 (2H, dd, J =
	11.3, 2.8 Hz), 3.04 (2H, d, J = 11.3 Hz), 3.23 (2H, ddd, J = 13.6, 10.9, 2.6 Hz), 3.47-3.57 (1H,
	m), 3.85-3.93 (2H, m), 6.34 (1H, s), 6.84 (1H, dd, J = 8.0, 1.5 Hz), 6.89 (1H, t, J = 8.0 Hz),
	6.99-7.06 (1H, m).
156
	1H-NMR (CDCl3) δ: 1.10 (3H, t, J = 7.2 Hz), 1.18-1.29 (4H, m), 1.34 (3H, s), 1.58-1.76 (2H, m),
	1.92 (2H, tt, J = 6.4, 6.0 Hz), 2.14-2.25 (1H, m), 2.25-2.35 (2H, m), 2.61 (2H, q, J = 7.2 Hz),
	2.72-2.85 (4H, m), 3.02-3.11 (4H, m), 3.16-3.28 (2H, m), 3.88 (2H, dt, J = 8.8, 4.4 Hz), 6.92
	(1H, td, J = 7.6, 1.6 Hz), 7.05-7.12 (1H, m), 7.14 (1H, dd, J = 7.6, 1.6 Hz), 8.17 (1H, dd,
	J = 8.0, 1.6 Hz), 8.39 (1H, s).
157
	1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.2 Hz), 1.17-1.28 (4H, m), 1.33 (3H, s), 1.45-1.58 (2H, m),
	1.68 (2H, ddd, J = 13.6, 10.8, 4.0 Hz), 1.90 (2H, tt, J = 6.4, 5.6 Hz), 2.14-2.24 (1H, m), 2.25-
	2.35 (2H, m), 2.45-2.53 (2H, m), 2.74-2.85 (4H, m), 3.01-3.09 (4H, m), 3.22 (2H, ddd, J = 14.0,
	10.4, 2.8 Hz), 3.88 (2H, dt, J = 8.8, 4.4 Hz), 6.91 (1H, td, J = 7.6, 1.6 Hz), 7.05-7.11 (1H,
	m), 7.13 (1H, dd, J = 7.6, 1.6 Hz), 8.17 (1H, dd, J = 8.0, 1.6 Hz), 8.39 (1H, s).
158
	1H-NMR (CDCl3) δ: 1.11 (6H, d, J = 6.8 Hz), 1.44 (3H, s), 1.52-1.64 (2H, m), 1.96 (2H, d, J = 11.2
	Hz), 2.37-2.50 (2H, m), 2.63-2.76 (2H, m), 2.76-2.90 (1H, m), 3.13-3.30 (4H, m), 4.11 (2H, d, J =
	14.0 Hz), 5.66-5.73 (1H, m), 6.14 (1H, bs), 7.07-7.14 (2H, m), 7.28-7.35 (1H, m).
159
	1H-NMR (CDCl3) δ: 1.44 (3H, s), 1.52-1.82 (4H, m), 1.86-2.01 (4H, m), 2.03-2.15 (2H, m), 2.37-2.47
	(2H, m), 2.47-2.57 (2H, m), 2.76-2.89 (1H, m), 2.94-3.03 (2H, m), 3.14-3.30 (2H, m), 4.10 (2H,
	d, J = 14.0 Hz), 5.66-5.71 (1H, m), 6.08 (1H, bs), 7.07-7.14 (2H, m), 7.27-7.34 (1H, m).
160
	1H-NMR (CDCl3) δ: 0.96 (6H, d, J = 6.0 Hz), 1.17-1.29 (4H, m), 1.35 (3H, s), 1.72 (2H, ddd, J =
	14.8, 11.2, 4.4 Hz), 2.15-2.24 (1H, m), 2.24-2.33 (2H, m), 2.39 (1H, sept, J = 6.0 Hz), 3.08-3.14
	(2H, m), 3.22 (2H, ddd, J = 13.2, 10.4, 2.4 Hz), 3.70-3.77 (2H, m), 3.86 (2H, dt, J = 9.0, 4.8
	Hz), 4.74 (1H, quin, J = 5.6 Hz), 6.02-6.09 (1H, br), 6.51-6,58 (1H, m), 6.98-7.06 (2H, m).

• Example 122: N-[2-(4-ethylpiperazin-1-yl)phenyl]-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 123: 4-(4-methylphenyl)-N-[2-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide
• Example 124: 4-(4-methylphenyl)-N-{2-[4-(oxolan-3-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide
• Example 125: N-{2-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 126: N-{2-[4-(1-methoxypropan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 127: N-{2-ethoxy-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 128: N-{2-[1-(butan-2-yl)piperidin-4-yl]-6-ethoxyphenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 129: 4-(4-methylphenyl)-N-{2-[(propan-2-yl)oxy]-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}piperidine-1-carboxamide
• Example 130: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 131: N-[2-chloro-6-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 132: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 133: N-{2-chloro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 134: N-{2-fluoro-6-[1-(1-fluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 135: N-{2-[1-(1,1-difluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-6-fluorophenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 136: N-{2-[1-(1,3-difluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-6-fluorophenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 137: N-{2-fluoro-6-[1-(1-fluoropropan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 138: N-{2-[1-(1,1-difluoropropan-2-yl)piperidin-4-yl]-6-fluorophenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 139: N-{2-fluoro-6-[1-(propan-2-yl)-2,5-dihydro-1H-pyrrol-3-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 140: N-[2-fluoro-6-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)phenyl]-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 141: N-{2-chloro-6-[1-(1-fluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 142: N-{2-chloro-6-[1-(1-fluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 143: N-{2-chloro-6-[1-(1-fluoropropan-2-yl)piperidin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 144: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 145: N-{2-chloro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 146: N-{2-chloro-6-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide
• Example 147: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 148: N-{2-chloro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 149: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-fluorophenyl}-4-methylpiperidine-1-carboxamide
• Example 150: N-{2-fluoro-6-[(1S,4S)-5-(propan-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 151: N-{2-fluoro-6-[(1R,4R)-5-(propan-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 152: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[(1R,4R)-5-(propan-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 153: N-[2-(4-ethyl-1,4-diazepan-1-yl)phenyl]-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 154: N-{2-fluoro-6-[8-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide
• Example 155: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[8-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]phenyl}-4-methylpiperidine-1-carboxamide
• Example 156: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[2-(4-ethyl-1,4-diazepan-1-yl)phenyl]-4-methylpiperidine-1-carboxamide
• Example 157: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-[2-(4-propyl-1,4-diazepan-1-yl)phenyl]piperidine-1-carboxamide
• Example 158: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-cyano-4-methylpiperidine-1-carboxamide
• Example 159: N-[2-chloro-6-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-4-cyano-4-methylpiperidine-1-carboxamide
• Example 160: N-(2-chloro-6-{[1-(propan-2-yl)azetidin-3-yl]oxy}phenyl)-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

Example 161

N-{2-Fluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide

Step (i):

A mixture of compound 150 (0.079 g), palladium hydroxide (0.020 g) and ethanol (2 mL) was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction mixture was filtrated with Celite and the filtrate was concentrated in vacuo. The resulting residue was then used directly in the next step.

Step (ii)

The title compound 245 (0.066 g) was prepared from the crude product of compound 244 in the same manner as Step (iii) in Reference Example 20.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.7 Hz), 1.61 (3H, s), 1.74 (2H, ddd, J=25.4, 13.1, 4.0 Hz), 1.83-1.96 (6H, m), 2.33 (3H, s), 2.55 (2H, d, J=9.8 Hz), 2.62-2.76 (4H, m), 3.03 (2H, ddd, J=13.1, 13.1, 2.2 Hz), 3.60-3.65 (2H, m), 4.29-4.37 (2H, m), 6.17 (1H, s), 6.66 (1H, d, J=8.3 Hz), 6.77 (1H, dd, J=8.6, 8.3 Hz), 6.94-7.01 (1H, m), 7.11 (2H, d, J=8.6 Hz), 7.14 (2H, d, J=8.6 Hz).

Example 162

4-Methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide

Step (i):

A mixture of (Z)-N′-hydroxyacetimidamide (0.0125 g), sodium hydride (0.0134 g) and THE (1 mL) was stirred with heating under reflux for 2 hours. The mixture was cooled to room temperature, compound 237 in Reference Example 101 (0.035 g) was added thereto, and the mixture was stirred with heating under reflux for 5 hours. The mixture was cooled to room temperature, water was added to the reaction mixture at 0° C., and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was then purified by amino silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 246 (0.005 g).

LCMS: [M+H]⁺/Rt(min): 427/0.70

Examples 163-164

The compounds of Examples 163-164 shown in the table below were synthesized in the same manner as Example 162 by using each corresponding commercial compound or compound of Reference Example.

TABLE 9
	Spectral Data
Example	Structural Formula	Material
163
	1H-NMR (CDCl3) δ: 1.38 (8H, d, J = 6.8 Hz), 1.86-
	1.85 (3H, m), 2.10 (3H, s), 2.40 (2H, m), 3.13-
	3.08 (2H, m), 3.30-3.29 (3H, m), 3.59-3.47 (6H,
	m), 3.96-3.95 (4H, m), 4.39-4.37 (2H, m), 7.25-
	7.22 (1H, m), 7.39-7.35 (1H, m), 7.48 (1H, d, J =
	8.0 Hz), 7.77 (1H, d, J = 8.0 Hz), 8.54 (1H, brs)
164
	LCMS: [M + H] + / Rt = 431/1.52 min (Method B)

• Example 163: 4-methyl-4-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide hydrochloride
• Example 164: 4-fluoro-4-(3-methl-1,2,4-oxadiazol-5-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide

Example 165

4-Methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide

To a mixture of compound 237 in Reference Example 101 (0.056 g), THE (0.5 mL), MeOH (0.5 mL) and water (0.5 mL) was added sodium hydroxide (0.027 g) and the mixture was stirred at 60° C. for 1 hour. The mixture was neutralized with 10% aqueous hydrochloric acid solution and extracted with chloroform/methanol (4:1) solution. The solvent was concentrated in vacuo and the resulting residue was dissolved in DMF (0.5 mL). Diisopropylethylamine (0.059 mL), acetylhydrazine (0.020 g) and HATU (0.128 g) were added thereto and the mixture was stirred at room temperature for 14 hours. To the reaction solution was saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The solvent was concentrated in vacuo and the resulting residue was dissolved in acetonitrile (0.5 mL). Triphenylphosphine (0.071 g), triethylamine (0.057 mL) and carbon tetrachloride (0.052 mL) were added thereto and the mixture was stirred with heating under reflux for 7 hours. The mixture was cooled and concentrated in vacuo. The resulting residue was then purified by amino silica gel column chromatography (Eluate: hexane/ethyl acetate) to give the title compound 247 (0.010 g).

LCMS: [M+H]⁺/Rt(min): 427/1.43

Example 166

4-(4-Methylphenyl)-N-{2-[(2R,5S)-5-(propan-2-yl)morpholin-2-yl]phenyl}piperidine-1-carboxamide

Step (i):

The title compound 248 (0.045 g) was prepared from compound 41 (0.036 g) in the same manner as Step (iv) in Reference Example 23.

LCMS: [M+H]⁺/Rt(min): 522/1.25

Step (ii):

The title compound 249 (0.031 g) was synthesized from compound 248 (0.042 g) in the same manner as Step (ii) in Reference Example 14.

¹H-NMR (CDCl₃) δ: 0.92 (3H, d, J=7.0 Hz), 0.97 (3H, d, J=7.0 Hz), 1.51-1.62 (1H, m), 1.66-1.77 (2H, m), 1.86-1.94 (2H, m), 2.33 (3H, s), 2.53-2.60 (1H, m), 2.67-2.76 (1H, m), 2.95-3.04 (2H, m), 3.07 (1H, dd, J=12.5, 2.7 Hz), 3.16 (1H, dd, J=11.3, 11.3 Hz), 3.48 (1H, dd, J=10.4, 10.4 Hz), 4.09 (1H, dd, J=11.3, 2.7 Hz), 4.21-4.32 (2H, m), 4.53 (1H, dd, J=10.4, 3.0 Hz), 6.95 (1H, dd, J=7.3, 7.3 Hz), 7.06 (1H, d, J=7.3 Hz), 7.11 (4H, d, J=8.5 Hz), 7.14 (4H, d, J=8.5 Hz), 7.27 (1H, dd, J=7.3, 7.3 Hz), 8.10 (1H, d, J=8.5 Hz), 8.71 (1H, s).

Examples 167-168

The compounds of Examples 167-168 shown in the table below were synthesized in the same manner as Example 166 by using each corresponding commercial compound or compound of Reference Example.

TABLE 10
	Spectral Data
Example	Structural Formula	Material
167
	1H-NMR (CDCl3) δ: (mixture of rotamers) 0.93 (3H,
	d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.35
	(3H, s), 1.50-1.80 (5H, m), 2.12-2.25 (2H, m),
	2.25-2.35 (2H, m), 2.47-2.56 (1H, m), 2.88 (1H,
	dd, J = 12.4, 10.4 Hz), 2.94-3.05 (2H, m), 3.12-
	3.30 (2H, m), 3.34-3.46 (2H, m) 3.80-3.92 (2H,
	m), 4.05 (1H, dd, J = 11.2, 3.2 Hz), 4.53 (1H,
	dd, J = 10.4, 2.4 Hz), 6.89 (1H, br s), 7.13
	(1H, t, J = 8.0 Hz), 7.21-7.29 (1H, m), 7.36 (1H,
	dd, J = 8.0, 1.6 Hz).
168
	1H-NMR (CDCl3) δ: (mixture of rotamers) 0.90-
	1.06 (6H, m), 1.35 (3H, s), 1.51-1.63 (1H, m) 1.62-
	1.81 (4H, m), 2.12-2.24 (2H, m), 2.24-2.35 (2H,
	m), 2.35-2.59 (1H, m), 2.87 (0.6H, dd, J = 12.0,
	10.8 Hz), 2.90-3.97 (8.8H, m) 4.05 (0.6H, dd, J =
	11.2, 3.2 Hz), 4.50-4.68 (1H, m), 4.97-5.03
	(0.3H, m), 6.80-6.96 (0.7H, br s), 7.10-7.19 (1H,
	m), 7.22-7.29 (1H, m), 7.36 (0.7H, dd, J = 8.0,
	1.2 Hz), 7.43 (0.3H, dd, J = 8.0, 1.2 Hz).

• Example 167: Rac-N-{2-chloro-6-[(2R,5S)-5-(propan-2-yl)morpholin-2-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-13-yl)-4-methylpiperidine-1-carboxamide
• Example 168: Rac-N-{2-chloro-6-[(2R,5R)-5-(propan-2-yl)morpholin-2-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

Examples 169-170

The compounds of Examples 169-170 shown in the table below were synthesized in the same manner as Example 1 by using each corresponding commercial compound or compound of Reference Example.

TABLE 11
	Spectral Data
Example	Structural Formula	Material
169
	1H-NMR (CDCl3) δ: 7.16 (1H, dd, J = 7.9, 1.2 Hz),
	7.07 (1H, dd, J = 7.9, 7.9 Hz), 6.97 (1H, dd, J =
	7.9, 1.2 Hz), 6.28 (1H, s), 3.81-3.75 (2H, m),
	3.51-3.39 (3H, m), 3.04-2.96 (2H, m), 2.95-2.87
	(4H, m), 2.75-2.59 (5H, m), 2.27-2.12 (3H, m),
	2.05-1.96 (2H, m), 1.24-1.18 (4H, m), 1.07 (6H, d,
	J = 6.7 Hz).
170
	1H-NMR (CDCl3) δ: 7.16 (1H, dd, J = 7.9, 1.2 Hz),
	7.06 (1H, dd, J = 7.9, 7.9 Hz), 6.96 (1H, dd, J =
	7.9, 1.2 Hz), 6.26 (1H, s), 3.74-3.68 (2H, m), 3.53
	(2H, dd, J = 10.7, 3.4 Hz), 3.35-3.24 (1H, m),
	2.95-2.82 (6H, m), 2.75-2.58 (5H, m), 2.43-2.35
	(2H, m), 2.20-2.12 (1H, m), 1.88-1.78 (2H, m),
	1.23-1.17 (4H, m), 1.07 (6H, d, J = 6.1 Hz).

• Example 169: (3aR,5s,6aS)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-5-(5-cyclopropyl-1,2,4-oxadiazol-13-yl) hexahydrocyclopenta [c]pyrrol-2 (1H)-carboxamide
• Example 170: (3aR,5r,6aS)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-5-(5-cyclopropyl-1,2,4-oxadiazol-13-yl) hexahydrocyclopenta [c]pyrrol-2 (1H)-carboxamide

Test Example 1: Measurement of Agonist Activity for Orexin Receptor 2 Type

Human orexin receptor type 2 and apoaequorin were transiently expressed in CHO cells, and the agonist activity was evaluated based on intracellular calcium mobilization with ligand stimulation. The CHO cells transiently-expressed human orexin receptor type 2 and apoaequorin were seeded on a 384-well plate by 2,000 cells/well, and then incubated for 16-22 hours. After the plate was returned to room temperature, Coelenterazine hcp (final concentration: 1 μM) was added to the plate, and the plate was allowed to stand at room temperature for 2 hours. And then, Orexin A or each test compound was added to the plate, and the luminescence of the cells was measured with FDSS7000 (Hamamatsu Photonics K. K.), wherein Orexin A and each test compound were dissolved in DMSO (final concentration: 0.1%), and diluted with a buffer (Hanks, 20 mM HEPES, 0.1% BSA). The agonist activity of each test compound for orexin receptor type 2 was calculated as relative percentage of luminescence for the luminescence (100%) of Orexin A (100 μM).

Test Result:

The results that each compound obtained in Examples 1 to 168 was evaluated about the agonist activity for orexin receptor type 2 showed that the present compounds have agonist activity for orexin receptor type 2. Each agonist activity of the compounds obtained in Examples 1 to 168 (10 μm) for orexin receptor type 2 is shown in the table below as relative percentage of luminescence for the luminescence (100%) of Orexin A (100 μM).

TABLE 12
Example Agonist Activity (%)
1       77
2       35
3       27
4       125
5       156
6       151
7       154
8       145
9       132
10      34
11      142
12      123
13      99
14      126
15      101
16      82
17      133
18      128
19      133
20      111
21      156
22      97
23      92
24      127
25      136
26      63
27      129
28      104
29      77
30      36
31      164
32      30
33      150
34      161
35      163
36      123
37      47
38      119
39      106
40      122
41      47
42      128
43      135
44      143
45      127
46      49
47      165
48      146
49      196
50      187
51      151
52      155
53      140
54      140
55      154
56      44
57      171
58      71
59      158
60      102
61      156
62      75
63      26
64      140
65      93
66      129
67      154
68      68
69      129
70      45
71      88
72      144
73      141
74      145
75      131
76      148
77      158
78      170
79      156
80      157
81      145
82      156
83      146
84      110
85      145
86      138
87      142
88      161
89      152
90      164
91      195
92      196
93      203
94      179
95      178
96      160
97      69
98      165
99      75
100     160
101     157
102     160
103     178
104     180
105     165
106     185
107     163
108     157
109     161
110     148
111     146
112     151
113     157
114     155
115     159
116     136
117     158
118     149
119     154
120     125
121     130
122     122
123     105
124     27
125     141
126     139
127     145
128     136
129     138
130     142
131     150
132     171
133     156
134     135
135     103
136     105
137     126
138     44
139     121
140     75
141     121
142     130
143     109
144     143
145     148
146     104
147     167
148     176
149     146
150     116
151     97
152     136
153     54
154     40
155     55
156     38
157     94
158     133
159     150
160     141
161     90
162     100
163     110
164     128
165     96
166     72
167     183
168     184

Test Example 2: Measurement of Agonist Activity for Orexin Receptor 2 Type

Human orexin receptor type 2 and apoaequorin were transiently expressed in CHO cells, and the agonist activity was evaluated based on intracellular calcium mobilization with ligand stimulation. The CHO cells transiently-expressed human orexin receptor type 2 and apoaequorin were seeded on a 384-well plate by 2,000 cells/well, and then incubated for 16-22 hours. After the plate was returned to room temperature, Coelenterazine hcp (final concentration: 1 μM) was added to the plate, and the plate was allowed to stand at room temperature for 2 hours. And then, Orexin A (PEPTIDE INSTITUTE, INC., Lot. 671009) or each test compound was added to the plate, and the luminescence of the cells was measured with FDSS7000 (Hamamatsu Photonics K. K.), wherein Orexin A and each test compound were dissolved in DMSO (final concentration: 0.1%), and diluted with a buffer (Hanks, 20 mM HEPES, 0.1% BSA). The agonist activity of each test compound for orexin receptor type 2 was calculated as relative percentage of luminescence for the luminescence (100%) of Orexin A (100 μM).

Test Result:

The results that each compound obtained in Examples 169 to 170 was evaluated about the agonist activity for orexin receptor type 2 showed that the present compounds have agonist activity for orexin receptor type 2. Each agonist activity of the compounds obtained in Examples 169 to 170 (10 μm) for orexin receptor type 2 is shown in the table below as relative percentage of luminescence for the luminescence (100%) of Orexin A (100 pM).

TABLE 13
Example Agonist Activity (%)
169     444
170     357

INDUSTRIAL APPLICABILITY

The compounds of the present invention exhibit a potent agonist activity for orexin receptor, thereby they are useful as a medicament for treating or preventing a disease such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body.

Claims

1. A compound of formula (1):

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein in R2 to R6, the optional substituent of “optionally-substituted C1-6 alkyl” is each independently the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkoxy, or C3-7 cycloalkyl, and the optional substituent of “optionally-substituted C1-6 alkoxy” is each independently the same or different one or more substituents selected from halogen atom, hydroxy group, or C3-7 cycloalkyl, in R1, the optional substituent of C6-10 aromatic carbocyclyl group, 5- to 10-membered aromatic heterocyclyl group, C3-6 saturated carbocyclyl group, and 4- to 10-membered saturated heterocyclyl group is each independently one or more substituents selected from the group consisting of halogen atom, hydroxy group, C6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl), C1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkoxy or C3-7 cycloalkyl), C3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl), C1-6 alkylamino (the alkyl group of which may be optionally substituted with halogen atom, hydroxy group or C3-7 cycloalkyl), C3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl, C1-6 alkoxy or C3—, cycloalkyl), cyano, C1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C3-7 cycloalkyl), and 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl), andin ring E and ring G, the optional substituent of C6-10 aromatic carbocyclyl group, 5- to 10-membered aromatic heterocyclyl group, C3-6 saturated carbocyclyl group, and 4- to 10-membered saturated heterocyclyl group is each independently one or more substituents selected from the group consisting of halogen atom, C1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkoxy or C3-7 cycloalkyl), C6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl), C1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C3-7 cycloalkyl), C1-6 alkylamino (the alkyl group of which may be optionally substituted with halogen atom, hydroxy group or C3-7 cycloalkyl), C3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl, C1-6 alkoxy or C3-7 cycloalkyl), and C3-7 cycloalkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl, C1-4 alkoxy or C3-7 cycloalkyl), or when there are plural optional substituents, two of them may be taken together via C1-6 alkylene to form a chemically-possible bicyclic structure selected from a fused ring, a spiro ring, or bridged ring.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the formula is represented by formula (2):

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from cyano or the following formulae (1a-1) to (1a-6):

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein ring G is selected from the following formulae (1b-1) to (1b-7):

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein ring E is selected from the following formulae (1c-1) to (1c-4):

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein ring E is selected from the following formulae (1c-11) to (1c-41):

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein the formula is represented by formula (3):

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein L1 is single bond, —CH2— or oxygen atom.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the following formulae (1a-1) to (1a-3):

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein ring G is selected from the following formulae (1b-1) to (1b-3):

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R2 is halogen atom selected from F, Cl or Br, and A is oxygen atom.

13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R1 is the following formula (1a-1):

14. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R1 is the following formula (1a-2):

15. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the following formulae (1a-21) to (1a-25):

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein Ra4 is (if there are plural CRa4, each Ra4 is independently) C6-10 aromatic carbocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl or C1-6 alkoxy), C1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkoxy or C3-7 cycloalkyl), C3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl or C1-6 alkoxy), or 5- to 10-membered aromatic heterocyclyl group (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl or C1-6 alkoxy).

17. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R1 is the following formula (1a-3):

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the following formulae (1a-31) to (1a-34):

19. The compound according to claim 17 or 18 or a pharmaceutically acceptable salt thereof, wherein Ra4 is (if there are plural CRa4, each Ra4 is independently) C1-6 alkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkoxy or C3-7 cycloalkyl), C3-7 cycloalkyl (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group, C1-6 alkyl or C1-6 alkoxy), or C1-6 alkoxy (which may be optionally substituted with the same or different one or more substituents selected from halogen atom, hydroxy group or C1-6 alkoxy).

20. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein ring G is the following formula (1b-2):

21. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein ring G is the following formula (1b-1):

22. The compound according to any one of Items 1 to 19 or a pharmaceutically acceptable salt thereof, wherein ring G is the following formula (1b-3):

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamideN-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamideN-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamideN-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamideN-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

26. A medicament for treating a disease associated with orexin receptor type 2, comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

27. A medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (for example, Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (for example, malignant mast cell, extrinsic obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophysial obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer, impaired consciousness such as coma, side effect or complication caused by anesthesia, sleep disturbance, sleep problem, insomnia, intermittent sleep, night myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of shift workers, dyssomnia, sleep terror, depression, major depression, sleepwalking, enuresis, sleep disorder, Alzheimer's sundown syndrome, disease associated with circadian rhythm, fibromyalgia, condition resulting from decrease in sleeping quality, bulimia, obsessive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin level/insulin resistance, hyperlipemia, hyperlipidaemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstone, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, decrease of fecundability, infertility, hypogonadism in men, sexual/reproductive-function dysfunction such as hirsutism in women, fetal defect associated with maternity obesity, gastrointestinal motility disorder such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory disease such as respiratory distress, inflammation such as vascular systemic inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, secondary risk of obesity such as risk of left ventricle hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweat, disease in genitalium/urinary system, disease associated with sexual function or fecundability, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorder such as cerebral deficiency developed after heart bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, periparturient hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorder associated with muscle spasm, delirium, amnestic disorder, age-associated cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorder, chronic fatigue syndrome, fatigue, medication-induced parkinsonian syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptom, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, or traumatic brain injury, comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

28. A medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body, comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

29. A medicament for treating narcolepsy, comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

30. A medicament for treating idiopathic hypersomnia, comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

31. A medicament for treating hypersomnia associated with Parkinson's disease, comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

32. A medicament for treating hypersomnia associated with dementia with Lewy body, comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

33. A method of treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body, which comprises administering a therapeutically effective amount of the compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

34. Use of the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body.

35. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof for use in the treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy body.