JP2022064180A - Heterocyclic compound - Google Patents

Abstract

To provide a heterocyclic compound with orexin type 2 receptor agonist activity.SOLUTION: A compound represented by formula (I), where each symbol is as described in the specification, or a salt thereof has orexin type 2 receptor agonist activity and is useful as an agent for preventing or treating narcolepsy.SELECTED DRAWING: None

Description

The present invention relates to heterocyclic compounds, particularly heterocyclic compounds having orexin type 2 receptor agonistic activity.

(Background of invention)
Orexin is a neuropeptide specifically produced by specific nerve cells scattered in the lateral hypothalamic area of the brain and its surrounding area, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptor, which is a G protein-coupled receptor mainly present in the brain, and two subtypes of the orexin receptor, type 1 and type 2, are known. (Non-Patent Document 1).

Since orexin-producing neurons (orexin neurons) are localized near the feeding center, and intracerebroventricular administration of orexin peptides is observed to increase the amount of orexin, orexin is a nerve that regulates feeding. Although it attracted attention as a peptide, it was subsequently reported that the cause of canine narcolepsy was a gene mutation in the orexin type 2 receptor (Non-Patent Document 2), and the role of orexin in sleep / wake control was also attracting attention. There is.

From studies using a transgenic mouse in which orexin neurons have been denatured and a double transgenic mouse obtained by crossing this mouse with an orexin overexpressing transgenic mouse, narcolepsy-like symptoms appearing due to degeneration of orexin neurons have been observed. It was revealed that it disappeared by the continuous expression of orexin. Similarly, when orexin peptide was intraventricularly administered to transgenic mice in which orexin neurons were denatured, improvement in narcolepsy-like symptoms was observed (Non-Patent Document 3). In addition, studies of orexin type 2 receptor knockout mice suggest that orexin type 2 receptors are important for maintaining arousal (Non-Patent Documents 4 and 5). Against this background, it has been suggested that orexin type 2 receptor agonists may be therapeutic agents for narcolepsy and other sleep disorders exhibiting hypersomnia (Non-Patent Document 6).

In addition, it has been suggested that a peptidic agonist that selectively acts on the orexin type 2 receptor improves obesity due to a high-fat diet load in mice (Non-Patent Document 7).
In addition, it has been suggested that intracerebroventricular administration of orexin peptide shortens the general anesthesia time in rats (Non-Patent Document 8).
In addition, it has been suggested that patients with sleep apnea syndrome have low plasma orexin A concentration levels (Non-Patent Document 9).
In addition, it has been suggested that intracerebroventricular administration of orexin peptide improves memory retention in aging-promoting model mice (SAMP8) with cognitive dysfunction (Non-Patent Document 10).
Further, it has been suggested that the orexin type 2 receptor agonist may be a therapeutic agent for heart failure (Patent Document 1, Non-Patent Document 11).
It has also been suggested that daytime sleepiness in Parkinson's disease patients is caused by the loss of orexin nerves (Non-Patent Document 12).
In addition, orexin controls bone formation and bone loss, and it has been suggested that orexin type 2 receptor agonists may be therapeutic agents for diseases related to bone loss such as osteoporosis and rheumatoid arthritis (Patent Documents). 2).
In addition, in septic shock model mice, a significant improvement in mortality was observed only by continuous administration of orexin from the periphery, so orexin receptor agonists are useful for the prevention or treatment of sepsis, severe sepsis, and septic shock. It has been suggested that there is (Patent Document 3).

Therefore, compounds with olexin type 2 receptor activating activity include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, consciousness disorders such as coma, narcolepsy syndrome with narcolepsy-like symptoms, and daytime hypersomnia. Hypersomnia syndrome (eg Parkinson's disease, Gillan Valley syndrome and Kleinelevin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, therapeutic agents for septicemia, and narcolepsy antagonists, It is expected to be useful as a preventive or therapeutic agent for side effects and complications caused by anesthesia.

On the other hand, as a sulfonamide derivative,
formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 4) has been reported.

In addition, the following compounds have been reported as compounds having orexin type 2 receptor activating activity.
formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 5).
formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 6).
formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 7).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 8).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 9).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 10).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 11).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 12).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 13).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 14).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 15).

formula

(Each symbol in the formula is as described in the literature.)
(Patent Document 16).

However, these compounds are considered to be inadequate in terms of activity, pharmacokinetics or safety, and it is desired to develop a compound having orexin type 2 receptor agonistic activity.

WO 2015/073707 A1 WO 2015/048091 A1 WO 2015/147240 A1 WO 2012/137982 A9 WO 2017/135306 A1 WO 2018/164191 A1 WO 2018/164192 A1 WO 2019/027003 A1 WO 2019/027058 A1 WO 2020/004536 A1 WO 2020/004537 A1 WO 2020/122092 A1 WO 2020/122093 A1 WO 2020/158958 A1 WO 2020/167701 A1 WO 2020/167706 A1

Cell, Vol. 92, pp. 573-585, 1998 (Cell, Vol.92, 573-585, 1998) Cell, Vol. 98, pp. 365-376, 1999 (Cell, Vol.98, 365-376, 1999) Proceedings of National Academy of Science of United States of America, Vol. 101, pp. 4649-4654, 2004 (Proc. Natl. Acad. Sci. USA, Vol.101, 4649-4654, 2004) Cell, Vol. 98, pp. 437-451, 1999 (Cell, Vol.98, 437-451, 1999) Neuron, Vol. 38, pp. 715-730, 2003 (Neuron, Vol.38, 715-730, 2003) CNS Drugs, Vol. 27, pp. 83-90, 2013 (CNS Drugs, Vol.27, 83-90, 2013) Cell Metabolism, Vol. 9, pp. 64-76, 2009 (Cell Metabolism, Vol.9, 64-76, 2009) Neuroscience, Vol. 121, pp. 855-863, 2003 (Neuroscience, Vol.121, 855-863, 2003) Respiration, Vol. 71, pp. 575-579, 2004 (Respiration, Vol.71, 575-579, 2004) Peptides, Vol. 23, pp. 1683-1688, 2002 (Peptides, Vol.23, 1683-1688, 2002) Journal of the American College of Cardiology, Vol. 66, pp. 2522-2533, 2015 (Journal of the American College of Cardiology. Vol. 66, 2015, Pages 2522-2533) Brain, Vol. 130, pp. 1586-1595, 2007 (Brain. Vol. 130, 2007, Pages 1586-1595)

An object of the present invention is to provide a heterocyclic compound having orexin type 2 receptor working activity.

The present inventors have determined that the compound represented by the following formula (I) or a salt thereof (sometimes referred to as compound (I) in the present specification) has olexin type 2 receptor activating activity. As a result of finding and further research, the present invention has been completed.

That is, the present invention relates to the following.
[1] Equation:

［式中、
環Wは、さらに置換されていてもよい環を；
環Xは、さらに置換されていてもよい5または6員の芳香環を；
環Yは、さらに置換されていてもよいシクロプロピルを；
環Zは、さらに置換されていてもよい含窒素複素環を；
Lは、結合手、または置換されていてもよいメチレンを；
Rは、置換されていてもよいC_1-6アルキル、置換されていてもよいC_3-10シクロアルキル、または置換されていてもよいジC_1-6アルキルアミンを示す。］
で表される化合物またはその塩。
［２］［１］記載の化合物またはその塩を含有する医薬。
［３］オレキシン２型受容体作動薬である、［２］記載の医薬。
［４］ナルコレプシーの予防または治療剤である、［２］記載の医薬。

[During the ceremony,
Ring W is a ring that may be further substituted;
Ring X is a 5- or 6-membered aromatic ring that may be further substituted;
Ring Y contains cyclopropyl which may be further substituted;
Ring Z is a nitrogen-containing heterocycle that may be further substituted;
L is a bond, or methylene that may be substituted;
R indicates a C _1-6 alkyl which may be substituted, a C _3-10 cycloalkyl which may be substituted, or a di C _1-6 alkyl amine which may be substituted. ]
A compound represented by or a salt thereof.
[2] A drug containing the compound according to [1] or a salt thereof.
[3] The drug according to [2], which is an orexin type 2 receptor agonist.
[4] The drug according to [2], which is a prophylactic or therapeutic agent for narcolepsy.

The compound of the present invention has orexin type 2 receptor activating activity and is useful as a prophylactic or therapeutic agent for narcolepsy.

(Detailed description of the invention)
Hereinafter, the definition of each substituent used in the present specification will be described in detail. Unless otherwise specified, each substituent has the following definitions.
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, the "C _1-6 alkyl group" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl and hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
In the present specification, the "C _1-6 alkyl group which may be halogenated" includes, for example, C _1-6 which may have 1 to 7 halogen atoms, preferably 1 to 5 halogen atoms. Alkyl groups can be mentioned. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-. Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Fluoropentyl, hexyl, 6,6,6-trifluorohexyl can be mentioned.
In the present specification, the "C _2-6 alkenyl group" includes, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-. Examples thereof include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, the "C _2-6 alkynyl group" includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-. Examples thereof include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.
In the present specification, the "C _3-10 cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] Octyl, Adamantyl.
In the present specification, the "C _{3-10 cycloalkyl} group which may be halogenated" may have, for example, 1 to 7, preferably 1 to 5 halogen atoms. Examples include ₁₀ cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
In the present specification, examples of the "C _3-10 cycloalkenyl group" include cyclopropenium, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
In the present specification, examples of the "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
In the present specification, examples of the "C _7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the "C _1-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.
In the present specification, the "C _1-6 alkoxy group which may be halogenated" includes, for example, C _1-6 which may have 1 to 7 halogen atoms, preferably 1 to 5 halogen atoms. Alkoxy groups can be mentioned. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, and pentyl. Examples include oxy and hexyloxy.
In the present specification, examples of the "C _3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
In the present specification, examples of the "C _1-6 alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, the "C _1-6 alkylthio group which may be halogenated" includes, for example, C _1-6 which may have 1 to 7 halogen atoms, preferably 1 to 5 halogen atoms. Halogen thio groups can be mentioned. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
In the present specification, the "C _1-6 alkyl-carbonyl group" includes, for example, acetyl, propanoyl, butanoyl, 2-methylpropanol, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-. Examples thereof include dimethylpropanoyl, hexanoyl and heptanoyle.
In the present specification, as the "C _1-6 alkyl-carbonyl group which may be halogenated", for example, C ₁ which may have 1 to 7 halogen atoms, preferably 1 to 5 halogen atoms. _-6 Alkyl-carbonyl group can be mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, the "C _1-6 alkoxy-carbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and the like. Examples thereof include pentyloxycarbonyl and hexyloxycarbonyl.
In the present specification, examples of the "C _6-14 aryl-carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the "C _7-16 aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl.
In the present specification, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include nicotinoyle, isonicotinoyl, tenoyl, and floyl.
In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclic carbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

In the present specification, examples of the "mono- or di-C _1-6 alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.
In the present specification, examples of the "mono- or di-C _7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.
In the present specification, examples of the "C _1-6 alkyl sulfonyl group" include methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, sec-butyl sulfonyl and tert-butyl sulfonyl.
In the present specification, as the "C _1-6 alkylsulfonyl group which may be halogenated", for example, C _1- which may have 1 to 7 halogen atoms, preferably 1 to 5 halogen atoms. ₆ Alkylsulfonyl groups can be mentioned. Specific examples include methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4,4,4-trifluorobutyl sulfonyl, pentyl sulfonyl and hexyl sulfonyl.
In the present specification, examples of the "C _6-14 aryl sulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

In the present specification, the "substituted group" includes, for example, a halogen atom, a cyano group, a nitro group, a optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and substituted groups. Amino group which may be substituted, carbamoyl group which may be substituted, thiocarbamoyl group which may be substituted, sulfamoyl group which may be substituted, hydroxy group which may be substituted, sulfanyl which may be substituted (sulfanyl which may be substituted). Examples include SH) groups and optionally substituted silyl groups.
In the present specification, the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") includes, for example, a C _1-6 alkyl group, a C _2-6 alkenyl group, and the like. Examples thereof include a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group and a C _7-16 aralkyl group.

In the present specification, examples of the "hydrocarbon group which may be substituted" include a hydrocarbon group which may have a substituent selected from the following substituent group A.
[Substituent group A]
(1) Halogen atom,
(2) Nitro group,
(3) Cyano group,
(4) Oxo group,
(5) Hydroxy group,
(6) C _1-6 alkoxy group, which may be halogenated,
(7) C _6-14 aryloxy groups (eg, phenoxy, naphthoxy),
(8) C _7-16 aralkyloxy group (eg, benzyloxy),
(9) 5- to 14-membered aromatic heterocyclic oxy groups (eg, pyridyloxy),
(10) 3- to 14-membered non-aromatic heterocyclic oxy groups (eg, tetrahydropyranyloxy, morpholinyloxy, piperidinyloxy),
(11) C _1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy),
(12) C _6-14 aryl-carbonyloxy group (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
(13) C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),
(14) Mono- or di-C _1-6 alkyl-carbamoyloxy groups (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
(15) C _6-14 aryl-carbamoyloxy group (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy),
(16) 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyyloxy),
(17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, morpholinylcarbonyloxy, piperidinylcarbonyloxy),
(18) C _1-6 alkylsulfonyloxy groups that may be halogenated (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy),
(19) C _6-14 arylsulfonyloxy groups optionally substituted with C _1-6 alkyl groups (eg, phenylsulfonyloxy, toluenesulfonyloxy),
(20) C _1-6 alkylthio group, which may be halogenated,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3- to 14-membered non-aromatic heterocyclic group,
(23) Holmil group,
(24) Carboxy group,
(25) C _1-6 alkyl-carbonyl group, which may be halogenated,
(26) C _6-14 aryl-carbonyl group,
(27) 5- to 14-membered aromatic heterocyclic carbonyl group,
(28) 3- to 14-membered non-aromatic heterocyclic carbonyl group,
(29) C _1-6 alkoxy-carbonyl group,
(30) C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
(31) C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl),
(32) Carbamic acid group,
(33) Thiocarbamoyl group,
(34) Mono- or di-C _1-6 alkyl-carbamoyl group,
(35) C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl),
(36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl, thienylcarbamoyl),
(37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (eg, morpholinylcarbamoyl, piperidinylcarbamoyl),.
(38) C _1-6 alkylsulfonyl group, which may be halogenated,
(39) C _6-14 arylsulfonyl group,
(40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (eg, pyridylsulfonyl, thienylsulfonyl),
(41) C _1-6 alkylsulfinyl group, which may be halogenated,
(42) C _6-14 arylsulfinyl group (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) 5- to 14-membered aromatic heterocyclic sulfinyl groups (eg, pyridylsulfinyl, thienylsulfinyl),
(44) Amino group,
(45) Mono- or di-C _1-6 alkylamino groups (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N) -Methylamino),
(46) Mono- or di-C _6-14 arylamino groups (eg, phenylamino),
(47) 5- to 14-membered aromatic heterocyclic amino groups (eg, pyridylamino),
(48) C _7-16 aralkylamino group (eg, benzylamino),
(49) Formylamino group,
(50) C _1-6 alkyl-carbonylamino group (eg, acetylamino, propanoylamino, butanoylamino),
(51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino),
(52) C _6-14 aryl-carbonylamino group (eg, phenylcarbonylamino, naphthylcarbonylamino),
(53) C _1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
(54) C _7-16 aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino),
(55) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino),
(56) C _6-14 arylsulfonylamino groups optionally substituted with C _1-6 alkyl groups (eg, phenylsulfonylamino, toluenesulfonylamino),
(57) C _1-6 alkyl group, which may be halogenated,
(58) C _2-6 alkenyl group,
(59) C _2-6 alkynyl group,
(60) C _3-10 cycloalkyl group,
(61) C _3-10 cycloalkenyl group and (62) C _6-14 aryl group.

The number of the above-mentioned substituents in the "hydrocarbon group which may be substituted" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
In the present specification, the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") includes, for example, a nitrogen atom, a sulfur atom and a sulfur atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered heterobridged ring groups each containing 1 to 4 heteroatoms selected from oxygen atoms. ..

In the present specification, the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") is selected from, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing 1 to 4 heteroatoms.
Suitable examples of the "aromatic heterocyclic group" include thienyl, frill, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1. , 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and other 5- or 6-membered monocyclic aromatic heterocyclic groups;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazolypyridinyl, thienopyridinyl, flopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolo Pyrizinyl, thiazolopyridinyl, imidazolopyridinyl, imidazolipyrimidinyl, thienopyrimidinyl, flopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazorotriadinyl, naphtho [2,3 -B] Thienyl, phenoxatiinyl, indrill, isoindrill, 1H-indazolyl, prynyl, isoquinolyl, quinolyl, phthalazinyl, naphthyldinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, pheno. Examples thereof include 8- to 14-membered fused polycyclic (preferably 2- or 3-cyclic) aromatic heterocyclic groups such as thiazinyl and phenoxadinyl.

In the present specification, the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") is, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from.
Suitable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxylanyl, thiylanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl. Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyrani 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as le, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl;
Dihydrobenzofuranyl, dihydrobenzoimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisodiazepine, dihydronaphtho [2,3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, Indolinyl, Isoindrinyl, Tetrahydrothieno [2,3-c] pyridinyl, Tetrahydrobenzoazepineyl, Tetrahydroquinoxalinyl, Tetrahydrophenanthridinyl, Hexahydrophenothiazine, Hexahydrophenoxadinyl, Tetrahydrophthaladinyl, Tetrahydro 9-14 such as naphthyldinyl, tetrahydroquinazolinyl, tetrahydrosinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacryldinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl, etc. Included are member-fused polycyclic (preferably 2- or tricyclic) non-aromatic heterocyclic groups.

Preferred examples of the "7 to 10-membered complex crosslinked ring group" in the present specification include quinucridinyl and 7-azabicyclo [2.2.1] heptanyl.
In the present specification, the "nitrogen-containing heterocyclic group" includes a "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the above-mentioned substituent group A.
The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

In the present specification, the "acyl group" is selected from, for example, a "halogen atom, a C _1-6 alkoxy group which may be halogenated, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group1". Or may have 3 substituents, respectively, C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl. Group, C _7-16 aralkyl group, 5 to 14-membered aromatic heterocyclic group and 1 or 2 substituents selected from 3 to 14-membered non-aromatic heterocyclic group, respectively. Examples thereof include a group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group.
Further, examples of the "acyl group" include a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group.
Here, the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded, and the hydrocarbon-sulfinyl group is a hydrocarbon group. Means a sulfinyl group bonded to a hydrocarbon, and a heterocyclic-sulfinyl group means a sulfinyl group to which a heterocyclic group is bonded.
Suitable examples of "acyl groups" include formyl groups, carboxy groups, C _1-6 alkyl-carbonyl groups, C _2-6 alkenyl-carbonyl groups (eg, crotonoyles), C _3-10 cycloalkyl-carbonyl groups (eg, clotonoyles). Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C _3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C _6-14aryl -carbonyl group, C _7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl) , Naftyloxycarbonyl), C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _2-6 alkenyl-carbonyl group (eg, diallyl carbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropyl carbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg, cyclopropyl carbamoyl) Eg, phenylcarbamoyl), mono- or di-C _7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C _1-6 . Alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg, diallylthiocarbamoyl), mono- or di-C _{3 -10} Cycloalkyl-thiocarbamoyl group (eg, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14aryl -thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _{7 -16} Aralkyl-thiocarbamoyl group (eg, benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (eg, pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (eg). , Methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 a Examples include rukirsulfonyl groups, C _6-14 arylsulfonyl groups, phosphono groups, mono- or di-C _1-6 alkylphosphono groups (eg, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono). ..

In the present specification, the "optionally substituted amino group" is, for example, a "C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively". , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl 1 or one selected from a group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _1-6 alkyl sulfonyl group and C _6-14 aryl sulfonyl group. Examples thereof include amino groups which may have "two substituents".
Suitable examples of optionally substituted amino groups include amino groups, mono- or di- (possibly halogenated C _1-6 alkyl) amino groups (eg, methylamino, trifluoromethylamino, etc.). Didimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-6 alkenylamino group (eg, diallylamino), mono- or di-C _3-10 cycloalkylamino group (eg,, eg, diallylamino). Cyclopropylamino, cyclohexylamino), mono- or di-C _6-14 arylamino groups (eg, phenylamino), mono- or di-C _7-16 aralkylamino groups (eg, benzylamino, dibenzylamino), Mono- or di- (C _1-6 alkyl which may be halogenated) -carbonylamino group (eg, acetylamino, propionylamino), mono- or di-C _6-14 aryl-carbonylamino group (eg, eg) Benzoylamino), mono- or di-C _7-16 aralkyl-carbonylamino groups (eg, benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino groups (eg, nicotinoyleamino, iso). Nicothinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino groups (eg, piperidinylcarbonylamino), mono- or di-C _1-6 alkoxy-carbonylamino groups (eg, tert). -Butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino), carbamoylamino group, (mono- or di-C _1-6 alkyl-carbamoyl) amino group (eg, methylcarbamoylamino), (Mono- or di-C _7-16 aralkyl-carbamoyl) Amino group (eg, benzylcarbamoylamino), C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino), C _{6-14arylsulfonyl} Amino groups (eg, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) Amino groups (eg, N-acetyl-N-methylamino), (C _1-6 alkyl) (C _6-14 aryl-carbonyl) amino groups (eg, N-benzoyl-N-methylamino) can be mentioned.

In the present specification, the "optionally substituted carbamoyl group" is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl A carbamoyl group may have one or two substituents selected from a group, a mono- or di-C _1-6 alkyl-carbamoyl group and a mono- or di-C _7-16 aralkyl-carbamoyl group. Can be mentioned.
Suitable examples of optionally substituted carbamoyl groups are carbamoyl groups, mono- or di-C _1-6 alkyl-carbamoyl groups, mono- or di-C _2-6 alkenyl-carbamoyl groups (eg, diallyl carbamoyl). ), Mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14aryl -carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, mono- or di-C _1-6 alkyl-carbonyl-carbamoyl group (eg, acetylcarbamoyl, propionylcarbamoyl), mono- or di-C _6-14aryl -carbonyl-carbamoyl Examples include groups (eg, benzoylcarbamoyl), 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

In the present specification, the "optionally substituted thiocarbamoyl group" includes, for example, "C _1-6 alkyl which may have 1 to 3 substituents selected from the substituent group A, respectively." Group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, Thiocarbamoyl may have one or two substituents selected from a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group and a mono- or di-C _7-16 aralkyl-carbamoyl group. The group is mentioned.
Suitable examples of optionally substituted thiocarbamoyl groups are thiocarbamoyl groups, mono- or di-C _1-6 alkyl-thiocarbamoyl groups (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio). Carbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg, diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group (eg, diallylthiocarbamoyl). Examples, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14aryl -thiocarbamoyl groups (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl groups (eg). , Benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C _1-6 alkyl-carbonyl-thiocarbamoyl groups (eg, acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C _6-14 aryl-carbonyl Included are thiocarbamoyl groups (eg, benzoylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

In the present specification, the “optionally substituted sulfamoyl group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl A sulfamoyl group may have one or two substituents selected from a group, a mono- or di-C _1-6 alkyl-carbamoyl group and a mono- or di-C _7-16 aralkyl-carbamoyl group. Can be mentioned.
Suitable examples of optionally substituted sulfamoyl groups are sulfamoyl groups, mono- or di-C _1-6 alkyl-sulfamoyl groups (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl). Sulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _2-6 alkenyl-sulfamoyl group (eg, diallyl sulfamoyl), mono- or di-C _3-10 cycloalkyl- Sulfamoyl group (eg, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14aryl -sulfamoyl group (eg, phenylsulfamoyl), mono- or di-C _7-16 aralkyl- Sulfamoyl group (eg, benzyl sulfamoyl, phenethyl sulfamoyl), mono- or di-C _1-6 alkyl-carbonyl-sulfamoyl group (eg, acetylsulfamoyl, propionyl sulfamoyl), mono- or di- Examples thereof include a C _6-14aryl -carbonyl-sulfamoyl group (eg, benzoyl sulfamoyl) and a 5- to 14-membered aromatic heterocyclic sulfamoyl group (eg, pyridyl sulfamoyl).

In the present specification, the “optionally substituted hydroxy group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Substituent selected from group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _1-6 alkyl sulfonyl group and C _6-14 aryl sulfonyl group A hydroxy group which may have a "" may be mentioned.
Preferable examples of the optionally substituted hydroxy group are hydroxy group, C _1-6 alkoxy group, C _2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy). ), C _3-10 cycloalkyloxy group (eg cyclohexyloxy), C _6-14 aryloxy group (eg phenoxy, naphthyloxy), C _7-16 aralkyloxy group (eg benzyloxy, phenethyloxy), C _1-6 alkyl-carbonyloxy group (eg acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 aryl-carbonyloxy group (eg benzoyloxy), C _7-16 aralkyl- Carbonyloxy group (eg, benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyleoxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, piperidinylcarbonyloxy) ), C _1-6 alkoxy-carbonyloxy group (eg, tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), carbamoyloxy group, C _1-6 alkyl-carbamoyloxy Group (eg, methylcarbamoyloxy), C _7-16 aralkyl-carbamoyloxy group (eg, benzylcarbamoyloxy), C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy), C _6-14 Examples include the arylsulfonyloxy group (eg, phenylsulfonyloxy).

In the present specification, the “optionally substituted sulfanyl group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group which may have a "substituted group selected from a 14-membered aromatic heterocyclic group" and a halogenated sulfanyl group.
Suitable examples of optionally substituted sulfanyl groups include sulfanyl (-SH) groups, C _1-6 alkylthio groups, C _2-6 alkenylthio groups (eg, allylthio, 2-butenylthio, 2-pentenylthio, etc. 3-hexenylthio), C _3-10 cycloalkylthio group (eg, cyclohexylthio), C _6-14 arylthio group (eg, phenylthio, naphthylthio), _C7-16 aralkylthio group (eg, benzylthio, phenethylthio), C _1-6 Alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C- _6-14aryl -carbonylthio group (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio group (Eg, pyridylthio), a halide thio group (eg, pentafluorothio) can be mentioned.

In the present specification, the “optionally substituted silyl group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group and C _7-16 aralkyl group may have 1 to 3 substituents. Can be mentioned.
Preferable examples of optionally substituted silyl groups include tri-C _1-6 alkylsilyl groups (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).

In the present specification, examples of the "hydrocarbon ring" include C _6-14 aromatic hydrocarbon ring, C _3-10 cycloalkane, and C _3-10 cycloalkene.
In the present specification, examples of the "C _6-14 aromatic hydrocarbon ring" include benzene and naphthalene.
In the present specification, examples of "C _3-10 cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
In the present specification, examples of "C _3-10 cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
In the present specification, the "heterocycle" includes, for example, an aromatic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples include non-aromatic heterocycles.

In the present specification, the "aromatic heterocycle" includes, for example, 5 to 14 members (for example, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Preferred are 5- to 10-membered aromatic heterocycles. Suitable examples of the "aromatic heterocycle" are thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isooxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi. 5- or 6-membered monocyclic aromatic heterocycles such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine;
Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazolepyridine, thienopyridine, flopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazolepyridine, Imidazopyrimidine, thienopyrimidine, flopyrimidine, pyrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazorotriadin, naphtho [2,3-b] thiophene, phenoxatiin, indol, 8- to 14-membered fused polycycles of isoindole, 1H-imidazole, purine, isoquinoline, quinoline, phthalazine, naphthylidine, quinoxalin, quinazoline, cinnoline, carbazole, β-carboline, phenanthridin, acridin, phenazine, phenothiazine, phenoxazine, etc. Aromatic heterocycles of the formula (preferably two or three rings) may be mentioned.

In the present specification, the "non-aromatic heterocycle" is, for example, 3 to 14 members containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include non-aromatic heterocycles (preferably 4 to 10 members). Suitable examples of the "non-aromatic heterocycle" are aziridine, oxylan, thiirane, azetidine, oxetane, thietan, tetrahydrothiophene, tetrahydrofuran, pyrrolin, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazolin. , Thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazin, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyranidin, tetrahydropyrandazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholin, azepan, 3- to 8-membered monocyclic non-aromatic heterocycles such as diazepan, azepine, azocan, diazocan, oxepan;
Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphthophen [2,3-b] thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinoline, indolin, isoindrin, tetrahydrothieno [2] , 3-c] Pyridine, Tetrahydrobenzoazepine, Tetrahydroquinoline, Tetrahydrophenanthridin, Hexahydrophenothiazine, Hexahydrophenoxazine, Tetrahydrophthalazine, Tetrahydronaphthylidine, Tetrahydroquinazoline, Tetrahydrocinnoline, Tetrahydrocarbazole, Tetrahydro-β-carboline , Tetrahydroaclydin, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline and the like, 9 to 14-membered fused polycyclic (preferably 2 or 3 ring) non-aromatic heterocycles.
In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the "4- to 6-membered heterocyclic group" include aromatic or non-aromatic 4- to 6-membered heterocyclic groups, and specifically, oxetanyl, frills, pyrazolyl, pyridyl, and the like. Pyrimidinyl can be mentioned.
In the present specification, examples of the "ring" include a "hydrocarbon ring" and a "heterocycle".

The definition of each symbol in the formula (I) will be described in detail below.

In the formula, ring W represents a ring that may be further substituted.

As a ring W,
(1) 3- to 8-membered monocyclic non-aromatic heterocycles (eg, piperidine),
(2) A 5- to 6-membered monocyclic aromatic heterocycle (eg, furan, pyridine), which may be further substituted with 1 to 3 halogen atoms (eg, fluorine atom),
(3) (i) Halogen atom (eg, fluorine atom, chlorine atom),
(ii) C _1-6 alkyl groups (eg, methyl), which may be substituted with 1 to 3 C _1-6 alkoxy groups (eg, methoxy), and
(iii) C _1-6 alkoxy group (eg, methoxy)
A C _6-14 aromatic hydrocarbon ring (eg, benzene), which may be further substituted with 1 to 3 substituents selected from, or
(4) C _3-10 cycloalkane (eg cyclobutane, cyclopentane, cyclohexane)
Is preferable.

Among them, the ring W is preferably a C _6-14 aromatic hydrocarbon ring (eg, benzene) which may be further substituted with 1 to 3 halogen atoms (eg, a fluorine atom).
In particular, as the ring W, a C _6-14 aromatic hydrocarbon ring (eg, benzene) further substituted with 1 to 3 halogen atoms (eg, a fluorine atom) is preferable.

Ring X represents a 5- or 6-membered aromatic ring that may be further substituted.

As ring X,
(1) (i) Halogen atom (eg, fluorine atom, chlorine atom),
(ii) C _1-6 alkyl groups that may be halogenated (eg, methyl, difluoromethyl), and
(iii) C _1-6 alkoxy group (eg, methoxy)
A benzene ring which may be further substituted with 1 to 3 substituents selected from, or
(2) A 5- or 6-membered monocyclic aromatic heterocycle (eg, thiophene, thiazole, pyridine) that may be further substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl).
Is preferable.

Above all, as Ring X,
(i) Halogen atoms (eg, fluorine atoms), and
(ii) C _1-6 alkyl group (eg, methyl),
A benzene ring which may be further substituted with 1 to 3 substituents selected from the above is preferred.

Ring Y represents cyclopropane which may be further substituted.

As ring Y,
(i) Halogen atom (eg, fluorine atom),
(ii) Cyano group and
(iii) C _1-6 alkyl group (eg, methyl)
Cyclopropane, which may be further substituted with 1 to 3 substituents selected from the above, is preferred.

Of these, cyclopropane, which may be further substituted with 1 to 3 halogen atoms (eg, a fluorine atom), is preferable as the ring Y.

Ring Z represents a nitrogen-containing heterocycle that may be further substituted.

As a ring Z,
(i) Halogen atom (eg, fluorine atom),
(ii) Hydroxy group,
(iii) C _1-6 alkyl groups (eg, methyl), and
(iv) C _1-6 Alkoxy group (eg, methoxy)
A 3- to 14-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine, piperidine, morpholine, azepane, azabicyclo [3.1.0] hexane, azaspiro] which may be further substituted with 1 to 3 substituents selected from. 3.3] heptane, azabicyclo [3.2.0] heptane, azabicyclo [3.2.1] octane, oxazepane, octahydrocyclopenta [c] pyrrole) are preferred.

Among them, the ring Z may be further substituted with 1 to 3 substituents selected from a halogen atom (eg, fluorine atom), a hydroxy group and a C _1-6 alkyl group (eg, methyl). A 14-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine, piperidine, azepane, oxazepane, octahydrocyclopenta [c] pyrrole) is preferred.

L indicates a bond or a methylene group that may be substituted.

As L, a bond or a methylene group is preferable.

R indicates a optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, or an optionally substituted di-C _1-6 alkylamine group.

As R,
(1) (i) Halogen atoms (eg, fluorine atoms, bromine atoms), and
(ii) C _1-6 Alkoxy (eg, methoxy)
C _1-6 alkyl groups (eg, methyl, ethyl), which may be substituted with 1 to 3 substituents selected from,
(2) C _3-10 cycloalkyl group (eg cyclopropyl), or
(3) Di C _1-6 alkylamino group (eg, dimethylamino)
Is preferable.

Especially for R,
(1) C _1-6 alkyl group (eg, methyl, ethyl), or
(2) Di C _1-6 alkylamino group (eg, dimethylamino)
Is preferable.

As the compound (I), a compound which is an optically active substance is preferable, and as the solid, a compound having a three-dimensional structure represented by the following formula (I') in the portion of the ring Y is preferable.

As compound (I),
Ring W,
(1) 3- to 8-membered monocyclic non-aromatic heterocycles (eg, piperidine),
(2) A 5- to 6-membered monocyclic aromatic heterocycle (eg, furan, pyridine), which may be further substituted with 1 to 3 halogen atoms (eg, fluorine atom),
(3) (i) Halogen atom (eg, fluorine atom, chlorine atom),
(ii) C _1-6 alkyl groups (eg, methyl), which may be substituted with 1 to 3 C _1-6 alkoxy groups (eg, methoxy), and
(iii) C _1-6 alkoxy group (eg, methoxy)
A C _6-14 aromatic hydrocarbon ring (eg, benzene), which may be further substituted with 1 to 3 substituents selected from, or
(4) C _3-10 cycloalkane (eg cyclobutane, cyclopentane, cyclohexane)
And;
Ring X is
(1) (i) Halogen atom (eg, fluorine atom, chlorine atom),
(ii) C _1-6 alkyl groups that may be halogenated (eg, methyl, difluoromethyl), and
(iii) C _1-6 alkoxy group (eg, methoxy)
A benzene ring which may be further substituted with 1 to 3 substituents selected from, or
(2) A 5- or 6-membered monocyclic aromatic heterocycle (eg, thiophene, thiazole, pyridine) that may be further substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl).
And;
Ring Y
(i) Halogen atom (eg, fluorine atom),
(ii) Cyano group and
(iii) C _1-6 alkyl group (eg, methyl)
Cyclopropane may be further substituted with 1 to 3 substituents selected from;
Ring Z,
(i) Halogen atom (eg, fluorine atom),
(ii) Hydroxy group,
(iii) C _1-6 alkyl groups (eg, methyl), and
(iv) C _1-6 Alkoxy group (eg, methoxy)
A 3- to 14-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine, piperidine, morpholine, azepane, azabicyclo [3.1.0] hexane, azaspiro] which may be further substituted with 1 to 3 substituents selected from. 3.3] Heptane, Azabicyclo [3.2.0] Heptane, Azabicyclo [3.2.1] Octane, Oxazepane, Octahydrocyclopenta [c] Pyrrole);
L is a bond or methylene group; and
R is
(1) (i) Halogen atoms (eg, fluorine atoms, bromine atoms), and
(ii) C _1-6 Alkoxy (eg, methoxy)
C _1-6 alkyl groups (eg, methyl, ethyl), which may be substituted with 1 to 3 substituents selected from,
(2) C _3-10 cycloalkyl group (eg cyclopropyl), or
(3) Di C _1-6 alkylamino group (eg, dimethylamino)
The compound is preferable.

Among them, as compound (I),
Ring W is a C _6-14 aromatic hydrocarbon ring (eg, benzene) which may be further substituted with 1 to 3 halogen atoms (eg, fluorine atom);
Ring X is
(i) Halogen atoms (eg, fluorine atoms), and
(ii) C _1-6 alkyl group (eg, methyl),
A benzene ring which may be further substituted with 1 to 3 substituents selected from;
Ring Y is cyclopropane which may be further substituted with 1 to 3 halogen atoms (eg, fluorine atom);
Ring Z may be further substituted with 1 to 3 substituents selected from halogen atoms (eg, fluorine atoms), hydroxy groups and C _1-6 alkyl groups (eg, methyl) of 3 to 14 members. It is a nitrogen-containing heterocycle (eg, azetidine, pyrrolidine, piperidine, azepane, oxazepane, octahydrocyclopenta [c] pyrrole);
L is a bond or methylene group; and
R is
(1) C _1-6 alkyl group (eg, methyl, ethyl), or
(2) Di C _1-6 alkylamino group (eg, dimethylamino)
The compound is preferable.

Specific examples of the compound (I) include the compounds of Examples 1 to 12, 14 to 132, 134 to 138, 140 to 230, and 232 to 320 described later.

The salt of the compound represented by the formula (I) is preferably a pharmacologically acceptable salt, and examples of such a salt include a salt with an inorganic base, a salt with an organic base, and an inorganic acid. Examples thereof include salts, salts with organic acids, salts with basic or acidic amino acids, and the like.
Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Suitable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, etc. Examples thereof include salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Suitable examples of salts with organic acids are formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid. , P-toluene sulfonic acid and the like.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with an acidic amino acid include a salt with aspartic acid, glutamic acid and the like.

The method for producing the compound of the present invention will be described below.

The raw materials and reagents used in each step in the following production methods, and the obtained compounds may each form salts. Examples of such a salt include those similar to the salt of the compound represented by the above-mentioned formula (I).

When the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se. On the contrary, when the compound obtained in each step is a salt, it can be converted into a free form or another kind of salt of interest by a method known per se.

The compound obtained in each step can be used as a reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. Can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like.

When a compound of a raw material or a reagent for each step is commercially available, the commercially available product can be used as it is.

In the reaction of each step, the reaction time may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

In the reaction of each step, the reaction temperature may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually −78 ° C. to 300 ° C., preferably −78 ° C. to 150 ° C.

In the reaction of each step, the pressure may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

In the reaction of each step, for example, a microwave synthesizer such as an Initiator manufactured by Biotage may be used. The reaction temperature may vary depending on the reagent and solvent used, but is usually room temperature to 300 ° C, preferably 50 ° C to 250 ° C, unless otherwise specified. The reaction time may vary depending on the reagent and solvent used, but is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

In the reaction of each step, the reagent is 0.5 equivalents to 20 equivalents, preferably 0.8 equivalents to 5 equivalents, with respect to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent also serves as a reaction solvent, the solvent amount is used for the reagent.

Unless otherwise specified, in the reaction of each step, these reactions are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include the solvents described in Examples, or the following.
Alcohols: Methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc .;
Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc .;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc .;
Saturated hydrocarbons: cyclohexane, hexane, etc .;
Amides: N, N-dimethylformamide, N-methylpyrrolidone, etc .;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc .;
Nitriles: acetonitrile, etc .;
Sulfoxides: Dimethyl sulfoxide, etc .;
Aromatic organic bases: pyridine, etc .;
Acid anhydrides: acetic anhydride, etc .;
Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .;
Inorganic acids: hydrochloric acid, sulfuric acid, etc .;
Esters: Ethyl acetate, etc .;
Ketones: acetone, methyl ethyl ketone, etc .;
water.
The above solvent may be used by mixing two or more kinds at an appropriate ratio.

When a base is used in the reaction of each step, for example, the base shown below or the base described in Examples is used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, etc .;
Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-Undecene, imidazole, piperidine, etc .;
Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc .;
Alkali metal hydrides: sodium hydride, etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .;
Organolithiums: n-butyllithium, etc.

When an acid or an acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in Examples is used.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .;
Lewis acid: Boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

Unless otherwise specified, the reaction of each step is a method known per se, for example, 5th Edition Experimental Chemistry Course, Volumes 13-19 (edited by the Japanese Society of Chemistry); New Experimental Chemistry Course, Volumes 14-15 (Japan). Chemistry Society); Precision Organic Chemistry Revised 2nd Edition (LF Tietze, Th. Eicher, Nanedo); Revised Organic Name Reaction Mechanism and Points (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII ( John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experiments (Jie Jack Li), published by Jie Jack Li 1-Vol. 14 (Elzevia Japan Co., Ltd.); Organic synthesis strategy learned from name reaction (translated by Kiyoshi Tomioka, published by Kagaku-Dojin); Method described in Comprehensive Organic Transformations Inc., 1989, etc. Alternatively, it is carried out according to the method described in the examples.

In each step, the protecting or deprotecting reaction of the functional group is carried out by a method known per se, for example, Wiley-Interscience, 2007, "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. et al. Written); The method is described in "Protecting Groups 3rd Ed." (Written by PJ Kocienski), published by Thieme, 2004, or the method described in Examples.
Examples of the protecting group for hydroxyl groups such as alcohol and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; and carboxylic acid ester-type protecting groups such as acetate. Examples include sulfonic acid ester-type protecting groups such as methane sulfonic acid ester; and carbonate ester-type protecting groups such as tert-butyl carbonate.
Examples of the protecting group for the carbonyl group of the aldehyde include an acetal-type protecting group such as dimethyl acetal; and a cyclic acetal-type protecting group such as 1,3-dioxane.
Examples of the protective group for the carbonyl group of the ketone include a ketal-type protective group such as dimethyl ketal; a cyclic ketal-type protective group such as 1,3-dioxane; an oxime-type protective group such as O-methyloxime; N, N-dimethyl. Examples include hydrazone-type protective groups such as hydrazone.
Examples of the carboxyl-protecting group include an ester-type protecting group such as a methyl ester; and an amide-type protecting group such as N, N-dimethylamide.
Examples of the thiol protecting group include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetic acid ester, thiocarbonate, and thiocarbamate.
Examples of the protective group for the amino group and the aromatic heterocycle such as imidazole, pyrrole, and indol include a carbamate-type protecting group such as benzylcarbamate; an amide-type protecting group such as acetamide; and an alkylamine such as N-triphenylmethylamine. Examples thereof include a type protecting group and a sulfonamide type protecting group such as methanesulfonamide.
Protecting groups can be removed by methods known per se, such as acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (eg, trimethylsilyl iodide). It can be carried out by using a method using (do, trimethylsilyl bromide) or a reduction method.

When the reducing reaction is carried out in each step, the reducing agents used include lithium aluminum borohydride, sodium triacetoxyborohydride, sodium borohydride sodium, diisobutylaluminum hydride (DIBAL-H), and sodium borohydride. , Metal hydrides such as triacetoxyborohydride tetramethylammonium hydride; boranes such as borane tetrahydrofuran complex; lane nickel; lane cobalt; hydrogen; formic acid; triethylsilane and the like. When reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as a palladium-carbon or a Lindlar catalyst.

When the oxidation reaction is carried out in each step, the oxidizing agents used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide and tert-butylhydroperoxide; and tetrabutylammonium perchlorate. Perchlorates; Chlorates such as sodium chlorate; Subchlorates such as sodium chlorite; Periodates such as sodium periodate; High valence iodine reagents such as iodosylbenzene; Manganese dioxide, Reagents with manganese such as potassium permanganate; Leads such as lead tetraacetate; Reagents with chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagents; N-bromosuccinimide (NBS) ) And the like; oxygen; ozone; sulfur trioxide / pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When the radical cyclization reaction is carried out in each step, the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4-4'-azobis-4-cyanopentanoic acid (ACCA). Water-soluble radical initiators such as; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reaction reagent used include tributylstanan, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

When the Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphorans and the like. Alkylidene phosphorans can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is carried out in each step, the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums. Can be mentioned.

When performing the Friedel-Crafts reaction in each step, the reagents used include a combination of Lewis acid and acid chloride, or Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.). The combination of. Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

When performing an aromatic nucleophilic substitution reaction in each step, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

A base used to generate a carbanion when performing a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion in each step. Examples thereof include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.

When the Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metallic magnesium using ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation reaction is carried out in each step, the reagents include active methylene compounds (eg, malonic acid, diethyl malonate, malononitrile, etc.) and bases (eg, organic bases, etc.) sandwiched between two electron attracting groups. Metal alkoxides, inorganic bases) are used.

When the Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (eg, N, N-dimethylformamide, etc.) are used as reagents.

When the azidization reaction of alcohols, alkyl halides and sulfonic acid esters is carried out in each step, examples of the azidizing agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide and sodium azide. For example, when azide alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), a method using trimethylsilyl azide and Lewis acid, and the like.

When the reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine and the like.

When the Mitsunobu reaction is carried out in each step, azodicarboxylate esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

When an esterification reaction, an amidation reaction, or a urea conversion reaction is carried out in each step, the reagents used include acid halides, acid bromides and other halide acylates; acid anhydrides, active esters and sulfate esters. Examples thereof include activated carboxylic acids. Carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other triazine-based condensing agents; 1,1-carbonyldiimidazole (CDI) and other carbonic acid ester-based condensing agents; diphenyl Phosphic acid azide (DPPA); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukoyama reagent); thionyl chloride; halogic acid such as ethyl chlorogitate Lower alkyl; O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. .. When a carbodiimide-based condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be further added to the reaction.

When the coupling reaction is carried out in each step, the metal catalysts used are palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), and dichlorobis (triethyl). Palladium compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride; tetrakis (triphenylphosphine) nickel (0) ) And the like; a rhodium compound such as tris (triphenylphosphine) chloride (III); a cobalt compound; a copper compound such as copper oxide and copper (I) iodide; a platinum compound and the like. Further, a base may be added to the reaction, and examples of such a base include inorganic bases and the like.

When the thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent, but in addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) is used. ) -1,3,2,4-dithiadiphosfetan-2,4-disulfide (Lawesson's reagent) and other reagents having a 1,3,2,4-dithiadiphosphetan-2,4-disulfide structure May be used.

When the Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine and sulfuryl chloride. .. Furthermore, the reaction can be accelerated by adding radical initiators such as heat, light, benzoyl peroxide, and azobisisobutyronitrile to the reaction.

When the hydroxy group halogenation reaction is carried out in each step, the halogenating agent used is an acid halide of a hydrohalic acid and an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, oxy. For bromination such as phosphorus chloride, 48% hydrobromic acid and the like can be mentioned. Further, a method of obtaining an alkyl halide from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method of synthesizing an alkyl halide through a two-step reaction such as converting an alcohol into a sulfonic acid ester and then reacting with lithium bromide, lithium chloride or sodium iodide may be used.

When the Arbuzov reaction is carried out in each step, the reagents used include alkyl halides such as ethyl bromoacetate; phosphites such as triethyl phosphite and tri (isopropyl) phosphite.

When the sulfonic acid esterification reaction is carried out in each step, examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, p-toluenesulfonic acid anhydride and the like.

When the hydrolysis reaction is carried out in each step, an acid or a base is used as the reagent. Further, when the acid hydrolysis reaction of tert-butyl ester is carried out, formic acid, triethylsilane or the like may be added in order to reduceally trap the tert-butyl cation produced as a by-product.

When the dehydration reaction is carried out in each step, examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

Of the compounds (3) used in the reaction formula 3 described later, the compounds (3) -1 and (3) -2 shown in the figure below can be produced from the compound (1) by the method shown in the following reaction formula 1. can. In the formula, R ¹ indicates a optionally substituted C _1-6 alkyl group, and R ² , R ³ and R ⁴ are independently hydrogen atoms, halogen atoms or optionally substituted C ₁ respectively. _-6 Alkyl groups are shown, and the other symbols are synonymous with the above.

As the "optionally substituted C _1-6 alkyl group" represented by R ¹ , R ² , R ³ and R ⁴ , the hydrocarbon group among the above-mentioned "optionally substituted hydrocarbon groups" is Examples thereof include those having a C _1-6 alkyl group.

The compound (1) can be produced by using a commercially available product as it is, or by a method known per se or a method similar thereto.

Compound (3) -1 can be produced by a Corey-Chaykovsky reaction between compound (2) and a sulfonium salt in the presence of a base. Examples of the sulfonium salt used include trimethylsulfonium iodide and the like. Examples of the base used include inorganic bases, metal alkoxides, alkali metal hydrides and the like.

Compound (6) can be produced by a condensation reaction between compound (1) and hydrazine hydrate.

Compound (3) -2 can be produced by a cyclopropanation reaction between compound (4) and compound (5) in the presence of a metal catalyst. Examples of the metal catalyst used include rhodium compounds such as rhodium (II) acetate dimer and ruthenium compounds such as dichloro (p-cymene) ruthenium (II) dimer.

Compound (3) -2 can also be produced by a cyclopropanation reaction between compound (6) and compound (7) in the presence of an oxidizing agent. Examples of the oxidizing agent used include hypervalent iodine compounds such as iodosobenzene and manganese oxide (IV).

Among the compounds (3) used in the reaction formula 3 described later, the compounds (3) -3 shown in the figure below can be produced from the compound (8) by the method shown in the following reaction formula 2. In the formula, LG ¹ and LG ² each independently indicate a leaving group, R ⁵ indicates a hydrogen atom, a halogen atom or an optionally substituted C _1-6 alkyl group, and the other symbols are used. It is synonymous with the above.

The "leaving group" represented by LG ¹ includes a halogen atom, C _1-6 alkyl sulfonyl oxy (eg, methane sulfonyl oxy, ethane sulfonyl oxy, trifluoro methane sulfonyl oxy) which may be halogenated, C _1- . Examples thereof include C _6-14 aryl sulfonyl oxy (eg, benzene sulfonyl oxy, toluene sulfonyl oxy) which may be substituted with ₆ alkyl.

Examples of the “leaving group” represented by LG ² include optionally substituted dihydroxyboryl (eg, dihydroxyboryl, pinacholateboryl) and the like.

The "optionally substituted C _1-6 alkyl group" represented by R ⁵ is one in which the hydrocarbon group is a C _1-6 alkyl group among the above-mentioned "optionally substituted hydrocarbon groups". Can be mentioned.

The compound (8) and the compound (9) can be produced by using commercially available products as they are, or by a method known per se or a method similar thereto.

Compound (3) -3 can be produced by a cyclopropanation reaction between compound (10) and compound (5) in the presence of a metal catalyst. Examples of the metal catalyst used include rhodium compounds such as rhodium (II) acetate dimer and ruthenium compounds such as dichloro (p-cymene) ruthenium (II) dimer.

Compound (11) can be produced from compound (3) by the method shown in Reaction Scheme 3 below. In the formula, each symbol has the same meaning as described above.

Compound (15) can be produced from compound (12) by the method shown in Reaction Scheme 4 below. In the formula, LG ³ indicates a leaving group, P indicates a protecting group, and the other symbols have the same meanings as described above.

The "leaving group" represented by LG ³ includes a halogen atom, C _1-6 alkyl sulfonyl oxy (eg, methane sulfonyl oxy, ethane sulfonyl oxy, trifluoro methane sulfonyl oxy) which may be halogenated, C _1- . Examples thereof include C _6-14 aryl sulfonyl oxy (eg, benzene sulfonyl oxy, toluene sulfonyl oxy) which may be substituted with ₆ alkyl.

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

The compound (12) can be produced by using a commercially available product as it is, or by a method known per se or a method similar thereto.

Compound (14) can be produced by a sulfonamide reaction between compound (12) and compound (13). Examples of the compound (13) used include sulfonyl chloride, sulfamoyl chloride and the like. The compound (13) can be produced by using a commercially available product as it is, or by a method known per se or a method similar thereto.

Compound (I) can be produced from compound (11) and compound (15) by the method shown in Reaction Scheme 5 below. In the formula, each symbol has the same meaning as described above.

In the compound (I) thus obtained, the intramolecular functional group can also be converted into a desired functional group by combining a chemical reaction known per se. Here, examples of chemical reactions include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, urea formation reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like. Can be mentioned.

In the above production method, when the raw material compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a substituent, a protective group generally used in peptide chemistry or the like is introduced into these groups. However, the target compound can be obtained by removing the protective group as necessary after the reaction.

The compound (I) obtained by the above-mentioned production method can be isolated and purified by known means such as solvent extraction, liquid conversion, dissolution, crystallization, recrystallization, chromatography and the like.
When the compound (I) contains an optical isomer, a steric isomer, a positional isomer, and a rotational isomer, these are also contained as the compound (I), and they are also contained as the compound (I) by a synthetic method and a separation method known per se. Can be obtained as a single item. For example, when the optical isomer is present in the compound (I), the optical isomer separated from the compound is also included in the compound (I).
Here, the optical isomer can be produced by a method known per se.
Compound (I) may be crystalline.
The crystal of compound (I) (hereinafter, may be abbreviated as the crystal of the present invention) can be produced by applying a crystallization method known per se to compound (I) and crystallizing it.

In the present specification, the melting point is measured using, for example, a micro melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) device (METTTLER TOLEDO, DSC1). Means the melting point.
Generally, the melting point may fluctuate depending on the measuring instrument, measuring conditions, and the like. The crystal in the present specification may be a crystal having a value different from the melting point described in the present specification as long as it is within a normal error range.
The crystals of the present invention have excellent physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), medicinal effects), and are extremely pharmaceutical. It is useful.

Compound (I) may be used as a prodrug. The prodrug of the compound (I) is a compound that is converted into the compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in the living body, that is, the compound (I) is enzymatically oxidized, reduced, hydrolyzed, or the like. It is a compound that changes to compound (I) by causing hydrolysis or the like due to gastric acid or the like.
As a prodrug of compound (I),
Compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-). 1,3-Dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds);
Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or booxidized (eg, the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated. , Alanylated or dimethylaminomethylcarbonylated compounds);
Compounds in which the carboxyl group of compound (I) is esterified or amidated (eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxy). Methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamidation Compounds) and the like. These compounds can be produced from compound (I) by a method known per se.

In addition, the prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals," Vol. 7, Molecular Design, pp. 163 to 198. May be.
In the present specification, the prodrug may form a salt, and examples of such a salt include those exemplified as the salt of the compound represented by the above-mentioned formula (I).
Further, the compound (I) may be labeled with an isotope (eg, ^3H , ^13C , ^14C , ^18F , ^35S , ^125I ) or the like.
The compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis.
Further, compound (I) may be a hydrate, a non-hydrate, a solvate (eg, an anhydride), or a solvate (eg, a hydrate). May be.
Further, a deuterium converter obtained by converting ¹ H to ² H (D) is also included in the compound (I).
Further, compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt is unique to two or more at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.

Compound (I) or a prodrug thereof (hereinafter, may be simply abbreviated as the compound of the present invention) is used as it is or mixed with a pharmacologically acceptable carrier or the like to form a pharmaceutical composition (also referred to as a pharmaceutical product). Thereby, it can be used as a prodrug or therapeutic agent for various diseases described later for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys).
Here, as the pharmacologically acceptable carrier, various conventional organic or inorganic carrier substances are used as the pharmaceutical material, and excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations. , Dissolving aid, suspending agent, tonicity agent, buffering agent, soothing agent, etc. If necessary, pharmaceutical additives such as preservatives, antioxidants, colorants, and sweeteners can also be used.

Suitable examples of excipients are lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low substitution hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, pullulan, light Examples thereof include anhydrous silicate, synthetic aluminum silicate, and magnesium aluminometasilicate.
Preferable examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
Suitable examples of binders are pregelatinized starch, sucrose, gelatin, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxy. Examples thereof include propylmethyl cellulose and polyvinylpyrrolidone.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low degree of substitution hydroxypropyl cellulose.
Preferable examples of the solvent include water for injection, saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
Suitable examples of solubilizers are polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Can be mentioned.
Suitable examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; polyvinyl alcohol, polyvinylpyrrolidone. , Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; polysorbates, polyoxyethylene hydrogenated castor oil and the like.
Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
Preferable examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates and citrates.
Preferable examples of soothing agents include benzyl alcohol.
Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Preferable examples of the antioxidant include sulfites, ascorbic acid salts and the like.
Suitable examples of colorants include water-soluble food tar pigments (eg, food dyes such as Edible Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, and Food Blue Nos. 1 and 2), water-insoluble lake pigments. (Example, aluminum salt of the water-soluble food coloring), natural dyes (eg, β-carotene, chlorophyll, red iron oxide).
Preferable examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), capsules (including soft capsules and microcapsules), suppositories, and the like. Oral preparations such as granules, powders, troches, suppositories, liquids, emulsions, suspensions, aerosols, films (eg, orally disintegrating films, oral mucosal patches); and injections (eg, subcutaneous injections). Agents, intravenous injections, intramuscular injections, intraperitoneal injections, instillations), external preparations (eg, percutaneous absorption type preparations, ointments, lotions, patches), suppositories (eg, rectal suppositories) , Vaginal suppository), pellets, nasal agents, pulmonary agents (injectors), parenteral agents such as eye drops. The compounds of the present invention and the pharmaceuticals of the present invention are oral or parenteral (eg, intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instilled, intracerebral, intravaginal, peritoneal). It can be safely administered to the inside, inside the tumor, proximal to the tumor, etc. and directly to the lesion).
These formulations may be release controlled formulations (eg, sustained release microcapsules) such as immediate release formulations or sustained release formulations.

The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, the method described in the Japanese Pharmacopoeia.
The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention and the like, but is, for example, about 0.1 to 100% by weight.
When producing the oral preparation, if necessary, a coating may be applied for the purpose of masking the taste, enteric solubility or persistence.

Examples of the coating base used for coating include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base.
As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose; polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer E [Eudragit E (trade name). ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as purulan.
Examples of the enteric film coating base include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name)). ], Acrylic acid-based polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as cellac.
Examples of the sustained-release film coating base include cellulose-based polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit]. Acrylic acid-based polymers such as NE (trade name)] can be mentioned.
The above-mentioned coating base may be used by mixing two or more of them in an appropriate ratio. Further, a light-shielding agent such as titanium oxide or iron sesquioxide may be used for coating.

The compounds of the present invention have low toxicity (eg, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, etc.). It can be used as a prophylactic or therapeutic agent for various diseases or a diagnostic agent for monkeys, mice, rats).

The compounds of the present invention have excellent orexin type 2 receptor activating activity and can treat, prevent and ameliorate the risks of various neurological and psychiatric disorders associated with orexin type 2 receptors. The compounds of the present invention include, for example, narcolepsy, idiopathic obesity, obesity, sleep obesity syndrome, narcolepsy syndrome with narcolepsy-like symptoms, obesity syndrome with daytime obesity (eg, Kleinelevin syndrome). , Obesity with obesity, Levy body dementia, Parkinson's disease, progressive nuclear palsy, Pradawilly syndrome, Mobius syndrome, hypoventilation syndrome, Niemannpic disease type C, brain contusion, cerebral infarction, brain tumor, Muscle dystrophy, multiple sclerosis, acute diffuse encephalomyelitis, Gillan Valley syndrome, Rasmussen encephalitis, Wernicke encephalitis, marginal encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (eg, malignant obesity cells, extrinsic obesity) , Hyperinsulin obesity, hyperplasma obesity, pituitary obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, Decreased obesity, systemic obesity cytology, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, consciousness disorders such as coma, side effects and complications due to anesthesia, sleep disturbance, sleep problems, insomnia , Intermittent sleep, nocturnal muscle spasm, REM sleep interruption, stagger, stagger syndrome, shift worker sleep disorders, sleep abnormalities, night surprise, depression, obesity, dream play, obesity, sleep Disorders, Alzheimer's dusk, diseases associated with circadian rhythm, fibromyalgia, conditions resulting from poor sleep quality, overeating, compulsive feeding disorders, obesity-related diseases, hypertension, diabetes, plasma insulin levels and insulin Increased resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obese sleep aspiration, cholelithiasis, bile stones, heart disease, Abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, cranial pharyngoma, Florich syndrome, growth hormone deficiency, normal mutation Sex such as short stature, Turner syndrome, children with acute lymphocytic leukemia, syndrome X, reproductive hormonal abnormalities, decreased fertility, infertility, decreased gonad function in men, and male hypertension in women And reproductive dysfunction, fetal defects associated with obesity in pregnant women, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory disorders such as respiratory distress, vasculature Obesity such as inflammation such as systemic inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, bile sac disease, gout, kidney cancer, left ventricular hypertrophy Risk of secondary consequences, migraine, headache, neuropathic pain, Parkinson's disease, mental illness, schizophrenia, facial erythema, sleep sweat, genital / urinary system disorders, sexual function or fertility disorders, mood Modulatory Disorder, Bipolar Disorder, Bipolar I Disorder, Bipolar II Disorder, Circulatory Disorder, Acute Stress Disorder, Square Fear, General Anxiety Disorder, Compulsive Disorder, Panic Attack, Panic Disorder, Posttraumatic Stress Disorder, Acute neurological and psychiatric disorders such as segregation anxiety disorder, social phobia, anxiety disorder, cardiac bypass surgery and post-transplant cerebral deficiency, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, Perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, muscle atrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, muscle Disorders associated with spasm, manic-depressive disorder, forgetfulness disorder, age-related cognitive decline, schizophrenia, emotional disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced Parkinson syndrome, Jill Do・ La Tourette Syndrome, Butoh Disease, Myocronus, Chick, Lower Extremity Itching Syndrome, Gistonia, Diskinesis, Attention Defect Hyperactivity Disorder (ADHD), Behavioral Disorders, Urinary Incontinence, Withdrawal Symptoms, Triangular Nerve Pain, Hearing Loss, Ear Ringing, Nerve Injury, It is useful as a preventive or therapeutic agent for various diseases such as retinopathy, yellow spot degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexic, and traumatic brain disorder.

In particular, the compounds of the present invention include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia (eg, Parkinson's disease, etc.). Gillan Valley Syndrome and Kleine Levin Syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, hypersomnia, consciousness disorders such as coma, treatment or prevention of side effects and complications due to anesthesia, and anesthesia It is useful as an antagonist.

The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc., but for example, when orally or parenterally administered to an adult patient, the usual single dose is about 0.01 to 100 mg / mg. The body weight is kg, preferably 0.1 to 50 mg / kg body weight, more preferably 0.5 to 20 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

The compound of the present invention can be used in combination with other drugs (hereinafter, abbreviated as concomitant drugs).
By combining the compound of the present invention with a concomitant drug,
(1) The dose can be reduced as compared with the case where the compound of the present invention or the concomitant drug is administered alone.
(2) A drug to be used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.).
(3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer.
(4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained.
(5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

Hereinafter, the combined use of the compound of the present invention and the concomitant drug is referred to as "the concomitant agent of the present invention".
When using the concomitant drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are simultaneously administered to the administration subject. It may be administered at a time lag. The dose of the concomitant drug may be according to the dose clinically used, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like.
The administration form of the concomitant drug of the present invention is not particularly limited, and the compound of the present invention and the concomitant drug may be combined at the time of administration. As such an administration form, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) the compound of the present invention and the concomitant drug are separately formulated. Simultaneous administration of the two obtained formulations on the same administration route, (3) Administration of the two formulations obtained by separately formulating the compound of the present invention and the concomitant drug on the same administration route with a time lag. (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Obtaining by separately formulating the compound of the present invention and the concomitant drug 2 Examples thereof include administration of the pharmaceutical product at different administration routes with a time lag (for example, administration of the compound of the present invention; administration in the order of concomitant drugs, or administration in the reverse order).
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like.
For example, the content of the compound of the present invention in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the entire preparation. More preferably, it is about 0.5 to 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the entire preparation. It is about 0.5 to 20% by weight.
The content of the additive such as a carrier in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. ..
Further, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.

Examples of concomitant drugs include the following. Narcolepsy therapeutic agents (eg, methylphenylate, amphetamine, pemoline, phenergine, protryptyrin, sodium oxybate, modafinyl, caffeine), anti-obesity drugs (amphetamine, benzfetamine, bromocroptin, bupropion, diethylpropion, exenatide, phen) Fluramine, Riotyronine, Rilaglutide, Magindole, Methanfetamine, Octreotide, Octreotide, Orlistat, Fendimethrazine, Fendimethrazine, Fenmethrazine, Fentermine, Qnexa®, Phenylpropanolamine, Plumlintide, Ppropylhexedrin , Recombinant leptin, cibutramine, topiramate, dimeridine, zonisamide, lolcaserin, methformin), acetylcholinesterase inhibitors (eg, donepezil, rivastigmin, galantamine, zanapezil, idebenone, taclin), nootropics (eg, memantin), β-amiroid Production, secretion, accumulation, aggregation and / or deposition inhibitor, β-secretase inhibitor (eg, 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- ( 4-Biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetraline, 6- (4-biphenylyl) methoxy-2- (N, N-dipropylamino) methyltetraline, 2- (N, N-dimethyl) Amino) Methoxy-6- (4'-methoxybiphenyl-4-yl) methoxytetraline, 6- (4-biphenylyl) methoxy-2- [2- (N, N-diethylamino) ethyl] tetraline, 2- [2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methylbiphenyl-4-yl) methoxytetraline, 2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methoxy) Biphenyl-4-yl) methoxytetraline, 6- (2', 4'-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetraline, 6- [4- (4-() 1,3-benzodioxol-5-yl) phenyl] methoxy-2- [2- (N, N-dimethylamino) ethyl] tetraline, 6- (3', 4'-dimethoxybiphenyl-4-yl) Methoxy-2- [2- (N, N-dimethylamino) ethyl] tetraline, its optically active substance, its salt and its hydrate, OM99-2 (International Publication 01/00663) ), Γ-secretase inhibitor, β-amyloid protein aggregation inhibitor (eg, PTI-00703, ALZHEMEED (NC-531), PPI-368 (Special Table 11-5143333), PPI-558 (Special Table 2001-500852). ), SKF-74652 (Biochem. J. (1999), 340 (1), 283-289)), β-amyloid vaccine, β-amyloid degrading enzyme, etc., brain function activators (eg, anilacetam, nicergoline), Parkinson's disease therapeutic agents [(eg, dopamine receptor agonists) (Eg, L-dopa, bromocriptin, pergolide, talipexol, pramipexol, cabergolin, amantazine), monoamine oxidase (MAO) inhibitors (eg, deprenyl, sergiline (selegillin), remasemide, lylsole), anticholinergic agents (eg, trihe) Xyphenidil, Viperiden), COMT inhibitors (eg, Entakapon)], therapeutic agents for myotrophic lateral sclerosis (eg, rilzole, neuronutrient factors), abnormal behavior associated with the progression of dementia, treatment of wandering, etc. Drugs (eg, sedatives, anti-anxiety agents), apoptosis inhibitors (eg, CPI-1189, IDN-6556, CEP-1347), neurodifferential differentiation / regeneration promoters (eg, leteprinim, Xaliproden; SR-57746- A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3 -Dihydro-1-benzofuran-5-yl] isoindrin, 5,6-dimethoxy-2- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro- 1-benzofuran-5-yl] isoindrin, 6- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]- 6,7-Dihydro-5H- [1,3] dioxolo [4,5-f] isoindole and its optically active substances, salts, hydrates), non-steroidal anti-inflammatory agents (meroxycam, tenoxycam, indomethacin, ibprofen) , Celecoxib, lofecoxib, aspirin, etc.), steroid drugs (dexamesazone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-cytogenic drugs (eg, TNF inhibitors, MAP kinase inhibitors), urine Incontinence / frequent urine therapeutic agents (eg, flavoxate hydrochloride, oxybutinine hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (eg, sildenafil (citrate)), dopamine agonists (eg, apomorphin), anti-arrhythmic drugs (eg, mexiretin), Sex hormones or derivatives thereof (eg, progesterone, estradiol, cheap Estradiol breamate), osteoporosis treatments (eg, alphacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavon, disodium pamidronate, sodium alendronate hydrate, disodium incadronate), parathyroid Standards such as hormones (PTHs), calcium receptor antagonists, insomnia treatments (eg, benzodiazepines, non-benzodiazepines, melatonin agonists, olexin receptor antagonists), schizophrenia (eg, haloperidol) Antipsychotics; atypical antipsychotics such as clozapine, olanzapine, risperidone, alipiprazole; agents that act on metabolic glutamate receptors or ion channel-conjugated glutamate receptors; phosphodiesterase inhibitors), benzodiazepines (chlordiazepoxide, diazepam, Potassium chlorazebate, lorazepam, chronazepam, alprazolam, etc.), L-type calcium channel blocker (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptiline hydrochloride, decipramine hydrochloride, chromipramine hydrochloride, etc.), selection Serotonin reuptake inhibitor (fluboxamine maleate, floxetine hydrochloride, citaloplum bromide, celtralin hydrochloride, paroxetine hydrochloride, escitaloplum oxalate, etc.), serotonin-noradrenaline reuptake inhibitor (benrafaxin hydrochloride, duroxetine hydrochloride, desvenrafa hydrochloride) Xin, etc.), noradrenaline reuptake inhibitor (leboxetine mesylate, etc.), mirtazapine, trazodon hydrochloride, nefazodon hydrochloride, bupropion hydrochloride, cetiputilin maleate, 5-HT1A antagonist (buspyrone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5 -HT2A antagonists, 5-HT2A antagonists, 5-HT3 antagonists (siamemazine, etc.), non-cardiac-selective β-inhibitors (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxydin hydrochloride, etc.) Etc.), CRF antagonists, other anxiety agents (meprobamate, etc.), takikinin antagonists (MK-869, saledutant, etc.), drugs that act on metabolic glutamate receptors, CCK antagonists, β3 adrenaline antagonists (amibeglon hydrochloride) Etc.), GAT-1 inhibitor (thiagabin hydrochloride, etc.), N-type calcium channel inhibitor, type 2 carbonate dehydrogenase inhibitor, NMDA glycine site agonist, NMDA antagonist (Mema) Antin, etc.), Peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, tyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenerzine sulfate, tranylicipromin sulfate, moclobemid, etc.), therapeutic agents for bipolar disorders (lithium carbonate, sodium valproate, lamotridin, lysole, ferlumate, etc.), cannabinoid CB1 antagonism Drugs (Limonavant, etc.), FAAH inhibitors, sodium channel inhibitors, anti-ADHD drugs (methylphenylate hydrochloride, methanefetamine hydrochloride, etc.), alcohol dependence drugs, autism drugs, chronic fatigue syndrome drugs, spasm drugs , Fibromyalgia treatment, headache treatment, quitting treatment, severe myasthenia treatment, cerebral infarction treatment, manic disease treatment, hypersomnia treatment, pain treatment, dysthymia treatment , Autonomous dysfunction drug, male and female sexual dysfunction drug, migraine pain drug, pathological gambling drug, lower limb immobility syndrome drug, substance dependence drug, alcohol-related drug, hypersensitivity Treatments for dysplasia such as genital syndrome and cholesterol-lowering drugs (statin series (Plavastatin sodium, atrovastatin, simvastatin, rosbatatin, etc.), fibrates (clofibrate, etc.), squalane synthesis inhibitors), treatment for abnormal behavior Drugs or drugs that suppress wandering habits due to dementia (sedatives, anti-anxiety drugs, etc.), diabetes drugs, diabetic complications drugs, hypertension drugs, hypotension drugs, diuretics, chemotherapeutic agents, immunotherapeutic agents, Anti-thrombotic agents, anti-cancer agents, etc.

The above-mentioned concomitant drug may be used in combination of two or more kinds at an appropriate ratio.
Furthermore, when the compound of the present invention is applied to each of the above diseases, it can be used in combination with a biological product (eg, antibody drug, nucleic acid or nucleic acid derivative, aptamer drug, vaccine preparation), and also with a gene therapy method or the like. It can be used in combination with a drug-free treatment in the psychiatric field.
Examples of antibody drugs and vaccine preparations include vaccine preparations for angiotensin II, vaccine preparations for CETP, CETP antibodies, antibodies against TNFα antibody and other cytokines, amyloid β vaccine preparations, and type 1 diabetes vaccines (eg, Pipetor's DIAPEP-). 277) In addition to anti-HIV antibodies and HIV vaccine preparations, antibodies or vaccine preparations against cytokines, renin-angiotensin enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, blood coagulation -Examples include antibodies or vaccines related to enzymes and proteins involved in fibrinolytic systems, antibodies or vaccine preparations against proteins involved in glucose metabolism and insulin resistance, and the like. In addition, it can be used in combination with biologics related to growth factors such as GH and IGF.
As a gene therapy method, for example, a therapy method using a cytokine, a renin-angiotensin system enzyme and its product, a G protein, a G protein-conjugated receptor and a gene related to its phosphorylating enzyme, and a DNA decoy such as NFκB decoy are used. Therapies used, antisense therapies, genes associated with enzymes and proteins involved in blood lipid metabolism (eg, cholesterol or triglycerides or HDL-cholesterol or genes associated with blood phospholipid metabolism, excretion, absorption) ), Therapies using genes related to enzymes and proteins (eg, growth factors such as HGF and VEGF) involved in angiogenesis therapy for peripheral vascular obstruction, glucose metabolism and insulin Therapeutic methods using genes related to proteins involved in resistance, antisense against cytokines such as TNF, and the like can be mentioned.
Examples of therapies in the psychiatric field that do not use drugs include modified electric spasm therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, and psychotherapy including cognitive behavioral therapy.
In addition, the compound of the present invention is used for various organ regeneration methods such as heart regeneration, renal regeneration, pancreatic regeneration, and blood vessel regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs using tissue engineering (tissue engineering). For example, artificial blood vessels, myocardial cell sheets) can also be used in combination.

The present invention will be further described in detail with reference to the following Examples, Test Examples and Formulation Examples, which are not limited to the present invention and may be changed without departing from the scope of the present invention.
"Room temperature" in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates weight% unless otherwise specified.
Elution in column chromatography of the examples was carried out under observation by TLC (Thin Layer Chromatography, thin layer chromatography) unless otherwise specified. In the TLC observation, 60 F ₂₅₄ manufactured by Merck Group was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the developing solvent. In addition, a UV detector was used for detection. In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when it was described as NH, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when it was described as DIOL. Preparative HPLC (High Speed Liquid Chromatography) includes columns: Boston Prime C18 (150 mm x 30 mm, 5 μm), Xtimate C18 (100 mm x 30 mm, 3 μm), Gemini NX C18 (150 mm x 30 mm,). 5 μm), YMC Triart C18 (250 mm x 50 mm, 7 μm), Exsil plus C18 (150 mm x 50 mm, 5 μm), or Water Xbridge C18 (150 mm x 30 mm, 5 μm), mobile phase: Conditions such as 0.05% aqueous ammonia / MeCN were used. When described as C18, octadecyl-bonded silica gel was used. The ratio shown in the elution solvent indicates the volume ratio unless otherwise specified.
¹ ACD / SpecManager (trade name) software or the like was used for the analysis of 1 H NMR. Peaks with very gentle proton peaks such as hydroxyl groups and amino groups may not be described.
MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. The data show the measured value (found). Usually, a molecular ion peak is observed, but it may be observed as a fragment ion. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.
The 6-bromopyridin-2-ol in the examples may be present as the tautomer 6-bromopyridin-2 (1H) -one.
The following abbreviations are used in the following examples.
MS: Mass spectrum M: Molar concentration N: Normality CDCl ₃ : Deuterated chloroform DMSO-d ₆ : Deuterated dimethyl sulfoxide
¹ H NMR: Proton nuclear magnetic resonance
LC / MS: Liquid chromatograph mass spectrometer
ESI: electrospray ionization, electrospray ionization APCI: atmospheric pressure chemical ionization, atmospheric chemical ionization
IPE: Diisopropyl ether
IPA: 2-propanol
DMF: N, N-dimethylformamide
THF: Tetrahydrofuran
MeOH: Methanol
MeCN: acetonitrile
NMP: N-methylpyrrolidone
CPME: Cyclopentyl methyl ether
DME: 1,2-dimethoxyethane
DMSO: Dimethyl sulfoxide
DCM: dichloromethane
DCE: dichloroethane
EtOH: Ethanol
XPhos Pd G3: (2-Dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] palladium (II) ) Methanesulfonate
SFC: Supercritical Fluid Chromatography
HATU: 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
HOBt: 1-Hydroxybenzotriazole
EDCI: N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride
TEA: Triethylamine
DIPEA: N, N-diisopropylethylamine
NaH: Sodium hydride
Boc: tert-butoxycarbonyl
DMAP: 4-dimethylaminopyridine
CO ₂ : Carbon dioxide
Pd / C: Palladium on carbon

Example 23
N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] pyrrolidine-3- Il} methanesulfonamide

A) tert-butyl (S) -3- (methyl sulfonamide) pyrrolidine-1-carboxylate
To a mixture of tert-butyl (S) -3-aminopyrrolidine-1-carboxylate (4.93 g) and THF (20 mL), add triethylamine (5.53 mL) and methanesulfonic acid anhydride (4.61 g) at 0 ° C. , Stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and water at 0 ° C. and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, passed through a silica gel pad, and concentrated under reduced pressure to give the title compound (6.39 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.39 (9H, s), 1.69-1.88 (1H, m), 1.97-2.14 (1H, m), 2.94 (3H, s), 3.08 (1H, dd) , J = 10.9, 5.6 Hz), 3.14-3.27 (1H, m), 3.28-3.38 (1H, m), 3.43-3.53 (1H, m), 3.80-3.93 (1H, m), 7.34 (1H, s) ).

B) (S) -N- (pyrrolidin-3-yl) methanesulfonamide hydrochloride
A mixture of tert-butyl (S) -3- (methylsulfonamide) pyrrolidine-1-carboxylate (6.39 g) and a 4 M ethyl acetate solution of hydrogen chloride (72.5 mL) was stirred overnight at room temperature. Heptane (50 mL) was added to the resulting suspension with stirring, the precipitate was collected, washed with ethyl acetate and dried at 50 ° C. to give the title compound (3.71 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.81-1.96 (1H, m), 2.09-2.23 (1H, m), 2.99 (3H, s), 3.05 (1H, dd, J = 12.0, 5.3 Hz) ), 3.13-3.28 (2H, m), 3.33-3.39 (1H, m), 3.96-4.10 (1H, m), 7.48 (1H, br s), 8.93 (2H, br s).

C) rac-Ethyl (1R, 2R) -2- (2-bromophenyl) Cyclopropane-1-carboxylate Potassium tert-butoxide (42.2 g) and DMSO (400 mL) in a mixture of trimethylsulfoxonium iodide (82.8 g) was added little by little at room temperature. After stirring at the same temperature for 1 hour, a solution of ethyl (E) -3- (2-bromophenyl) acrylate (80.0 g) in DMSO (400 mL) was added, and the mixture was further stirred at the same temperature for 12 hours. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (34.4 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.27-1.36 (4H, m), 1.61-1.67 (1H, m), 1.75-1.83 (1H, m), 2.66-2.75 (1H, m), 4.14-4.28 (2H, m), 6.98-7.05 (1H, m), 7.06-7.13 (1H, m), 7.19-7.26 (1H, m), 7.56 (1H, dd, J = 8.0, 1.2 Hz).

D) rac-ethyl (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate
rac-ethyl (1R, 2R) -2- (2-bromophenyl) cyclopropane-1-carboxylate (5.00 g), 2,6-difluorophenylboronic acid (8.80 g), DME (60 mL), and water To the mixture (50 mL), Xphos Pd G3 (1.57 g) and tripotassium phosphate (11.8 g) were added, and the mixture was stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (3.73 g).
MS: [M + H] ⁺ 303.3.

E) rac- (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid
rac-ethyl (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate (3.73 g) and EtOH (40 mL) Aqueous sodium hydroxide solution (4.93 g / 20 mL) was added to the mixture, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, diluted with water, adjusted to pH 4 with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.37 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.30-1.37 (1H, m), 1.40-1.47 (1H, m), 1.70-1.76 (1H, m), 2.39-2.46 (1H, m), 6.94-7.03 (2H, m), 7.15 (1H, t, J = 7.2 Hz), 7.26-7.41 (4H, m)

F) N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] pyrrolidine- 3-yl} methanesulfone amide and N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane- 1-carbonyl] pyrrolidine-3-yl} methanesulfone amide mixture
rac- (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (2.00 g), (S) -N-( DIPEA (3.77 g) was added to a mixture of pyrrolidine-3-yl) methanesulfonamide hydrochloride (1.46 g), HATU (2.91 g) and DMF (15 mL), and the mixture was stirred at room temperature for 12 hours. The mixture was purified by reverse phase silica gel column chromatography (C18, methanol / water) to give the title compound (1.53 g).
MS: [M + H] ⁺ 421.1.

G) N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] pyrrolidine- 3-Il} methanesulfonamide
N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] pyrrolidine-3- Il} methanesulfone amide and N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1- Carbonyl] pyrrolidine-3-yl} methanesulfone amide mixture (4.10 g) with SFC (column: Phenomenex-Cellulose-2, 250 mm x 50 mm, 10 μm, mobile phase: CO ₂ / 0.1% Ammonia water-containing EtOH = Fractions with a short retention time were concentrated by fractionation at 55/45 v / v). The residue was dissolved in MeCN (10 mL) and water (50 mL) and lyophilized. The obtained solid was pulverized with petroleum ether / ethyl acetate to give the title compound (1.31 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24-1.32 (1H, m), 1.42-1.52 (1H, m), 1.58-1.72 (1H, m), 1.78-2.10 (1H, m), 2.10-2.30 (1H, m), 2.32-2.43 (1H, m), 2.98 (3H, d, J = 12.0 Hz), 3.27-3.76 (4H, m), 3.94-4.12 (1H, m), 4.67-4.99 (1H) , m), 6.91-7.05 (2H, m), 7.14 (1H, d, J = 7.6 Hz), 7.22-7.41 (4H, m).

Example 24
N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] piperidine-3- Il} methanesulfonamide

A) tert-butyl (S) -3- (methyl sulfonamide) piperidine-1-carboxylate
To a mixture of tert-butyl (S) -3-aminopiperidine-1-carboxylate (11.4 g) and THF (50 mL), add triethylamine (11.9 mL) and methanesulfonic acid anhydride (9.92 g) at 0 ° C. , Stirred overnight at room temperature. The mixture was diluted with ethyl acetate and water at 0 ° C. and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, passed through a silica gel pad, and concentrated under reduced pressure to give the title compound (14.9 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40-1.80 (12H, m), 1.87-2.01 (1H, m), 3.01 (3H, s), 3.19-3.34 (2H, m), 3.35-3.57 (2H) , m), 3.62-3.75 (1H, m), 4.54 (1H, br d, J = 6.0 Hz).

B) (S) -N- (piperidine-3-yl) methanesulfonamide hydrochloride
A mixture of tert-butyl (S) -3- (methylsulfonamide) piperidin-1-carboxylate (14.9 g) and 4 M hydrogen chloride CPME solution (134 mL) was stirred at room temperature for 3 hours. CPME was decanted and the remaining gum-like material was dried to give the title compound (10.0 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.37-2.00 (4H, m), 2.62-2.85 (2H, m), 2.98 (3H, s), 3.04-3.17 (1H, m), 3.20-3.33 (1H, m), 3.47-3.61 (1H, m), 7.45 (1H, d, J = 7.2 Hz), 8.87-9.26 (2H, m).

C) N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] piperidine- 3-Il} methanesulfonamide and N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane- 1-carbonyl] piperidin-3-yl} methanesulfonamide mixture
rac- (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carboxylic acid (3.00 g), (S) -N-( DIPEA (5.65 g) was added to a mixture of piperidin-3-yl) methanesulfonamide hydrochloride (2.35 g), HATU (4.37 g) and DMF (30 mL), and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (4.93 g).
MS: [M ⁺ H] +435.1.

D) N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] piperidine- 3-Il} methanesulfonamide
N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] piperidine-3- Il} Methane sulfone amide and N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1- Carbonyl] piperidine-3-yl} methane sulfone amide mixture (4.93 g) with SFC (column: Phenomenex-Cellulose-2, 250 mm x 50 mm, 10 μm, mobile phase: CO ₂ / 0.1% Ammonia water-containing EtOH = Fractions with a short retention time were concentrated by fractionation at 55/45 v / v). The residue was dissolved in MeCN (10 mL) and water (50 mL) and lyophilized to give the title compound (1.56 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.22-1.36 (1H, m), 1.43-1.50 (1H, m), 1.51-1.61 (1H, m), 1.78-2.02 (4H, m), 2.20-2.42 (1H, m), 2.77-3.04 (3H, m), 3.27-3.92 (5H, m), 4.47-4.77 (1H, m), 6.92-7.42 (7H, m).

Example 25
N-{(4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] azepan-4- Il} methanesulfonamide

A) tert-Butyl 4- (methylsulfonamide) azepan-1-carboxylate
Triethylamine (18.9 g) and methanesulfonyl chloride (13.9 g) were added to a mixture of tert-butyl 4-aminoazepan-1-carboxylate (20.0 g) and DCM (180 mL) at 0 ° C, and the mixture was stirred at room temperature for 16 hours. .. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (28.5 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 (9H, s), 1.65-2.15 (5H, m), 2.95 (3H, s), 3.06-3.67 (6H, m), 4.64 (1H, d, J) = 7.6 Hz).

B) N- (azepan-4-yl) methanesulfonamide hydrochloride
A mixture of tert-butyl 4- (methylsulfonamide) azepan-1-carboxylate (28.5 g) and a 4 M hydrogen chloride dioxane solution (100 mL) was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to give the title compound (23.5 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.53-2.14 (6H, m), 2.90-3.21 (7H, m), 3.35-3.52 (1H, m), 7.23 (1H, d, J = 6.8 Hz) ), 9.16 (2H, brs).

C) rac-N-{(4R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] Azepan-4-yl} methanesulfonamide and rac-N-{(4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl ) Cyclopropane-1-carbonyl] Azepan-4-yl} Mix of methanesulfonamide
rac- (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carboxylic acid (150 mg), N- (azepan-4-) Iru) HATU (312 mg) was added to a mixture of methanesulfonamide hydrochloride (150 mg), DIPEA (212 mg) and DMF (5.0 mL) at 0 ° C. and stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (105 mg).
MS: [M + H] ⁺ 449.3.

D) N-{(4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] azepane- 4-yl} methanesulfonamide
rac-N-{(4R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] azepan- 4-yl} methanesulfonamide and rac-N-{(4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclo Propane-1-carbonyl] Azepan-4-yl} Methanesulfonamide mixture (105 mg) with SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 5 μm, mobile phase: CO ₂ / 0.1% ammonia Fractionate with water-containing MeOH = 45/55 v / v), concentrate the fraction with the shortest retention time, dissolve the residue in MeCN (3.0 mL) and water (3.0 mL), freeze dry and crude product. (45 mg) was obtained. This is further fractionated by SFC (column: DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm, mobile phase: CO ₂ / 0.1% ammonia water-containing IPA = 60/40 v / v), and the retention time is short. The fraction was concentrated. The residue was dissolved in MeCN (3.0 mL) and water (3.0 mL) and lyophilized to give the title compound (13 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.25-1.28 (1H, m), 1.46-1.53 (1H, m), 1.57-2.40 (8H, m), 2.95-2.97 (3H, m), 3.17-3.78 (5H, m), 4.15-4.19 (1H, m), 6.90-7.14 (3H, m), 7.26-7.41 (4H, m).

Example 195
N-{(3S) -1-[(1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] pyrrolidine -3-yl} methanesulfone amide, or N-{(3S) -1-[(1S, 2S) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2- Ill) Cyclopropane-1-carbonyl] Pyrrolidine-3-yl} Methansulphonamide

A) 60% NaH (60% NaH) in a mixture of ethyl (2E) -3- (2-bromo-6-fluorophenyl) propa-2-enoate ethyl 2-diethoxyphosphoryl acetate (64.6 g) and THF (450 mL). 10.6 g) was added at 0 ° C. After stirring at room temperature for 15 minutes, 2-bromo-6-fluorobenzaldehyde (45.0 g) was added, and the mixture was stirred at the same temperature for 2 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (59.8 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.2 Hz), 4.28 (2H, q, J = 7.2 Hz), 6.61-6.69 (1H, m), 7.04-7.11 (1H, m), 7.12-7.20 (1H, m), 7.43 (1H, d, J = 8.0 Hz), 7.83 (1H, d, J = 16.4 Hz).

B) rac-ethyl (1R, 2R) -2- (2-bromo-6-fluorophenyl) cyclopropane-1-carboxylate potassium tert-butoxide (14.7 g) and DMSO (250 mL) in a mixture of trimethylsulfone. Xonium iodine (28.8 g) was added at room temperature. After stirring at the same temperature for 30 minutes, a solution of ethyl (2E) -3- (2-bromo-6-fluorophenyl) propa-2-enoate (29.8 g) in DMSO (250 mL) was added, and the mixture was further heated at the same temperature. The mixture was stirred for 6 hours. The reaction was stopped by adding saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether). The same reaction was carried out in 2 batches to give the title compound (42.2 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.30 (3H, t, J = 7.2 Hz), 1.44-1.52 (1H, m), 1.63-1.74 (1H, m), 1.92-2.02 (1H, m), 2.38-2.48 (1H, m), 4.16-4.28 (2H, m), 6.93-7.00 (1H, m), 7.02-7.11 (1H, m), 7.34-7.39 (1H, m).

C) rac-ethyl (1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate
rac-ethyl (1R, 2R) -2- (2-bromo-6-fluorophenyl) cyclopropane-1-carboxylate (15.0 g), 2,6-difluorophenylboronic acid (33.0 g), and DME (100) Aqueous tripotassium phosphate solution (33.3 g / 100 mL) and Xphos Pd G3 (4.42 g) were added to the mixture of mL), and the mixture was stirred at 100 ° C. for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (2.00 g).
MS: [M + H] ⁺ 321.0.

D) rel-ethyl (1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate
rac-ethyl (1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate (1.00 g) in SFC (column) : DAICEL CHIRALCEL OD-H, 250 mm x 30 mm, 5 μm, Mobile phase: CO ₂ / 0.1% Ammonia water-containing IPA = 90/10 v / v) Obtained as (320 mg).
MS: [M + H] ⁺ 321.0.

E) rel- (1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid rel synthesized by step D) -Ethyl (1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate (320 mg), aqueous sodium hydroxide solution A mixture of (400 mg / 1.5 mL) and EtOH (4.5 mL) was stirred at room temperature for 16 hours. The mixture was adjusted to pH 5-6 with 2 M hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (330 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.15-1.30 (1H, m), 1.34-1.43 (1H, m), 1.64-1.71 (1H, m), 2.35-2.44 (1H, m), 6.94-7.14 (4H, m), 7.25-7.40 (2H, m).

F) N-{(3S) -1-[(1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl ] Pyrrolidine-3-yl} methanesulfone amide, or N-{(3S) -1-[(1S, 2S) -2- (2', 3,6'-trifluoro [1,1'-biphenyl]- 2-Il) Cyclopropane-1-carbonyl] Pyrrolidine-3-yl} Methanesulfone Amide
(S) -N- (pyrrolidin-3-yl) methanesulfonamide hydrochloride (60.4 mg), rel- (1R, 2R) -2- (2', 3,6'-trifluoro) synthesized in step E) Add HATU (125 mg) and DIPEA (106 mg) to a mixture of [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (80.0 mg) and DMF (3 mL) at room temperature. The mixture was stirred for 16 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (70.5 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94-1.04 (1H, m), 1.27-1.35 (1H, m), 1.68-2.12 (2H, m), 2.15-2.31 (1H, m), 2.33-2.40 (1H, m), 3.01 (3H, s), 3.38-3.76 (4H, m), 3.97-4.16 (1H, m), 4.45-4.75 (1H, m), 6.96-7.12 (4H, m), 7.27 -7.43 (2H, m).

Example 200
N-{(3S) -1-[(1R, 2R) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] pyrrolidine -3-yl} methanesulfone amide, or N-{(3S) -1-[(1S, 2S) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2- Ill) Cyclopropane-1-carbonyl] Pyrrolidine-3-yl} Methansulfonamide

A) 60% NaH (60% NaH) in a mixture of ethyl (2E) -3- (2-bromo-4-fluorophenyl) propa-2-enoate ethyl 2-diethoxyphosphoryl acetate (35.9 g) and THF (250 mL). 5.91 g) was added at 0 ° C. After stirring at room temperature for 15 minutes, 2-bromo-4-fluorobenzaldehyde (25.0 g) was added, and the mixture was stirred at the same temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (36.9 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, t, J = 7.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 6.34 (1H, d, J = 16.0 Hz), 7.02-7.13 (1H, m), 7.37 (1H, dd, J = 8.0, 2.8 Hz), 7.60 (1H, dd, J = 8.8, 6.0 Hz), 7.99 (1H, d, J = 16.0 Hz).

B) rac-ethyl (1R, 2R) -2- (2-bromo-4-fluorophenyl) cyclopropane-1-carboxylate potassium tert-butoxide (18.5 g) and DMSO (150 mL) in a mixture of trimethylsulfone. Xonium iodine (36.2 g) was added at room temperature. After stirring at the same temperature for 30 minutes, add a mixture of ethyl (2E) -3- (2-bromo-4-fluorophenyl) propa-2-enoate (37.4 g) and DMSO (150 mL), and then add the mixture at the same temperature. The mixture was stirred for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (13.0 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.27-1.32 (4H, m), 1.59-1.66 (1H, m), 1.71-1.81 (1H, m), 2.60-2.68 (1H, m), 4.17-4.25 (2H, m), 6.91-7.04 (2H, m), 7.33 (1H, dd, J = 8.4, 2.8 Hz).

C) rac-ethyl (1R, 2R) -2- [4-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] cyclopropane-1 -Carboxylate
Mixture of rac-ethyl (1R, 2R) -2- (2-bromo-4-fluorophenyl) cyclopropane-1-carboxylate (5.00 g), bis (pinacolato) diboron (6.63 g) and DMSO (50 mL) Dichloromethane complex (1.42 g) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and potassium acetate (3.42 g) were added to the mixture, and the mixture was stirred at 100 ° C. for 16 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (3.96 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.25-1.35 (16H, m), 1.49-1.58 (1H, m), 1.63-1.76 (1H, m), 3.01-3.19 (1H, m), 4.04-4.28 (2H, m), 6.90-6.96 (1H, m), 6.98-7.05 (1H, m), 7.45 (1H, dd, J = 9.2, 2.8 Hz).

D) rac-ethyl (1R, 2R) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate
rac-ethyl (1R, 2R) -2- [4-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] cyclopropane-1-carboxy To a mixture of late (3.96 g) and 1,3-difluoro-2-iodobenzene (2.84 g) and DME (35 mL), add Xphos Pd G3 (1.00 g) and tripotassium phosphate (7.55 g) to nitrogen. The mixture was stirred at 100 ° C for 16 hours under an atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (2.32 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.17-1.26 (4H, m), 1.35-1.41 (1H, m), 1.61-1.68 (1H, m), 2.28-2.37 (1H, m), 3.91-4.08 (2H, m), 6.92-7.02 (3H, m), 7.03-7.09 (1H, m), 7.10-7.16 (1H, m), 7.31-7.39 (1H, m).

E) rac- (1R, 2R) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid sodium hydroxide (578 mg) , EtOH (20 mL), and water (5 mL) in a mixture of rac-ethyl (1R, 2R) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2- Il) Cyclopropane-1-carboxylate (2.32 g) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with water, adjusted to pH 5-6 with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.99 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.25-1.31 (1H, m), 1.38-1.48 (1H, m), 1.58-1.71 (1H, m), 2.29-2.44 (1H, m), 6.97-7.16 (5H, m), 7.30-7.38 (1H, m).

F) rel- (1R, 2R) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid
rac- (1R, 2R) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carboxylic acid (500 mg) in SFC (column: column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO ₂ / 0.1% Ammonia water-containing MeOH = 80/20 v / v), and the one with the smaller retention time is freeze-dried. The title compound (82.0 mg) was obtained.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.07-1.21 (1H, m), 1.21-1.33 (1H, m), 1.56-1.69 (1H, m), 1.89-2.04 (1H, m), 7.14 -7.30 (5H, m), 7.49-7.58 (1H, m).

G) N-{(3S) -1-[(1R, 2R) -2- (2', 5,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl ] Pyrrolidine-3-yl} methanesulfonamide, or N-{(3S) -1-[(1S, 2S) -2- (2', 5,6'-trifluoro [1,1'-biphenyl]- 2-yl) cyclopropan-1-carbonyl] pyrrolidine-3-yl} methanesulfonamide rel- (1R, 2R) -2- (2', 5,6'-trifluoro [1,1] obtained in step F '-Biphenyl] -2-yl) cyclopropane-1-carboxylic acid (30.0 mg), (S) -N- (pyrrolidin-3-yl) methanesulfonamide hydrochloride (20.6 mg) and DMF (1 mL) HATU (39.0 mg) and DIPEA (66.3 mg) were added to the mixture at 0 ° C. and stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (18.0 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.17-1.27 (1H, m), 1.40-1.48 (1H, m), 1.52-1.63 (1H, m), 1.80-2.38 (3H, m), 2.98-3.01 (3H, m), 3.28-3.72 (4H, m), 3.92-4.12 (1H, m), 4.50-5.00 (1H, m), 6.94-7.16 (5H, m), 7.30-7.45 (1H, m) ..

Example 215
N-{(3R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] -4,4 -Difluoropiperidin-3-yl} methanesulfonamide, or N-{(3R) -1-[(1S,2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2- Il) Cyclopropan-1-carbonyl] -4,4-difluoropiperidin-3-yl} Methanesulfonamide

A) tert-butyl {(3R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl]- 4,4-difluoropiperidin-3-yl} carbamalate and tert-butyl {(3R) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2 -Il) Cyclopropane-1-carbonyl] -4,4-difluoropiperidine-3-yl} Carbamate mixture
rac- (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (80 mg), tert-butyl N-[(( To a mixture of 3R) -4,4-difluoro-3-piperidyl] carbamate (83 mg) and DMF (5 mL), add HOBt (39 mg), EDCI (84 mg), and TEA (118 mg). The mixture was stirred at room temperature for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (200 mg).
MS, found: 437.1.

B) N-{(3R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] -4 , 4-Difluoropiperidin-3-yl} methanesulfonamide and N-{(3R) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2 -Il) Cyclopropan-1-carbonyl] -4,4-difluoropiperidin-3-yl} Mixture of methanesulfonamide
tert-butyl {(3R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4, 4-Difluoropiperidin-3-yl} carbamate and tert-butyl {(3R) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) ) Cyclopropan-1-carbonyl] -4,4-difluoropiperidin-3-yl} Carbamate mixture (200 mg), trifluoroacetic acid (3 mL), and DCM (5 mL) mixed at room temperature for 13 hours. bottom. The mixture was concentrated under reduced pressure and [(3R) -3-amino-4,4-difluoropiperidine-1-yl] [(1R, 2R) -2- (2', 6'-difluoro [1,1]. '-Biphenyl] -2-yl) cyclopropyl] methanone trifluoroacetate and [(3R) -3-amino-4,4-difluoropiperidine-1-yl] [(1S, 2S) -2- (2' A mixture of 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropyl] methanone trifluoroacetate was obtained (201 mg).
[(3R) -3-amino-4,4-difluoropiperidine-1-yl] [(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) Cyclopropyl] methanone trifluoroacetic acid and [(3R) -3-amino-4,4-difluoropiperidine-1-yl] [(1S, 2S) -2- (2', 6'-difluoro [1,1] '-Biphenyl] -2-yl) cyclopropyl] methanone Trifluoroacetic acid mixture (201 mg) and DCM (5 mL) mixed with methanesulfonyl chloride (68 mg) and TEA (161 mg) at room temperature Was stirred for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (38.9 mg).
MS: [M ⁺ H] +471.2.

C) N-{(3R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4 , 4-Difluoropiperidin-3-yl} methanesulfonamide, or N-{(3R) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl]- 2-yl) Cyclopropane-1-carbonyl] -4,4-difluoropiperidin-3-yl} methanesulfonamide
N-{(3R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4,4 -Difluoropiperidin-3-yl} methanesulfone amide and N-{(3R) -1-[(1S,2S) -2-(2', 6'-difluoro [1,1'-biphenyl] -2-yl) ) Cyclopropan-1-carbonyl] -4,4-difluoropiperidin-3-yl} methanesulfone amide mixture (37 mg) in SFC (column: DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm, mobile phase: Sort with CO ₂ / 0.1% aqueous ammonia containing EtOH = 70/30 v / v), concentrate the fraction with the smaller retention time, and dissolve the residue in MeCN (1 mL) and water (30 mL). The mixture was lyophilized to give the title compound (10.6 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.15-1.24 (2H, m), 1.98-2.30 (4H, m), 2.65-3.26 (5H, m), 3.41-3.93 (2H, m), 4.02 -4.25 (1H, m), 7.15-7.27 (4H, m), 7.29-7.55 (3H, m), 7.80 (1H, brs).

Example 216
N-{(3R, 4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4 -Fluoropiperidin-3-yl} methanesulfonamide, or N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro [1,1'-biphenyl]- 2-Il) Cyclopropane-1-carbonyl] -4-Fluoropiperidin-3-yl} Methanesulfonamide

A) tert-butyl {(3R, 4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl ] -4-Fluoropiperidin-3-yl} Carbamate and tert-butyl {(3R, 4S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl]] -2-yl) Cyclopropane-1-carbonyl] -4-fluoropiperidine-3-yl} Carbamate mixture
rac- (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (100 mg), tert-butyl N- (3R) , 4S) -4-Fluoro-3-piperidyl] Carbamate (96 mg) and DMF (3 mL) mixed with HOBt (49 mg), EDCI (105 mg), and TEA (148 mg) at room temperature. Was stirred for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (215 mg).
MS, found: 375.1.

B) N-{(3R, 4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4-Fluoropiperidin-3-yl} Methanesulfonamide and N-{(3R, 4S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl]] -2-yl) Cyclopropan-1-carbonyl] -4-fluoropiperidin-3-yl} Mix of methanesulfonamide
tert-butyl {(3R, 4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl]- 4-Fluoropiperidin-3-yl} carbamate and tert-butyl {(3R, 4S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2 -Il) Cyclopropan-1-carbonyl] -4-fluoropiperidin-3-yl} A mixture of carbamate (215 mg), trifluoroacetic acid (3 mL), and DCM (5 mL) is stirred at room temperature for 13 hours. bottom. The mixture was concentrated under reduced pressure and [(3R, 4S) -3-amino-4-fluoropiperidine-1-yl] [(1R, 2R) -2- (2', 6'-difluoro [1,1]. '-Biphenyl] -2-yl) cyclopropyl] methanone trifluoroacetate and [(3R, 4S) -3-amino-4-fluoropiperidine-1-yl] [(1S, 2S) -2- (2' A mixture of 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropyl] methanone trifluoroacetate was obtained (250 mg).
[(3R, 4S) -3-amino-4-fluoropiperidine-1-yl] [(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) Cyclopropyl] methanone trifluoroacetic acid and [(3R, 4S) -3-amino-4-fluoropiperidine-1-yl] [(1S, 2S) -2- (2', 6'-difluoro [1,1] '-Biphenyl] -2-yl) cyclopropyl] methanone Trifluoroacetic acid mixture (250 mg) and DCM (5 mL) mixed with methanesulfonyl chloride (115 mg) and TEA (270 mg) at room temperature Was stirred for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (47.2 mg).
MS: [M + H] ⁺ 453.2.

C) N-{(3R, 4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4-Fluoropiperidin-3-yl} Methanesulfonamide, or N-{(3R, 4S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl) ] -2-yl) Cyclopropan-1-carbonyl] -4-Fluoropiperidin-3-yl} Methanesulfonamide
N-{(3R, 4S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] -4 -Fluoropiperidin-3-yl} methanesulfone amide and N-{(3R, 4S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2 -Il) Cyclopropan-1-carbonyl] -4-fluoropiperidin-3-yl} Mixture of methanesulfone amide (44 mg) to SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, transfer Phase: CO ₂ / 0.1% Ammonia water-containing EtOH = 65/35 v / v), concentrate the fraction with the smaller retention time, and turn the residue into MeCN (1 mL) and water (30 mL). It was thawed and lyophilized to give the title compound (14.6 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.11-1.23 (2H, m), 1.58-2.05 (3H, m), 2.12-2.26 (1H, m), 2.63-3.24 (5H, m), 3.39 -3.81 (2H, m), 3.85-4.15 (1H, m), 4.79-5.01 (1H, m), 7.15-7.27 (4H, m), 7.29-7.55 (4H, m).

Example 226
N- {4,4-difluoro-1- [2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] pyrrolidine-3-yl } Methanesulfonamide Optical isomer

A) 1-Benzyl-4,4-difluoropyrrolidine-3-yl trifluoromethanesulfonate
A mixture of 1-benzyl-4,4-difluoropyrrolidin-3-ol (1.50 g) and DCM (50 mL) with pyridine (2.78 g) at -10 ° C, trifluoromethanesulfonic anhydride (6.95 g) and A mixture of DCM (5.0 mL) was added dropwise and stirred at the same temperature for 2 hours. The mixture was poured into water and extracted with DCM. The organic layer was washed with 5% aqueous citric acid solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (2.00 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 2.83-2.88 (1H, m), 2.9-3.01 (1H, m), 3.07-3.16 (1H, m), 3.27-3.31 (1H, m), 3.69 (2H) , s), 5.05-5.18 (1H, m), 7.27-7.39 (5H, m).

B) 4-Azido-1-benzyl-3,3-difluoropyrrolidine
Tetrabutylammonium azide (2.97 g) was added to a mixture of 1-benzyl-4,4-difluoropyrrolidine-3-yltrifluoromethanesulfonate (1.8 g) and MeCN (30 mL), and the mixture was stirred at 80 ° C. for 2 hours. .. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (1.10 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 2.59-2.64 (1H, m), 2.83-3.16 (3H, m), 3.55-3.72 (2H, m), 3.82-3.98 (1H, m), 7.27-7.37 (5H, m).

C) rac-N-[(3S) -1-benzyl-4,4-difluoropyrrolidin-3-yl] methanesulfonamide
4-Azido-1-benzyl-3,3-difluoropyrrolidine (500 mg), THF (15 mL), and water (2.0 mL) with triphenylphosphine (2.19 g, 20% purity in resin). In addition, the mixture was stirred at 70 ° C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 1-benzyl-4,4-difluoropyrrolidine-3-amine (460 mg).
To a mixture of 1-benzyl-4,4-difluoropyrrolidin-3-amine (860 mg), TEA (820 mg), and DCM (10 mL), methanesulfonyl chloride (650 mg) was added at 0 ° C. at room temperature. Stirred for 1 hour. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (1.01 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.32 (1H, t, J = 9.0 Hz), 2.58-2.70 (1H, m), 2.93 (3H, s), 3.10-3.26 (2H, m), 3.49-3.71 (2H, m), 3.90-4.12 (1H, m), 7.23-7.40 (5H, m), 7.80 (1H, d, J = 9.2 Hz).

D) rel-N-[(3R) -1-benzyl-4,4-difluoropyrrolidin-3-yl] methanesulfonamide
rac-N-[(3S) -1-benzyl-4,4-difluoropyrrolidin-3-yl] methanesulfonamide (800 mg) transferred to SFC (column: DAICEL CHIRALPAK AD, 250 mm x 30 mm, 10 μm) Phase: CO ₂ / 0.1% Ammonia water-containing EtOH = 85/15 v / v) was used for fractionation, and fractions with long retention times were concentrated. The residue was dissolved in MeCN (3.0 mL) and water (3.0 mL) and lyophilized to give the title compound (368 mg).
MS: [M + H] ⁺ 291.3.

E) N- {4,4-difluoro-1- [2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] pyrrolidine-3 -Il} methanesulfonamide Optical isomers rel-N-[(3R) -1-benzyl-4,4-difluoropyrrolidin-3-yl] methanesulfonamide (368 mg) synthesized in step D) and 12 M chloride 10% Pd / C (50 mg) was added to the mixture of hydrogen EtOH solution (5.0 mL), and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to give rel-N-[(3R) -4,4-difluoropyrrolidin-3-yl] methanesulfonamide hydrochloride (305 mg).
Rel- (1R, 2R) -2- (2', 3,6'-trifluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid synthesized in step E) of Example 195. HATU (59 mg), DIPEA (53 mg), and rel-N-[(3R) -4,4-difluoropyrrolidin-3-yl] above in a mixture of acid (30.0 mg) and DMF (2 mL). Methanesulfonamide hydrochloride (38 mg) was added, and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (23.9 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 0.09-1.10 (1H, m), 1.32-1.41 (1H, m), 1.62-1.76 (1H, m), 2.30-2.44 (1H, m), 3.06-3.15 (3H, m), 3.20-3.40 (1H, m), 3.63-4.20 (3H, m), 4.20-4.38 (1H, m), 4.85-5.00 (1H, m), 6.95-7.16 (4H, m) , 7.27-7.45 (2H, m).

Example 232
N-{(3S, 5R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -5 -Fluoropiperidin-3-yl} Methanesulfonamide

A) Dichloro, a mixture of ethyl (1R, 2R) -2- (2-bromophenyl) cyclopropane-1-carboxylate and ethyl (1S, 2S) -2- (2-bromophenyl) cyclopropane-1-carboxylate (p-Simen) Luthenium (II) (Dimer) (1.74 g), (S, S) -2,6-bis (4-isopropyl-2-oxazoline-2-yl) pyridine (1.71 g), and THF ( A mixture of 2-bromostyrene (20.0 g) and THF (100 mL) was added dropwise to a mixture of 200 mL) at 20 ° C in a nitrogen atmosphere, the mixture was heated to 55 ° C, and ethyldiazoacetate (31.2) was added thereto. A mixture of g) and toluene (200 mL) was added dropwise over 3 hours under a nitrogen atmosphere. The mixture was stirred at 55 ° C. for 14 hours. The mixture was cooled and the reaction was stopped with 10% aqueous acetic acid solution (50 mL). The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title mixture (18.6 g).
MS: [M + H] ⁺ 268.9.

B) Ethyl (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate and ethyl (1S, 2S) -2- ( 2', 6'-Difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate mixture Ethyl (1R, 2R) -2- (2-bromophenyl) cyclopropane-1-carboxylate A mixture of late and ethyl (1S, 2S) -2- (2-bromophenyl) cyclopropane-1-carboxylate (10.0 g) and DME (150 mL) with 2,6-difluorophenylboronic acid (17.6). g), Xphos Pd G3 (3.15 g), and 1 M aqueous tripotassium phosphate (112 mL) were added, and the mixture was stirred at 100 ° C. for 14 hours under a nitrogen atmosphere. Allow the mixture to cool to room temperature, add 2,6-difluorophenylboronic acid (17.6 g), Xphos Pd G3 (3.15 g), and 1 M aqueous tripotassium phosphate solution (112 mL), and add at 100 ° C. under a nitrogen atmosphere. The mixture was stirred for 14 hours. The mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and further purified by reverse phase silica gel column chromatography (C18, methanol / water) to give the title compound (7.52 g).
MS: [M + H] ⁺ 303.0.

C) Ethyl (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate Ethyl (1R, 2R) -2- (2) ', 6'-Difluoro [1,1'-biphenyl] -2-yl) Cyclopropane-1-carboxylate and ethyl (1S, 2S) -2- (2', 6'-difluoro [1,1'- Biphenyl] -2-yl) cyclopropane-1-carboxylate mixture (7.52 g), SFC (column: DAICEL CHIRALPAK IC, 250 mm x 50 mm, 10 μm, mobile phase: CO ₂ / 0.1% containing ammonia water The mixture was fractionated at IPA = 85/15 v / v), and the one with the longer retention time was obtained as the title compound (6.51 g).
MS: [M + H] ⁺ 302.9.

D) (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate ethyl (1R, 2R) -2- (2') , 6'-Difluoro [1,1'-biphenyl] -2-yl) Cyclopropane-1-carboxylate (6.51 g) and EtOH (100 mL) in a mixture of aqueous sodium hydroxide solution (8.61 g / 50 mL). Was added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, diluted with water, adjusted to pH 5-6 with 4 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title mixture (5.90 g).
MS: [MH ^] --272.9.

E) tert-butyl {(3S, 5R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl ] -5-Fluoropiperidin-3-yl} Carbamate
(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (40 mg), tert-butyl N-[(3S,,) To a mixture of 5R) -5-fluoro-3-piperidyl] carbamate (35 mg) and DMF (2 mL), add EDCI (42 mg), HOBt (20 mg), and TEA (59 mg) at room temperature. The mixture was stirred for 14 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate / petroleum ether) to give the title compound (48 mg).
MS, found: 375.0.

F) N-{(3S, 5R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -5-Fluoropiperidin-3-yl} Methanesulfonamide
tert-butyl {(3S, 5R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl]- Trifluoroacetic acid (1 mL) was added to a mixture of 5-fluoropiperidine-3-yl} carbamate (48 mg) and DCM (1 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and [(3S, 5R) -3-amino-5-fluoropiperidin-1-yl] [(1R, 2R) -2- (2', 6'-difluoro [1,1]. '-Biphenyl] -2-yl) cyclopropyl] methanone trifluoroacetate (58 mg) was obtained.
[(3S, 5R) -3-amino-5-fluoropiperidine-1-yl] [(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) To a mixture of cyclopropyl] methanone trifluoroacetic acid (58 mg) and DCM (5 mL), TEA (48 mg) and methanesulfonyl chloride (20 mg) were added at 0 ° C. and stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (33.0 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.23-1.42 (2H, m), 1.87-2.37 (3H, m), 2.40-3.04 (5H, m), 3.25-5.15 (6H, m), 6.87-7.26 (4H, m), 7.28-7.43 (3H, m).

Example 238
N-2-[(2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] octahydrocyclopenta [c] pyrrole-4-yl} methane Sulfonamide optical isomer

A) rac-tert-butyl (3aR, 4S, 6aS) -4-[(methanesulfonyl) amino] hexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate
A mixture of rac-tert-butyl (3aR, 4S, 6aS) -4-aminohexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate (500 mg) and THF (8 mL) with methanesulfonyl chloride (8 mL) 301 mg) and TEA (447 mg) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (664 mg).
MS, found: 249.0.

B) rac-N-[(3aR, 4S, 6aS) -octahydrocyclopenta [c] pyrrole-4-yl] methanesulfonamide trifluoroacetate
rac-tert-butyl (3aR, 4S, 6aS) -4-[(methanesulfonyl) amino] hexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate (664 mg) and DCM (12 mL) mixture Trifluoroacetic acid (6 mL) was added to the mixture, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to give the title compound (868 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.28-1.43 (1H, m), 1.45-1.61 (1H, m), 1.85-2.04 (2H, m), 2.54-2.63 (1H, m), 2.73 -2.86 (1H, m), 2.85-2.98 (4H, m), 3.04-3.14 (1H, m), 3.15-3.34 (2H, m), 3.39-3.58 (1H, m), 7.29 (1H, d, J = 6.8 Hz), 8.69-9.05 (2H, m).

C) rac-N-{(3aR, 4S, 6aS) -2-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane- 1-carbonyl] octahydrocyclopenta [c] pyrrol-4-yl} methanesulfonamide and rac-N-{(3aS, 4R, 6aR) -2-[(1R, 2R) -2- (2', 6) '-Difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] octahydrocyclopenta [c] pyrrol-4-yl} methanesulfonamide mixture
rac- (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carboxylic acid (43 mg), rac-N-[(3aR) , 4S, 6aS) -Octahydrocyclopenta [c] pyrrol-4-yl] methanesulfonamide Trifluoroacetic acid salt (50 mg), HATU (63 mg), and DMF (3 mL) in a mixture of DIPEA (81). mg) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (4.3 mg).
MS: [M + H] ⁺ 461.2.

D) N-2-[(2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] octahydrocyclopenta [c] pyrrole-4-yl } Methane sulfonamide optical isomer
rac-N-{(3aR, 4S, 6aS) -2-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1- Carbonyl] Octahydrocyclopenta [c] pyrrol-4-yl} methanesulfone amide and rac-N-{(3aS, 4R, 6aR) -2-[(1R, 2R) -2- (2', 6'- Difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] octahydrocyclopenta [c] pyrrol-4-yl} methanesulfone amide mixture (250 mg) in SFC (column: Phenomenex- Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO ₂ / 0.1% with aqueous ammonia EtOH = 55/45 v / v), and the first and second fractions of retention time Concentrated as a mixture. This is further separated by SFC (column: DAICEL CHIRALPAK IC, 250 mm x 30 mm, 10 μm, mobile phase: CO ₂ / 0.1% ammonia water-containing EtOH = 60/40 v / v), and the retention time is long. The fraction of the one was concentrated. The residue was dissolved in MeCN (10 mL) and water (50 mL) and lyophilized to give the title compound (36.7 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.39-1.56 (3H, m), 1.60-1.86 (2H, m), 1.99-2.13 (1H, m), 2.18-2.39 (2H, m), 2.45-2.67 (1H, m), 2.68-2.86 (1H, m), 2.87-2.98 (3H, m), 3.32 (1H, dd, J = 11.6, 4.4 Hz), 3.45-3.80 (4H, m), 4.24-4.34 (1H, m), 6.88-7.03 (2H, m), 7.12 (1H, d, J = 7.6 Hz), 7.21-7.41 (4H, m).

Example 259
N'-({(2S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] azetidine- 2-Il} Methyl) -N, N-dimethylsulfate diamide

A) tert-butyl (S) -2-(((N, N-dimethylsulfamoyl) amino) methyl) azetidine-1-carboxylate
(S) -2-Aminomethyl-1-Boc-Azetidine (509 mg), DMAP (66.8 mg), TEA (1.14 mL) and THF (12 mL) in a mixture with N, N-dimethylsulfamoyl chloride ( 0.440 mL) was added at 0 ° C., and the mixture was stirred overnight at room temperature. The reaction was stopped by adding saturated aqueous sodium hydrogen carbonate solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (498 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.37 (9 H, s), 1.94 --2.25 (2 H, m), 2.60 --2.74 (6 H, m), 3.08 (1 H, dt, J = 13.3, 6.7 Hz), 3.24 (1 H, ddd, J = 13.3, 6.3, 4.1 Hz), 3.58 --3.80 (2 H, m), 4.09 --4.23 (1 H, m), 7.19 --7.34 (1 H,) m).

B) N'-({(2S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] Azetidine-2-yl} methyl) -N, N-dimethylsulfate diamide
A mixture of tert-butyl (S) -2-(((N, N-dimethylsulfamoyl) amino) methyl) azetidine-1-carboxylate (104 mg) and trifluoroacetic acid (0.500 mL) at room temperature 1 Stir for hours. The mixture was concentrated under reduced pressure and azeotroped with toluene. The resulting residue (67.6 mg), (1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (106 mg), A mixture of HATU (160 mg), TEA (0.146 mL), and DMF (2 mL) was stirred overnight at room temperature. The reaction was stopped by adding water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (140 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 1.07-1.17 (1H, m), 1.21-1.31 (1H, m), 1.47-1.60 (1H, m), 1.72-1.80 (1H, m), 2.01 -2.33 (2H, m), 2.61-2.66 (6H, m), 3.01-3.28 (2H, m), 3.56-3.74 (1H, m), 3.79-3.91 (1H, m), 4.04-4.18 (1H, m) m), 7.12-7.61 (8H, m).

Example 262
N-{(3S, 5S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -5 -Methylpyrrolidine-3-yl} methanesulfonamide

A) N-[(3S, 5S) -5-methylpyrrolidine-3-yl] methanesulfonamide trifluoroacetate
Methanesulfonyl chloride (43 mg) in a mixture of tert-butyl (2S, 4S) -4-amino-2-methylpyrrolidine-1-carboxylate (50 mg), TEA (51 mg) and DCM (5 mL). The mixture was added at 0 ° C. and stirred at room temperature for 2 hours. The mixture was poured into ice water and extracted with DCM. The organic layer is washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and tert-butyl (2S, 4S) -4-[(methanesulfonyl) amino] -2-methylpyrrolidine-1-carboxylate. (83 mg) was obtained.
Add trifluoroacetic acid (1 mL) to a mixture of tert-butyl (2S, 4S) -4-[(methanesulfonyl) amino] -2-methylpyrrolidine-1-carboxylate (83 mg) and DCM (3 mL). In addition, the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (93 mg).
MS: [M + H] ⁺ 179.1.

B) N-{(3S, 5S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -5-Methylpyrrolidine-3-yl} Methanesulfonamide
N-[(3S, 5S) -5-Methylpyrrolidin-3-yl] Methanesulfonamide Trifluoroacetic acid salt (93 mg), (1R, 2R) -2- (2', 6'-difluoro [1,1] Add EDCI (73 mg), HOBt (52 mg), and TEA (129 mg) to a mixture of'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (87 mg) and DMF (5 mL). , Stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (34.2 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.10-1.27 (3H, m), 1.29-1.56 (3H, m), 1.88-1.95 (1H, m), 2.00-2.17 (1H, m), 2.32-2.48 (1H, m), 2.99 (3H, s), 3.33-3.45 (1H, m), 3.61-3.82 (1H, m), 3.95-4.24 (2H, m), 4.42-4.60 (1H, m), 6.92 -7.26 (4H, m), 7.27-7.42 (3H, m).

Example 264
N-{(3S, 4R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4 -Methylpyrrolidine-3-yl} methanesulfonamide

A) N-[(3S, 4R) -4-methylpyrrolidine-3-yl] methanesulfonamide trifluoroacetate
Methanesulfonyl chloride (51 mg) in a mixture of tert-butyl (3S, 4R) -3-amino-4-methylpyrrolidine-1-carboxylate (60 mg), TEA (61 mg) and DCM (5 mL). The mixture was added at 0 ° C. and stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and tert-butyl (3S, 4R) -3-[(methanesulfonyl) amino] -4-methylpyrrolidin-1-carboxylate. (67 mg) was obtained.
Add trifluoroacetic acid (1 mL) to a mixture of tert-butyl (3S, 4R) -3-[(methanesulfonyl) amino] -4-methylpyrrolidine-1-carboxylate (67 mg) and DCM (3 mL). In addition, the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (97 mg).
MS: [M + H] ⁺ 179.1.

B) N-{(3S, 4R) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -4-Methylpyrrolidine-3-yl} Methanesulfonamide
N-[(3S, 4R) -4-Methylpyrrolidin-3-yl] Methanesulfonamide Trifluoroacetic acid salt (97 mg), (1R, 2R) -2- (2', 6'-difluoro [1,1] Add EDCI (76 mg), HOBt (54 mg), and TEA (134 mg) to a mixture of'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (91 mg) and DMF (5 mL). , Stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (20.2 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.10-1.16 (3H, m), 1.24-1.30 (1H, m), 1.43-1.52 (1H, m), 1.61-1.71 (1H, m), 1.93-2.43 (2H, m), 2.84-3.33 (5H, m), 3.41-3.61 (1H, m), 3.66-3.79 (1H, m), 3.83-3.92 (1H, m), 4.45-4.63 (1H, m) , 6.92-7.26 (4H, m), 7.29-7.41 (3H, m).

Example 294
N-{(6S) -4-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -1,4 -Oxazepan-6-yl} ethane sulfonamide, or N-{(6R) -4-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl ) Cyclopropane-1-carbonyl] -1,4-oxazepan-6-yl} ethane sulfonamide

A) tert-Butyl 6- (ethyl sulfonamide) -1,4-oxazepan-4-carboxylate
A mixture of 4-Boc-6-amino-1,4-oxazepan (454 mg), DMAP (51.3 mg), TEA (0.878 mL) and THF (7 mL) with ethanesulfonyl chloride (0.298 mL) at 0 ° C. In addition, the mixture was stirred at room temperature for 2 hours. The reaction was stopped by adding saturated aqueous sodium hydrogen carbonate solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (501 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.13-1.25 (3H, m), 1.41 (9H, s), 2.91-3.26 (4H, m), 3.48-3.84 (7H, m), 7.22 (1H) , br s).

B) N- (1,4-oxazepan-6-yl) ethane sulfonamide hydrochloride
To a mixture of tert-butyl 6- (ethyl sulfonamide) -1,4-oxazepan-4-carboxylate (267 mg) and ethyl acetate (2 mL), add 2 M hydrogen chloride CPME solution (4 mL) and room temperature. Stirred overnight. The resulting solid was collected by filtration to give the title compound (186 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.20 (3H, t, J = 7.3 Hz), 3.07-3.30 (5H, m), 3.35 (1H, d, J = 3.8 Hz), 3.50-3.64 ( 1H, m), 3.79-3.95 (4H, m), 7.47 (1H, d, J = 7.9 Hz), 9.46 (2H, br s).

C) N-{(6S) -4-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -1 , 4-Oxazepan-6-yl} ethane sulfonamide, or N-{(6R) -4-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2 -Il) Cyclopropane-1-carbonyl] -1,4-Oxazepan-6-yl} Etan sulfonamide
(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropan-1-carboxylic acid (166 mg), N- (1,4-oxazepan- HATU (261 mg) was added to a mixture of 6-yl) ethanesulfonamide hydrochloride (140 mg), TEA (0.319 mL) and DMF (2 mL) at 0 ° C and stirred at the same temperature for 3 hours. The reaction was stopped by adding water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (NH, ethyl acetate / hexane) and preparative HPLC (column: DAICEL CHIRALPAK IC, 250 mm x 20 mm, 5 μm, mobile phase: hexane / ethanol / diethylamine = 700/300 / The mixture was fractionated by 1 v / v / v), and the one having the smaller retention time was obtained as the title compound (94.1 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93-1.42 (5H, m), 1.89-2.40 (2H, m), 2.73-3.09 (2H, m), 3.40-3.74 (8H, m), 3.77-4.23 (2H, m), 6.84-7.70 (7H, m).

Example 304
N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carbonyl] Pyrrolidine-3-yl} methanesulfone amide, or N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl)) -2-Fluorocyclopropane-1-carbonyl] pyrrolidine-3-yl} methanesulfone amide

A) 2,6-difluoro-2'-(1-fluoroethenyl) -1,1'-biphenyl
Xphos Pd in a mixture of 1-bromo-2- (1-fluoroethenyl) benzene (16.2 g), 2,6-difluorophenylboronic acid (63.6 g), DME (150 mL), and water (50 mL). G3 (6.82 g) and tripotassium phosphate (51.3 g) were added, and the mixture was stirred at 100 ° C. for 16 hours. The mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (4.60 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 4.37-4.81 (2H, m), 6.94-7.01 (2H, m), 7.30-7.36 (2H, m), 7.45-7.51 (2H, m), 7.58-7.70 (1H, m).

B) rac-ethyl (1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carboxylate
Add rhodium (II) acetate (dimer) (353 mg) to a mixture of 2,6-difluoro-2'-(1-fluoroethenyl) -1,1'-biphenyl (7.50 g) and DCE (100 mL). In addition, a mixture of ethyl diazoacetate (10.9 g) and DCE (100 mL) was added dropwise at 70 ° C. over 6 hours. At the same temperature, the mixture was stirred for 6 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a crude product. This was further purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), the fraction with the smaller retention time was concentrated and lyophilized to give the title compound (1.60 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.22 (3H, t, J = 7.2 Hz), 1.38-1.50 (1H, m), 1.87-1.99 (1H, m), 2.01-2.13 (1H, m), 3.93-4.21 (2H, m), 6.92-7.04 (2H, m), 7.29-7.64 (5H, m).

C) rel- (1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carboxylic acid
rac-ethyl (1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carboxylate (800 mg), SFC (Column: DAICEL CHIRALPAK IC, 250 mm x 30 mm, 10 μm, Mobile phase: CO ₂ / 0.1% Ammonia water-containing EtOH = 80/20 v / v) It was obtained as ethyl (1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carboxylate (370 mg).
The above rel-ethyl (1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carboxylate (370 mg), Sodium hydroxide (462 mg) was added to a mixture of MeOH (2 mL), THF (2 mL), and water (2 mL) and stirred at room temperature for 12 hours. The mixture was diluted with water, adjusted to pH 5-6 with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title mixture (330 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.44-1.56 (1H, m), 1.58-1.72 (1H, m), 2.00-2.11 (1H, m), 7.17 (2H, t, J = 8.4 Hz), 7.35-7.42 (1H, m), 7.46-7.69 (4H, m), 12.2 (1H, brs).

D) N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1- Carbonyl] pyrrolidine-3-yl} methanesulfonamide, or N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2- Il) -2-fluorocyclopropane-1-carbonyl] pyrrolidine-3-yl} methanesulfonamide rel- (1S, 2S) -2- (2', 6'-difluoro [1,1] synthesized in step C) '-Biphenyl] -2-yl) -2-fluorocyclopropane-1-carboxylic acid (50 mg), (S) -N- (pyrrolidin-3-yl) methanesulfonamide hydrochloride (38 mg), and pyridine To (2 mL) of the mixture was added EDCI (49 mg) and stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (36 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.13-1.30 (1H, m), 1.83-2.34 (4H, m), 2.88-3.02 (3H, m), 3.49-4.14 (5H, m), 4.74-5.83 (1H, m), 6.85-7.07 (2H, m), 7.26-7.43 (4H, m), 7.45-7.50 (1H, m).

Example 306
N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carbonyl] Piperidine-3-yl} methanesulfonamide, or N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl)) -2-Fluorocyclopropan-1-carbonyl] piperidin-3-yl} methanesulfonamide rel- (1S, 2S) -2- (2', 6'-difluoro [1', 6'-difluoro] synthesized in step C) of Example 304 , 1'-biphenyl] -2-yl) -2-fluorocyclopropane-1-carboxylic acid (50.0 mg), (S) -N- (piperidine-3-yl) methanesulfonamide hydrochloride (38.5 mg), EDCI (65.6 mg) was added to the mixture of pyridine (3 mL) and pyridine, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (28.8 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.20-1.32 (1H, m), 1.60-1.73 (2H, m), 1.78-2.10 (3H, m), 2.23-2.67 (1H, m), 2.75-3.04 (3H, m), 3.30-4.11 (5H, m), 4.47 (1H, br d, J = 7.2 Hz), 6.90-7.04 (2H, m), 7.30-7.64 (5H, m).

Example 318
N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] Pyrrolidine-3-yl} methanesulfone amide, or N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl]- 2-yl) cyclopropan-1-carbonyl] pyrrolidine-3-yl} methanesulfone amide

A) 60% NaH (60% NaH) in a mixture of ethyl (2E) -3- (2-bromo-4-methylphenyl) propa-2-enoate ethyl 2-diethoxyphosphoryl acetate (7.32 g) and THF (50 mL). 1.21 g) was added at 0 ° C. After stirring at room temperature for 30 minutes, 2-bromo-4-methylbenzaldehyde (5.00 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. 60% NaH (400 mg) was added to a mixture of ethyl 2-diethoxyphosphoryl acetate (7.32 g) and THF (50 mL), and the reaction mixture was added to the mixture. After further stirring at room temperature for 12 hours, water was added at 0 ° C. to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (6.50 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.6 Hz), 2.34 (3H, s), 4.19-4.37 (2H, q, J = 7.2 Hz), 6.35 (1H, d, J = 16.0 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.37-7.60 (2H, m), 8.02 (1H, d, J = 16.0 Hz).

B) rac-ethyl (1R, 2R) -2- (2-bromo-4-methylphenyl) cyclopropane-1-carboxylate
To a mixture of 60% NaH (1.06 g) and DMSO (50 mL), trimethyl sulfoxide (7.97 g) was added at 0 ° C, stirred at room temperature for 30 minutes, and then ethyl (2E) -3- (2). A mixture of -bromo-4-methylphenyl) propa-2-enoate (6.50 g) and DMSO (40 mL) was added dropwise, and the mixture was further stirred at the same temperature for 14 hours. Water was added at 0 ° C. to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (2.14 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.27-1.32 (4H, m), 1.59-1.63 (1H, m), 1.68-1.83 (1H, m), 2.29 (3H, s), 2.58-5.73 (1H) , m), 4.13-4.27 (2H, m), 6.89 (1H, d, J = 8.0 Hz), 7.02 (1H, d, J = 8.0 Hz), 7.39 (1H, s).

C) rac-ethyl (1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylate
2,6-Difluorophenylboronic acid in a mixture of rac-ethyl (1R, 2R) -2- (2-bromo-4-methylphenyl) cyclopropane-1-carboxylate (500 mg) and DME (15 mL) (1.39 g), tripotassium phosphate aqueous solution (5.30 mL) and Xphos Pd G3 (150 mg) were added, and the mixture was stirred at 100 ° C. for 14 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (461 mg).
MS: [M + H] ⁺ 317.0.

D) rac- (1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2-yl) cyclopropan-1-carboxylic acid sodium hydroxide (132 mg) ), EtOH (4 mL), and water (3 mL) in a mixture of rac-ethyl (1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl]- A mixture of 2-yl) cyclopropane-1-carboxylate (87 mg) and EtOH (3 mL) was added and stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with DCM. The aqueous layer was adjusted to pH 3-4 with 1 M hydrochloric acid and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (85 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.12-1.19 (1H, m), 1.25-1.33 (1H, m), 1.53-1.60 (1H, m), 1.95-2.04 (1H, m), 2.30 (3H, s), 6.92-7.28 (5H, m), 7.40-7.54 (1H, m), 12.05 (1H, br s).

E) N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2-yl) cyclopropane-1- Carbonyl] pyrrolidine-3-yl} methanesulfone amide and N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl]] -2-yl) Cyclopropan-1-carbonyl] Pyrrolidine-3-yl} Methane sulfone amide mixture
rac- (1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (28 mg) and DMF (1) To the mixture of mL) was added (S) -N- (pyrrolidin-3-yl) methanesulfonamide hydrochloride (18 mg), HATU (38 mg), and DIPEA (47 mg), and the mixture was stirred at room temperature for 14 hours. .. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (16 mg).
MS: [M ⁺ H] +435.2.

F) N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2-yl) cyclopropane-1- Carbonyl] pyrrolidine-3-yl} methanesulfone amide, or N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] ] -2-yl) Cyclopropane-1-carbonyl] Pyrrolidine-3-yl} Methanesulfonamide
N-{(3S) -1-[(1R, 2R) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2-yl) cyclopropan-1-carbonyl] Pyrrolidine-3-yl} Methane sulfone amide and N-{(3S) -1-[(1S, 2S) -2- (2', 6'-difluoro-5-methyl [1,1'-biphenyl] -2 -Il) Cyclopropane-1-carbonyl] Pyrrolidine-3-yl} Methane sulfone amide mixture (16 mg) with SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO ₂ Separation was performed with MeOH = 60/40 v / v) containing /0.1% aqueous ammonia, and the fraction with the smaller retention time was concentrated. The residue was dissolved in MeCN (3 mL) and water (30 mL) and lyophilized to give the title compound (5.2 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.26-1.34 (1H, m), 1.39-1.50 (1H, m), 1.63-1.70 (1H, m), 1.76-2.10 (1H, m), 2.13-2.29 (1H, m), 2.29-2.39 (4H, m), 3.00 (3H, s), 3.27-3.81 (4H, m), 3.94-4.12 (1H, m), 4.42 (1H, s), 6.92-7.05 (3H, m), 7.07 (1H, s), 7.18 (1H, d, J = 7.8 Hz), 7.27-7.39 (1H, m).

Example 319
N-{(3S, 5S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -5 -Hydroxypiperidine-3-yl} methanesulfonamide

A) tert-butyl (3S, 5S) -3-hydroxy-5-[(methanesulfonyl) amino] piperidine-1-carboxylate
A mixture of tert-butyl (3S, 5S) -3-amino-5-hydroxypiperidine-1-carboxylate (50 mg) and DCM (3 mL) with TEA (35 mg) and methanesulfonyl chloride (32 mg). The mixture was added at 0 ° C. and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (54 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.47 (9H, s), 1.77-2.08 (2H, m), 2.93-3.11 (4H, m), 3.28-3.57 (2H, m), 3.75-3.85 (1H) , m), 3.95-4.10 (1H, m), 4.25-4.44 (1H, m).

B) N-{(3S, 5S) -1-[(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carbonyl] -5-Hydroxypiperidine-3-yl} Methanesulfonamide
Add trifluoroacetic acid (2 mL) to a mixture of tert-butyl (3S, 5S) -3-hydroxy-5-[(methanesulfonyl) amino] piperidine-1-carboxylate (47 mg) and DCM (6 mL). In addition, the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give N-[(3S, 5S) -5-hydroxypiperidine-3-yl] methanesulfonamide trifluoroacetate (75 mg).
(1R, 2R) -2- (2', 6'-difluoro [1,1'-biphenyl] -2-yl) cyclopropane-1-carboxylic acid (50 mg), N-[(3S, 5S)- HOBt (25 mg), EDCI (52 mg), and TEA (74 mg) in a mixture of 5-hydroxypiperidin-3-yl] methanesulfonamide trifluoroacetic acid salt (67 mg) and DMF (2 mL). In addition, it was stirred at room temperature for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (27 mg).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 1.20-1.50 (2H, m), 1.79-2.50 (5H, m), 2.75-3.00 (3H, m), 3.33-3.65 (3H, m), 3.67-4.05 (3H, m), 4.58-5.15 (1H, m), 6.91-7.24 (4H, m), 7.26-7.44 (3H, m).

The example compounds are shown in the table below. MS in the table shows the measured value. Examples 1-12, 14-22, 26-132, 134-138, 140-194, 196-199, 201-214 in the following table according to the methods shown in the above Examples or similar methods. , 217-225, 227-230, 233-237, 239-258, 260, 261, 263, 265-293, 295-303, 305, 307-317, 320.

Test Example 1: Acquisition of Stable Expression of Human Orexin Type 2 Receptor (hOX2R) In order to obtain a cell clone that stably expresses the human orexin type 2 receptor, human orexin type 2 was added to the pcDNA3.1 (+) plasmid vector (Invitrogen). The receptor cDNA was inserted and the plasmid DNA for expressing the human orexin type 2 receptor (pcDNA3.1 (+) / hOX2R) was cloned. This plasmid DNA was introduced into CHO-K1 cells by the electroporation method, and human orexin type 2 receptor-expressing cloned cells were obtained by the limiting dilution method using G418 drug resistance as a selectable marker.

Test Example 2: Measurement of orexin type 2 receptor agonist activity
CHO cells forcibly expressing the human OX2 receptor were seeded on a 384-well black transparent bottom plate (BD Falcon) at 10,000 cells / well and cultured at 37 ° C. in a 5% CO ₂ incubator for one day. After removing the cell plate medium, assay buffer containing calcium indicator A (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4 AM ( Dojin Kagaku), 0.08% Pluronic F127 (Dojin Kagaku), 1.25 mM probenecid (Dojin Kagaku)) was added at 30 μL / well. After allowing to stand in a 5% CO ₂ incubator at 37 ° C for 30 minutes, it was allowed to stand at room temperature for another 30 minutes. Add 10 μL / well of the test compound diluted with Assay Buffer B (HBSS, 20 mM HEPES, 0.1% BSA), and use FDSS μCELL (Hamamatsu Photonics) to set the fluorescence value every 1 second for 1 minute, and then every 2 seconds. It was measured for 1 minute and 40 seconds. The amount of change in fluorescence value when DMSO is added instead of the test compound is defined as 0%, and the amount of change in fluorescence when orexin A (human) (Peptide Institute) with a final concentration of 10 nM is defined as 100%. The activity (%) of the test compound was calculated. Table 2 shows the activity of each compound at a concentration of 3 μM. As is clear from this result, the compound of the present invention was shown to have orexin type 2 receptor activating activity.

Pharmaceutical example 1 (manufacturing of capsule)
1) Compound 30 mg of Example 1
2) Fine powdered cellulose 10mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60mg in total
1), 2), 3) and 4) are mixed and filled in gelatin capsules.

Pharmaceutical example 2 (manufacturing of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50g
3) Corn starch 15g
4) Carboxymethyl cellulose calcium 44g
5) Magnesium stearate 1 g
1000 tablets total 140g
1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sizing powder and locked with a locking machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

The compound of the present invention has orexin type 2 receptor activating activity and is useful as a prophylactic or therapeutic agent for narcolepsy.

Claims (4)

formula:

[During the ceremony,
Ring W is a ring that may be further substituted;
Ring X is a 5- or 6-membered aromatic ring that may be further substituted;
Ring Y contains cyclopropyl which may be further substituted;
Ring Z is a nitrogen-containing heterocycle that may be further substituted;
L is a bond, or methylene that may be substituted;
R indicates a C _1-6 alkyl which may be substituted, a C _3-10 cycloalkyl which may be substituted, or a di C _1-6 alkyl amine which may be substituted. ]
A compound represented by or a salt thereof. A pharmaceutical substance containing the compound according to claim 1 or a salt thereof. The pharmaceutical product according to claim 2, which is an orexin type 2 receptor agonist. The medicine according to claim 2, which is a prophylactic or therapeutic agent for narcolepsy.