JP4943826B2 - Pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition comprising a novel pyrrolidine derivative having an excellent central cannabinoid (CB1) receptor antagonistic activity or a pharmacologically acceptable salt thereof as an active ingredient.

  It is well known that cannabis can cause various neuropsychiatric reactions such as confusion in time and space, euphoria, memory impairment, decreased pain, and hallucinations. Many of these actions are due to compounds collectively referred to as cannabinoids, including delta 9-tetrahydrocannabinol (delta 9-THC). The effects of cannabinoids are thought to be due to interactions with specific high affinity receptors present in the body. So far, two cannabinoid receptors (CB1 receptor, CB2 receptor) have been identified and cloned, and CB1 receptors are distributed in the central nervous system (CNS) such as the brain (Non-patent Document 1). Receptors are distributed in immune tissues such as the spleen (Non-patent Document 2).

Substances having an affinity for these cannabinoid receptors (agonists, antagonists, and inverse agonists) exhibit various pharmacological actions like cannabis, and in particular, substances having an affinity for the central CB1 receptor are It is useful for the treatment of CNS diseases such as psychological disorders and neurological disorders.
Examples of substances having affinity for the CB1 receptor include 4,5-dihydro-1H-pyrazole derivatives described in Patent Documents 1 to 3, 1H-imidazole derivatives described in Patent Documents 4 to 7, and Patent Documents 8 and 9. Pyrazine derivatives, 1H-pyrazole derivatives described in Patent Documents 10 and 11, pyridine derivatives described in Patent Documents 12 to 14, azetidine derivatives described in Patent Documents 15 and 16, arylamide derivatives described in Patent Documents 17 and 18, and Patent Document 19 described 1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine derivatives, pyrrole derivatives described in Patent Document 20, 1,2,4-triazole derivatives described in Patent Document 21, and the like are known.

  On the other hand, in Patent Document 22, a specific pyrrolidine derivative 4-amino-5-chloro-2-methoxy-N- [1- (diphenylmethyl) -5-hydroxymethylpyrrolidin-3-yl] benzamide is present in the stomach of a mouse. Although it is described to promote excretion ability, there is no description regarding antagonism to the CB1 receptor.

WO01 / 70700 WO03 / 026648 WO03 / 026647 WO03 / 027076 WO03 / 007887 WO03 / 063781 WO03 / 040107 WO03 / 051850 WO03 / 051851 US5624941 US6509367 WO03 / 084930 WO03 / 084943 WO03 / 082191 WO01 / 64632 WO03 / 020314 WO03 / 087027 WO03 / 082190 WO03 / 027114 WO03 / 027069 WO03 / 082833 JP-A-5-17434 Nature, 346, 561-564, 1990 Nature, 365, 61-65, 1993

  The object of the present invention is to provide a pharmaceutical composition comprising a novel pyrrolidine derivative having an excellent CB1 receptor antagonistic action as an active ingredient.

  The present invention relates to general formula [I]:

[Where:
R ¹ and R ² are
(A) Independently
(1) a halogen atom,
(2) a cyano group,
(3) an alkyl group which may be substituted with 1 to 3 identical or different groups selected from a halogen atom and an alkyloxy group;
(4) an alkyloxy group which may be substituted with the same or different 1 to 3 groups selected from a halogen atom, a cycloalkyl group, an alkyloxy group, a mono- or dialkylamino group, a pyrrolidinyl group and a morpholino group;
(5) an amino group optionally substituted with a group selected from an alkyl group, an alkyloxyalkyl group, a cycloalkyl group, and a mono- or dialkylaminoalkyl group,
(6) a carbamoyloxy group optionally substituted by 1 or 2 alkyl groups,
(7) an alkylsulfonyl group,
(8) a cycloalkyloxy group,
(9) a carbamoyl group optionally substituted by 1 or 2 alkyl groups,
(10) a nitro group,
(11) an alkylthio group,
(12) an aminosulfonyl group which may be substituted with one or two alkyl groups,
(13) an alkylsulfinyl group,
(14) an alkyleneoxy group, and (15) an aryl (or heteroaryl) group optionally substituted with 1 to 3 identical or different groups selected from the group consisting of alkylenedioxy groups, or (B) each other Together with adjacent CH groups, the formula:

A cyclic group represented by
One of R ³ and R ⁴ is a hydrogen atom, and the other is a hydrogen atom, a hydroxyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, a carboxyl group, an alkyloxycarbonyl A group, a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group, a carbamoyl group or a mono- or dialkylcarbamoyl group (the alkyl part of the group is a halogen atom, a hydroxyl group, a mono- or dialkylamino group and a saturated or An unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group, which may be substituted with a group selected from these groups, or an oxo group together.
R ⁵ represents a hydrogen atom or an alkyl group,
Y is a single bond, an oxygen atom or a group represented by the formula: —N (R ⁷ ) —
R ⁶ is (1) a linear or branched hydrocarbon group which may have a substituent (the hydrocarbon group may contain one or more double or triple bonds in the molecule); Or (2) a cyclic group which may have a substituent (the cyclic group may contain one or more hetero atoms selected from a sulfur atom, an oxygen atom and a nitrogen atom),
R ⁷ represents an alkyl group or an alkyloxycarbonylalkyl group. However, when Y is a single bond and one of R ³ and R ⁴ is a hydrogen atom and the other is a hydroxymethyl group, R ⁶ is a 4-amino-5-chloro-2-methoxyphenyl group. There is no. ]
Or a pharmacologically acceptable salt thereof as an active ingredient.

  Since the compound [I] or a pharmacologically acceptable salt thereof has an excellent antagonistic action on the CB1 receptor, the pharmaceutical composition of the present invention can be used for various diseases involving the receptor (for example, It is useful for the prevention and treatment of psychiatric disorders including schizophrenia and appetite disorders (eg, bulimia, anorexia). In addition, the compound [I] of the present invention is useful for chronic treatment and withdrawal from alcohol or drug abuse (for example, opioids). Furthermore, the pharmaceutical composition of the present invention is useful as an analgesic activity enhancer or a smoking cessation aid. In addition, the compound [I] of the present invention or a pharmacologically acceptable salt thereof has a feature of low toxicity and high safety as a medicine.

In the compound [I] which is the active ingredient of the present invention, specific examples of the aryl group in R ¹ and R ² include a 5-6 membered aryl group such as a phenyl group. Specific examples of the heteroaryl group As at least one heteroatom selected from sulfur atom, oxygen atom and nitrogen atom such as thienyl group, pyridyl group, pyrimidinyl, pyrazinyl group, thiazolyl group, benzofuryl group, benzimidazolyl group, quinolyl group, benzothiazolyl group, etc. And a 5- to 10-membered heteroaryl group having The aryl (or heteroaryl) group may be substituted with the same or different 1 to 3 groups selected from (1) a halogen atom, (2) a cyano group, (3) a halogen atom and an alkyloxy group. Alkyl group, (4) alkyloxy group optionally substituted by 1 to 3 same or different groups selected from halogen atom, cycloalkyl group, alkyloxy group, mono- or dialkylamino group, pyrrolidinyl group and morpholino group (5) an amino group which may be substituted with a group selected from an alkyl group, an alkyloxyalkyl group, a cycloalkyl group and a mono- or dialkylaminoalkyl group, (6) substituted with 1 or 2 alkyl groups Carbamoyloxy group, (7) alkylsulfonyl group, (8) cycloalkyl group (9) a carbamoyl group optionally substituted with 1 or 2 alkyl groups, (10) a nitro group, (11) an alkylthio group, (12) substituted with 1 or 2 alkyl groups May be substituted with 1 to 3 identical or different groups selected from the group consisting of an aminosulfonyl group, (13) alkylsulfinyl group, (14) alkyleneoxy group, and (15) alkylenedioxy group. .

Examples of the saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group in R ³ and R ⁴ include heterocyclic groups such as a pyrrolidinyl group, a morpholinyl group, and a pyridyl group. Of these, a saturated or unsaturated 5- to 6-membered nitrogen-containing heterocyclic group is preferred.

When R ⁶ is an optionally substituted linear or branched hydrocarbon group, such a hydrocarbon group includes a C _1-12 linear or branched hydrocarbon group. More specifically, (1) a C _1-12 linear or branched alkyl group which may have a substituent, and (2) a C which may have a substituent. _Examples thereof include a _2-12 linear or branched alkenyl group or (3) a C _2-12 linear or branched alkynyl group which may have a substituent.

When R ⁶ is a linear or branched hydrocarbon group having a substituent, examples of such a hydrocarbon group include the following (1) to (15):
(1) a cycloalkyl group optionally condensed with a benzene ring,
(2) amino group (the amino group is an alkyl group, an alkyloxycarbonyl group, an alkylcarbonyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, a morpholinocarbonyl group, a mono- or dialkylcarbamoyl group, a mono- or dialkylaminosulfonyl group, Optionally substituted with the same or different 1 to 2 groups selected from a halogenoalkylcarbonyl group and an alkyloxycarbonylcarbamoyl group),
(3) Aryl (or biaryl) group (the group is a halogen atom, a hydroxyl group, an alkyl group, an alkyloxy group, a trihalogenoalkyl group, a trihalogenoalkyloxy group, an alkyloxyalkyloxy group, a morpholinoalkyloxy group, an alkyloxycarbonyl group) Group, a mono- or dialkylamino group and an alkyloxycarbonylamino group which may be substituted with the same or different 1 to 3 groups),
(4) Saturated or unsaturated 3- to 14-membered, sulfur-containing, oxygen-containing or nitrogen-containing heterocyclic group (the heterocyclic group is a halogen atom, oxo group, alkyl group, alkyloxycarbonyl group, aryl Optionally substituted with the same or different 1 to 3 groups selected from alkyloxycarbonyl group, trihalogenoalkyl group, alkylthio group and aryl group),
(5) hydroxyl group,
(6) an alkyloxy group (the alkyl part of the group may be substituted with the same or different 1 to 3 groups selected from alkyloxy and aryl groups),
(7) an alkenyloxy group,
(8) Aryloxy group (the aryl part of the group may be condensed with a cycloalkyl ring and substituted with 1 to 3 identical or different groups selected from a halogen atom, an alkyl group and a trihalogenoalkyloxy group) May be)
(9) Formula: _a group represented by —SR _a (wherein, R _a represents an aryl group, an arylalkyl group, or a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group) ,
(10) an alkyloxycarbonyl group,
(11) an arylalkyloxycarbonyl group,
(12) a cycloalkylcarbonyl group,
(13) an arylcarbonyl group (the aryl part of the group may be substituted with 1 to 3 identical or different groups selected from a halogen atom and a trihalogenoalkyl group),
(14) an arylsulfonyl group, and (15) a hydrocarbon group substituted with 1 to 3 identical or different groups selected from the group consisting of halogen atoms.

In the above, when R ⁶ is a linear or branched hydrocarbon group substituted with a saturated or unsaturated 3- to 14-membered sulfur-containing, oxygen-containing or nitrogen-containing heterocyclic group, the heterocyclic ring Specific examples of the formula group include, for example, the formula:

And a heterocyclic group selected from the groups represented by the above (the heterocyclic group may be further partially hydrogenated).

When R ⁶ is an optionally substituted cyclic group, examples of the cyclic group include (1) 6 to 14-membered monocyclic, bicyclic or tricyclic aryl groups, (2) a C _3-10 monocyclo, bicyclo or tricycloalkyl group (the cycloalkyl group may be condensed with a benzene ring), and (3) a saturated or unsaturated 3 to 14 membered, sulfur-containing, Examples thereof include a cyclic group selected from the group consisting of oxygen-containing or nitrogen-containing heterocyclic groups (which may be spiro-bonded to a cycloalkyl ring).

When the cyclic group represented by R ⁶ is an aryl group, examples of the aryl group include a phenyl group, a naphthyl group, a fluorenyl group, and the like.

When the cyclic group represented by R ⁶ is a monocyclo, bicyclo or tricycloalkyl group, the cycloalkyl group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tricyclo [2.2 .1.0] heptyl group and the like.

Further, when the cyclic group represented by R ⁶ is a heterocyclic group, examples of the heterocyclic group include (1) pyrrolyl group, imidazolyl group, pyrazolyl group, pyrrolidinyl group, pyrrolinyl group, 3H— Pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, thiazolidinyl group, piperidyl group, piperazinyl group, azetidinyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, thienyl group, thiyl group , Furyl group, pyranyl group and morpholinyl group, (1) 1H-indazolyl group, indolizinyl group, indolyl group, 3H-indolyl group, isoindolyl group, indolinyl group, isoindolinyl group, purinyl group , Kinori Group, tetrahydroquinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, pyrazolopyrimidinyl group, chromanyl group, isochromanyl group, chromenyl group, benzoyl group Triazolyl group, 2H-benzotriazolyl group, benzofuranyl group, dihydrobenzofuranyl group, isobenzofuranyl group, phthalimide group, benzothienyl group, benzoxazolyl group, benzoisoxazolyl group, benzoxa Dinyl group, benzimidazolyl group, furopyridyl group and formula:

(3) Furonaphtyl group, dihydrofuronaphthyl group, carbazolyl group, β-carbolinyl group and formula:

And a saturated or unsaturated heterocyclic group selected from (4) oxaspirodecyl group, and part of the heterocyclic group is further hydrogenated. It may be made.

  Among the above, preferred heterocyclic groups include, for example, the formula:

(The heterocyclic group may be partly further hydrogenated).

When R ⁶ is a substituted cyclic group, the cyclic group includes
(1) a halogen atom,
(2) an oxo group,
(3) Nitro group,
(4) a cyano group,
(5) an alkyl group (the alkyl group is a saturated or unsaturated 4- to 10-membered group which may be substituted with a halogen atom, an arylcarbonyl group, a mono-, di- or trihalogenoarylcarbonyl group, an aryl group, a hydroxyl group or an oxo group) A nitrogen-containing (or oxygen-containing) heterocyclic group, an alkyloxy group and an imino group may be substituted with the same or different 1 to 3 groups),
(6) Aminoalkyl group (the amino part of the group is the same or different one or two selected from alkyloxycarbonyl group, arylcarbonyl group, arylalkyloxycarbonyl group, alkyl group, alkyloxyalkyl group and cycloalkyl group) May be substituted with a group of
(7) a cycloalkyl group,
(8) an alkyloxycarbonylalkenyl group,
(9) Amino group (the amino group is substituted with one or two identical or different groups selected from an alkyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group, an alkyloxyalkyl group, and a halogenoalkylcarbonyl group. You may)
(10) an aryl group (the aryl group is substituted with 1 to 3 identical or different groups selected from a halogen atom and a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group You may)
(11) a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group (the heterocyclic group includes a halogen atom, an oxo group, and a saturated or unsaturated 4- to 10-membered nitrogen-containing (or Oxygenated) may be substituted with 1 to 3 identical or different groups selected from heterocyclic groups),
(12) an alkyloxy group (the alkyl part of the group is a halogen atom, an alkyloxy group, an aryl group, a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group, and a mono- or dialkylamino group) May be substituted with the same or different 1 to 3 groups selected from
(13) a cycloalkyloxy group,
(14) a cycloalkenyloxy group,
(15) an aryloxy group,
(16) an arylcarbonyl group (the aryl part of the group may be substituted with the same or different 1 to 3 halogen atoms),
(17) an alkylcarbonyl group,
(18) an alkyloxycarbonyl group,
(19) arylalkyloxycarbonyl group,
(20) Formula: a group represented by —SO ₂ R _b (wherein R _b is an alkyl group, an aryl group which may be substituted with 1 to 3 halogen atoms, or a substituent with 1 to 2 alkyl groups) An amino group which may be substituted, or a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group which may be substituted with the same or different 1 to 3 alkyl groups),
(21) an alkynyl group (the alkynyl group may be substituted with a group selected from a mono- or dialkylamino group and a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group),
(22) an alkylthio group (the alkyl part of the group may be substituted with a group selected from a hydroxyl group and an alkyloxy group),
(23) A group consisting of a carbamoyl group (the carbamoyl group may be substituted with an alkyl group), and (24) a carbamoyloxy group (the group may be substituted with 1 to 2 alkyl groups). And cyclic groups having the same or different 1 to 4 substituents selected from:

In the compound [I] which is an active ingredient of the present invention, when the substituent on the linear or branched hydrocarbon group or cyclic group represented by R ⁶ is an aryl group or an aryl group-containing group, Specific examples of the aryl group include 6 to 14-membered monocyclic, bicyclic or tricyclic aryl groups such as a phenyl group, a naphthyl group, and a fluorenyl group, and among them, a phenyl group is preferable. Examples of the biaryl group include a biphenyl group.

The linear or branched hydrocarbon group represented by R ⁶ or a substituent on the cyclic group is a saturated or unsaturated 4- to 10-membered nitrogen-containing (or oxygen-containing) heterocyclic group or the cyclic group Specific examples of such heterocyclic groups include a furyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a pyridyl group, a piperazinyl group, a benzimidazolyl group, and the like.

The compound [I], which is an active ingredient of the present invention, will be described more specifically. For example, in the general formula [I],
(A) R ¹ and R ² are (i) a phenyl group which is the same or different and may be substituted with 1 to 3 groups selected from a halogen atom, a C _1-6 alkyloxy group and a cyano group. Or (ii) both of which together with adjacent CH groups have the formula:

In which one of R ³ and R ⁴ is a hydrogen atom, the other is a hydrogen atom or a hydroxyl group, R ⁵ is a hydrogen atom or a C _1-6 alkyl group, and Y is a single bond or —O—. And R ⁶ is the following (1) to (17):
(1) C _3-8 cycloalkyl group; (2) benzo-C _3-8 cycloalkyl group; (3) amino group (the group is a C _1-6 alkyl group, C _1-6 alkyloxy-carbonyl- Carbamoyl group, C _1-6 alkyloxy-carbonyl group, C _1-6 alkyl-carbonyl group, trihalogeno-C _1-6 alkyl-carbonyl group, phenyl-C _1-6 alkyloxy-carbonyl group, C _1-6 alkyl a sulfonyl group, a morpholinocarbonyl group 1 to 2, selected from one or two _{C 1-6} alkyl-substituted carbamoyl group by group, and one to two _{C 1-6} aminosulfonyl group substituted with an alkyl group (4) an aryl group selected from a phenyl group, a naphthyl group and a fluorenyl group (the aryl group is a halogen atom, a hydroxy group) , _{C 1-6 alkyl, C 1-6} alkyloxy group, a trihalogeno _{-C 1-6} alkyl group, a trihalogeno _{-C 1-6} alkyl group, di _{(C 1-6} alkyl) amino group and a _{C 1-6} (Optionally substituted with 1 to 3 groups selected from alkyloxy-carbonyl-amino groups); (5) a biphenyl group optionally substituted with a halogen atom; (6) saturated or unsaturated 5-14 A sulfur-containing, nitrogen-containing or oxygen-containing heterocyclic group (the heterocyclic group includes a halogen atom, an oxo group, a C _1-6 alkyl group, a C _1-6 alkyloxy-carbonyl group, phenyl-C _{1- 6} alkyloxy - group, trihalogeno _{-C 1-6} alkyl _group, optionally substituted with one to two groups selected from _{C 1-6} alkylthio group and a phenyl group); (7) hydroxyl ; _{(8) C 1-6} alkyloxy (in which the group _may be substituted with one to two groups selected from _{C 1-6} alkyl group and phenyl _group); (9) _{C 2-} ( ₆ ) an aryloxy group selected from a phenoxy group and a naphthyloxy group (the aryl part of the group is selected from a halogen atom, a C _1-6 alkyl group and a trihalogeno-C _1-6 alkyloxy group) Optionally substituted with 1 to 2 groups and optionally condensed with a C _3-8 cycloalkyl group); (11) phenylthio group; (12) pyridylthio group; (13) C _1-6. An alkyloxy-carbonyl group (the alkyl part of the group may be substituted with a phenyl group); (14) a C _3-8 cycloalkylcarbonyl group; (15) a benzoyl group; Sulfonyl group; and (17) a halogen atom;
A compound which is a linear or branched C _1-10 alkyl group optionally substituted with 1 to 3 groups selected from the group consisting of:
(B) R ¹ and R ² are the same or different and may be substituted with 1 to 3 halogen atoms, R ³ and R ⁴ are both hydrogen atoms, R ⁵ is a hydrogen atom, and Y is Single bond, R ⁶ is the following (1) to (3):
(1) a phenyl group (the group includes a halogen atom, a C _1-6 alkyl group, a trihalogeno-C _1-6 alkyl group, a C _1-6 alkyloxy group, a C _1-6 alkyloxy-carbonyl group, a C _{1- And} optionally substituted with 1 to 3 groups selected from a ₆ alkyloxy-C _1-6 alkyloxy group and a morpholino-C _1-6 alkyloxy group);
(2) a saturated or unsaturated 5- to 10-membered nitrogen-containing or oxygen-containing heterocyclic group (the heterocyclic group may be substituted with a halogen atom); and (3) a phenyl-C _1-6 alkylthio group ;
A compound which is a linear or branched C _2-6 alkenyl (or C _2-6 alkynyl) group optionally substituted by 1 to 2 groups selected from the group consisting of:
(C) R ¹ and R ² are the same or different and (i) the following (1) to (16):
(1) a halogen atom; (2) a cyano group; (3) a nitro group; (4) a C _1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms); (5) C _1-6 alkyloxy-C _1-6 alkyl group; (6) C _1-6 alkyloxy group (the group is selected from a halogen atom, a di (C _1-6 alkyl) amino group, a pyrrolidinyl group, and a morpholino group) (7) a C _1-6 alkyloxy-C _1-6 alkyloxy group; (8) an amino group (the group is a C _1-6 alkyl group). Substituted with 1 to 2 groups selected from C _1-6 alkyloxy-C _1-6 alkyl group, C _3-8 cycloalkyl group and di (C _1-6 alkyl) amino-C _1-6 alkyl group may be); (9) di _{(C 1-6} alkyl) Karubamoi Group; _{(10) C 1-6} alkylthio group; _{(11) C 1-3} alkylene group; _{(12) C 1-3} alkylenedioxy group; (13) di _{(C 1-6} alkyl) aminosulfonyl group; (14) a C _1-6 alkylsulfonyl group; (15) a di (C _1-6 alkyl) carbamoyloxy group; and (16) a C _1-6 alkylsulfinyl group;
A phenyl group optionally substituted with 1 to 3 groups selected from the group consisting of: or (ii) the following (1) to (6):
(1) a halogen atom; (2) a cyano group; (3) a C _1-6 alkyl group (which may be substituted with 1 to 3 groups selected from a halogen atom and a C _1-6 alkyloxy group) (4) a di (C _1-6 alkyl) amino group; (5) a C _3-8 cycloalkyloxy group; and (6) a C _1-6 alkyloxy group (the group is a halogen atom, C _3- Optionally substituted with 1 to 3 groups selected from an ₈ cycloalkyl group and a C _1-6 alkyloxy group);
A sulfur-containing, nitrogen-containing or oxygen-containing 5- to 10-membered monocyclic or bicyclic heteroaryl group optionally substituted by 1 to 3 groups selected from the group consisting of R ³ and R ⁴ are (i ) One is a hydrogen atom, the other is a hydrogen atom, a hydroxyl group, a carboxyl group, a hydroxy-C _1-6 alkyl group, a C _1-6 alkyloxy group, a C _1-6 alkyloxy-C _1-6 alkyl group, C _{1 -6} alkyloxy-carbonyl group, di (C _1-6 alkyl) amino-C _1-6 alkyl group, carbamoyl group (the group is di (C _1-6 alkyl) amino-C _1-6 alkyl group, morpholino 1-2 groups selected from a -C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a C _1-6 alkyl group, a halogeno-C _1-6 alkyl group and a pyridyl-C _1-6 alkyl group Is replaced with Or a C _1-6 alkyloxy-C _1-6 alkyloxy group, a morpholino group or a pyrrolidinyl group, or (ii) both R ³ and R ⁴ are combined together to form an oxo group, R ⁵ Is a hydrogen atom or a C _1-6 alkyl group, Y is a single bond, R ⁶ is the following (1) to (25):
(1) halogen atom; (2) oxo group; (3) nitro group; (4) cyano group; (5) C _1-6 alkyl group (the group is a halogen atom, hydroxyl group, C _1-6 alkyloxy group) , Phenyl group, morpholino group, pyrrolidinyl group, oxopyrrolidinyl group and benzimidazolyl group, which may be substituted with 1 to 3 groups); (6) amino-C _1-6 alkyl group The amino part of the group is a C _1-6 alkyl group, a C _1-6 alkyloxy-C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkyloxy-carbonyl group and a phenyl-C _1-6 (7) a C _3-8 cycloalkyl group; (8) a C _1-6 alkyloxy-carbonyl-C _2-6, which may be substituted with 1 to 2 groups selected from alkyloxy-carbonyl groups); Alkenyl group (9) an amino group (said _{group, C 1-6 alkyl, C 1-6} alkyloxy _{-C 1-6} alkyl group, a trihalogeno _{-C 1-6} alkyl - carbonyl _{group, C 1-6} alkyloxy - carbonyl and phenyl _{-C 1-6} alkyloxy - may be substituted with one to two groups selected from carbonyl group); (10) a phenyl group; (11) a pyrazolyl group, a pyrrolyl group, a pyrrolidinyl group, piperidyl A heterocyclic group selected from a group and a morpholino group (the heterocyclic group may be substituted with 1 to 3 groups selected from a halogen atom, an oxo group and a pyrimidinyl group); (12) C _{1 -9} alkyloxy (in which the group, a halogen _{atom, C 1-6} alkyl group, a phenyl group, a substituted with a morpholino group and one to two _{C 1-6} alkyl groups Bruno may be substituted with 1 to 3 groups selected from the group); _{(13) C 3-8} cycloalkyloxy group, _{(14) C 3-8} cycloalkenyl group; (15) a phenoxy group; (16) Benzoyl group; (17) C _1-6 alkyl-carbonyl group; (18) C _1-6 alkyloxy-carbonyl group; (19) Aminosulfonyl group (the group is 1-2 C _1-6 (20) a piperazinylsulfonyl group (this group may be substituted with 1 to 3 alkyl groups); (21) a C _2-6 alkynyl group (which may be substituted with an alkyl group); The group may be substituted with one or two groups selected from an amino group substituted with one or two C _1-6 alkyl groups and a pyrrolidinyl group); (22) substituted with a hydroxyl group also a _{C 1-6} alkylthio group _{(23) C 1-6} alkyloxy _{-C 1-6} alkylthio group; (24) one to two _{C 1-6} alkyl carbamoyl group which may be substituted with a group; and (25) di _{(C 1- 6} alkyl) carbamoyloxy group;
A compound which is a 6-11 membered monocyclic, bicyclic or tricyclic aryl group optionally substituted with 1 to 3 groups selected from the group consisting of:
(D) R ¹ and R ² are the same or different and may be substituted with 1 to 3 halogen atoms, one of R ³ and R ⁴ is a hydrogen atom, and the other is a hydrogen atom or C _1-6 alkyloxy group, R ⁵ is a hydrogen atom, Y is a single bond, R ⁶ is the following (1) to (6):
(1) an oxo group; (2) a C _1-6 alkyl group (the group may be substituted with a halogenophenylcarbonyl group); (3) an amino-C _1-6 alkyl group (the amino part of the group is , C _1-6 alkyloxy-carbonyl group may be substituted); (4) amino group (the group may be substituted with C _1-6 alkyloxy-carbonyl group); (5) phenyl A group (the group may be substituted with 1 to 3 halogen atoms); and (6) a benzoyl group (the group may be substituted with 1 to 3 halogen atoms);
A C _3-10 mono-, bi-, or tricycloalkyl group (which may be condensed with a benzene ring) _optionally substituted with 1 to 4 groups selected from the group consisting of A compound,
(E) R ¹ and R ² are the same or different and (i) the following (1) to (6):
(1) halogen atom; (2) cyano group; (3) C _1-6 alkyloxy group; (4) trifluoro-C _1-6 alkyl group; (5) C _1-6 alkyl group and C _1-6 An amino group substituted with 1 to 2 groups selected from an alkyloxy-C _1-6 alkyl group; and (6) a di (C _1-6 alkyl) carbamoyloxy group;
A phenyl group optionally substituted with 1 to 3 groups selected from the group consisting of: (ii) the following (1) to (5):
(1) C _1-6 alkyloxy group; (2) di (C _1-6 alkyl) amino group; (3) C _3-8 cycloalkyloxy group; (4) C _3-8 cycloalkyl-C _{1- 6} alkyloxy groups; and (5) trihalogeno-C _1-6 alkyloxy groups;
One of sulfur-containing, oxygen-containing or nitrogen-containing monocyclic or bicyclic heteroaryl group, R ³ and R ⁴ which may be substituted with 1 to 3 groups selected from the group consisting of A hydrogen atom, the other is a hydrogen atom or a C _1-6 alkyloxy group, R ⁵ is a hydrogen atom, Y is a single bond, and R ⁶ is the following (1) to (15):
(1) oxo group; (2) halogen atom; (3) cyano group; (4) C _1-6 alkyl group (the group is a halogen atom, C _1-6 alkyloxy group, imino group, phenyl group and pyrrolidinyl) (May be substituted with 1 to 3 groups selected from a group); (5) amino-C _1-6 alkyl group (the amino part of the group is substituted with 1 to 2 C _1-6 alkyl groups) (6) amino group (the group may be substituted with 1 to 2 C _1-6 alkyl groups); (7) phenyl group (the group is 1 to 3 (Optionally substituted with a halogen atom); (8) a heterocyclic group selected from a furyl group, a pyridyl group and a pyrimidinyl group; (9) a C _1-6 alkyloxy group (the group is a halogen atom and a phenyl group) (It may be substituted with 1 to 3 groups selected from :); (10) _1-6 alkyl - carbonyl group; _{(11) C 1-6} alkyloxy - group; _{(12) C 1-6} alkylsulfonyl group; (13) aminosulfonyl groups, (14) a benzenesulfonyl group (of the group benzene The moiety may be substituted with 1 to 3 halogen atoms); and (15) a morpholinosulfonyl group;
A saturated or unsaturated 3 to 14-membered monocyclic, bicyclic or tricyclic heterocyclic group optionally substituted with 1 to 3 groups selected from the group consisting of _A compound that may be spiro-bonded to a _3-8 cycloalkyl ring, or
(F) R ¹ and R ² may be substituted with 1 to 3 halogen atoms, R ³ and R ⁴ are both hydrogen atoms, R ⁵ is a hydrogen atom, Y is a formula: —NR ⁷ — A group represented by the formula: R ⁶ is a C _1-6 alkyl group which may be substituted with a phenyl group or a phenyl group which may be substituted with 1 to 3 halogen atoms, and R ⁷ is a C _1-6 alkyl group Or a compound that is a C _1-6 alkyloxy-carbonyl-C _1-6 alkyl group,
Etc.

In the above compound [I], which is an active ingredient of the present invention, when the cyclic group represented by R ⁶ is an aryl group having a substituent, preferred examples of such an aryl group include, for example, an oxo group, a cyano group Group, nitro group, halogen atom, C _1-6 alkyl group, trifluoro-C _1-6 alkyl group, diphenyl-C _1-6 alkyl group, di (C _1-6 alkyl) amino-C _1-6 alkyl group , Phenyl-C _1-6 alkyl group, pyrrolidinyl-C _1-6 alkyl group, benzimidazolyl-C _1-6 alkyl group, C _1-9 alkyloxy group, di- or trifluoro-C _1-6 alkyloxy group , phenyl group, a phenyl _{-C 1-6} alkyl _{group, C 1-6} alkyloxy _{-C 1-6} alkyl group, aminosulfonyl group, di _{(C 1-6} A Kill) aminosulfonyl group, di _{(C 1-6} alkyl) amino _{group, C 1-6} alkyloxy - carbonylamino _{group, C 1-6} alkyloxy - carbonyl group, a phenyl _{-C 1-6} alkyloxy - carbonylamino group C _1-6 alkyloxy-carbonyl-C _2-6 alkenyl group, C _1-6 alkyl-carbonyl group, benzoyl group, phenyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyloxy group, C _3-8 cycloalkyloxy group, pyrrolyl group, oxopyrrolidinyl group, piperidyl group, C _1-6 alkylpiperazinylsulfonyl group, pyrimidinyl-substituted pyrazolyl group, C _1-6 alkyloxy-carbonylamino-C _1-6 alkyl group, a phenyl _{-C 1-6} alkyloxy - carbonylamino _{-C 1-6} alkyl group Di _{(C 1-6} alkyl) amino _{-C 2-6} alkynyl group, _{N-(C 1-6} alkyloxy _{-C 1-6 alkyl)-N-(C 1-6} alkyl) amino _{-C 1-6} alkyl Group, N- (C _3-8 cycloalkyl) -N- (C _1-6 alkyl) amino-C _1-6 alkyl group, N- (trifluoro-C _1-6 alkylcarbonyl) -N- (C _{1 -6} alkyl) amino group, pyrrolidinyl-C _2-6 alkynyl group, C _1-6 alkyloxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, morpholino-C _1-6 alkyl group, di ( C _1-6 alkyl) amino-C _1-6 alkyloxy group, morpholino-C _1-6 alkyloxy group, C _1-6 alkylthio group, C _1-6 alkyloxy-C _1-6 alkylthio group, hydroxy-C _1- Alkylthio groups, di (C _1-6 alkyl) carbamoyl group, and di (C _1-6 alkyl) the same or different one to three aryl group substituted with a group selected from a carbamoyloxy group.

In addition, when the cyclic group represented by R ⁶ is a cycloalkyl group having a substituent, preferred examples of such a cycloalkyl group include, for example, an oxo group, a C _1-6 alkyl group, a halogenobenzoyl-C _1-6 alkyl group, C _1-6 alkyloxy-carbonylamino group, halogenobenzoyl group, phenyl group, halogenophenyl group and C _1-6 alkyloxy-carbonylamino-C _1-6 alkyl group Examples thereof include a monocyclo-, bicyclo- or tricycloalkyl group substituted with the same or different 1 to 4 groups (the cycloalkyl group may be condensed with a benzene ring).

Furthermore, when the cyclic group represented by R ⁶ is a heterocyclic group having a substituent, preferred examples of such a heterocyclic group include, for example, an oxo group, a chlorine atom, a bromine atom, a cyano group, C _1-6 alkyl group, C _1-6 alkyloxy group, diphenyl-C _1-6 alkyl group, C _1-6 alkylcarbonyl group, trifluoro-C _1-6 alkyl group, trifluoro-C _1-6 alkyl Oxy group, C _1-6 alkyloxy-carbonyl group, di (C _1-6 alkyl) amino-C _1-6 alkyl group, di (C _1-6 alkyl) amino group, phenyl group, chlorophenyl group, pyrrolidinyl-C _1-6 alkyl group, pyridyl group, pyrimidinyl group, furyl group, C _1-6 alkylsulfonyl group, aminosulfonyl group, morpholinosulfonyl group, benzenesulfonyl group, A heterocyclic group substituted with 1 to 3 identical or different groups selected from the group consisting of a chlorobenzenesulfonyl group, a benzyl group, a benzyloxy group and a C _1-6 alkyloxy-imino-C _1-6 alkyl group; can give.

Among the compounds [I] that are the active ingredients of the present invention, preferred compounds include, for example, R ¹ is represented by the formula:

R ² is a group represented by the formula:

R ¹¹ and R ²¹ each independently represents a hydrogen atom, a cyano group, a halogen atom, or a C _1-6 alkyloxy group (the group is selected from a halogen atom and a C _1-6 alkyloxy group) A C _1-6 alkyl group (this group may be substituted with 1 to 3 groups selected from a halogen atom and a C _1-6 alkyloxy group) , Di (C _1-6 alkyl) carbamoyloxy group, C _3-8 cycloalkyloxy group, C _3-8 cycloalkyl-C _1-6 alkyloxy group, C _1-6 alkylthio group, di (C _1-6 ) Alkylamino-C _1-6 alkyloxy group or formula:

R ¹² and R ²² are each independently a hydrogen atom, a halogen atom or a morpholino-C _1-6 alkyloxy group, R ¹³ and R ²³ are each independently a hydrogen atom or a halogen atom, R ¹⁴ and R ¹⁵ is the same or different and is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkyloxy-C _1-6 alkyl group, a C _3-8 cycloalkyl group and a di (C _1-6 alkyl) amino-C. _Examples thereof include a group selected from _1-6 alkyl groups and a compound in which Y is a single bond.

Among the above, more preferable compounds include compounds in which one of R ³ and R ⁴ is a hydrogen atom and the other is a hydrogen atom, a hydroxyl group, a C _1-6 alkyloxy group, or a morpholino group.

  Among the compounds [I] that are the active ingredients of the present invention, more preferred compounds include, for example, the following general formula [IA]:

[Where:
Ring A has the formula:

A group represented by
Ring B has the formula:

A group represented by
One of Z ¹ and Z ² is a group represented by the formula: = N-, the other is a group represented by the formula: = CH- or = N-,
R ^11a and R ^21a are the same or different and are (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a C _1-6 alkyloxy group (the group is a halogen atom and a C _1-6 alkyl). Optionally substituted with 1 to 3 groups selected from oxy groups), (5) mono- or trifluoro-C _1-6 alkyl groups, (6) di (C _1-6 alkyl) carbamoyloxy groups, (7) C _1-6 alkylthio group, (8) amino group substituted with C _1-6 alkyl group and C _1-6 alkyloxy-C _1-6 alkyl group, (9) C _3-8 cycloalkyloxy A group, (10) a C _3-8 cycloalkyl-C _1-6 alkyloxy group, or (11) a C _1-6 alkyloxy-C _1-6 alkyl group,
R ^14a is a C _1-6 alkyloxy group,
R ^13a is a hydrogen atom or a halogen atom,
R ³¹ is a hydrogen atom, a hydroxyl group, a C _1-6 alkyloxy group or a morpholino group,
R ⁶¹ is (1) a halogen atom, a trifluoro-C _1-6 alkyl group, a C _1-6 alkyloxy group, a trifluoro-C _1-6 alkyloxy group, a di (C _1-6 alkyl) carbamoyloxy group, A phenyl group substituted with one or two groups selected from the same or different groups selected from a C _1-6 alkylthio group and a cyano group; (2) a pyridyl group substituted with one or two groups selected from a halogen atom and a cyano group; Or (3) a thienyl group substituted with a halogen atom or a trifluoro-C _1-6 alkyl group,
Represents. ]
Or a pharmacologically acceptable salt thereof.

Specific examples of particularly preferable compounds among the compounds [I] which are active ingredients of the present invention include, for example,
1- [bis- (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
1- [bis- (4-ethyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-isopropyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-hydroxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1-[(4-chlorophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-methyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-methyloxy-4-[(4-chlorobenzoyl) amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(4-chlorobenzoyl) amino] pyrrolidine;
1- [bis- (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1-[(2-chlorophenyl) (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-morpholino-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-hydroxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(4-chlorobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-methyloxy-4-[(4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-morpholino-4-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-methyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-methyloxy-4-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[(4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[[3-fluoro-4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-methyloxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(S)-(4-cyanophenyl) (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(S)-(4-cyanophenyl) (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-methyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-methyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2-fluoro-4- (trifluoromethyl) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-chloro-2-fluorophenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-chlorophenyl) methyl] -3-[[5- (trifluoromethyl) -2-thenoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-methylthiophenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(S)-(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-ethyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2-difluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine ;
(3R) -1-[(4-cyanophenyl) (6-ethyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2-difluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- [2- (methyloxy) ethyloxy] pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-fluoromethylphenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-fluoromethylphenyl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] [6- (isopropyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxythiazol-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxythiazol-5-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) [6- (methyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] [6- (methyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (methyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2-fluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-ethyloxybenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-methylthiobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(5-bromo-2-thenoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxythiazol-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxythiazol-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-methyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-methyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-methyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-ethyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-ethyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-ethyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (2,2,2-trifluoroethyloxy) pyrimidin-5-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (2,2,2-trifluoroethyloxy) pyrimidin-5-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) Amino] pyrrolidine;
(3R) -1-[(4-Cyanophenyl) [2- (2,2,2-trifluoroethyloxy) pyrimidin-5-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine ;
(3R) -1-[(4-cyanophenyl) (2-ethyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (1-fluoromethyl-2-fluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[[4- (dimethylcarbamoyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[[4- (dimethylcarbamoyloxy) benzoyl] amino] pyrrolidine;
(3R) -1- [bis- (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxythiazol-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxythiazol-5-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1- [bis- (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1- [bis- (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (dimethylcarbamoyloxy) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (dimethylcarbamoyloxy) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (dimethylcarbamoyloxy) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (dimethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (dimethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (dimethylamino) pyrimidin-5-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (diethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (diethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (diethylamino) pyrimidin-5-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-isopropylamino) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-ethylamino) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) Amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-isopropylamino) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-ethylamino) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-Nn-propylamino) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-Nn-propylamino) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Cyanophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine ;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-isopropylamino) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-ethylamino) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-Nn-propylamino) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclobutyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclobutyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclobutyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopentyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopentyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopentyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopropylmethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopropylmethyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopropylmethyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (1-ethyl-n-propyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Cyanophenyl) [6- (1-ethyl-n-propyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] Pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (1-ethyl-n-propyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2,2-trifluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2,2-trifluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) Amino] pyrrolidine; and
(3R) -1-[(4-Cyanophenyl) [6- (2,2,2-trifluoroethyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine ;
Or a pharmacologically acceptable salt thereof.

  When the compound [I], which is an active ingredient of the present invention, has an asymmetric carbon atom, it can exist as a plurality of stereoisomers (diastereoisomers, optical isomers) based on the asymmetric carbon atom. The active ingredient of the present invention includes any one of these stereoisomers or a mixture thereof.

  Compound [I], which is an active ingredient of the present invention, can be used for pharmaceutical use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfone. And organic acid salts such as acid salts, benzenesulfonate, tosylate and maleate. In addition, when the compound has a carboxyl group in the molecule, the pharmacologically acceptable salt includes a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth such as a calcium salt). Metal salts).

  Compound [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, includes any of its internal salts and adducts, solvates or hydrates thereof.

  Since the compound [I] or a pharmacologically acceptable salt thereof has an excellent antagonistic action on the CB1 receptor, the pharmaceutical composition of the present invention can be used for various diseases involving the receptor, for example, Psychosis, including schizophrenia, anxiety disorders, stress, depression, epilepsy, neurodegeneration, cerebellar and old cerebellum (Spinocerebellar) disorders, cognitive impairment, cranial trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, obsessive compulsive disorder, amnesia, senile dementia, thymic disorder, Tourette's syndrome, tardive dyskinesia, bipolar disorder, cancer, drug-induced movement disorder, ataxia, internal Toxemia shock, hemorrhagic shock, hypotension, insomnia, immunological diseases including inflammation, multiple sclerosis, vomiting, diarrhea, Breath, appetite disorder (bulimia, anorexia), obesity, non-insulin dependent diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism Abnormal, arteriosclerosis, hypertension, coronary disease, memory disorder, urological disease, cardiovascular disease, infertility, infection, demyelinating disease, neuritis, viral encephalitis, cerebrovascular disorder, cirrhosis, or intestinal disorder It is useful for the prevention and treatment of gastrointestinal diseases including transdisorders).

  The pharmaceutical compositions of the present invention are also useful for chronic treatment and withdrawal from substances (such as alcohol) or drug abuse (eg opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclides, hallucinogenics, benzodiazepines).

  Furthermore, the pharmaceutical composition of the present invention is also useful as an analgesic agent or an analgesic activity enhancer or an smoking cessation aid (withdrawal from smoking) of anesthetic and non-anesthetic drugs.

  The compound [I] of the present invention or a pharmacologically acceptable salt thereof has a low toxicity and also has a feature of high safety as a pharmaceutical.

  Compound [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, can be administered orally or parenterally, and can also be used for tablets, granules, capsules, powders, injections. It can be used as a conventional pharmaceutical preparation such as an inhalant.

  The dose of Compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, and condition. About 0.0001 to 1.0 mg / kg per day, especially about 0.001 to 0.1 mg / kg, orally, usually about 0.001 to 100 mg / kg per day, especially about 0.01 to It is preferably about 10 mg / kg.

  Compound [I], which is an active ingredient of the present invention, can be produced by the following method, but is not limited thereto.

(Method A)
Compound [I], which is an active ingredient of the present invention, is represented by the general formula [II]:

[Wherein the symbols have the same meaning as above]
And a compound of the general formula [III]:
^{R 6 -Y-COOR 0 [III} ]
[Wherein, R ⁰ represents a hydrogen atom, an alkyl group or a benzyl group, and other symbols have the same meaning as described above. ]
It can manufacture by making the compound or its salt shown by react.

When R ⁰ is a hydrogen atom, this reaction can be carried out in a solvent in the presence of a condensing agent, in the presence or absence of an activator, in the presence or absence of a base. Any solvent may be used as long as it does not affect the reaction. For example, methylene chloride, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, 1, Examples include 2-dimethoxyethane. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), Diethyl cyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), carbonylditriazole, N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (PS) -Carbodiimide), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), hexafluorophosphate 2- (7-azabenzo) Triazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl hexafluorophosphate Uronium (HBTU), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBroP), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate ( TBTU), chloro-1,1,3,3-tetramethyluronium hexachloroantimonate (ACTU) and the like. Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), penta Examples thereof include fluorophenol (Pfp-OH), 1-hydroxybenzotriazole-6-sulfonamidomethylpolystyrene (PS-HOBt) and the like. Examples of the base include pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -undecene (DBU), and the like.

  In this reaction, the amount of compound [II] used can be 0.33 to 1.5 equivalents, preferably 0.5 to 1.0 equivalents, relative to compound [III]. The amount of the condensing agent to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [II] or [III]. The amount of the base to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [II] or [III]. The amount of the activator to be used can be 0.1 to 2.0 equivalents, preferably 0.2 to 1.0 equivalents, relative to compound [II] or [III]. This reaction can be carried out at 0 to 150 ° C, preferably 20 to 80 ° C.

In the general formula [III], when R ⁰ is a hydrogen atom, the compound is converted into a reactive derivative such as a corresponding acid halide or mixed acid anhydride, and then the reactive derivative is removed in the presence of the above-mentioned base in a solvent. Compound [I] can also be produced by reacting with compound [II] in the middle or without solvent.

Further, in the general formula [III], when R ⁰ is an alkyl group or a benzyl group, this reaction can be carried out by subjecting the ester compound to conventional hydrolysis, acid decomposition with hydrochloric acid, formic acid, trifluoroacetic acid or the like, or reduction reaction. It can also be carried out by treating the carboxylic acid compound and compound [II] in the same manner as described above after conversion to the corresponding carboxylic acid compound.

(Method B)
In addition, compound [I], which is an active ingredient of the present invention, is represented by the general formula [IV]:

[Wherein X represents a reactive residue, and other symbols have the same meaning as described above]
And a compound represented by the general formula [V]:

[Wherein the symbols have the same meaning as above]
It can also manufacture by making the compound shown by react.

  This reaction can be carried out in a solvent in the presence of a base, in the presence or absence of an additive. The solvent may be any solvent that does not affect the reaction. For example, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethanol, isopropyl alcohol, acetonitrile, 1,4-dioxane, 1,3-dimethyl-2- Examples include imidazolidinone. Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, and the like. Examples of the additive include sodium iodide, copper iodide (I), copper iodide (II ), Copper powder, potassium iodide, tetrabutylammonium chloride, and tetraalkylammonium halides such as tetraethylammonium chloride.

  Examples of the reactive residue X include a halogen atom such as a fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, hydroxyl group and the like. It is done.

  When the reactive residue X is a hydroxyl group, Mitsunobu reagents such as triphenylphosphine-diethylazodicarboxylate and triphenylphosphine-diisopropylazodicarboxylate can also be used.

  In this reaction, the amount of compound [IV] used can be 0.33 to 3.0 equivalents, preferably 0.66 to 1.5 equivalents, relative to compound [V]. The amount of the base to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [IV] or [V]. The usage-amount of an additive can be 0.1-2.0 equivalent with respect to compound [IV] or [V], Preferably it can be 0.2-1.0 equivalent. This reaction can be carried out at 50 to 150 ° C, preferably 80 to 120 ° C.

(Method C)
Among the active ingredient compounds of the present invention, the general formula [Ia]:

[Wherein, R ⁸ and R ⁹ are each independently a group selected from an alkyl group, an arylalkyl group, an alkyloxycarbonylalkyl group and an aryl group optionally substituted with a halogen atom, or adjacent to each other by bonding. May form a heterocyclic group together with the nitrogen atom (the heterocyclic group may be condensed with a benzene ring and may be substituted with a halogenoaryl group), and other symbols are: It has the same meaning as above]
The compound represented by the formula [II] and the general formula [VI]:
^{(R 8) (R 9)} N-H [VI]
[Wherein the symbols have the same meaning as above]
And a compound represented by the general formula [VII]:

[Wherein W ¹ and W ² are the same or different and represent a leaving group]
It can also manufacture by making it react in presence of the compound shown by these.
Examples of W ¹ and W ² in compound [VII] include an imidazolyl group, a halogen atom, or a phenoxy group. Specific examples of such compound [VII] include, for example, 1,1′-carbonyldiethyl Examples include imidazole, phosgene, and triphosgene. Moreover, the solvent used for this reaction should just be a thing which does not have a bad influence on reaction, For example, acetonitrile, a dichloromethane, tetrahydrofuran etc. are mention | raise | lifted as such a solvent.

  In this reaction, the amount of compound [II] used can be 0.33 to 2.0 equivalents, preferably 0.66 to 1.0 equivalents, relative to compound [VI]. The amount of compound [VII] to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [II] or [VI]. This reaction can be carried out at 0 to 150 ° C, preferably 20 to 80 ° C.

  Further, the compound [Ia] is obtained by reacting the compound [II] with the compound [VII] to give a compound represented by the general formula [VIII].

[Wherein the symbols have the same meaning as above]
And if necessary, the compound [VIII] is converted to its reactive derivative and then reacted with the compound [VI], or the compound [VI] and the compound [VII] are reacted to give a compound of the general formula [IX] :

[Wherein the symbols have the same meaning as above]
If the compound [IX] is required, it can be converted into its reactive derivative and then reacted with the compound [II].

As a reactive derivative of compound [VIII] or compound [IX], for example, W ² is represented by the formula:

The reactive derivative can be obtained, for example, by reacting compound [IX] in which W ² is an imidazolyl group with methyl iodide.

  The reaction of compound [II] or compound [VI] and compound [VII] can be carried out, for example, at 0 to 150 ° C., preferably 20 to 80 ° C. The amount of compound [VII] used is the compound [II]. ] Or [VI] can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents. As the solvent, any solvent can be used as long as it does not affect the reaction. For example, acetonitrile, dichloromethane, tetrahydrofuran and the like can be appropriately used.

  The reaction for converting compound [VIII] or compound [IX] into its reactive derivative may be carried out, for example, by treating the compound with methyl iodide or the like. This reaction is carried out, for example, at 0 to 150 ° C., preferably 40 to It can be carried out at 80 ° C. The amount of compound [VII] to be used can be 1.0 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound [VIII] or [IX]. The solvent may be any solvent that does not affect the reaction, and examples thereof include acetonitrile, dichloromethane, tetrahydrofuran, and the like.

  The reaction between compound [VIII] (or a reactive derivative thereof) and compound [VI] or the reaction between compound [IX] (or a reactive derivative thereof) and compound [II] is carried out in the presence of a base, for example, 0 It can be carried out at ˜150 ° C., preferably 20˜80 ° C. The usage-amount of a reactive derivative can be 0.33-3.0 equivalent with respect to compound [VI] or [II], Preferably it can be 0.66-1.5 equivalent. Further, as the base, for example, triethylamine can be used, and as the solvent, any solvent that does not affect the reaction may be used, and examples thereof include acetonitrile, dichloromethane, tetrahydrofuran, and the like.

Compound [I], which is an active ingredient of the present invention, is a substituent on R ¹ , R ² , R ^{6 of the} compound obtained as described above, or another substituent for further R ³ , R ^4. It can also be manufactured by converting into Such a substituent conversion method may be appropriately selected according to the type of the target substituent, and can be carried out, for example, as in (Method a) to (Method l).

(Method a)
The active ingredient compound [I] of the present invention in which the substituent on R ¹ and / or R ² is a cyano group is the active ingredient compound [I] of the present invention in which the substituent on R ¹ and / or R ² is a halogen atom [ I] and zinc cyanide can be reacted in the presence of a catalyst and an additive. Examples of the catalyst include palladium catalysts such as palladium acetate, tris (dibenzylideneacetone) dipalladium, trans-dichlorobis (tricyclohexylphosphine) palladium, and tetrakis (triphenylphosphine) palladium. As additives, 1,1′-bis (diphenylphosphino) ferrocene, racemic-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) Examples thereof include phosphine compounds such as biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ′-(N, N′-dimethylamino) biphenyl, and tri-t-butylphosphine.

(Method b)
The active ingredient compound [I] of the present invention in which the substituent on R ¹ and / or R ² is an alkylamino group or a cycloalkylamino group corresponds to the substituent on R ¹ and / or R ² being a halogen atom It can be obtained by reacting compound [I] with a mono- or dialkylamine or cycloalkylamine in a suitable solvent in the presence of a catalyst, an additive and a base. Examples of the catalyst include the palladium catalyst described in the above (a). Examples of the additive include the phosphine compound described in the above (a), and examples of the base include potassium carbonate and cesium carbonate.

(Method c)
The active ingredient compound [I] of the present invention in which R ³ and R ⁴ are combined together to form an oxo group is a compound [I] in which one of R ³ and R ⁴ is a hydrogen atom and the other is a hydroxyl group. Obtained by oxidation. This oxidation reaction can be carried out in a suitable solvent in the presence of an oxidizing agent such as activated dimethyl sulfoxide. The activation of dimethyl sulfoxide can be carried out using oxalyl chloride, dicyclohexylcarbodiimide, trifluoroacetic anhydride, acetic anhydride, chlorine, sulfur trioxide-pyridine complex and the like.

(Method d)
The active ingredient compound [I] of the present invention in which R ³ or R ⁴ is an alkyloxy group is obtained by reacting the corresponding compound [I] in which R ³ or R ⁴ is a hydroxyl group with an alkyl halide in an appropriate solvent. Is obtained.

(Method e)
Among the compounds [I] which are active ingredients of the present invention, the general formula [Ib]:

[Wherein the symbols have the same meaning as above]
The compound represented by the general formula [Ic]:

The active ingredient compound of the present invention represented by formula (II) is treated with methanesulfonyl chloride and then heated to give the general formula [X]:

It can be obtained by hydrolyzing this compound.

(Method f)
The active ingredient compound [I] of the present invention in which R ³ or R ⁴ is a hydroxyalkyl group can be produced by reducing the corresponding compound [I] in which R ³ or R ⁴ is an alkyloxycarbonyl group. This reduction reaction can be carried out in the presence of a reducing agent such as lithium borohydride.

(G method)
The active ingredient compound [I] of the present invention in which R ⁶ is a heterocyclic group substituted with an alkylamino group (for example, an alkylaminopyridyl group) is a heterocyclic group in which R ⁶ is substituted with a halogen atom. It can be obtained by reacting the corresponding compound [I] with an alkylamine in a solvent in the presence of a base (potassium carbonate, cesium carbonate, etc.).

(Method h)
The active ingredient compound [I] of the present invention in which R ⁶ is a heterocyclic group substituted with an alkyloxy group (for example, an alkyloxypyridyl group) is a heterocyclic group in which R ⁶ is substituted with a halogen atom. It can be obtained by reacting the corresponding compound [I] with an alcohol in a solvent in the presence of a base (potassium carbonate, cesium carbonate, etc.).

(I method)
Examples of the substituent on R ⁶ include an alkyloxycarbonyl group, an alkylcarbonyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, a morpholinocarbonyl group, a mono- or dialkylcarbamoyl group, a mono- or dialkylaminosulfonyl group, and a halogenoalkylcarbonyl group. The active ingredient compound [I] of the present invention having a group containing an amino group substituted with an acyl group includes the corresponding compound [I] having a group containing an amino group as a substituent on R ⁶ and the target substituent It is obtained by treating with an acylating agent having

(J method)
R ³ or R ⁴ is a nitrogen-containing heterocyclic group such as a 1-pyrrolidinyl group, that is, the formula:

[Wherein, ring A represents a 4- to 10-membered nitrogen-containing heterocyclic group]
Active ingredient compound of the invention which are a group represented by [I], the active ingredient compound of the present invention R ³ or R ⁴ is a hydroxyl group [I], a reactive derivative at the hydroxy group (e.g., R ^3, or R ^A compound wherein ⁴ is a methanesulfonyloxy group, etc.), then the reactive derivative and the formula:

[Wherein the symbols have the same meaning as above]
It is obtained by reacting with a cyclic amine compound represented by the above in the presence of a base.

(K method)
The active ingredient compound [I] of the present invention in which R ³ or R ⁴ is a mono- or dialkylcarbamoyl group includes the corresponding compound [I] in which R ³ or R ⁴ is a carboxyl group, and the mono- or dialkylamine compound, It can manufacture by making it react like a method.

(L method)
In the active ingredient compound [I] of the present invention in which the substituent on R ¹ and / or R ² is an alkylsulfinyl group (or alkylsulfonyl group), the substituent on R ¹ and / or R ² is an alkylthio group Obtained by oxidizing the corresponding compound. The oxidation can be carried out in a solvent (eg, methylene chloride, etc.) in the presence of an oxidizing agent (eg, m-chloroperbenzoic acid, etc.).

  The active ingredient compound [I] of the present invention obtained by the methods [A] to [C] and [a] to [l] described above is converted into a pharmacologically acceptable salt, if desired. You can also Conversion to a pharmacologically acceptable salt may be performed according to methods known to those skilled in the art.

  The above compound [II], which is a synthetic intermediate of the active ingredient compound [I] of the present invention, is compound [IV] and general formula [XI]:

[Wherein G represents an amino-protecting group, and other symbols have the same meaning as described above]
And then removing the amino protecting group from the product. Reaction of compound [IV] and [XI] can be implemented according to the said (Method B). Examples of the amino-protecting group include arylalkyloxycarbonyl groups such as benzyloxycarbonyl group, alkyloxycarbonyl groups such as ethyloxycarbonyl group, tert-butyloxycarbonyl group, and the like.

  The compound [V] is represented by the general formula [XII]:

[Wherein the symbols have the same meaning as above]
And the compound [III] can be reacted, and then the amino protecting group can be removed from the product. The reaction of compounds [XII] and [III] can be carried out according to the above (Method A).

  Among the compounds [IV], the compound [IV-a] in which the reactive residue X is a hydroxyl group is, for example, according to the following reaction scheme: (1) aldehyde compound [VIII] and Grignard reagent (or organolithium reagent) [ XIV] or (2) the ketone compound [XV] can be reduced.

[Wherein M represents magnesium halide or lithium, and other symbols have the same meaning as described above]
The reaction between the compound [XIII] and the Grignard reagent (or organolithium reagent) [XIV] can be carried out in the presence or absence of a solvent, as long as the solvent does not affect the reaction. For example, tetrahydrofuran, diethyl ether, 1,4-dimethoxyethane and the like can be mentioned.

  The reduction reaction of compound [XV] is carried out in the presence of a conventional reducing agent (sodium borohydride, lithium borohydride, lithium aluminum hydride, bis (2-methoxyethoxy) sodium aluminum hydride, etc.). The hydroxyl group (group X) in the reaction product (compound [IV-a]) can be easily converted to other reactive residues (for example, fluorine atom, chlorine atom, bromine atom or iodine atom) by a conventional method. Or a halogen atom such as trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, hydroxyl group, etc.).

  In the production of the active ingredient compound of the present invention and synthetic intermediates thereof, when the raw material compound or each intermediate has a functional group, in addition to the above, an appropriate protecting group is added to each functional group by a conventional synthetic chemistry method. Introducing them, and if necessary, their protecting groups may be removed as appropriate.

In the active ingredient compound of the present invention, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkyl include C _1-12 , preferably C _1-6 linear or branched. Alkenyl includes C _2-12 , preferably C _2-6 linear or branched. Alkynyl includes C _2-12 , preferably C _2-6 linear or branched ones. Cycloalkyl includes C _3-10 , preferably C _3-8 . Cycloalkenyl includes C _3-10 , preferably C _3-8 . Examples of alkyleneoxy include C _1-6 , preferably C _1-3 linear or branched. Alkylenedioxy includes C _1-6 , preferably C _1-3 straight or branched chain.

  Specific examples (production examples) of the active ingredient compound [I] of the present invention synthesized by each of the exemplified methods are shown below, but the present invention is not limited thereby.

Production Example 1
(1) (3R) -1- [Bis- (4-chlorophenyl) methyl] -3-aminopyrrolidine (compound obtained in Reference Example 11) (2.05 g) and triethylamine (1.35 mL) in methylene chloride (30 mL) were ice-cooled. Then, 1.21 mL of 4- (trifluoromethyloxy) benzoyl chloride is added dropwise and stirred at room temperature for 1 hour. Add water to the reaction mixture and extract twice with chloroform. The organic layer is filtered through 10 g of NH silica gel (Chromatorex NH silica gel manufactured by Fuji Silysia Chemical), and then the solvent is distilled off under reduced pressure. The resulting crude product was tritiated with ethyl acetate / hexane to give (3R) -1- [bis- (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] Pyrrolidine (2.70 g, 83% yield) is obtained as crystals.
MS (APCI) m / z; 508/510 [M + H] ^< +>.

Production Example 2
(1) 2.01 g of the compound obtained in Reference Example 8 was treated in the same manner as in Reference Example 11 (2) and Reference Example 6 (2) to give (3,4-trans) -1- [bis- (4-chlorophenyl). ) Methyl] -3-hydroxy-4-aminopyrrolidine dihydrochloride (2.13 g, 51% yield).
MS (APCI) m / z; 337/339 [M + H] ^< +>.

(2) 635 μL of 4- (trifluoromethyloxy) benzoyl chloride was added dropwise to a mixed solution of 1.50 g of the compound obtained in (1) above, 1.55 g of sodium hydrogen carbonate in 50 mL of ethyl acetate and 50 mL of water under ice cooling. And stirring at the same temperature for 1 hour. The organic layer is separated from the reaction solution and filtered through 5 g of NH silica gel (Chromatorex NH silica gel manufactured by Fuji Silysia Chemical), and then the solvent is distilled off under reduced pressure. The resulting crude product was tritiated with ethyl acetate / hexane to give (3,4-trans) -1- [bis- (4-chlorophenyl) methyl] -3-hydroxy-4-[[4- (tri Fluoromethyloxy) benzoyl] amino] pyrrolidine (1.61 g, 84% yield) is obtained as crystals.
MS (APCI) m / z; 525/527 [M + H] ^< +>.

Production Example 3
To a solution of 26.9 mg of the compound obtained in Reference Example 11 and 20.5 mg of 6-methylnicotinic acid in 1 mL of chloroform was added 0.4 M of 0.5 M 1-hydroxybenzotriazole-dimethylformamide solution, and 0.5 M of 1 Add 0.4 mL of ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride-chloroform solution and stir at room temperature overnight. Saturated aqueous sodium bicarbonate solution (1 mL), water (2 mL), and chloroform (2 mL) are added to the reaction mixture, and the mixture is stirred for 15 minutes. The chloroform layer is separated and the solvent is concentrated under reduced pressure. The resulting crude product was purified by high performance liquid chromatography (XTerra PrepMS C18 column, solvent; 10 mM ammonium carbonate / methanol = 80: 20 to 5:95), dissolved in 1.5 mL of t-butyl alcohol, and lyophilized. Thus, (3R) -1- [bis- (4-chlorophenyl) methyl] -3-[(6-methylnicotinoyl) amino] pyrrolidine (40.7 mg, yield 92%) is obtained as a powder.
MS (ESI) m / z; 440/442 [M + H] ^< +>.

Production Example 4
To a 1 mL ethanol solution of 35 mg methyl 6-methyloxynicotinate is added 0.14 mL of 2N aqueous sodium hydroxide solution, and the mixture is stirred at 60 ° C. for 2 hours. After the reaction solution is cooled to room temperature, 5N hydrochloric acid 0.06 mL is added, and the solvent is distilled off under reduced pressure to obtain 6-methyloxynicotinic acid. The compound was then treated in the same manner as in Preparation Example 3 to give (3R) -1- [bis- (4-chlorophenyl) methyl] -3-[(6-methyloxynicotinoyl) amino] pyrrolidine (28.0 mg). Yield 61%) as a powder.
MS (ESI) m / z; 456/458 [M + H] ^< +>.

Production Example 5
(1) The corresponding starting material compound is treated in the same manner as in Reference Example 2 and Reference Example 4 (3) to obtain bis- (4-ethyloxyphenyl) methyl chloride.

(2) 545 mg of the compound obtained in (1) above was treated in the same manner as in Reference Example 11, and (3R) -1- [bis- (4-ethyloxyphenyl) methyl] -3- (tert-butyloxycarbonylamino) was obtained. ) Pyrrolidine (671 mg, 76% yield) is obtained.
MS (APCI) m / z; 441 [M + H] ^< +>.

(3) To a solution of 52 mg of the compound obtained in (2) above and 1 mL of 1.5 M 2,6-lutidine-methylene chloride, 1 mL of 1.0 M trimethylsilyl trifluoromethanesulfonate-methylene chloride solution was added, and 25 hours at room temperature. Stir. Add 500 μL of methanol to the reaction solution, dilute with chloroform, and then wash with saturated aqueous sodium bicarbonate. The organic layer is filtered through NH silica gel, and the solvent is distilled off under reduced pressure. To a 2 mL solution of the resulting residue in methylene chloride, add 28 μL of triethylamine and 26 μL of 4- (trifluoromethoxy) benzoyl chloride, and stir at room temperature for 15 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to high performance liquid chromatography (XTerra PrepMS C18 column; Waters, solvent; water / methanol = 1: 1 to 1). 5:95) to give (3R) -1- [bis- (4-ethyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (27.2 mg, Yield 38%) is obtained as an amorphous powder.
MS (APCI) m / z; 529 [M + H] ^< +>.

Production Example 6
[Bis- (4-chlorophenyl)] chloromethane (compound obtained in Reference Example 11 (1)) 342 mg, (3,4-trans) -3- (ethyloxycarbonyl) -4-[[4- (trifluoro 375 mg of methyloxy) benzoyl] amino] pyrrolidine (compound obtained in Reference Example 7) and 0.44 mL of diisopropylamine are stirred in dioxane at 85 ° C. overnight. After dioxane was distilled off from the reaction solution, purification was performed with a silica gel column (n-hexane: ethyl acetate = 4: 1), and (3,4-trans) -1- [bis- (4-chlorophenyl) methyl] -3 was obtained. -(Ethyloxycarbonyl) -4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (249 mg, 51% yield) is obtained as a powder.
MS (APCI) m / z; 581/583 [M + H] ^< +>.

Production Example 7
(1) 243 μL of 4-methyloxybenzaldehyde is treated in the same manner as in Reference Example 5 (1) to obtain (4-chlorophenyl) (4-methyloxyphenyl) methanol (279 mg, yield 56%).
MS (APCI) m / z; 231/233 [M + H-H 2 O] +.

(2) To a solution of 220.6 mg of the compound obtained in (1) above, 250 μL of triethylamine and 2 mL of methylene chloride, 82 μL of methanesulfonyl chloride is added under ice cooling. After stirring for 1 hour at the same temperature, 364 mg of (3R) -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (compound obtained in Reference Example 6) and 3 mL of acetonitrile were added and the mixture was stirred at 80 ° C. for 16 hours. Stir. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate, and the solvent is distilled off under reduced pressure. The resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 4: 1 to 2: 1), dissolved in 1.5 mL of t-butyl alcohol, and lyophilized to give (3R) -1. -[(4-Chlorophenyl) (4-methyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (241.5 mg, 54% yield) is obtained as a powder.
MS (ESI) m / z; 505/507 [M + H] ^< +>.

Production Example 8
60 mg of the compound obtained in Production Example 1, 8.6 mg of tris (dibenzylideneacetone) dipalladium, 10.4 mg of 1,1′-bis (diphenylphosphino) ferrocene, 16.6 mg of zinc cyanide, 3.7 mg of zinc powder A dimethylacetamide 0.5 mL solution is stirred at 200 ° C. for 10 minutes with a microwave synthesis system (Discover, manufactured by CEM). The reaction solution is diluted with ethyl acetate, and water is added to separate the organic layer. After the solvent is distilled off under reduced pressure, the resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1/1). The product obtained is dissolved in t-butyl alcohol and freeze-dried to give (3R) -1- [bis- (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] Amino] pyrrolidine (32.1 mg, 56% yield) is obtained as a powder.
MS (APCI) m / z; 491 [M + H] ^< +>.

Production Example 9
50 mg of the compound obtained in Production Example 1, 0.9 mg of tris (dibenzylideneacetone) dipalladium, 1.5 mg of 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, 24 μL of cyclopentylamine, 1.0 M A mixture of 0.35 mL of a lithium bis (trimethylsilyl) amide-tetrahydrofuran solution is stirred at 110 ° C. for 10 minutes in a microwave synthesis system (Discover, manufactured by CEM). The reaction solution is diluted with ethyl acetate, and water is added to separate the organic layer. After distilling off the solvent under reduced pressure, the resulting crude product is purified by high performance liquid chromatography (XTerra PrepMS C18 column; manufactured by Waters, solvent; water / methanol = 1: 1 to 5:95). The product obtained is dissolved in t-butyl alcohol and lyophilized to give (3R) -1- [bis- [4- (cyclopentylamino) phenyl] methyl] -3-[[4- (trifluoromethyloxy ) Benzoyl] amino] pyrrolidine (18.7 mg, 32% yield) is obtained as a powder.
MS (ESI) m / z; 639 [M + H + MeOH] ^< +>.

Production Example 10
50 mg of the compound obtained in Production Example 1, 0.9 mg of tris (dibenzylideneacetone) dipalladium, 1.5 mg of 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, 29 μL of n-butylmethylamine, A mixture of 0.35 mL of 1.0 M lithium bis (trimethylsilyl) amide-tetrahydrofuran solution is stirred at 110 ° C. for 10 minutes in a microwave synthesis system (Discover, manufactured by CEM). The reaction solution is diluted with ethyl acetate, and water is added to separate the organic layer. After distilling off the solvent under reduced pressure, the resulting crude product is purified by high performance liquid chromatography (XTerra PrepMS C18 column; manufactured by Waters, solvent; water / methanol = 1: 1 to 5:95). The product obtained is dissolved in t-butyl alcohol and lyophilized to give (3R) -1-[[4- (n-butylmethylamino) phenyl] (4-chlorophenyl) methyl] -3-[[4 -(Trifluoromethyloxy) benzoyl] amino] pyrrolidine (12.6 mg, 23% yield, compound a) and (3R) -1- [bis- [4- (n-butylmethylamino) phenyl] methyl]- 3-[[4- (Trifluoromethyloxy) benzoyl] amino] pyrrolidine (18.0 mg, 30% yield, compound b) is obtained as a powder.
Compound a: MS (ESI) m / z; 560/562 [M + H] ⁺ .
Compound b: MS (ESI) m / z; 643 [M + H + MeOH] ⁺ .

Production Example 11
Under a nitrogen atmosphere, 86 μL of trifluoroacetic anhydride is added to a solution of 54 μL of dimethyl sulfoxide in 2 mL of methylene chloride under dry ice-acetone cooling. After stirring for 10 minutes, a suspension of 99 mg of the compound obtained in Production Example 2 in 4 mL of methylene chloride is added and stirred at the same temperature for 1 hour. Add 215 μL of diisopropylethylamine to the reaction mixture, stir for 40 minutes, add 0.2 mL of methanol, and stir at room temperature for 3 hours. Water is added to the reaction solution, extracted with chloroform, and the solvent is distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9: 1 to 2: 1) to give 1- [bis- (4-chlorophenyl) methyl] -3-oxo-4-[[ 4- (Trifluoromethyloxy) benzoyl] amino] pyrrolidine (41.5 mg, 43% yield) is obtained as an amorphous powder.
MS (ESI) m / z; 523/525 [M + H] ^< +>.

Production Example 12
(3S, 4R) -1- [Bis- (4-chlorophenyl) methyl] -3-hydroxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (Optical of compound obtained in Production Example 2) Activator) To a solution of 75.6 mg, acetonitrile 8 mL, and dimethylformamide 2 mL are added methyl iodide 233 μL and silver oxide 216.8 mg in this order, and the mixture is stirred at room temperature for 23 hours. The reaction solution is filtered through Celite, washed with acetonitrile, and then the solvent is distilled off under reduced pressure. The resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 4: 1 to 2: 1) to give (3S, 4R) -1- [bis- (4-chlorophenyl) methyl] -3- Methyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (39.5 mg, 51% yield) is obtained as an amorphous powder.
MS (ESI) m / z; 539/541 [M + H] ^< +>.

Production Example 13
(1) Under a nitrogen atmosphere, 83 μL of methanesulfonyl chloride is added dropwise to a solution of 400 mg of the compound obtained in Production Example 2 and 215 μL of triethylamine in 8 mL of chloroform under ice cooling, followed by stirring at 60 ° C. for 2 hours. The reaction solution is allowed to cool to room temperature, water is added to separate the organic layer, and the solvent is distilled off under reduced pressure. The resulting crude product is purified by NH silica gel flash column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 2: 1 to 0: 1) to give 5- [bis- (4- Chlorophenyl) methyl] -2- [4- (trifluoromethyloxy) phenyl] -3a, 6a-dihydro-3-pyrrolino [3,4-d] oxazole (361 mg, 94% yield) is obtained as an amorphous powder.
MS (APCI) m / z; 507/509 [M + H] ^< +>.

(2) To a solution of the compound obtained in (1) above (360 mg) in methanol (2.5 mL) is added 6N hydrochloric acid (1.5 mL), and the mixture is stirred at 65 ° C. for 30 minutes. The reaction solution is allowed to cool to room temperature, diluted with tetrahydrofuran, and treated with a cation exchange resin (ISOLUTE SCX, manufactured by IST, methanol / tetrahydrofuran = 1: 1 to 1 N ammonia / methanol). (3,4-cis) -1- [bis- (4-chlorophenyl) methyl] -3-hydroxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine by distilling off the solvent under reduced pressure (301 mg, 81% yield) is obtained as an amorphous powder.
MS (APCI) m / z; 525/527 [M + H] ^< +>.

Production Example 14
13 mg of lithium borohydride is added to a tetrahydrofuran / ethanol solution of 100 mg of the compound obtained in Production Example 482, and the mixture is stirred at room temperature for 15 hours. The reaction mixture is evaporated under reduced pressure, aqueous potassium hydrogen sulfate is added, and the mixture is extracted with ethyl acetate. After the organic layer was distilled off under reduced pressure, the resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane = 1: 1) to give (2S, 4R) -1- [bis- (4-chlorophenyl) methyl. ] -2-Hydroxymethyl-4-[(4-chlorobenzoyl) amino] pyrrolidine (72 mg, 73% yield) is obtained as a powder.
MS (APCI) m / z; 489/491 [M + H] ^< +>.

Production Example 15
26 mg of potassium carbonate and 0.5 mL of 1N dimethylamine methanol solution are added to an N-methylpyrrolidone solution of 32 mg of the compound obtained in Production Example 27 and stirred at 100 ° C. for 15 hours. Add water to the reaction mixture and extract with chloroform. After the organic layer was distilled off under reduced pressure, the resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane = 1: 1) to give (3R) -1- [bis- (4-chlorophenyl) methyl]- 3-[[6- (Dimethylamino) nicotinoyl] amino] pyrrolidine (8 mg, 37% yield) is obtained as a powder.
MS (APCI) m / z; 469/471 [M + H] ^< +>.

Production Example 16
(3R) -1- [Bis- (4-chlorophenyl) methyl] -3-[(5-bromonicotinoyl) amino] pyrrolidine 50 mg in toluene solution 7 mg copper iodide, 15 mg cesium carbonate, 15 mg sodium iodide, phenanthroline Add 14 mg and 0.1 mL of ethanol and stir at 100 ° C. for 15 hours. The reaction mixture is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate is added, and the mixture is extracted with ethyl acetate. After the organic layer was distilled off under reduced pressure, the resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane = 1: 1) to give (3R) -1- [bis- (4-chlorophenyl) methyl]- 3-[(5-Ethyloxynicotinoyl) amino] pyrrolidine (12 mg, 26% yield) is obtained as a powder.
MS (APCI) m / z; 470/472 [M + H] ^< +>.

Production Example 17
After adding 4N hydrochloric acid dioxane solution to 20 mg of the compound obtained in Production Example 46 and stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure to give (3R) -1- [bis- (4-chlorophenyl) methyl] -3- [((2S) -2-amino-3-phenylpropionyl) amino] pyrrolidine is obtained. Then, 0.03 mL of 4-morpholinecarbonyl chloride is added dropwise to a solution obtained by adding 0.05 mL of triethylamine and chloroform under ice-cooling, followed by stirring at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer was separated, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane = 1: 1) to give (3R) -1- [bis- (4 -Chlorophenyl) methyl] -3-[[(2S) -2- (morpholinocarbonylamino) -3-phenylpropionyl] amino] pyrrolidine (12 mg, 58% yield) is obtained as a powder.
MS (ESI) m / z; 581 [M + H] ^< +>.

Production Example 18
(1) 11 μL of methanesulfonyl chloride is added dropwise to a solution of 60 mg of the compound obtained in Production Example 13 and 24 μL of triethylamine in 1 mL of methylene chloride under ice cooling, followed by stirring for 30 minutes. After diluting with ethyl acetate, water is added to separate the organic layer, and the solvent is distilled off under reduced pressure. The resulting crude product was purified by NH silica gel flash column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical Ltd., solvent; hexane / ethyl acetate = 4: 1 to 0: 1), and then added to 1.5 mL of t-butyl alcohol. (3,4-cis) -1- [bis- (4-chlorophenyl) methyl] -3-methanesulfonyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino by dissolution and lyophilization ] Pyrrolidine (38.2 mg, 56% yield) is obtained as a powder.
MS (APCI) m / z; 603/605 [M + H] ^< +>.

(2) To a solution of 31.3 mg of the compound obtained in (1) above in 0.3 mL of dimethylformamide is added 45 μL of pyrrolidine, and the mixture is stirred at 150 ° C. for 10 minutes with a microwave synthesis system (Discover, manufactured by CEM). The reaction solution is diluted with ethyl acetate, and water is added to separate the organic layer. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by high performance liquid chromatography (XTerra PrepMS C18 column; manufactured by Waters, solvent; water / methanol = 1: 1 to 5:95), and then t-butyl alcohol. (3,4-trans) -1- [bis- (4-chlorophenyl) methyl] -3- (1-pyrrolidinyl) -4-[[4- (trifluoromethyloxy) Benzoyl] amino] pyrrolidine (13.2 mg, 44% yield) is obtained as a powder.
MS (APCI) m / z; 578/580 [M + H] ^< +>.

Production Example 19
(1) 248.8 mg of the compound obtained in Production Example 6 is dissolved in a mixed solvent of 3 mL of methanol and 3 mL of tetrahydrofuran, and 0.86 mL of 1N aqueous sodium hydroxide solution is added under ice cooling, followed by stirring at room temperature for 4 hours. The solvent is distilled off under reduced pressure, adjusted to about pH = 3 with a saturated aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the solid was collected by filtration to obtain (3,4-trans) -1- [bis- (4-chlorophenyl) methyl] -3-carboxy-4-[[4- (trifluoromethyl Oxy) benzoyl] amino] pyrrolidine (181.1 mg, 76% yield) is obtained as a solid.
MS (APCI) m / z; 553/555 [M + H] ^< +>.

(2) 17 mg of 1-hydroxybenzotriazole and 21 mg of 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride are added to a 1.0 mL solution of 30.0 mg of the compound obtained in (1) above. Stir at room temperature for 30 minutes. Add 0.011 mL of N, N′-dimethylethylenediamine to the reaction mixture and stir at room temperature overnight. The reaction mixture is poured into water and ethyl acetate, and the organic layer is washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The resulting solid was collected by filtration to obtain (3,4-trans) -1- [bis- (4-chlorophenyl) methyl] -3- [2- (dimethylamino) ethylcarbamoyl] -4-[[4- ( Trifluoromethyloxy) benzoyl] amino] pyrrolidine (25.1 mg, 75% yield) is obtained as a powder.
MS (APCI) m / z; 623/625 [M + H] ^< +>.

Production Example 20
A tetrahydrofuran solution of 32 mg of the compound obtained in Reference Example 11 was dropped into a tetrahydrofuran solution of 16 mg of N, N′-carbonyldiimidazole under ice-cooling and stirred for 30 minutes, and then 13 mg of 1,2,3,4-tetrahydroisoquinoline was added. Add dropwise and stir at room temperature for 15 hours. The reaction mixture is evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate is added, and the mixture is extracted with chloroform. After evaporating the solvent from the extract under reduced pressure, the resulting crude product was purified by silica gel chromatography with ethyl acetate / hexane to give (3R) -1- [bis- (4-chlorophenyl) methyl] -3- [(2-1,2,3,4-tetrahydroisoquinolyl) carbonylamino] pyrrolidine (30 mg, 62% yield) is obtained as a powder.
MS (APCI) m / z; 480/482 [M + H] ^< +>.

Production Example 21
32.1 mg of the compound obtained in Reference Example 11, 29.4 mg of 4-cyanobenzoic acid, 20.4 mg of 1-hydroxyazabenzotriazole, 275 mg of N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide), dimethyl Add 2 mL of formamide and stir overnight at room temperature using a parallel reactor (MiniBlock; manufactured by METTLER TOLEDO). The reaction solution is filtered, and the resin residue is washed twice with 1 mL of dimethylformamide. Macroporous triethylammonium methylpolystyrene carbonate (265.2 mg) and tris (2-aminoethyl) aminomethylpolystyrene (82.9 mg) are added to the filtrate and stirred overnight at room temperature. The reaction solution was passed through a cation exchange resin (ISOLUTE SCX manufactured by IST) and washed with dimethylformamide, and then the target product was eluted with a 10% ammonia-methanol solution. After distilling off the solvent with a nitrogen purge, the residue is purified with a silica gel column (ISOLUTE SI manufactured by IST, chloroform: hexane = 20: 1 → chloroform → chloroform: ethyl acetate = 10: 1). After evaporating the solvent from the eluate under reduced pressure, the residue was freeze-dried to give (3R) -1- [bis- (4-chlorophenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine (30.9 mg) Yield 69%) as a powder.
MS (APCI) m / z; 450/452 [M + H] ^< +>.

Production Example 22
(1) 4.0 g of 4-bromobenzaldehyde is treated in the same manner as in Reference Example 5 to obtain chloro (4-chlorophenyl) (4-bromophenyl) methane (5.08 g, yield 75%).
MS (APCI) m / z; 279/281 [M + H-HCl] ^<+> .

(2) By treating 1.73 g of the compound obtained in (1) above in the same manner as in Production Example 6,
1-[(4-Bromophenyl) (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (1.65 g, 82% yield) is obtained.
MS (APCI) m / z; 553/555 [M + H] ^< +>.

(3) 60 mg of the compound obtained in the above (2), tris (dibenzylideneacetone) dipalladium 4.0 mg, 1,1′-bis (diphenylphosphino) ferrocene 4.8 mg, zinc cyanide 7.6 mg, water 50 μL A dimethylformamide 0.5 mL solution is stirred at 200 ° C. for 10 minutes using a microwave synthesis system (Discover, manufactured by CEM). The reaction solution is diluted with ethyl acetate, and water is added to separate the organic layer. After evaporating the solvent under reduced pressure, the resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to 1/1). The resulting product is dissolved in t-butyl alcohol and lyophilized to give 1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino. ] Pyrrolidine (13.4 mg, 25% yield) is obtained as a powder.
MS (APCI) m / z; 500/502 [M + H] ^< +>.

Production Examples 23 to 431
The corresponding raw material compounds are treated in the same manner as in any one of Production Examples 1 to 5 to obtain the compounds shown in Table 1 below.

Production Examples 432 to 475
The corresponding starting material compound is treated in the same manner as in any of Production Examples 1 to 5, and then treated in the same manner as in any of Production Examples 8 to 19 to obtain the compounds described in Table 2 below.

Production Examples 476 to 499
The corresponding starting material compounds are treated in the same manner as in Production Example 6 or 7 to give the compounds shown in Table 3 below.

Production Examples 500 to 507
The corresponding starting material compound is treated in the same manner as in any one of Production Examples 6 or 7, and then treated in the same manner as in any of Production Examples 8 to 19 to obtain the compounds described in Table 4 below.

Production Examples 508 to 512
The corresponding starting material compounds are treated in the same manner as in Production Example 20 to give the compounds shown in Table 5 below.

Production Example 513
To a 64 mg water-methanol solution of the compound obtained in Production Example 1, 21 μL of 6N hydrochloric acid water was added. The solvent was removed under reduced pressure to give (3R) -1- [bis- (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine hydrochloride (68 mg, yield) 100%) as a colorless solid.
MS (APCI) m / z; 509/511 [M + H] ^< +>.

Production Example 514
(1) 92 mg of the compound obtained in Reference Example 13 was treated in the same manner as in Production Example 6, and (3S, 4R) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxycarbonyl-4- [(4-Cyanobenzoyl) amino] pyrrolidine (24 mg, 15% yield) is obtained.
MS (APCI) m / z; 522/524 [M + H] ⁺
(2) 200 mg of the compound obtained in the above (1) is heated to reflux in 28.3 mg of sodium borohydride and tetrahydrofuran. Methanol 0.5mL is dripped here over 30 minutes, and it stirs at the same temperature for 1 hour after completion | finish. After distilling off the solvent, water and ethyl acetate are added for liquid separation, and the organic layer is washed with water and saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated, and the residue was purified with a silica gel column (n-hexane: ethyl acetate = 1: 1) to obtain (3S, 4R) -1- [bis- (4-chlorophenyl) methyl]. -3-Hydroxymethyl-4-[(4-cyanobenzoyl) amino] pyrrolidine (123.1 mg, 67% yield) is obtained.
MS (APCI) m / z; 480/482 [M + H] ^< +>.

(3) Dissolve 60 mg of the compound obtained in (2) above in 7 mL of acetonitrile, add 0.26 mL of iodoethane and 188 mg of silver oxide, and stir at room temperature for 3 days. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel plate (3S, 4R) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxymethyl-4-[(4 -Cyanobenzoyl) amino] pyrrolidine (13.2 mg, 21% yield) is obtained.
MS (APCI) m / z; 508/510 [M + H] ^< +>.

Production Examples 515 to 594
The corresponding raw material compounds are treated in the same manner as in any of Production Examples 1 to 5, 21 and, if necessary, further treated in the same manner as in any of Production Examples 8 to 19, 22, 513 to give the compounds described in Table 6 below. obtain.

Production Examples 595 to 619
The corresponding starting material compound is treated in the same manner as in any of Production Examples 6 or 7, and if necessary, it is further treated in the same manner as in any of Production Examples 8 to 19, 22, 514 to obtain the compounds described in Table 7 below.

Production Examples 620 to 631
The corresponding raw material compounds are treated in the same manner as in any one of Production Examples 1 to 5 to obtain the compounds described in Table 8 below.

Production Examples 632 to 708
The corresponding starting material compound is treated in the same manner as in Production Example 6 or 7, to give the compounds shown in Table 9 below.

Production Example 709
(3R) -1-[(4-chlorophenyl) (2-cyanophenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino was prepared by treating the corresponding starting material compound in the same manner as in Production Example 8. ] Pyrrolidine is obtained as a powder.
MS (APCI) m / z: 500/502 [M + H] ^< +>.

Production Example 710
By treating the compound (50 mg) obtained in Reference Example 21 and dimethylamine in the same manner as in Production Example 19 (2), (3R) -1-[(4-chlorophenyl) (3-dimethylcarbamoylphenyl) methyl] -3-[[(4-Trifluoromethyloxy) benzoyl] amino] pyrrolidine (52 mg, yield: 99%) is obtained.
MS (APCI) m / z: 546/548 [M + H] ^< +>.

Production Example 711
(3R) -1-[(4-Methylthiophenyl) (4-cyanophenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine was added to a solution of 45.3 mg of methylene chloride in 2 mL of methylene chloride under ice-cooling. Add 31 μL of acetic acid and stir at room temperature for 30 minutes. Under ice-cooling, 23 mg of m-chloroperbenzoic acid is added to the mixture, followed by stirring at the same temperature for 1 hour, and further stirring at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the organic layer is extracted with a diatomaceous earth column (ChemElut). The extract is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent; chloroform / methanol = 98/2 to 90/10). The product obtained is dissolved in t-butyl alcohol and freeze-dried to give (3R) -1-[(4-cyanophenyl) (4-methylsulfinylphenyl) methyl] -3-[(4-cyanobenzoyl) Amino] pyrrolidine (42.6 mg, 91% yield) is obtained as a powder.
MS (APCI) m / z; 469 [M + H] ^< +>.

Production Example 712
(3R) -1-[(4-Methylthiophenyl) (4-cyanophenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine was added to a solution of 45.3 mg of methylene chloride in 2 mL of methylene chloride under ice-cooling. Add 31 μL of acetic acid and stir at room temperature for 30 minutes. Under ice cooling, 46 mg of m-chloroperbenzoic acid is added to the mixture, followed by stirring at the same temperature for 1 hour and further stirring at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the organic layer is extracted with a diatomaceous earth column (ChemElut). The extract is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 40/60 to 60/40). The product obtained is dissolved in t-butyl alcohol and freeze-dried to give (3R) -1-[(4-cyanophenyl) (4-methylsulfonylphenyl) methyl] -3-[(4-cyanobenzoyl) Amino] pyrrolidine (27.4 mg, 57% yield) is obtained as a powder.
MS (APCI) m / z; 485 [M + H] ^< +>.

Production Example 713
[(4-Chlorophenyl) (4-chloro-2-methylphenyl)] methanol (40.1 mg) in methylene chloride (0.65 mL) is added with phosphorus tribromide (20 μL) and stirred overnight at room temperature. After adding water and chloroform to the reaction solution and stirring, the organic layer is extracted with a diatomaceous earth column (ChemElut), and the solvent is distilled off under reduced pressure. Add 105 μL of diisopropylethylamine and 1 mL of acetonitrile to the resulting residue, and heat to reflux for 2 days. After cooling the reaction solution to room temperature, water and ethyl acetate are added, and the organic layer is separated and concentrated under reduced pressure. The resulting crude product is purified by high performance liquid chromatography (XTerra PrepMS C18 column, solvent; water / methanol = 1: 1 to 5:95). The product obtained is dissolved in t-butyl alcohol and freeze-dried to give (3R) -1-[(4-chlorophenyl) (4-chloro-2-methylphenyl) methyl] -3-[(4-cyano Benzoyl) amino] pyrrolidine (37.3 mg, 54% yield) is obtained as a powder.
MS (APCI) m / z; 464/466 [M + H] ^< +>.

Production Examples 714 to 716
The corresponding starting material compounds are treated in the same manner as in Production Example 712 to give the compounds shown in Table 10 below.

Production Example 717
By treating the corresponding starting material compound in the same manner as in Production Example 1, the compounds shown in Table 11 below are obtained.

Production Examples 718 to 766
The corresponding starting material compounds are treated in the same manner as in Production Examples 6 and 7 to give the compounds described in Table 12 below.

Production Examples 767 to 769
The corresponding starting material compounds are treated in the same manner as in Production Example 3 to obtain the compounds shown in Table 13 below.

Production Examples 770-786
The corresponding starting material compounds are treated in the same manner as in Production Example 6 to obtain the compounds shown in Table 14 below.

Production Examples 787-791
The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 15 below.

Production Examples 792 to 829
The corresponding starting material compounds are treated in the same manner as in Production Example 6 to give the compounds shown in Table 16 below.

Reference example 1
(1) To a suspension of 2.0 g of 4-hydroxybenzaldehyde, 2.83 g of dimethylaminoethyl chloride hydrochloride, 8 mL of dimethylformamide, and 1 mL of diisopropyl ether, 5.53 g of potassium carbonate is added and stirred at 60 ° C. overnight. Water is added to the reaction mixture, and the mixture is extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 90/10) to give 4- [2- (dimethylamino) ethyloxy] benzaldehyde (674 mg, 21% yield) is obtained as an oil.
MS (APCI) m / z; 194 [M + H] ^< +>.

(2) Under a nitrogen atmosphere, a solution of 386.5 mg of the compound obtained in (1) above in 4 mL of tetrahydrofuran was added to 2 mL of a 1.0 M 4-chlorophenylmagnesium bromide-diethyl ether solution while cooling with dry ice-acetone. Stir at overnight. Water is added to the reaction mixture, and the mixture is extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by NH silica gel flash column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical, solvent; hexane / ethyl acetate = 1: 1 to 0: 1). (4-Chlorophenyl) [4- [2- (dimethylamino) ethyloxy] phenyl] methanol (208 mg, 34% yield) is obtained as an oil.
MS (APCI) m / z; 306/308 [M + H] ^< +>.

Reference example 2
(1) To a solution of 1.0 g of bis (4-hydroxyphenyl) ketone in 10 mL of dimethylformamide, 2.54 g of potassium carbonate and 1.40 mL of isopropyl iodide are sequentially added and stirred at room temperature for 18 hours. Water is added to the reaction mixture, and the mixture is extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5-60 / 40) to give bis (4-isopropyloxyphenyl) ketone (1.33 g, A yield of 96%) is obtained as a powder.
MS (APCI) m / z; 299 [M + H] ^< +>.

(2) 235 mg of sodium borohydride is added to a solution of the compound obtained in (1) above (1.33 g), ethanol 18 mL, and tetrahydrofuran 2 mL, and stirred at room temperature for 18 hours. The reaction mixture is concentrated, ethyl acetate and water are added, and the mixture is extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 95/5 to 40/60) to give bis (4-isopropyloxyphenyl) methanol (1.30 g, 97% yield) is obtained as an oil.
MS (APCI) m / z; 283 [M + H] ^< +>.

Reference example 3
(1) In a nitrogen atmosphere, 7.35 g of methanesulfonyl chloride is added dropwise to a solution of 9.98 g of 4-bromobenzyl alcohol and 11.2 mL of triethylamine in 100 mL of ethyl acetate under ice cooling, and the mixture is stirred for 1 hour under ice cooling. Water is added to the reaction mixture, and the mixture is extracted twice with ethyl acetate. Washing sequentially with water and saturated brine, and drying the organic layer over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure is tritiated with ethyl acetate-hexane to give 4-bromobenzyl methanesulfonate (13.54 g, yield 91%) as crystals.
MS (EI) m / z; 264/266 [M +] ^< +>.

(2) A methanol suspension of 1.2 g of the compound obtained in (1) above is stirred at 85 ° C. for 4 hours. Water is added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture is extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20-60 / 40) to give 4-bromobenzyl methyl ether (0.76 g, yield 83). %) As an oil.
MS (APCI) m / z; 200/202 [M +] ^< +>.

(3) Under a nitrogen atmosphere, 1.61 mL of a 1.59 M butyllithium-hexane solution is added dropwise to a solution of 515 mg of the compound obtained in (2) above in 4 mL of tetrahydrofuran under dry ice-acetone cooling, and the mixture is stirred for 10 minutes. Add a solution of 4-chlorobenzaldehyde (360 mg) in tetrahydrofuran (1 mL) and stir at room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted twice with ethyl acetate. The organic layer is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20-60 / 40). This gives (4-chlorophenyl) [4- (methyloxymethyl) phenyl] methanol (459 mg, 68% yield) as an oil.
MS (APCI) m / z; 247/202 [M + H-H 2 O] +.

Reference example 4
(1) Under a nitrogen atmosphere, 3.4 mL of oxalyl chloride and 200 μL of dimethylformamide were added to a suspension of 5.0 g of bis- (4-carboxyphenyl) ketone in 100 mL of methylene chloride, and the mixture was stirred at room temperature for 4 hours. To do. Add 50 mL of tetrahydrofuran and stir at room temperature for 18 hours. After distilling off the solvent from the reaction solution under reduced pressure, 100 mL of tetrahydrofuran, 7.75 mL of triethylamine, and 4.86 mL of tert-butylamine are sequentially added to the residue, followed by stirring at room temperature for 1 hour and 30 minutes. Water is added to the reaction mixture, and the precipitated crystals are collected by filtration to give bis [4- (tert-butylcarbamoyl) phenyl] ketone (6.44 g, yield 92%) as crystals.
MS (EI) m / z; 381 [M + H] ^< +>.

(2) Add 232 mg of sodium borohydride to a suspension of 2.9 g of the compound obtained in (1) above, 15.2 mL of 2-propanol, and 0.9 mL of water, and stir at 85 ° C. for 30 minutes. After allowing to cool to room temperature, water is added, and the precipitated crystals are collected by filtration to give bis [4- (tert-butylcarbamoyl) phenyl] methanol (2.85 g, yield 97%) as crystals.
MS (APCI) m / z; 383 [M + H] ^< +>.

  (3) A solution of 4.96 g of the compound obtained in (2) above in 40 mL of thionyl chloride is heated to reflux for 5 hours. The reaction mixture is concentrated under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give chloro [bis- (4-cyanophenyl)] methane (3.59 g, yield 100). %) As an oil.

Reference Example 5
(1) Under a nitrogen atmosphere and cooling with dry ice-methanol, 30 mL of a 1.0 M 4-chlorophenylmagnesium bromide-diethyl ether solution was dropped into a tetrahydrofuran solution of 3.93 g of 4-cyanobenzaldehyde, and the same temperature was maintained for 10 minutes. Stir. 10% aqueous hydrochloric acid is added to the reaction mixture, and the aqueous layer is extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether was added to the resulting crude product, and the solid was collected by filtration to give (4-chlorophenyl) (4-cyanophenyl). ) Methanol is obtained as a pale yellow solid (6.98 g, 96%).
MS (APCI) m / z; 268,280 [M + Cl] ^< +>.

  (2) 12.4 g of the compound obtained in (1) above and 30 mL of thionyl chloride are refluxed for 3 hours. The reaction mixture is concentrated under reduced pressure, and the residue is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain chloro (4-chlorophenyl) (4-cyanophenyl) methane (12.4 g, yield 93%). ) As an oil.

Reference Example 6
(1) Under a nitrogen atmosphere, a solution of 10.0 g of (3R) -3- (tert-butyloxycarbonylamino) pyrrolidine and 5.43 g of triethylamine in 100 mL of methylene chloride is cooled with ice under cooling of 7.7 mL of benzyloxycarbonyl chloride. Methylene 20 mL solution is added dropwise over 15 minutes and stirred at room temperature for 1 hour. Add 70 mL of water to the reaction mixture and extract with chloroform. After sequentially washing with 70 mL of water, 70 mL of 5% aqueous citric acid solution and 70 mL of saturated saline, the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was tritiated with diisopropyl ether to give (3R) -1-benzyloxycarbonyl-3- (tert-butyloxycarbonylamino) pyrrolidine (11.8 g, yield 70). %) As crystals.
MS (APCI) m / z; 321 [M + H] ^< +>.

(2) To 100 mL of 1,4-dioxane in 12.1 g of the compound obtained in (1) above, 50 mL of 4N hydrochloric acid-dioxane is added and stirred at room temperature for 19 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was tritiated with diisopropyl ether to obtain (3R) -3-amino-1-benzyloxycarbonylpyrrolidine monohydrochloride (9.2 g, yield 94%). MS (APCI) m / z obtained as crystals; 283 [M + H] ⁺ .

(3) 8.23 g of the compound obtained in the above (2), 6.61 g of 4- (trifluoromethyloxy) benzoic acid, 6.7 mL of triethylamine, 6.38 g of 1-hydroxybenzotriazole, 82.3 mL of methylene chloride. Add 7.40 g of 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride to the suspension and stir at room temperature overnight. Add 58 mL of water to the reaction mixture and stir for 10 minutes. The chloroform layer is separated and washed successively with 58 mL of saturated aqueous sodium bicarbonate and 58 mL of saturated brine, and then the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1/1) to give (3R) -1-benzyloxycarbonyl-3-[[ 4- (Trifluoromethyloxy) benzoyl] amino] pyrrolidine (11.29 g, 87% yield) is obtained as an oil.
MS (APCI) m / z; 409 [M + H] ^< +>.

(4) To a solution of 11.29 g of the compound obtained in (3) above in 114 mL of methanol is added 10% palladium-carbon (0.32 g), and the mixture is stirred at room temperature for 1.5 hours in an atmospheric hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give (3R) -3-[[4- (trifluoromethoxy) benzoyl] amino] pyrrolidine (7.76 g, yield 87%) as an oil. .
MS (APCI) m / z; 275 [M + H] ^< +>.

Reference Example 7
(1) 0.64 mL of triethylamine was added to a solution of 1.04 g of (3,4-trans) -4-amino-3-ethyloxycarbonyl-1- (tert-butyloxycarbonyl) pyrrolidine in 20 mL of methylene chloride, and ice-cooled. 4- (Trifluoromethyloxy) benzoyl chloride is added dropwise thereto and stirred at room temperature for 24 hours. Chloroform is added to the reaction solution, washed with saturated aqueous citric acid and saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform / ethyl acetate = 10/1) to give (3,4-trans) -3-ethyloxycarbonyl-1- (tert -Butyloxycarbonyl) -4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (1.34 g, 75% yield) is obtained as an oil.
MS (APCI) m / z; 447 [M + H] ^< +>.

(2) To a solution of the compound obtained in (1) (1.34 g) in chloroform (15 mL) is added 4N hydrochloric acid-ethyl acetate (5 mL), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, and the resulting residue is neutralized with 1N aqueous sodium hydroxide solution. The organic layer is dried over magnesium sulfate, the solvent is concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (chloroform / methanol = 49/1) to obtain (3,4-trans) -3-ethyl. Oxycarbonyl-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (943 mg, 91%) is obtained as an oil.
MS (APCI) m / z; 347 [M + H] ^< +>.

Reference Example 8
(1) To a solution of 5.0 g of 1-benzyloxycarbonyl-3-pyrroline in 125 mL of methylene chloride is added 12.17 g of metachloroperbenzoic acid and stirred at room temperature for 3 days. Add 100 mL of saturated aqueous sodium thiosulfate solution to the reaction mixture and stir for 30 minutes. The reaction solution is extracted twice with chloroform, and then the extract is washed with 100 mL of 2N aqueous sodium hydroxide solution twice and with saturated brine, and the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain benzyl 6-oxa-3-azabicyclo [3,1,0] hexane-3-carboxylate (5.58 g, yield 100%) as an oil.
MS (APCI) m / z; 220 [M + H] ^< +>.

(2) A mixture of 5.58 g of the compound obtained in (1) above and 100 mL of 28% aqueous ammonia solution is stirred at 40 ° C. for 2 days. 2N aqueous sodium hydroxide solution (50 mL) is added, and the mixture is extracted 3 times with chloroform. The organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain (3,4-trans) -4-amino-1-benzyloxycarbonyl-3-hydroxypyrrolidine (5.34 g, yield 92%) as an oil.
MS (APCI) m / z; 237 [M + H] ^< +>.

(3) To a solution of 5.34 g of the compound obtained in (2) above in 50 mL of chloroform, a solution of 7.40 g of di-tert-butyl dicarbonate in 10 mL of chloroform is added dropwise under ice cooling, and the mixture is stirred at room temperature for 19 hours. The reaction solution is washed with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1/1). (3,4-trans) -1-benzyloxycarbonyl-3-hydroxy-4- (tert-butyloxycarbonylamino) pyrrolidine (5.55 g, 73% yield) as crystals.
MS (APCI) m / z; 337 [M + H] ^< +>.

(4) Add 500 mg of 20% palladium hydroxide carbon to a mixture of 3.54 g of the compound obtained in (3) above, 31 mL of methanol and 7 mL of tetrahydrofuran, and stir overnight at room temperature under hydrogen pressure (40-45 Parr). The insoluble material is filtered through Celite, and the filtrate is concentrated under reduced pressure. The resulting crude product was tritiated with ethyl acetate-diisopropyl ether to give (3,4-trans) -3-hydroxy-4- (tert-butyloxycarbonylamino) pyrrolidine (2.0 g, 94% yield). Is obtained as a powder.
MS (APCI) m / z; 203 [M + H] ^< +>.

Reference Example 9
(1) In a nitrogen atmosphere, 26.5 g of the compound obtained in Reference Example 8 (1), (1R, 2R)-(−)-[1,2-cyclohexanediamino-N, N′-bis (3,5) chloride -Di-t-butylsalicylidene)] A mixture of 1.57 g of chromium and 17.7 mL of trimethylsilyl azide is stirred at room temperature for 2 days. Chloroform is added to the reaction solution, which is washed successively with water and saturated brine, and then the organic layer is dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography (hexane / ethyl acetate = 10/1 to 2/1 and then chloroform / methanol = 20/1 to 9/1) ( 3S, 4S) -4-azido-1-benzyloxycarbonyl-3-trimethylsilyloxypyrrolidine (compound a, 20.6 g, 55% yield) and (3S, 4S) -4-azido-1-benzyloxycarbonyl- 3-Hydroxypyrrolidine (compound b, 8.16 g, 28% yield) is obtained as an oil.
Compound a: MS (APCI) m / z; 335 [M + H] ⁺ .
Compound b: MS (APCI) m / z; 263 [M + H] ⁺ .

(2) Add 26.67 g of triphenylphosphine to a solution of 20.6 g and 8.16 g of tetrahydrofuran (740 mL) obtained in the above (1), respectively, and stir at room temperature overnight. To the residue obtained by concentrating the reaction solution under reduced pressure, 380 mL of methanol and 380 mL of 0.5N aqueous sodium hydroxide solution are added and stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, adjusted to pH 3 with 6N aqueous hydrochloric acid, and washed with chloroform. The aqueous layer is adjusted to pH 9 with 5N aqueous sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (3S, 4S) -4-amino-1-benzyloxycarbonyl-3-hydroxypyrrolidine (19.6 g, yield 90%) as an oil. Get as a thing.
MS (APCI) m / z; 237 [M + H] ^< +>.

(3) By treating 14.61 g of the compound obtained in the above (2) in the same manner as in Reference Example 8 (3), (3S, 4S) -1-benzyloxycarbonyl-3-hydroxy-4- (tert-butyl) Oxycarbonylamino) pyrrolidine (18.59 g, 94% yield) is obtained as crystals.
MS (APCI) m / z; 337 [M + H] ^< +>.

(4) To a solution of 18.56 g of the compound obtained in (3) above in 200 mL of methanol is added 1.16 g of 10% palladium carbon, and the mixture is stirred at room temperature for 3 hours in an atmospheric hydrogen atmosphere. The insoluble material is filtered through Celite, and the filtrate is concentrated under reduced pressure. The resulting product was tritiated with methanol-diisopropyl ether to give (3S, 4S) -3-hydroxy-4- (tert-butyloxycarbonylamino) pyrrolidine (10.8 g, yield 97%) as crystals. obtain.
MS (APCI) m / z; 203 [M + H] ^< +>.

Reference Example 10
(1) 6 mg of dimethylaminopyridine was added to a dichloromethane solution of 122 mg of (2S, 4R) -2-carboxy-4-[(9-fluorenyl) methyloxycarbonylamino] -1-tert-butyloxycarbonylpyrrolidine, and ice-cooled. 1-Ethyl-3- (3′-dimethylaminopropyl) carbodiimide 120 mg in dichloromethane and methanol 0.5 mL are added dropwise and stirred at the same temperature for 2 hours. After adding water to the reaction solution, the organic layer is extracted with a diatomaceous earth column (Chem Elut, manufactured by Varian). The extract is concentrated under reduced pressure to give crude product (2S, 4R) -4-[(9-fluorenyl) methyloxycarbonylamino] -2-methyloxycarbonyl-1-tert-butyloxycarbonylpyrrolidine. To the obtained crude product, 5 mL of 20% piperidine / dichloromethane solution is added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (2S, 4R) -4-amino-2-methyloxycarbonyl-1-tert-butyloxy. Carbonylpyrrolidine (38 mg, 38% yield) is obtained as an oil.
MS (APCI) m / z; 245 [M + H] ^< +>.

(2) A solution of 36 mg of the compound obtained in the above (1), 30 mg of 4-chlorobenzoic acid, 30 mg of N-hydroxybenzotriazole, 43 mg of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide in 0.5 mL of dimethylformamide Is stirred for 15 hours at room temperature. Saturated brine is added to the reaction mixture, and the aqueous layer is extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (2S, 4R) -4-[(4-chlorobenzoyl) amino] -2-methyloxy. Carbonyl-1-tert-butyloxycarbonylpyrrolidine (37 mg, 64% yield) is obtained as an oil.
MS (ESI) m / z; 383, 385 [M + H] ^< +>.

  (3) 37 mg of the compound obtained in (2) above and 5 mL of 4N hydrochloric acid / dioxane solution are stirred at room temperature for 15 hours. The reaction solution is concentrated under reduced pressure to obtain (2S, 4R) -4-[(4-chlorobenzoyl) amino] -2-methyloxycarbonylpyrrolidine.

Reference Example 11
(1) 100 g of bis- (4-chlorophenyl) methanol is treated in the same manner as in Reference Example 5 (2) to obtain chloro [bis (4-chlorophenyl)] methane (100.5 g, yield 94%).
MS (EI) m / z; 270 [M +] ^< +>.

(2) 14.5 g of the compound obtained in the above (1) and 10 g of (3R) -tert-butyloxycarbonylaminopyrrolidine were treated in the same manner as in Production Example 5 to give (3R) -1- [bis- (4- Chlorophenyl) methyl] -3-tert-butyloxycarbonylaminopyrrolidine (18.8 g, 83% yield) is obtained as an oil.
MS (APCI) m / z; 421 [M + H] ^< +>.

(3) 18 g of the compound obtained in (2) above and 30 mL of trifluoroacetic acid are stirred in 100 mL of methylene chloride at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, and aqueous hydrochloric acid is added to the residue to dissolve insolubles, followed by washing with diethyl ether. The aqueous layer is made alkaline by adding potassium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated to give a crude (3R) -3-amino-1- [bis- (4-chlorophenyl) methyl] pyrrolidine product as an oil. Get as.
MS (APCI) m / z; 321, 323 [M + H] ^< +>.

Reference Example 12
4-Oxo-3-ethyloxycarbonyl-1-tert-butyloxycarbonylpyrrolidine is treated in the same manner as described in WO03 / 024477, page 27 to give (3S, 4R) -4-amino-3-ethyloxy. Carbonyl-1-tert-butyloxycarbonylpyrrolidine is obtained.

Reference Example 13
(1) By treating 1.04 g of the compound obtained in Reference Example 12 and 662 mg of 4-cyanobenzoyl chloride in the same manner as in Reference Example 7 (1), (3S, 4R) -1- (tert-butyloxycarbonyl) -3-Ethyloxycarbonyl-4-[(4-cyanobenzoyl) amino] pyrrolidine (624 mg, 40% yield) is obtained as an oil.
MS (APCI) m / z; 388 [M + H] ^< +>.

(2) 624 mg of the compound obtained in the above (1) was treated in the same manner as in Reference Example 7 (2) to give (3S, 4R) -3-ethyloxycarbonyl-4-[(4-cyanobenzoyl) amino] pyrrolidine ( 94 mg, 20% yield).
MS (APCI) m / z; 288 [M + H] ^< +>.

Reference Example 14
(1) 2.07 g of the compound obtained in Reference Example 12 and 1.51 mL of 4- (trifluoromethyloxy) benzoyl chloride were treated in the same manner as in Reference Example 7, and (3S, 4R) -1- (tert- Butyloxycarbonyl) -3-ethyloxycarbonyl-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (3.3 g, 92% yield) is obtained.
MS (APCI) m / z; 447 [M + H] ^< +>.

(2) 3.3 g of the compound obtained in (1) above was treated in the same manner as in Production Examples 514 (2) and (3) to give (3S, 4R) -1- (tert-butyloxycarbonyl) -3-ethyl. Oxymethyl-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine (1.14 g, 35%) is obtained.
MS (APCI) m / z; 433 [M + H] ^< +>.

  (3) 1.14 g of the compound obtained in the above (2) was treated in the same manner as in Reference Example 7 (2) to give (3S, 4R) -3-ethyloxymethyl-4-[[4- (trifluoromethyloxy ) Benzoyl] amino] pyrrolidine (832.5 mg, 95% yield) is obtained.

Reference Example 15
(1) 48.8 g of the compound obtained in Reference Example 5 and 28.87 g of (3R) -3- (tert-butyloxycarbonylamino) pyrrolidine were treated in the same manner as in Production Example 6 to obtain (3R) -1-[( A diastereomeric mixture (58.1 g, 90.1% yield) of 4-cyanophenyl) (4-chlorophenyl) methyl] -3- (tert-butyloxycarbonylamino) pyrrolidine is obtained.

  (2) The mixture obtained in the above (1) was divided by a Kiram column (CHIRALPACK AD-H; Daicel Chemical) and the optically active substance (3R) -1-[(S)-(4-cyanophenyl) (4- Chlorophenyl) methyl] -3- (tert-butyloxycarbonylamino) pyrrolidine (22.2 g, 38.2% yield) and (3R) -1-[(R)-(4-cyanophenyl) (4-chlorophenyl) ) Methyl] -3- (tert-butyloxycarbonylamino) pyrrolidine (22.4 g, 38.6%).

Reference Example 16
(1) To a solution of 0.5 g of sodium hydride in 15 mL of dimethylformamide under ice cooling, add 10 mL of dimethylformamide of 2.2b of compound b obtained in Reference Example 9 (1) and stir at room temperature for 1 hour. Add 1.59 mL of 2-methoxyethyl bromide and stir overnight at room temperature. After cooling with ice, 0.5 g of sodium hydride is added and stirred at room temperature for 1 hour. Further, 1.59 mL of 2-methoxyethyl bromide is added and stirred at room temperature for 2 hours. After dilution with diethyl ether, water is added and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15-65: 35) to give (3S, 4S) -4-azido-1-benzyloxycarbonyl-3- [2- (Methyloxy) ethyloxy] pyrrolidine (1.78 g, 66% yield) is obtained as an oil.
MS (APCI) m / z; 321 [M + H] ^< +>.

(2) By treating 2.03 g of the compound obtained in the above (1) in the same manner as in Reference Example 9 (2), (3S, 4S) -4-amino-1-benzyloxycarbonyl-3- [2- ( Methyloxy) ethyloxy] pyrrolidine (1.82 g, 98% yield) is obtained as an oil.
MS (APCI) m / z; 295 [M + H] ^< +>.

(3) By treating 1.82 g of the compound obtained in the above (2) in the same manner as in Reference Example 8 (3), (3S, 4S) -1-benzyloxycarbonyl-3- [2- (methyloxy) ethyloxy ] -4- (tert-Butyloxycarbonylamino) pyrrolidine (2.25 g, 92% yield) is obtained as an oil.
MS (APCI) m / z; 395 [M + H] ^< +>.

(4) 200 mg of 10% palladium on carbon is added to a solution of the compound 2.25 g obtained in (3) above in 40 mL of methanol, and the mixture is stirred at room temperature for 4 hours in an atmospheric hydrogen atmosphere. The insoluble material was filtered through Celite, and the filtrate was evaporated under reduced pressure to give (3S, 4S) -3- [2- (methyloxy) ethyloxy] -4- (tert-butyloxycarbonylamino) pyrrolidine (1.46 g, 98% yield) is obtained as an oil.
MS (APCI) m / z; 261 [M + H] ^< +>.

Reference Example 17
(1) 555 μL of [bis (2-methoxyethyl) -amino] sulfur = trifluoroide was added to 555 mg of 4-bromobenzaldehyde under ice-cooling, and the mixture was further stirred for 60 minutes at room temperature (when necessary, under ice-cooling). Stir for 2 hours at ° C. The obtained crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 100/0 to 95/5) to give 1-bromo-4- (difluoromethyl) benzene (328 mg, yield 53). %).
GCMS (EI) m / z; 208/210.

  (2) To a solution of 310 mg of the compound obtained in (1) above in 3 mL of tetrahydrofuran is added dropwise 2.37 mL of 1.58 M n-butyllithium-hexane solution at −78 ° C. in a nitrogen atmosphere, and the mixture is stirred at the same temperature for 1 hour. To the reaction solution is added dropwise a solution of 197 mg of 4-cyanobenzaldehyde in 2 mL of tetrahydrofuran, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, water and ethyl acetate are added to the residue, and the mixture is stirred and extracted with ethyl acetate. The organic layer is filtered through 2 g of NH silica gel (Chromatorex NH silica gel), and then the filtrate is concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 65/35) to give (4-cyanophenyl) [4- (difluoromethyl) phenyl] methanol (83 .2 mg, 21% yield).

  (3) Add 2 mL of thionyl chloride to 38.9 mg of the compound obtained in (2) above, stir at 85 ° C. for 2 hours, and concentrate to give chloro (4-cyanophenyl) [4- (difluoromethyl) phenyl. ] Obtain methane.

Reference Example 18
(1) Add 277 mg of lithium aluminum hydride to a solution of 1 g of 6-methylnicotinic acid in 10 mL of tetrahydrofuran, and stir at room temperature for 1 hour. A sodium hydroxide aqueous solution and water are added to the reaction solution, and the mixture is stirred and then filtered. The organic layer was separated from the filtrate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; chloroform / methanol = 98/2 to 90/10) to give 6-methylpyridine-3- Ilmethanol (434 mg, 49% yield) is obtained.
MS (APCI) m / z; 124 [M + H] ^< +>.

(2) 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodooxol-3- (1H) was added to a solution of 430 mg of the compound obtained in (1) above in 10 mL of methylene chloride. -Add 1.48 g of ON and stir at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is stirred and extracted with chloroform. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 70/30 to 50/50) to give 6-methylpyridine-3-carbaldehyde (224 mg). Yield 53%).
MS (APCI) m / z; 122 [M + H] ^< +>.

(3) To a solution of 460 mg of 4-iodobenzonitrile in 5 mL of tetrahydrofuran is added dropwise 1.25 mL of a 1.58 M n-butyllithium-hexane solution at −78 ° C. in a nitrogen atmosphere, and the mixture is stirred at the same temperature for 30 minutes. To this, 220 mg of the compound obtained in (2) above is added and stirred at the same temperature for 1 hour. The reaction is warmed to room temperature, water and ethyl acetate are added and stirred. The organic layer was separated and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 50/50 to 0/100) to give (4-cyanophenyl) (6- Methylpyridin-3-yl) methanol (111 mg, 27% yield) is obtained.
MS (APCI) m / z; 225 [M + H] ^< +>.

Reference Example 19
(1) A mixed solution of 688 mg of 4-dimethylsulfamoylbenzoic acid and 5 mL of thionyl chloride is stirred at 90 ° C. overnight. By concentrating the reaction solution, 495 mg of 4-dimethylsulfamoylbenzoic acid chloride is obtained as a white solid.

  (2) To a solution of 4-cyanophenylboric acid 353 mg, [bis- (triphenylphosphino) -dichloro] palladium 28 mg, potassium phosphate trihydrate 692 mg in toluene 5 mL solution, 495 mg of the compound obtained in the above (1) is added. Add and stir at 110 ° C. for 1.5 hours. The reaction solution is cooled to room temperature, filtered through 5 g of silica gel, and the filtrate is concentrated under reduced pressure. By purifying the obtained crude product by silica gel column chromatography (solvent; hexane / ethyl acetate = 33/67 to 65/35), 234 mg of (4-cyanophenyl) (4-dimethylsulfamoylphenyl) ketone Is obtained as a white solid.

  (3) 56 mg of sodium borohydride is added at 0 ° C. to a solution of 234 mg of the compound obtained in (2) above in 5 mL of tetrahydrofuran / 1 mL of methanol, and stirred at the same temperature for 10 minutes, and further stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, water and ethyl acetate are added to the residue and stirred, and then the organic layer is extracted with a diatomaceous earth column (ChemElut). The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 70/30 to 50/50) to give (4-cyanophenyl) (4-dimethyl). Sulfamoylphenyl) methanol is obtained as a viscous liquid.

Reference Example 20
(1) Add 11.5 mL of isopropyl iodide to a chloroform 40 mL solution of 2 g of 5-bromo-1H-pyridin-2-one and 4.3 g of silver carbonate, and stir at room temperature for 2 hours. The reaction solution is filtered through 20 g of silica gel, and then the filtrate is concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 98/2 to 90/10) to give 5-bromo-2-isopropyloxypyridine (2.41 g, yield 97%). )
MS (APCI) m / z; 216/218 [M + H] ^< +>.

(2) By treating 2.4 g of the compound obtained in the above (1) in the same manner as in Reference Example 17 (2), (4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methanol (1. 88 g, 63% yield).
MS (APCI) m / z; 269 [M + H] ^< +>.

Reference Example 21
(1) (4-Chlorophenyl) (3-methoxycarbonylphenyl) methanol is obtained by treating the corresponding starting material compound in the same manner as in Reference Example 1 (2).
MS (APCI) m / z: 259, 261 [M + H] ^< +>.

(2) Bromo (4-chlorophenyl) (3-methoxycarbonylphenyl) methane is obtained by reacting the compound obtained in (1) with phosphorus tribromide. Then, the compound was treated in the same manner as in Production Example 6 with the compound obtained in Reference Example 6 to give (3R) -1-[(4-chlorophenyl) (3-methoxycarbonylphenyl) methyl] -3-[[ 4- (Trifluoromethyloxy) benzoyl] amino] pyrrolidine (427 mg) is obtained.
MS (APCI) m / z: 533, 535 [M + H] ^< +>.

(3) By treating the compound obtained in (2) above in the same manner as in Production Example 19 (1), (3R) -1-[(3-carboxyphenyl) (4-chlorophenyl) methyl] -3- [ [4- (Trifluoromethyloxy) benzoyl] amino] pyrrolidine (344 mg) is obtained.
MS (APCI) m / z: 519, 521 [M + H] ^< +>.

Reference Example 22
(1) To 10 mL of a tetrahydrofuran solution of 1.0 g of 5-methyl-2-pyrazinecarboxylic acid, 1.1 mL of triethylamine and 1.0 mL of isobutyl chloroformate are added and stirred at 0 ° C. for 30 minutes. At −78 ° C., 603 mg of sodium borohydride and 5 ml of methanol are added to the reaction solution, and after stirring, an aqueous ammonium chloride solution is added, and the reaction solution is extracted with ethyl acetate. The organic layer is separated and the crude product obtained by concentration under reduced pressure is purified by silica gel column chromatography (solvent: chloroform / methanol = 90: 10) to obtain 5-methylpyrazin-2-ylmethanol. .
MS (APCI) m / z: 125 [M + H] ^< +>.

(2) (4-Cyanophenyl) (5-methylpyrazin-2-yl) methanol is obtained by treating the compound obtained in (1) above in the same manner as in Reference Examples 18 (2) and (3).
MS (APCI) m / z: 226 [M + H] ^< +>.

Reference Example 23
(1) 1.934 g of 2-chloro-5-bromopyrimidine is added to 10 mL of an isopropanol solution of 984 mg of sodium isopropyl oxide, and the mixture is stirred at room temperature for 2 hours under a nitrogen atmosphere. Water and ethyl acetate are added and stirred, and then the organic layer is extracted with ethyl acetate. The extract is dried over magnesium sulfate and filtered, and the solvent is distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100/0 to 90/10) to give 2-isopropyloxy-5-bromopyrimidine (1.7 g, yield 78%). )
MS (APCI) m / z; 217/219 [M + H] ^< +>.

(2) To a solution of 434 mg of the compound obtained in (1) above in tetrahydrofuran / diethyl ether 20 mL / 20 mL, under nitrogen atmosphere, add 1.27 mL of butyllithium (hexane solution, 1.58 M) at <-100 ° C. over 5 minutes. Add dropwise and stir at the same temperature for 30 minutes. A solution of 262 mg of 4-cyanobenzaldehyde in 5 mL of tetrahydrofuran was added dropwise and stirred at the same temperature for 3 hours. After bringing to room temperature, water and ethyl acetate are added and stirred, and then the organic layer is extracted with ethyl acetate. The extract is dried over magnesium sulfate and filtered, and the solvent is distilled off under reduced pressure. The crude product obtained is purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 60 / 40-30 / 70) to give (4-cyanophenyl) (2-isopropyloxypyrimidin-5-yl) methanol. (174 mg, 32% yield) is obtained.
MS (APCI) m / z; 270 [M + H] ^< +>.

Reference Example 24
(1) To 3 mL of methylene chloride solution of 561 mg of 4-bromobenzyl alcohol, 590 μL of [bis (2-methoxyethyl) -amino] sulfur = trifluoroide is added over 5 minutes under ice cooling, and the mixture is stirred for 1 hour at the same temperature. . The mixture is further stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 100/0 to 95/5) to give 1-bromo-4-fluoromethylbenzene (340 mg, yield 60%). obtain.
GCMS (EI) m / z; 188/190.

  (2) By treating 300 mg of the compound obtained in (1) above in the same manner as in Production Example 3 (3), (4-cyanophenyl) (4-fluoromethylphenyl) methanol (227 mg, 59% yield) was obtained. obtain.

Reference Example 25
(1) 6.2 g of N-bromosuccinimide and 239 mg of 2,2′-azobis (2-methylpropionitrile) were added to a solution of 5.0 g of 5-bromo-2-methylpyridine in 50 mL of carbon tetrachloride, and the mixture was heated to 85 ° C. And stir for 1 hour. After standing to cool, insolubles are removed by filtration, the solvent is distilled off under reduced pressure, and the resulting crude product is purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 100/0 to 92/8). Gives 5-bromo-2-bromomethylpyridine (3.7 g, 51% yield).
MS (APCI) m / z; 250/252 [M + H] ^< +>.

(2) To a solution of 1.82 g of sodium isopropyl oxide in 24 ml of 2-propanol, add a solution of 1.85 g of the compound obtained in (1) above in 10 ml of 2-propanol at 85 ° C. and stir for 30 minutes. After allowing to cool, the solvent is concentrated under reduced pressure, water is added and the mixture is extracted with chloroform, and then the solvent is distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 99/1 to 90/10) to give 5-bromo-2-isopropyloxymethylpyridine (1.47 g, yield 87). %).
MS (APCI) m / z; 230/232 [M + H] ^< +>.

(3) By treating 400 mg of the compound obtained in (2) above in the same manner as in Reference Example 3 (3), (6-isopropyloxymethylpyridin-3-yl) (4-trifluoromethylphenyl) methanol (333 mg) Yield 57%).
MS (APCI) m / z; 326 [M + H] ^< +>.

Reference Example 26
(1) To a solution of 10.0 g of sodium isopropyloxide in 100 ml of 2-propanol is added 10.0 g of 2-bromothiazole at 85 ° C. and stirred for 15 hours. After allowing to cool, the solvent is concentrated under reduced pressure, water is added, and the mixture is extracted with diethyl ether. After washing with water and saturated saline, drying with magnesium sulfate, the solvent is distilled off under reduced pressure to obtain 2-isopropyloxythiazole (6.39 g, yield 73%).
MS (APCI) m / z; 144 [M + H] ^< +>.

(2) By treating 1.0 g of the compound obtained in the above (1) in the same manner as in Production Example 3 (3), (4-cyanophenyl) (2-isopropyloxythiazol-5-yl) methanol (1. 62 g, 85% yield).
MS (APCI) m / z; 275 [M + H] ^< +>.

Reference Example 27
To a solution of 3.1 g of 2,2,2-trifluoroethanol in 20 ml of dioxane, 1.4 g of sodium hydride is added at 0 ° C. and stirred at room temperature for 30 minutes in a nitrogen atmosphere. Add 3.0 g of 2-chloro-5-bromopyrimidine and stir at room temperature overnight. Water and ethyl acetate are added and stirred, and then the organic layer is extracted with ethyl acetate. The extract is dried over magnesium sulfate and filtered, and the solvent is distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 95/5 to 90/10) to give 2- (2,2,2-trifluoroethyloxy) -5-bromo. Pyrimidine (3.0 g, 38% yield) is obtained.
MS (APCI) m / z; 257/259 [M + H] ^< +>.

Reference Example 28
(1) To a solution of 1.0 g of the compound obtained in Reference Example 20 (1) in 10 mL of tetrahydrofuran was dropwise added 3.0 mL of a butyllithium hexane solution (1.58 M) at −78 ° C. in a nitrogen atmosphere at the same temperature. Stir for hours. A solution of 6-chloro-3-formylpyridine (660 mg) in tetrahydrofuran (2 mL) was added, and the mixture was stirred at the same temperature for 1 hour. After bringing to room temperature, water is added and extracted with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80 / 20-60 / 40) to give (6-chloropyridin-3-yl) ( 6-Isopropyloxypyridin-3-yl) methanol (733 mg, 57% yield) is obtained.
MS (APCI) m / z; 279/281 [M + H] ^< +>.

(2) To a solution of 733 mg of the compound obtained in (1) above and 735 μL of triethylamine in 12 mL of methylene chloride is added dropwise 245 μL of methanesulfonyl chloride under ice cooling, and the mixture is stirred for 1 hour at the same temperature. 637 mg of (3R)-(+)-(tert-butyloxycarbonylamino) pyrrolidine and 25 mL of acetonitrile are added and stirred at 85 ° C. for 18 hours. Add water, extract with ethyl acetate, wash with saturated brine, and dry over magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 90/10 to 67/33) to give (3R) -1-[(6-chloro Pyridin-3-yl) (6-isopropyloxypyridin-3-yl) methyl] -3- (tert-butyloxycarbonylamino) pyrrolidine (635 mg, 54% yield) is obtained.
MS (APCI) m / z; 447/449 [M + H] ^< +>.

  (3) 411 mg of sodium isopropyl oxide is added to a solution of 506 mg of the compound obtained in (2) above in 15 mL of 2-propanol, and the mixture is stirred at 155 ° C. for 2 hours using a microwave reactor (Biotage). Add saturated aqueous sodium bicarbonate, extract with chloroform, and dry over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 476 mg of (3R) -1- [bis- (6-isopropyloxypyridin-3-yl) methyl] -3- (tert-butyloxycarbonylamino) pyrrolidine as a brown oil.

Reference Example 29
2.17 g of potassium carbonate is added to a solution of 1.5 g of 4-fluorobenzaldehyde and 1.56 mL of methylethylamine in 9 mL of dimethyl sulfide, and the mixture is stirred at 120 ° C. for 2 hours using a microwave reactor (Biotage). Add water, extract with ethyl acetate, and dry over magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 95/5 to 80/20) to give 4- (N-ethyl-N-methylamino). ) Benzaldehyde (1.89 g, 96% yield) is obtained.
MS (APCI) m / z; 164 [M + H] ^< +>.

Reference Example 30
To a solution of 1.22 g of 4-hydroxybenzaldehyde in 5 mL of pyridine, 1.0 mL of dimethylcarbamyl chloride is added and stirred at 60 ° C. overnight. Dilute hydrochloric acid and ethyl acetate are added and stirred, and then the organic layer is extracted with a diatomaceous earth column for dehydration. The extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 80/20 to 60/40) to give 4- (dimethylcarbamoyloxy) benzaldehyde (1. 67 g, 86% yield).
MS (APCI) m / z; 194 [M + H] ^< +>.
Experimental example [human CB1 receptor binding test]
(1) Preparation of human CB1 receptor cell membrane fraction (materials and reagents)
Materials and reagents for preparation of cell membrane fraction are as follows.
Human CB1 receptor-expressing cell line: hCB1-c3 (Euroscreen)
Medium for cell line culture: F-12 (GIBCO) [containing 10% fetal bovine serum, 400 μg / mL Geneticin, 100 units / mL Penicillin G and 100 μg / mL Streptomycin]
Buffer for cell membrane fraction preparation: 50 mM Tris-HCl buffer (pH 7.5, containing 2.5 mM ethylenediaminetetraacetic acid, 5 mM magnesium chloride and 200 mM sucrose)
(Operating procedure)
A human CB1 receptor-expressing cell line cultured in a cell line culture medium was washed twice with ice-cold phosphate buffer, 2 mL of cell membrane fraction preparation buffer was added, and the cells were recovered with a cell scraper. After treatment with a microchip ultrasonic device for 20 seconds, centrifugation (500 × g, 15 minutes) was performed. The supernatant was collected and further centrifuged (43,000 × g, 60 minutes), and then the supernatant was removed. A cell membrane fraction preparation buffer was added to the precipitate, homogenized, and an equal amount of 80% glycerol-containing buffer was added to the resulting cell membrane suspension to obtain a human CB1 receptor cell membrane fraction. .
(2) Human CB1 receptor binding reaction (materials and reagents)
The reaction buffer, washing buffer, coating solution, and labeled ligand used in this reaction are as follows.
Buffer for reaction: 50 mM Tris-HCl buffer (including pH 7.5, 5 mM magnesium chloride, 2.5 mM ethylenediaminetetraacetic acid and 2 mg / mL bovine serum albumin (fatty acid free, SIGMA))
Washing buffer: 50 mM Tris-HCl buffer (containing pH 7.5, 5 mM magnesium chloride, 2.5 mM ethylenediaminetetraacetic acid and 2 mg / mL bovine serum albumin (fatty acid free, manufactured by SIGMA))
Coating solution: 0.3% ethyleneimine polymer (prepared by diluting with distilled water)
Labeled ligand: [ ³ H] CP55940 [diluted to 30 nM (7992 dpm / μL) in reaction buffer].
(Operating procedure)
In an assay plate (96-well, Coster), 140 μL of reaction buffer, dimethyl sulfoxide solution of the sample (final concentration 0.1%), labeled ligand 20 μL (30 nM), and cell membrane fraction 20 μL (0) (0) (0) 4-0.5 μg / μL) and incubated at room temperature for 90 minutes. After completion of the reaction, the cells were seeded on a microplate (Unifilter-96 GF / B, Packard) treated with the coating solution. The plate was washed with 200 μL of ice-cold washing buffer (× 10), dried at 37 ° C. overnight, Microscinti 40 (PerkinElmer) was added, and the radioactivity was measured with a micro scintillation counter (Topcount, PerkinElmer). The IC ₅₀ value of the specimen was calculated using Graphpad Prism 3.02 (Graphpad) based on the radioactivity measurement value.
(result)
The results are as shown in Table 17 below.

Claims (2)

General formula [IA]:

[Where:
Ring A has the formula:

A group represented by
Ring B has the formula:

A group represented by
One of Z ¹ and Z ² is a group represented by the formula: = N-, the other is a group represented by the formula: = CH- or = N-,
R ^11a and R ^21a are the same or different and are (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a C _1-6 alkyloxy group (the group is a halogen atom and a C _1-6 alkyl). Optionally substituted with 1 to 3 groups selected from oxy groups), (5) mono- or trifluoro-C _1-6 alkyl groups, (6) di (C _1-6 alkyl) carbamoyloxy groups, (7) C _1-6 alkylthio group, (8) amino group substituted with C _1-6 alkyl group and C _1-6 alkyloxy-C _1-6 alkyl group, (9) C _3-8 cycloalkyloxy A group, (10) a C _3-8 cycloalkyl-C _1-6 alkyloxy group, or (11) a C _1-6 alkyloxy-C _1-6 alkyl group,
R ^13a is a hydrogen atom or a halogen atom,
R ^14a is a C _1-6 alkyloxy group,
R ³¹ is a hydrogen atom, a hydroxyl group, a C _1-6 alkyloxy group or a morpholino group,
R ⁶¹ is (1) a halogen atom, a trifluoro-C _1-6 alkyl group, a C _1-6 alkyloxy group, a trifluoro-C _1-6 alkyloxy group, a di (C _1-6 alkyl) carbamoyloxy group, A phenyl group substituted with one or two groups selected from the same or different groups selected from a C _1-6 alkylthio group and a cyano group; (2) a pyridyl group substituted with one or two groups selected from a halogen atom and a cyano group; Or (3) represents a thienyl group substituted with a halogen atom or a trifluoro-C _1-6 alkyl group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. 1- [bis- (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
1- [bis- (4-ethyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-isopropyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-hydroxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1-[(4-chlorophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-methyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-methyloxy-4-[(4-chlorobenzoyl) amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(4-chlorobenzoyl) amino] pyrrolidine;
1- [bis- (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1-[(2-chlorophenyl) (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
1- [bis- (4-chlorophenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-morpholino-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-hydroxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(4-chlorobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-methyloxy-4-[(4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-ethyloxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1- [bis- (4-chlorophenyl) methyl] -3-morpholino-4-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (4-cyanophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-methyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-methyloxy-4-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[(4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[[3-fluoro-4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-ethyloxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3S, 4S) -1-[(4-chlorophenyl) (4-cyanophenyl) methyl] -3-methyloxy-4-[(2-fluoro-4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(S)-(4-cyanophenyl) (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(S)-(4-cyanophenyl) (4-chlorophenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-methyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-methyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2-fluoro-4- (trifluoromethyl) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[(4-chlorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyloxy) phenyl] methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-chloro-2-fluorophenyl) methyl] -3-[[4- (trifluoromethyl) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-chlorophenyl) methyl] -3-[[5- (trifluoromethyl) -2-thenoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-methylthiophenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(S)-(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-ethyloxyphenyl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-isopropyloxyphenyl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-ethyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2-difluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine ;
(3R) -1-[(4-cyanophenyl) (6-ethyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2-difluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- [2- (methyloxy) ethyloxy] pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-fluoromethylphenyl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (4-fluoromethylphenyl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] [6- (isopropyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxythiazol-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxythiazol-5-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-chlorophenyl) [6- (methyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[[4- (trifluoromethyl) phenyl] [6- (methyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (methyloxymethyl) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2-fluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-ethyloxybenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(4-methylthiobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[(5-bromo-2-thenoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxythiazol-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-isopropyloxythiazol-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-methyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-methyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-methyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-ethyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-ethyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-ethyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Isopropyloxyphenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (2,2,2-trifluoroethyloxy) pyrimidin-5-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (2,2,2-trifluoroethyloxy) pyrimidin-5-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) Amino] pyrrolidine;
(3R) -1-[(4-Cyanophenyl) [2- (2,2,2-trifluoroethyloxy) pyrimidin-5-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine ;
(3R) -1-[(4-cyanophenyl) (2-ethyloxypyrimidin-5-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxypyrimidin-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (1-fluoromethyl-2-fluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (6-isopropyloxypyridin-3-yl) methyl] -3-[[4- (dimethylcarbamoyloxy) benzoyl] amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (trifluoromethyl) phenyl] methyl] -3-[[4- (dimethylcarbamoyloxy) benzoyl] amino] pyrrolidine;
(3R) -1- [bis- (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxythiazol-5-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) (2-ethyloxythiazol-5-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1- [bis- (6-isopropyloxypyridin-3-yl) methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1- [bis- (6-isopropyloxypyridin-3-yl) methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (dimethylcarbamoyloxy) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (dimethylcarbamoyloxy) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (dimethylcarbamoyloxy) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (dimethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (dimethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (dimethylamino) pyrimidin-5-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (diethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (diethylamino) pyrimidin-5-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [2- (diethylamino) pyrimidin-5-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-isopropylamino) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-ethylamino) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) Amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-isopropylamino) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-ethylamino) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-Nn-propylamino) phenyl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-Nn-propylamino) phenyl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Cyanophenyl) [4- [N-methyl-N- (2-methyloxyethyl) amino] phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine ;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-isopropylamino) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-N-ethylamino) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [4- (N-methyl-Nn-propylamino) phenyl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclobutyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclobutyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclobutyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopentyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopentyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopentyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopropylmethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopropylmethyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (cyclopropylmethyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (1-ethyl-n-propyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-Cyanophenyl) [6- (1-ethyl-n-propyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) amino] Pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (1-ethyl-n-propyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicotinoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2,2-trifluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyanobenzoyl) amino] pyrrolidine;
(3R) -1-[(4-cyanophenyl) [6- (2,2,2-trifluoroethyloxy) pyridin-3-yl] methyl] -3-[(4-cyano-2-fluorobenzoyl) Amino] pyrrolidine; and (3R) -1-[(4-cyanophenyl) [6- (2,2,2-trifluoroethyloxy) pyridin-3-yl] methyl] -3-[(6-cyanonicoti Noyl) amino] pyrrolidine;
Or a pharmacologically acceptable salt thereof as an active ingredient.