WO2020203610A1 - Use of t-type calcium channel blocker for treating rheumatoid arthritis - Google Patents

Use of t-type calcium channel blocker for treating rheumatoid arthritis Download PDF

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WO2020203610A1
WO2020203610A1 PCT/JP2020/013543 JP2020013543W WO2020203610A1 WO 2020203610 A1 WO2020203610 A1 WO 2020203610A1 JP 2020013543 W JP2020013543 W JP 2020013543W WO 2020203610 A1 WO2020203610 A1 WO 2020203610A1
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Prior art keywords
trifluoromethyl
pyrrolidine
acetamide
pyridin
group
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PCT/JP2020/013543
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French (fr)
Japanese (ja)
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ダブリュ ザンポーニ ゲラルド
デ マリア ガドッティ ヴィニシウス
川畑　篤史
亨 小川
博人 田中
勲 大井
大祐 齊藤
康平 林田
広平 山元
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日本ケミファ株式会社
ユーティアイ リミテッド パートナーシップ
学校法人近畿大学
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Publication of WO2020203610A1 publication Critical patent/WO2020203610A1/en

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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/12—Organo silicon halides

Definitions

  • the present invention relates to a Cav3.2 channel inhibitor useful for the prevention or treatment of rheumatoid arthritis and its use.
  • RA Rheumatoid arthritis
  • the morbidity rate is about 1% of the total population, and in Japan, the male-female ratio is 1: 3-4, which is significantly higher in females, and the predominant age is more common in the 30s to 50s.
  • Drugs used to treat rheumatoid arthritis include non-steroidal anti-inflammatory drugs (NSAIDs) classified as symptomatic therapies (eg, diclofenac, ibprofen, selecoxib, etc.), corticosteroids (eg, prednisolone, etc.), and causative therapies.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Classified non-biological disease-modifying anti-rheumatic drugs (DMARD S ) eg, methotrexate, salazosulfapyridine, azathiopurine, cyclosporin, etc.
  • biological DMARD S eg, infliximab, etanercept, adalimumab, tosirizumab, etc.
  • NSAIDs treat RA symptoms by reducing joint swelling and pain, but do not prevent the progression of damage.
  • NSAIDs can damage the stomach as a side effect that is inseparable from their pharmacological effects.
  • Corticosteroids are powerful drugs that reduce RA inflammation and symptoms. Due to the risk of side effects, direct injection into the joint is preferred for use at minimal doses.
  • DMARD S can slow the progression of RA, but it can take weeks or months to be effective. While DMARD S , which has an immunosuppressive effect, can reduce damage to bones adjacent to joints, immunosuppression increases the risk of developing infections and certain cancers. In addition, biological DMARD S has a very high drug price.
  • Non-Patent Document 1 it has been reported that in Cav3.2 knockout mice, the pain-related behavior of the formalin test 2nd Phase, which is said to be involved in inflammatory pain, is significantly reduced.
  • the expression of Cav3.2 channel was increased even though the expression of Cav3.1 and Cav3.3 was not changed in the DRG on the same limb side to which carrageenin was administered, and T. It has been reported that an analgesic effect is observed by intrafoot administration of mibefradil and NNC 55-0396, which are type calcium channel blockers (Non-Patent Document 2).
  • One object of the present invention is to provide a medicine for treating or preventing rheumatoid arthritis useful for mammals including humans.
  • the present inventors have found that a cyclic amine compound having an amide bond has an excellent inhibitory effect on T-type calcium channels, particularly Cav3.2 channels. Then, they have found that the prevention or treatment of rheumatoid arthritis can be achieved by using the Cav3.2 channel inhibitor, and have completed the present invention.
  • the active ingredient contains a compound represented by the following general formula (I), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug for the treatment or prevention of rheumatoid arthritis is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • R 1 And R 2 May have substituents, and bonds to adjacent Xs via the carbon atoms that make up these rings
  • R 1 And R 2 May be the same or different, hydrogen atom, halogen atom, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Represents an alkyl group Or R 1 , R 2 And R 1 And R 2
  • the carbon atoms to which the bonds are attached may be combined to form a 3- to 5-membered cycloalkyl group.
  • R 3 Is a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group, C.
  • 1-8 Alkyl group, C 1-8 Alkoxycarbonyl group, C 1-8 C substituted with an alkoxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with alkyl group and acyloxy group 1-8 Represents an alkyl group Or R 2 And R 3 May be combined to form methylene or ethylene, X is Or Represents Here, the wavy line represents the coupling position and R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the bond is attached.
  • n and m may be the same or different, 0 or 1, p represents 1 and 2.
  • the above A 1 Phenyl, A above 1 Heteroaryl ring and A above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8
  • the cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C
  • X is The pharmaceutical according to (1) above.
  • a 1 The pharmaceutical according to (1) or (2) above, wherein is a phenyl which may have a substituent.
  • a 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent.
  • the medicament according to the above (1) or (2) which is a 4- to 6-membered heteroaryl ring composed of atoms.
  • a 1 The medicament according to (4) above, wherein the heteroaryl ring of is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine or pyridazine.
  • a 1 The medicament according to (4) above, wherein the heteroaryl ring of the above is pyridine.
  • a 1 A 4- to 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents.
  • a 1 The medicament according to (7) above, wherein the heterocondensation ring of the above is quinoline or benzo [d] thiazole.
  • B 1 The medicament according to any one of (1) to (8) above, wherein is a phenyl which may have a substituent.
  • B 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent.
  • B 1 The medicament according to the above (10), wherein the heteroaryl ring of the above is pyridine.
  • B 1 When is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position) above (9). )-(11).
  • B 1 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents.
  • the medicament according to any one of (1) to (8) above, which is a heterofused ring with a benzene ring.
  • B 1 The pharmaceutical according to (13) above, wherein the heterocondensation ring of the above is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
  • B 1 The medicament according to the above (13), wherein the heterocondensation ring of the above is indazole.
  • n is 1 and m is 0.
  • R 1 And R 2 The pharmaceutical according to any one of (1) to (17) above, wherein is a hydrogen atom.
  • R 3 The pharmaceutical according to any one of (1) to (18) above, wherein is a hydrogen atom.
  • the active ingredient comprises a compound represented by the following general formula (II), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug for the treatment or prevention of rheumatoid arthritis In the formula, D, E, F, G and J are CRs in which any two are N and the other may be the same or different, or any one is N and the other may be the same or different. All are CRs that may be the same or different.
  • R is a hydrogen atom, C.
  • R a1 , R a2 , R b1 And R b2 May be the same or different hydrogen atom, halogen atom, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Represents an alkyl group Or R a1 , R a2 And R a1 And R a2 The carbon atoms to which are bonded together, or R b1 , R b2 And R b1 And R b2 The carbon atoms to which the bonds are attached may be combined to form a 3- to 5-membered cycloalkyl group. s represents 0, 1, 2 and t represents 1 and 2.
  • B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the is bonded.
  • the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino group, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cycl
  • the cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C
  • the active ingredient comprises a compound represented by the following general formula (II), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug for the treatment or prevention of rheumatoid arthritis In the formula, D, E, F, G and J are CRs in which any two are N and the other may be the same or different, or any one is N and the other may be the same or different. All are CRs that may be the same or different.
  • R is a hydrogen atom, C.
  • R a1 , R a2 , R b1 And R b2 May be the same or different hydrogen atom, halogen atom, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Represents an alkyl group Or R a1 , R a2 And R a1 And R a2 The carbon atoms to which are bonded together, or R b1 , R b2 And R b1 And R b2 The carbon atoms to which the bonds are attached may be combined to form a 3- to 5-membered cycloalkyl group. s represents 0, 1, 2 and t represents 1 and 2.
  • B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the is bonded.
  • the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino group, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cycl
  • the cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C
  • the 6-membered ring composed of D to J is phenyl which may have a substituent or pyridazine which may have a substituent, and X is At that time, B 1 Is a heterofused ring which may have the above-mentioned substituent.
  • X is The medicament according to the above (20) or (21).
  • B 1 The medicament according to any one of (20) to (25) above, wherein D, E, F and J are CRs which may be the same or different and G is N.
  • B 1 The medicament according to any one of (20) to (25) above, wherein is a phenyl which may have a substituent.
  • B 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent.
  • B 1 The medicament according to the above (27), wherein the heteroaryl ring of the above is pyridine.
  • B 1 When is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position) above (26). )-(28).
  • B 1 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents.
  • the medicament according to any one of (20) to (34) above, wherein is a hydrogen atom.
  • the active ingredient comprises a compound represented by the following general formula (III), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug for the treatment or prevention of rheumatoid arthritis In the formula, A 1 Is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group Or R 4 , R 5 And and R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the bond is attached.
  • the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen
  • the cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C
  • the active ingredient comprises a compound represented by the following general formula (III), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug for the treatment or prevention of rheumatoid arthritis is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the bond is attached.
  • the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen
  • the cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C
  • a 1 when phenyl may have a substituent, pyridazine which may have a substituent, and quinazoline which may have a substituent, B 1 Is a heterocondensed ring which may have the above-mentioned substituent. ) (38) A 1 The medicament according to (36) or (37) above, wherein is a phenyl which may have a substituent. (39) A 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent.
  • a 1 The medicament according to (42) above, wherein the heterocondensation ring of the above is quinoline or benzo [d] thiazole.
  • B 1 The medicament according to any one of (36) to (43) above, wherein is a phenyl which may have a substituent.
  • B 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms that may have a substituent.
  • B 1 The medicament according to any one of (36) to (43) above, which is a 5- or 6-membered heteroaryl ring comprising.
  • B 1 The medicament according to (45) above, wherein the heteroaryl ring of the above is pyridine.
  • B 1 When is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position) above (44). )-(46).
  • B 1 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents.
  • B 1 The medicament according to the above (48), wherein the heterocondensation ring of the above is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
  • B 1 The medicament according to the above (48), wherein the heterocondensation ring of the above is indazole.
  • R 4 And R 5 The pharmaceutical according to any one of (36) to (50) above, wherein both are hydrogen atoms.
  • the active ingredient comprises a compound represented by the following general formula (IV), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 6 , R 7 And R 8 Are the same or different, hydrogen atom, halogen atom, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkoxy group, hydroxy group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 Represents an alkoxy group R 9 Is C substituted with 1 to 3 halogen atoms 1-8 Represents alkyl, t-butyl or cyclopropyl, And r represents 0, 1, 2.
  • the medicament according to (52) above which is an alkoxy group.
  • R 9 The medicament according to any one of (52) to (53) above, wherein is trifluoromethyl or cyclopropyl.
  • the active ingredient comprises a compound represented by the following general formula (V), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug for the treatment or prevention of rheumatoid arthritis is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent.
  • the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above
  • B above 1 Phenyl B above 1
  • the cyclic amino group of the substituent which the heteroaryl ring of B1 and the heterocondensation ring of B1 may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopiperidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1 -Dioxidethiomorpholino, 1,4-dioxo-8-azaspiro [4.5] decan-8-yl, 2-oxo-6-azaspiro [3.3] heptane-6-yl, 3-oxo-8-azabicyclo [3] .2.1] Octane-8-yl, 2-oxo-5-azabicyclo [2.2.2] octane-5-yl, 2-oxo-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C 1-8 It
  • a 1 The medicament according to (56) above, wherein is a phenyl which may have a substituent.
  • a 1 Is a 4- to 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents.
  • the medicament according to (56) above. (59) A 1 The medicament according to the above (58), wherein the heteroaryl ring is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
  • a 1 The medicament according to (58) above, wherein the heteroaryl ring of the above is pyridine.
  • (62) A 1 The medicament according to the above (61), wherein the heterocondensation ring of the above is quinoline or benzo [d] thiazole.
  • B 1 The medicament according to any one of (56) to (62) above, wherein is a phenyl which may have a substituent.
  • B 1 Is a 5- or 6-membered heteroaryl ring composed of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents.
  • (65) B 1 The medicament according to (63) above, wherein the heteroaryl ring is pyridine.
  • B 1 Is a 5- or 6-membered heteroaryl ring and benzene consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents.
  • B 1 The medicament according to the above (66), wherein the heterocondensation ring of the above is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
  • the active ingredient comprises a compound represented by the following general formula (VI), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a drug for the treatment or prevention of rheumatoid arthritis Is a phenyl that may have a substituent, or a 4- to 6-membered ring-constituting atom consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms.
  • B 2 Is a 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, and a benzene ring or 1 to 2 atoms.
  • the heteroaryl ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and B above 2 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy
  • Cyclic amino groups of substituents that the heterofused ring of Heptane may have are pyrrolidino, piperidino, piperazino, 2 or 3-oxopiperidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxo-8-azaspiro [4.5] decane-8-yl, 2-oxo-6-azaspiro [3.3] heptane-6-yl, 3-oxo-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxo-5-azabicyclo [2.2.2] octane-5-yl, 2-oxo-5-azabicyclo [2.2.1] heptane-5-yl selected from such a ring
  • the amino group is further C 1-8 It may be substituted with an alkyl group, a halogen atom, or
  • a 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms which may have a substituent.
  • the medicament according to (69) above which is a 4- to 6-membered heteroaryl ring composed of atoms.
  • (71) A 1 The medicament according to the above (70), wherein the heteroaryl ring of the above is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
  • (76) A method for treating rheumatoid arthritis in humans, wherein the method is an effective amount of the compound according to any one of (1) to (73) above, a tautomer, a stereoisomer, or a stereoisomer of the compound.
  • a method comprising the step of administering the pharmaceutically acceptable salt or solvate thereof to a subject in need thereof.
  • the compound of the present invention inhibits the Cav3.2 channel and has a pain-relieving effect associated with rheumatoid arthritis.
  • the C 1-8 alkyl group includes a methyl group, an ethyl group, a propyl group, an iso-propyl group, a butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an iso-butyl group and a tert-butyl group.
  • a straight-chain, branched or cyclic alkyl group such as a pentyl group or a hexyl group.
  • Examples of the C 1-8 alkyl group substituted with 1 to 3 halogen atoms include methyl group, ethyl group, and propyl group substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom and bromine atom. Examples thereof include an iso-propyl group, a butyl group and a tert-butyl group, and preferably a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group and the like.
  • Examples of the C 1-8 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso-butoxy group, a tert-butoxy group, a pentyloxy group or a hexyloxy group.
  • Examples of the C 1-8 alkoxy group substituted with 1 to 3 halogen atoms include a methoxy group, an ethoxy group, and a propoxy group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, or a bromine atom.
  • Examples thereof include iso-propoxy group, butoxy group, tert-butoxy group and the like, preferably a trifluoromethoxy group, a chloromethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, a 2-fluoroethoxy group, or 2,2. , 2-Trifluoroethoxy group and the like.
  • Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • Examples of the C 1-8 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group and the like.
  • the acyl group preferably includes an acyl group having 1 to 7 carbon atoms, and more preferably an acetyl group, a propionyl group, a benzoyl group and the like.
  • Examples of the C 1-8 alkyl group substituted with a hydroxy group include a hydroxymethyl group and a 2-hydroxypropan-2-yl group.
  • Examples of the C 1-8 alkyl group substituted with the acyloxy group include an acetyloxymethyl group.
  • Examples of the C 1-8 alkoxy group substituted with a hydroxy group include a 2-hydroxyethoxy group and the like.
  • Examples of the C 1-8 alkylsulfonyl group include a methanesulfonyl group.
  • Examples of the 3- to 5-membered cycloalkyl group include a cyclopropyl group and a cyclobutyl group.
  • Examples of the C 1-8 alkylamino group include an ethylamino group.
  • Examples of the C 2-12 dialkylamino group include a dimethylamino group and a diethylamino group.
  • the (C 1-8 alkyl) amino group (C 1-8 C 1-8 alkyl substituted with an alkoxy group), such as N- ethyl-N-(2-methoxyethyl) amino group.
  • Examples of the tri (C 1-8 alkyl) silyl group include a trimethylsilyl group and a triethylsilyl group.
  • Examples of the acylamino group include an acetylamino group.
  • Examples of the (N-acyl) ( NC 1-8 alkyl) amino group include a (N-acetyl) (N-ethyl) amino group.
  • Examples of the 3- to 6-membered cyclic ether include THF, oxetane and the like.
  • Examples of the C 1-8 alkyl group substituted with the C 1-8 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso-butoxy group, a tert-butoxy group, a pentyloxy group or Methyl group, ethyl group, propyl group, iso-propyl group, butyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, iso-butyl group, tert substituted with alkoxy group having 1 to 6 carbon atoms such as hexyloxy group.
  • C 1-8 alkoxy group substituted with the C 1-8 alkoxycarbonyl group include an isopropyloxy group substituted with ethoxycarbonyl and the like.
  • “Tautomers” include interconversion by proton transfer, such as keto-enol and imine-enamine isomerization.
  • “Stereoisomers” refer to compounds that have the same chemical structure but differ in the spatial arrangement of atoms or groups. For example, stereoisomers such as cis-trans isomers, optically active isomers, and racemates may be present, but all of them are included in the present invention, and a mixture of enantiomers and diastereomers is also included in the present invention. ..
  • the compound of the present invention also includes a compound in which pyridine is pyridine 1-oxide, as described in Example 134 below, and a compound in which pyrrolidine 1-oxide and piperidine 1-oxide are used.
  • Examples of the "pharmaceutically acceptable salt” of the compound represented by the above general formula (I) include acid addition salts such as mineral acid salts such as hydrochloric acid, sulfuric acid, nitrate and phosphoric acid, formic acid and acetic acid.
  • Organic acid salts such as citric acid, tartrate acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, and malic acid can be used, but are not limited thereto.
  • the base addition salt for example, a salt with an inorganic base such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, or a calcium salt, an ammonium salt, or an addition salt with an organic base such as a triethylamine salt or an ethanolamine salt.
  • an inorganic base such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, or a calcium salt, an ammonium salt, or an addition salt with an organic base such as a triethylamine salt or an ethanolamine salt.
  • the "solvate” means the form of a molecular complex containing the compound of the present invention and one or more pharmaceutically acceptable solvent molecules of a chemical quantity, and the solvent molecule is an alcohol such as ethanol. And water.
  • the solvent molecule is water, it may be called a hydrate, and examples of the hydrate include monohydrate and dihydrate.
  • the compounds of the present invention also include prodrugs and derivatives substituted with stable isotopes.
  • isotopes include hydrogen, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Treatment or prevention of rheumatoid arthritis includes not only the case of completely curing the disease, but also the case of alleviating at least one medical condition such as swelling and pain associated with rheumatoid arthritis, and the case of preventing the exacerbation of the medical condition. Is done.
  • a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof is used as a drug
  • it may be used as a drug itself or as an appropriate pharmaceutically acceptable carrier. It can be mixed and formulated.
  • pharmaceutically acceptable carriers include diluents, binders, excipients, lubricants, disintegrants, wetting agents, emulsifiers, surfactants, antioxidants, preservatives, colorants, and flavoring agents. And odorants and the like.
  • Dosage forms include oral preparations such as powders, granules, tablets and capsules, eye drops, nasal drops, coating agents, patches, sprays, gels, external preparations such as creams, injections, etc. It can be administered orally or parenterally.
  • the dose of the medicament of the present invention is not particularly limited, and can be appropriately increased or decreased according to age, sex, body weight, symptoms, therapeutic effect, administration method, type of substance or salt, sensitivity to drug, therapeutic effect, and the like.
  • the dose is 0.01 mg to 1000 mg, preferably 0.1 mg to 500 mg, and more preferably 0.1 mg to 300 mg once a day to 6 times. It is administered in batches, or in the case of external preparations, in the range of 0.01 mg to 2000 mg, preferably 0.05 mg to 1000 mg, and more preferably 0.1 mg to 500 mg, once to 6 times a day. It is used, or in the case of injections, it is used 1 to 6 times a day in the range of 0.001 mg to 1000 mg, preferably 0.1 mg to 100 mg, more preferably 0.1 mg to 50 mg at a time. To.
  • the compound of the present invention can be produced using a commercially available compound as a raw material by a known method or the method described below.
  • Known methods include the methods described in the 5th Edition Experimental Chemistry Course (Maruzen Publishing), New Heterocyclic Compounds (Kodansha), Protective Groups in Organic Synthesis (Wiley), and the like.
  • protection or deprotection, conversion or introduction of a functional group may be effective at each stage of production. In such a case, not only the operation or order of the described manufacturing method but also a known method can be used to apply an appropriate operation or order.
  • the prodrug of the compound of the present invention can be produced by applying known methods such as amidation, esterification, and alkylation at each stage of production. Some compounds produced using this production method may contain various salts, hydrates and polymorphs. Further, when optical isomers, geometric isomers or tautomer organisms can be present, and when not particularly limited, they may contain a mixture in any ratio. Mixtures of these isomers can be separated by known methods.
  • M Mol concentration
  • N Normal
  • MS Mass spectrum
  • [M + H] + Protonized molecular ion peak
  • [M + Na] + Sodium ion-added molecular ion peak
  • [MH] - Deprotonized molecular ion peak
  • CDCl 3 Heavy chloroform
  • DMSO-d 6 Heavy dimethyl sulfoxide
  • CD 3 OD Heavy methanol
  • 1 H NMR Proton nuclear magnetic resonance, Me: Methyl group, Et: Ethyl group, t-Bu: tert-butyl group
  • CN cyano group
  • CF 3 trifluoromethyl group
  • Ts p-toluenesulfonyl group
  • Boc tert-butoxycarbonyl group
  • DMF N, N-dimethylformamide
  • THF tetrahydrofuran
  • DME 1,2-d
  • a Z for example, A 1 in the compound represented by the general formula (I), or a compound represented by the general formula (II) Represents
  • X is a compound represented by the general formula (I) or a compound represented by the above general formula (II).
  • B Z represents, for example, B 1 in the compound represented by the general formula (I) or B 2 in the compound represented by the general formula (VI).
  • Compounds represented by the general formulas (III) to (VI) and the like can also be produced in the same manner.
  • the compound (Z) can be produced, for example, by the method shown below.
  • Compound (Z) is prepared by combining compound (ZA) and compound (ZB) in a suitable solvent such as DMF, a condensing agent such as HATU or WSC, and optionally an additive such as HOBT or DMAP, if necessary. It can be produced by reacting at 0 ° C. to 100 ° C. in the presence of a base such as triethylamine or DIPEA. Further, for compound (ZA), a carboxylic acid chloride or carboxylic acid anhydride corresponding to compound (ZB) is placed in a suitable solvent such as tetrahydrofuran, and if necessary, a base such as triethylamine, DIPEA or pyridine.
  • a suitable solvent such as DMF
  • a condensing agent such as HATU or WSC
  • an additive such as HOBT or DMAP
  • Compound (ZA) can be produced, for example, by the method shown below.
  • Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction.
  • Other symbols have the same meaning as described above.
  • Compound (ZA) is produced by reacting compound (ZA) in a suitable solvent such as methanol or in the absence of a solvent with an acid such as hydrogen chloride or trifluoroacetic acid at ⁇ 10 ° C. to 100 ° C. can do. Further, the compound (ZA) is produced by hydrogenating the compound (ZC) in a suitable solvent such as methanol at 0 ° C to 100 ° C using a catalyst such as palladium carbon or palladium hydroxide. Can be done. In addition, it can be produced from compound (ZC) or a compound equivalent thereto by using a deprotection reaction of a protecting group described in Protective Groups in Organic Synthesis (Wiley) or the like, or equivalent thereto.
  • Compound (ZC) can be produced, for example, by the method shown below.
  • Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction.
  • Lv indicates a leaving group.
  • Other symbols have the same meaning as described above.
  • Compound (ZC) is prepared by mixing compound (ZD) and compound (ZE) in a suitable solvent such as DMF, a metal catalyst such as tris (dibenzylideneacetone) dipalladium, copper iodide, if necessary. It can be produced by reacting at 0 ° C. to 200 ° C. in the presence of a ligand such as BINAP or ethylenediamine and, if necessary, a base such as triethylamine or DIPEA. As the leaving group, an appropriate functional group such as a halogen or a tosyl group is used. In addition, compound (ZC) is prepared by mixing compound (ZD) and compound (ZE) from 0 ° C.
  • a metal catalyst such as tris (dibenzylideneacetone) dipalladium, copper iodide, if necessary. It can be produced by reacting at 0 ° C. to 200 ° C. in the presence of a ligand such as BINAP
  • Compound (ZD) can be produced from a commercially available product or a commercially available product by a known method. For example, it is produced by combining known methods from appropriate starting materials according to a synthetic method described in, for example, known patent documents WO2014 / 1599969, WO2012 / 154274, WO2017 / 190609 or WO2016 / 027195, etc. Can be done.
  • the compound (ZE) can be produced from a commercially available product or a commercially available product by a known method.
  • a commercially available product or a commercially available product by a known method.
  • the well-known academic literature Cottet Fabrice, et al, Euro. J. Org. Chem. (2), 2002, 327-330. And known patent documents WO2013 / 088404, WO2010 / 064707, etc., or by combining known methods from appropriate starting materials according to a synthetic method similar thereto.
  • Compound (ZB) can be produced, for example, by the method shown below.
  • Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction.
  • Other symbols have the same meaning as described above.
  • Compound (Z-B) is prepared by reacting compound (Z-F) with a base such as lithium hydroxide or sodium hydroxide at 0 ° C. to 100 ° C. in a suitable solvent such as a mixed solvent of water and methanol or tetrahydrofuran. ) Can be manufactured. In addition, it can be produced from compound (ZF) or a compound equivalent thereto by using a deprotection reaction of a protecting group described in Protective Groups in Organic Synthesis (Wiley) or the like, or equivalent thereto.
  • a base such as lithium hydroxide or sodium hydroxide at 0 ° C. to 100 ° C.
  • a suitable solvent such as a mixed solvent of water and methanol or tetrahydrofuran.
  • the compound (ZF) can be produced from a commercially available product or a commercially available product by a known method.
  • the compound (ZB) can be produced from a commercially available product or a commercially available product by a known method.
  • it can be produced by combining known methods from appropriate starting materials according to a synthetic method described in known patent documents WO2013 / 144295, WO2014 / 01748, WO2008 / 125337, etc., or similar thereto.
  • the compound (Z) of the present invention comprises compound (ZE) and compound (ZG) in a suitable solvent such as DMF, and a metal catalyst such as tris (dibenzylideneacetone) dipalladium or copper iodide, if necessary. It can be produced by reacting at 0 ° C. to 200 ° C. in the presence of a ligand such as BINAP or ethylenediamine and, if necessary, a base such as triethylamine or DIPEA. As the leaving group, an appropriate functional group such as a halogen or a tosyl group is used.
  • compound (Z) is prepared by mixing compound (ZE) and compound (ZG) at 0 ° C to 200 ° C in a suitable solvent such as DMF in the presence of a base such as sodium hydride or cesium carbonate. It can be produced by reacting with. In addition, it can be produced from compound (ZE) and compound (GG), or a compound equivalent to each, by using a reaction similar thereto.
  • Compound (ZG) can be produced, for example, by the method shown below.
  • Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction.
  • Other symbols have the same meaning as described above.
  • Compound (ZG) is prepared by reacting compound (ZH) with an acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol or chloroform or in the absence of a solvent at ⁇ 10 ° C. to 100 ° C. Can be manufactured in.
  • compound (ZG) is produced by hydrogenating compound (ZH) in a suitable solvent such as methanol or THF at 0 ° C to 100 ° C using a catalyst such as palladium carbon or palladium hydroxide. can do.
  • it can be produced from compound (ZH) or a compound equivalent thereto by using a deprotection reaction of a protecting group described in Protective Groups in Organic Synthesis (Wiley) or the like, or equivalent thereto.
  • Compound (ZH) can be produced, for example, by the method shown below.
  • Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction.
  • Other symbols have the same meaning as described above.
  • Compound (ZH) is a condensing agent such as HATU or WSC, and optionally an additive such as HOBT or DMAP, in a suitable solvent such as DMF or the compound (ZB) and the compound (ZI). If necessary, it can be produced by reacting at 0 ° C to 100 ° C in the presence of a base such as triethylamine or DIPEA. Further, for compound (Z-I), a carboxylic acid chloride or carboxylic acid anhydride corresponding to compound (Z-B) is placed in a suitable solvent such as tetrahydrofuran, and if necessary, a base such as triethylamine, DIPEA or pyridine.
  • a suitable solvent such as tetrahydrofuran
  • Compound (Z-I) can be produced from a commercially available product or a commercially available product by a known method.
  • Reference example 7-2 2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methylpyrrolidine-3-yl) acetamide Ice on tert-butyl (2S, 4R) -4- (2- (4-cyclopropylphenyl) acetamide) -2-methylpyrrolidin-1-carboxylate (365 mg, 1.02 mmol) synthesized in Reference Example 7-1.
  • a 2N hydrochloric acid-methanol solution (15 mL) was added under cooling, and the mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure.
  • Reference example 8 (3- (5- (Trifluoromethyl) Pyridine-3-yl) -3-azabicyclo [3.1.0] Hexane-1-yl) tert-butyl carbamate Following the same procedure as in Reference Example 4, tert-butyl (3-azabicyclo [3.1.0] hexane-1-yl) carbamic acid (250 mg, 1.26 mmol) and 3-bromo-5- (trifluoromethyl) The title compound (colorless oil, 103 mg, 23%) was obtained using pyridine (342 mg, 1.51 mmol).
  • Reference example 14-2 (R) -2- (5- (3-Aminopyrrolidine-1-yl) Pyridine-3-yl) Propane-2-ol (R)-(1- (5- (2-Hydroxypropane-2-yl) pyridin-3-yl) pyrrolidine-3-yl synthesized in Reference Example 14-1 according to the same method as in Reference Example 7-2. )-Butyl carbamic acid (187 mg, 0.58 mmol) was used to give the title compound (brown oil, 114 mg, 88%).
  • Reference example 16 2- (4- (1,1-dioxidethiomorpholino) phenyl) ethyl acetate Following the same procedure as in Reference Example 3, the title compound (pale yellow) with 2- (4-bromophenyl) ethyl acetate (300 mg, 1.23 mmol) and 1,1-dioxidethiomorpholine (334 mg, 2.47 mmol). An oil, 30 mg, 8.2%) was obtained.
  • Reference example 17 2- (4- (Trimethylsilyl) phenyl) ethyl acetate Under a nitrogen atmosphere, a small amount of iodine was added to a round bottom flask containing magnesium (168 mg, 6.98 mmol) and THF (1.0 mL), and then 2- (4-bromophenyl) dissolved in THF (3.4 mL). Ethyl acetate (500 mg, 2.06 mmol) was added and the mixture was heated under reflux for 30 minutes. The reaction mixture was allowed to cool to room temperature, chlorotrimethylsilane (520 ⁇ L, 4.11 mmol) was added, and the mixture was heated under reflux for 2 hours.
  • Reference example 19 3-Cyano-3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-carboxylic acid tert-butyl Following the same procedure as in Reference Example 7-1, tert-butyl 3-amino-3-cyanopyrrolidine-1-carboxylate (300 mg, 1.42 mmol) and 2- (4-cyclopropyl) synthesized in Reference Example 33-2. The title compound (yellow oil, 454 mg, 86%) was obtained using phenyl) acetic acid (300 mg, 1.70 mmol).
  • Reference example 23-1 2- (4-morpholinophenyl) ethyl acetate 2- (4-Bromophenyl) ethyl acetate (1.28 g, 5.27 mmol), morpholine (917 ⁇ L, 10.5 mmol), palladium acetate (118 mg, 0.53 mmol), tert-butyl XPhos (447 mg, 1.05 mmol) And cesium carbonate (3.43 g, 10.5 mmol) was suspended in toluene (25 mL) and stirred at 110 ° C. for 16 hours under a nitrogen stream. The reaction solution allowed to cool to room temperature was filtered through Celite, and the solvent was distilled off under reduced pressure.
  • Reference example 23-2 2- (4-morpholinophenyl) acetic acid
  • Ethyl 2- (4-morpholinophenyl) acetate (760 mg, 3.05 mmol) synthesized in Reference Example 23-1 is dissolved in methanol (5.0 mL), and a 2N sodium hydroxide aqueous solution (4.6 mL) is added to room temperature. The mixture was stirred for 16 hours and the solvent was distilled off under reduced pressure. Water was added to the obtained residue, the mixture was washed with chloroform, neutralized by adding a 2N aqueous hydrochloric acid solution, and then the solvent was distilled off under reduced pressure.
  • Reference example 24 3- (2- (4-Cyclopropylphenyl) acetamide) -3-ethylpyrrolidine-1-carboxylic acid tert-butyl Following the same procedure as in Reference Example 7-1, tert-butyl 3-amino-3-ethylpyrrolidine-1-carboxylate (500 mg, 2.33 mmol) and 2- (4-cyclopropyl) synthesized in Reference Example 33-2. The title compound (white crystals, 782 mg, 90%) was obtained using phenyl) acetic acid (493 mg, 2.80 mmol).
  • Reference example 27 2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) ethyl acetate 2- (4-Bromophenyl) ethyl acetate (1.0 g, 4.11 mmol), 2-oxa-6-azaspiro [3.3] heptane (816 mg, 8.23 mmol), palladium acetate (92 mg, 0.41 mmol) , XPhos (270 mg, 0.57 mmol) and cesium carbonate (2.68 g, 8.23 mmol) were suspended in toluene (30 mL) and stirred at 110 ° C. for 16 hours under a nitrogen stream.
  • Reference example 29-2 Ethyl trans-2-((2-bromophenyl) carbamoyl) cyclopropane-1-carboxylate Trans-2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid (2.0 g, 12.6 mmol) and 2-bromoaniline (2) synthesized in Reference Example 29-1 according to the same method as in Reference Example 28-1.
  • the title compound (white powder, 3.42 g, 87%) was obtained using .61 g, 15.2 mmol).
  • Reference example 30-1 (1S, 2S) -2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid (1S, 2S) -cyclopropane-1,2-dicarboxylic acid (2.5 g, 19.2 mmol) is dissolved in ethanol (38 mL), thionyl chloride (3.48 mL, 48.0 mmol) and a small amount of DMF are added. After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the mixture was stirred for a while, and then the separated organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate.
  • Reference example 30-2 Ethyl (1S, 2S) -2-((2-bromo-5-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate (1S, 2S) -2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid (500 mg, 3.16 mmol) and 2-bromoaniline synthesized in Reference Example 30-1 according to the same procedure as in Reference Example 28-1. (721 mg, 3.79 mmol) was used to give the title compound (ivory powder, 530 g, 51%).
  • Reference example 31-1 (5- (Trifluoromethyl) Pyridine-2-yl) Dimethyl malonate 2-Chloro-5- (trifluoromethyl) pyridine (5.00 g, 27.5 mmol), dimethyl malonate (5.46 g, 41.3 mmol) and cesium carbonate (18.0 g, 55.1 mmol) in dimethyl sulfoxide (18.0 g, 55.1 mmol) It was dissolved in 10.0 mL) and stirred overnight at 110 ° C. under a nitrogen stream. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate.
  • Reference example 31-2 2- (5- (trifluoromethyl) pyridin-2-yl) acetic acid Dimethyl 2- (5- (trifluoromethyl) pyridine-2-yl) malonate (790 mg, 2.85 mmol) synthesized in Reference Example 31-1 was dissolved in methanol (18 mL) and dissolved in 2N sodium hydroxide aqueous solution (3). .6 mL) was added and stirred at 50 ° C. overnight.
  • Reference example 33-1 2- (4-Cyclopropylphenyl) ethyl acetate 4-Bromophenyl ethyl acetate (6.0 g, 24.7 mmol), cyclopropylboronic acid (2.76 g, 32.1 mmol), palladium acetate (276 mg, 1.23 mmol), tricyclohexylphosphine (0.6 M toluene solution, 4.2 mL, 2.46 mmol) and potassium phosphate monohydrate (19.9 g, 86.4 mmol) were suspended in toluene (60.0 mL) and water (3.0 mL) and 16 at 100 ° C. under a nitrogen stream. Stirred for hours.
  • the reaction solution allowed to cool to room temperature was filtered through a Celite pad, and the solvent of the filtrate was evaporated under reduced pressure.
  • the obtained residue was diluted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-30%) to give the title compound (yellow oil, 4.90 g, 97%).
  • Reference example 38-2 (R) -1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-amine (R)-(1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 38-1 according to the same method as in Reference Example 1-2.
  • the title compound (white solid, 45 mg, 75%) was obtained using butyl (86 mg, 0.26 mmol).
  • Reference example 40-1 (1S, 2S) -2-((2-formylphenyl) carbamoyl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl According to the same method as in Reference Example 28-1, (1S, 2S) -2-((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) cyclopropane-1-carboxylic acid A crude of the title compound was obtained using (1.17 g, 4.35 mmol) and 2-aminobenzaldehyde (988 mg, 8.12 mmol).
  • Reference example 40-2 (1S, 2S) -2- (quinazoline-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl
  • (1S, 2S) -2-((2-formylphenyl) carbamoyl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl synthesized in Reference Example 40-1 The body, ammonium acetate, was heated to reflux in toluene at 120 ° C. for 10 hours.
  • Reference example 40-3 (1S, 2S) -2- (quinazoline-2-yl) cyclopropane-1-carboxylic acid (1S, 2S) -2- (quinazoline-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl (277 mg, 0) synthesized in Reference Example 40-2 .79 mmol) was dissolved in isopropanol (2.1 mL) and water (170 ⁇ L), sodium hydroxide (63 mg, 1.57 mmol) was added, and the mixture was stirred at 80 ° C. for 25 hours, and then the solvent was distilled off under reduced pressure.
  • Reference example 41-2 (R) -1- (3- (Methylsulfonyl) phenyl) pyrrolidine-3-amine Tert-Butyl (R)-(1- (3- (methylsulfonyl) phenyl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 41-1 according to the same method as in Reference Example 1-2 (57 mg, 0) .17 mmol) was used to give the title compound (pale yellow oil, 12 mg, 30%).
  • Reference example 42-2 (R) -3- (3-aminopyrrolidine-1-yl) benzonitrile Tert-Butyl (R)-(1- (3-cyanophenyl) pyrrolidine-3-yl) carbamate (57 mg, 0.20 mmol) synthesized in Reference Example 42-1 according to the same method as in Reference Example 1-2. Was used to give the title compound (pale yellow oil, 32 mg, 85%).
  • the separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) (concentration gradient: 40-80%) to give the title compound (slight brown amorphous, 142 mg, 88%).
  • Reference example 45-2 (R) -1- (6- (trifluoromethyl) Pyridine-3-yl) Piperidine-3-amine (R)-(1- (6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) carbamic acid tert- synthesized in Reference Example 45-1 according to the same method as in Reference Example 1-2.
  • the title compound (light brown syrup, 50 mg, 97%) was obtained using butyl (72 mg, 0.21 mmol).
  • Reference example 46-3 (R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (R)-(1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 46-2 according to the same method as in Reference Example 1-2. Butyl (147 mg, 0.44 mmol) was used to give the title compound (pale yellow syrup, 94 mg, 91%).
  • Reference example 47-1 (R)-(1- (4- (Trifluoromethyl) phenyl) piperidine-3-yl) tert-butyl carbamic acid Following the same procedure as in Reference Example 1-1, 1-bromo-4- (trifluoromethyl) benzene (62 mg, 0.27 mmol) and tert-butyl (R) -piperidine-3-ylcarbamate (50 mg, 0. 25 mmol) was used to give the title compound (pale yellow solid, 59 mg, 68%).
  • Reference example 48-1 (R)-(1- (6-Methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid Following the same procedure as in Reference Example 1-1, 5-bromo-2-methoxy-3- (trifluoromethyl) pyridine (151 mg, 0.59 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (tert-butyl (R) -pyrrolidine-3-ylcarbamate). The title compound (pale yellow solid, 26 mg, 13%) was obtained using 100 mg (0.54 mmol).
  • Reference example 48-2 (R) -1- (6-Methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (R)-(1- (6-methoxy-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) synthesized in Reference Example 48-1 according to the same method as in Reference Example 1-2)
  • the title compound (pale yellow syrup, 18 mg, 100%) was obtained using tert-butyl carbamate (26 mg, 0.07 mmol).
  • Reference example 49-2 (R) -1- (4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-amine (R)-(1- (4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 49-1 according to the same method as in Reference Example 1-2.
  • the title compound (colorless oil, 65 mg, 91%) was obtained using butyl (103 mg, 0.32 mmol).
  • Reference example 53 (R)-(1- (6-Fluoroquinoline-2-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
  • tert-butyl (R) -pyrrolidine-3-ylcarbamic acid 50 mg, 0.268 mmol
  • 2-chloro-6-fluoroquinoline 54 mg, 0.295 mmol
  • toluene 1.5 mL
  • water 150 ⁇ L
  • potassium carbonate 44 mg, 0.322 mmol
  • Reference example 54-2 (1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (1S, 2S) -2- (1-cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2 synthesized in Reference Example 54-1 -Isopropyl-5-methylcyclohexyl (270 mg, 0.709 mmol) was suspended in isopropanol (2 mL) and water (150 ⁇ L), sodium hydroxide (57 mg, 1.42 mmol) was added, and the mixture was stirred at 80 ° C.
  • Reference example 55 (R)-(1- (5-Bromopyridine-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid Following the same procedure as in Reference Example 1-1, the title was used with 3,5-dibromopyridine (178 mg, 0.751 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (47 mg, 0.252 mmol). A compound (white powder, 71 mg, 83%) was obtained.
  • Reference example 56 2- (4- (trifluoromethyl) phenyl) acetic acid-2,2-d 2 After dissolving 4- (trifluoromethyl) phenylacetic acid (50 mg, 0.245 mmol) in heavy water (1 mL), add 40% sodium oxide solution (0.5 mL, 7.00 mmol) and heat overnight under a nitrogen atmosphere. Refluxed. Heavy water was added to the reaction solution allowed to cool to room temperature, washed with diethyl ether, 3N hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted with diethyl ether.
  • Reference example 58-1 (1- (5- (Trifluoromethyl) Pyridine-3-yl) Azetidine-3-yl) tert-Butyl Carbamic Acid
  • 3-bromo-5- (trifluoromethyl) pyridine (390 mg, 1.73 mmol)
  • azetidine-3-ylcarbamic acid tert-butyl hydrochloride 300 mg, 1.44 mmol
  • the title compound (pale yellow powder, 112 mg, 25%) was obtained.
  • Reference example 58-2 1- (5- (trifluoromethyl) Pyridine-3-yl) Azetidine-3-amine Tert-Butyl carbamic acid (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) synthesized in Reference Example 58-1 according to the same procedure as in Reference Example 1-2 (112 mg, 0.353 mmol) was used to give the title compound (white powder, 60 mg, 79%).
  • Reference example 60 2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) ethyl acetate
  • the title compound (yellow oil) was used with 2- (4-bromophenyl) ethyl acetate (300 mg, 1.23 mmol) and 4-piperidone ethylene ketal (317 ⁇ L, 2.46 mmol). , 16 mg, 4%).
  • Reference example 61-1 7- (5- (trifluoromethyl) Pyridine-3-yl) -3-oxa-1,7-diazaspiro [4.4] nonane-2-one According to the same procedure as in Reference Example 1-1, 3-bromo-5- (trifluoromethyl) pyridine (162 mg, 0.717 mmol) and N- (3- (hydroxymethyl) pyrrolidine-3-yl) carbamate benzyl ( The title compound (white powder, 106 mg, 51%) was obtained using 189 mg, 0.753 mmol).
  • Reference example 61-2 (3-Amino-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methanol 7- (5- (trifluoromethyl) pyridine-3-yl) -3-oxa-1,7-diazaspiro [4.4] nonane-2-one (95 mg, 0.331 mmol) synthesized in Reference Example 61-1 ) was dissolved in ethanol (4 mL) and water (1 mL), lithium hydroxide monohydrate (278 mg, 6.61 mmol) was added, and the mixture was heated under reflux overnight under a nitrogen atmosphere.
  • Reference example 64-2 (S) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (S)-(1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 64-1 according to the same method as in Reference Example 1-2.
  • the title compound (pale yellow crystals, 100 mg, 77%) was obtained using butyl (184 mg, 0.555 mmol).
  • tert-butyl 3-aminoazetidine-1-carboxylate 500 mg, 2.90 mmol
  • 2- (4-isopropylphenyl) acetic acid 624 mg, 3.50 mmol
  • the title compound (pale yellow amorphous, 964 mg, 100%) was obtained.
  • Reference example 73-2 (R) -N- (pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide (R) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-1-carbamic acid tert-butyl synthesized in Reference Example 73-1 according to the same method as in Reference Example 1-2 ( The title compound (white solid, 650 mg, 80%) was obtained using 1.12 g, 3.0 mmol).
  • tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 mL, 8.29 mmol) and 2- (4-cyclopropylphenyl) synthesized in Reference Example 33-2 The title compound (yellow crystals, 2.0 g, 70%) was obtained using acetic acid (1.8 g, 9.95 mmol).
  • Reference example 74-2 (R) -2- (4-Cyclopropylphenyl) -N- (pyrrolidine-3-yl) acetamide Tert-Butyl (R) -3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-carboxylate synthesized in Reference Example 74-1 according to the same procedure as in Reference Example 1-2 (2.0 g) , 5.81 mmol) was used to give the title compound (pale yellow crystals, 1.1 g, 77%).
  • Reference example 75-1 3- (2- (4-Cyclopropylphenyl) acetamide) azetidine-1-carbamic acid tert-butyl Following the same procedure as in Reference Example 7-1, tert-butyl 3-aminoazetidine-1-carbamic acid (276 mg, 1.6 mmol) and 2- (4-cyclopropylphenyl) acetic acid synthesized in Reference Example 33-2. (352 mg, 2.0 mmol) was used to give the title compound (white solid, 434 mg, 82%).
  • Example 1 (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and 2 synthesized in Reference Example 33-2.
  • -(4-Cyclopropylphenyl) acetic acid (30 mg, 0.09 mmol) is dissolved in DMF (2.0 mL), then DIPEA (29 ⁇ L, 0.17 mmol) and HATU (33 mg, 0.09 mmol) are added at room temperature.
  • Example 2 (R) -2- (5- (trifluoromethyl) pyridin-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 11 mg, 31%) was obtained using a crude product (26 mg) of 2- (5- (trifluoromethyl) pyridine-2-yl) acetic acid synthesized in Reference Example 31-2.
  • Example 5 2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-hydroxy-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide Carbamic acid synthesized in Reference Example 3 ((3S, 4S) -4-hydroxy-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) according to the same procedure as in Example 3. (3S, 4S) -4-amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-ol (white crystals) was synthesized from tert-butyl (106 mg, 0.31 mmol).
  • Example 6 (R) -2- (4-Cyclopropylphenyl) -N- (5- (5- (trifluoromethyl) Pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide (R)-(5-(5- (trifluoromethyl) pyridine-3-yl) -5-azaspiro [2.4] heptan-7-yl) synthesized in Reference Example 4 according to the same method as in Example 3.
  • Example 8 (R) -2- (4-Cyclopropylphenyl) -N- (5- (4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide (R)-(5-(4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptan-7-yl) synthesized in Reference Example 6 according to the same method as in Example 7.
  • Example 9 2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide 2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methylpyrrolidin-3-yl) acetamide (150 mg, 0.58 mmol), 3-bromo-5 synthesized in Reference Example 7-2.
  • Example 10 2- (4-Cyclopropylphenyl) -N- (3- (5- (trifluoromethyl) pyridine-3-yl) -3-azabicyclo [3.1.0] hexane-1-yl) acetamide (3- (5- (Trifluoromethyl) pyridine-3-yl) -3-azabicyclo [3.1.0] hexane-1-yl) carbamine synthesized in Reference Example 8 according to the same procedure as in Example 7.
  • Example 11 (R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-yl) acetamide Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 9 according to the same procedure as in Example 7 (159 mg, (R) -1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-amine was synthesized from 0.48 mmol), and 2- (4- (trifluoromethyl) phenyl) acetic acid (117 mg, 0.57 mmol) was used to give the title compound (white powder, 187 mg, 94%).
  • Example 12 (R) -N- (1- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide (R)-(1- (6-cyano-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 10 according to the same procedure as in Example 3. (R) -1- (6-cyano-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from butyl (139 mg, 0.39 mmol) and synthesized in Reference Example 33-2.
  • Example 13 Methyl 3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate Methyl 3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-3-carboxylate (94 mg, 0.31 mmol) and 3-bromo- synthesized in Reference Example 11-2 according to the same procedure as in Example 9. The title compound (white amorphous, 53 mg, 38%) was obtained using 5- (trifluoromethyl) pyridine (84 mg, 0.37 mmol).
  • Example 14 (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylic acid
  • Methyl 3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate (50 mg, 0.11 mmol) synthesized in Example 13. ) was dissolved in THF (2.0 mL), a 2N aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hours.
  • the reaction mixture was neutralized by adding a 1N aqueous hydrochloric acid solution, and then extracted with a mixed solution of chloroform and methanol.
  • the separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-90%), and then methanol and water were added to the obtained powder and stirred for a while.
  • the precipitated powder was filtered and dried at 100 ° C. for 3 hours under reduced pressure to give the title compound (white powder, 38 mg, 79%).
  • Example 15 (R) -2- (1H-indazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (66 mg, 0.28 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 82 mg, 74%) was obtained using 2- (1H-indazole-6-yl) acetic acid (50 mg, 0.28 mmol).
  • Example 16 (R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide (R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (33 mg, 0.14 mmol) synthesized in Reference Example 12-2 and the same procedure as in Example 1 and The title compound (yellowish green powder, 30 mg, 55%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (29 mg, 0.17 mmol) synthesized in Reference Example 33-2.
  • Example 17 2- (4-Isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 50 mg, 79%) was obtained using 2- (4-isobutylphenyl) propanoic acid (37 mg, 0.18 mmol).
  • Example 18 (R) -2- (4-Cyclopropylphenyl) -N- (1- (6-methyl-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R)-(1- (6-methyl-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 13 according to the same procedure as in Example 7. (R) -1- (6-methyl-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (white powder, 22 mg) was synthesized from butyl (22 mg, 0.06 mmol) and used as a reference example.
  • Example 21 3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxyamide 3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3- (5- (trifluoromethyl) pyridine-3-yl) synthesized in Example 14 according to the same procedure as in Example 1. Carboxylic acid (15 mg, 0.04 mmol) and ammonium acetate (5.3 mg, 0.07 mmol) were used to give the title compound (white powder, 11 mg, 73%).
  • Example 22 (R) -2- (4-Hydroxyphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (200 mg, 0.86 mmol) synthesized in Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 292 mg, 92%) was obtained using 2- (4-hydroxyphenyl) acetic acid (158 mg, 1.04 mmol).
  • Example 24 (R) -1- (4-chlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
  • R -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1.
  • the title compound (white amorphous, 70 mg, 79%) was obtained using 1- (4-chlorophenyl) cyclopropane-1-carboxylic acid (51 mg, 0.26 mmol).
  • Example 25 2- (4-Bromophenyl) -2-hydroxy-N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 68 mg, 71%) was obtained using 2- (4-bromophenyl) -2-hydroxyacetic acid (60 mg, 0.26 mmol).
  • Example 27 (R) -2- (4- (2-Hydroxy-2-methylpropoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-Hydroxyphenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 22 (30 mg, 0.
  • Example 28 2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-fluoro-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (3S, 4S) -3- (2- (4-cyclopropylphenyl) acetamide) -4-fluoropyrrolidin-1-carboxylate tert-butyl (369 mg, 1.02 mmol) synthesized in Reference Example 18 under ice-cooling.
  • Example 29 (R) -2- (4- (dimethylamino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (46 mg, 0.20 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1.
  • the title compound (white amorphous, 40 mg, 51%) was obtained using 2- (4- (dimethylamino) phenyl) acetic acid (43 mg, 0.24 mmol).
  • Example 30 (R) -2- (4-Nitrophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (150 mg, 0.65 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 219 mg, 86%) was obtained using 2- (4-nitrophenyl) acetic acid (141 mg, 0.78 mmol).
  • Example 31 (S) -2- (4-isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (15 mg, 0.06 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 22 mg, 81%) was obtained using (S) -2- (4-isobutylphenyl) propanoic acid (16 mg, 0.08 mmol).
  • Example 32 (R) -2- (3-Fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 25 mg, 66%) was obtained using 2- (3-fluoro-4- (trifluoromethyl) phenyl) acetic acid (23 mg, 0.10 mmol).
  • Example 33 (R) -2- (4-Aminophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -2- (4-nitrophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 30 (215 mg, 0. 55 mmol) was dissolved in methanol (20 mL), palladium carbon (20 mg) was added, and the mixture was stirred under a hydrogen stream for 6 hours at room temperature.
  • Example 35 (R) -2- (4-acetamide phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -2- (4-Aminophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 33 (30 mg, 0. 08 mmol) was dissolved in chloroform (1.0 mL), acetyl chloride (5.9 ⁇ L, 0.08 mmol) and DIPEA (30 ⁇ L, 0.16 mmol) were added, and the mixture was stirred at room temperature for 60 hours.
  • Example 36 N- (3-Cyano-1- (5- (trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) -2- (4-Cyclopropylphenyl) acetamide Trifluoroacetic acid (15 mL) was added to the 3-cyano-3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-carboxylic acid tert-butyl (454 mg, 1.23 mmol) synthesized in Reference Example 19 under ice-cooling.
  • Example 37 3- (2- (1H-indole-6-yl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylate methyl 3-((tert-butoxycarbonyl) amino) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylic synthesized in Reference Example 20-2 according to the same procedure as in Example 7. Methyl 3-amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate was synthesized from methyl acid (34 mg, 0.09 mmol) to synthesize 2- (1H-indole-6-).
  • Example 38 Methyl 3- (2- (4- (trifluoromethyl) phenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate Methyl 3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-3-carboxylate (294 mg, 0.89 mmol) synthesized in Reference Example 21-2, 3-bromo-5- (trifluoromethyl) ) Ppyridine (302 mg, 1.34 mmol), palladium acetate (20 mg, 0.09 mmol), XPhos (85 mg, 0.18 mmol) and cesium carbonate (628 mg, 1.78 mmol) suspended in toluene (9.0 mL) and nitrogen.
  • Example 39 (1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide Methyl (1S, 2S) -2- (benzo [d] oxazole-2-yl) cyclopropane-1-carboxylate (95 mg, 0.44 mmol) synthesized in Reference Example 25-2 according to the same procedure as in Example 26.
  • Example 40 (R) -2- (4-morpholinophenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide (R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (70 mg, 0.30 mmol) synthesized in Reference Example 12-2 and the same procedure as in Example 1 The title compound (white powder, 60 mg, 46%) was obtained using 2- (4-morpholinophenyl) acetic acid (98 mg, 0.44 mmol) synthesized in Reference Example 23-2.
  • Example 41 Methyl 3- (2- (4-morpholinophenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate 3-((tert-butoxycarbonyl) amino) -1-(5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylic acid synthesized in Reference Example 20-2 according to the same procedure as in Example 7. Methyl 3-amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate was synthesized from methyl acid (39 mg, 0.10 mmol), and was synthesized in Reference Example 23-2.
  • Example 42 (R) -2- (4-morpholinophenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (70 mg, 0.30 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 The title compound (white powder, 59 mg, 45%) was obtained using 2- (4-morpholinophenyl) acetic acid (100 mg, 0.45 mmol) synthesized in Reference Example 23-2.
  • Example 43 2- (4-Cyclopropylphenyl) -N- (3-ethyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide From tert-butyl 3- (2- (4-cyclopropylphenyl) acetamide) -3-ethylpyrrolidin-1-carboxylate (782 mg, 2.10 mmol) synthesized in Reference Example 24 according to the same procedure as in Example 38.
  • Example 44 (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide Methyl (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate (105 mg,) synthesized in Reference Example 22-4 according to the same procedure as in Example 26.
  • Example 45 (1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine- 3-Il) Cyclopropane-1-carboxyamide Methyl (1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate synthesized in Reference Example 26-2 according to the same procedure as in Example 26.
  • Example 46 (R) -2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide 2.
  • Ethyl 2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) ethyl acetate synthesized in Reference Example 27 according to the same procedure as in Example 26 (1.26 g, 4.
  • Example 47 (1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide Methyl (1S, 2S) -2- (benzo [d] oxazole-2-yl) cyclopropan-1-carboxylate (110 mg, 0.51 mmol) synthesized in Reference Example 25-2 according to the same procedure as in Example 26.
  • Example 48 (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide Methyl (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylate synthesized in Reference Example 22-4 according to the same procedure as in Example 26 (121 mg, (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylic acid (dental powder) was synthesized from 0.51 mmol), and synthesized in Reference Example 22-2.
  • Example 49 (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide Methyl (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylate synthesized in Reference Example 28-2 according to the same procedure as in Example 26 (47 mg, (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylic acid (dental powder) was synthesized from 0.20 mmol), and synthesized in Reference Example 1-2.
  • Example 50 (1R, 2R) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide Trans-from ethyl trans-2- (benzo [d] oxazole-2-yl) cyclopropan-1-carboxylate (200 mg, 0.86 mmol) synthesized in Reference Example 29-3 according to the same procedure as in Example 26.
  • Example 51 (1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide
  • Example 52 Trans-2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate (273 mg, 0.83 mmol) synthesized in Reference Example 34 according to the same procedure as in Example 3.
  • Example 53 Trans-2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide (S)-(1- (4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) tert-butyl carbamate (236 mg, 0.72 mmol) synthesized in Reference Example 35 according to the same procedure as in Example 3.
  • Example 54 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 36 according to the same procedure as in Example 3 (429 mg, A crude compound (300 mg) of (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from 1.30 mmol), and (1S, 2S) -2- (1H) was synthesized.
  • Example 55 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-butyl (S)-(1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 37 according to the same procedure as in Example 3 (59 mg, A crude compound (37 mg) of (S) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from 0.18 mmol), and (1S, 2S) -2- (1H) was synthesized.
  • Example 56 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyrimidine-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide (R) -1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-amine (45 mg, 0.20 mmol) synthesized in Reference Example 38-2 and the same procedure as in Example 1 and The title compound (white powder, 28 mg, 68%) was prepared with (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
  • Example 57 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 39 according to the same procedure as in Example 3 (112 mg, A crude compound (80 mg) of (R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-amine was synthesized from 0.32 mmol), and (1S, 2S) -2- (1H) was synthesized.
  • Example 58 (1S, 2S) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) -2- (quinazoline-2-yl) cyclopropane-1- Carboxamide Tert-Butyl (R)-(1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 39 according to the same procedure as in Example 3 (112 mg, A crude compound (80 mg) of (R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-amine was synthesized from 0.32 mmol) and synthesized in Reference Example 40-3 (1S).
  • Example 59 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(3- (methylsulfonyl) phenyl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide (R) -1- (3- (methylsulfonyl) phenyl) pyrrolidine-3-amine (6 mg, 0.02 mmol) and (1S, 2S) synthesized in Reference Example 41-2 according to the same procedure as in Example 1.
  • Example 60 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (3-cyanophenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide (R) -3- (3-aminopyrrolidine-1-yl) benzonitrile (5 mg, 0.02 mmol) and (1S, 2S) -2 synthesized in Reference Example 42-2 according to the same procedure as in Example 1. -(1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (5 mg, 0.02 mmol) was used to give the title compound (pale yellow powder, 9 mg, 96%).
  • Example 61 Trans-2- (5-cyano-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (31 mg, 0.14 mmol) synthesized in Reference Example 1-2 and according to the same method as in Example 1.
  • Example 62 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyridin-4-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide From tert-butyl (R)-(1- (2- (trifluoromethyl) pyridine-4-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 44 according to the same procedure as in Example 3 (R).
  • Example 64 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide (R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (24 mg, 0.10 mmol) synthesized in Reference Example 46-3 and the same procedure as in Example 1.
  • Example 65 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) piperidine-3-yl) cyclopropane- 1-carboxyamide (R) -1- (4- (trifluoromethyl) phenyl) piperidine-3-amine (22 mg, 0.10 mmol) and (1S, 2S) synthesized in Reference Example 47.2 according to the same procedure as in Example 1.
  • Example 67 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-yl) Cyclopropane-1-carboxyamide (R) -1- (6-methoxy-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (18 mg, 0) synthesized in Reference Example 48-2 according to the same procedure as in Example 1.
  • Example 68 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide (R) -1- (4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-amine (22 mg, 0.10 mmol) synthesized in Reference Example 49-2 and the same procedure as in Example 1 and The title compound (white powder, 23 mg, 57%) was prepared with (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
  • Example 69 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 50 according to the same procedure as in Example 3 (90 mg, A crude compound (91 mg) of (R) -1- (6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-amine was synthesized from 0.271 mmol), and (1S, 2S) -2- (1H) was synthesized.
  • Example 70 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 51 according to the same procedure as in Example 3 (129 mg, A crude compound (101 mg) of (R) -1- (2- (trifluoromethyl) pyrimidin-5-yl) pyrrolidine-3-amine was synthesized from 0.388 mmol), and (1S, 2S) -2- (1H) was synthesized.
  • Example 71 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 1-1 according to the same procedure as in Example 3 ( A crude compound (79 mg) of (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from 102 mg, 0.308 mmol), and (1S, 2S) -2- The title compound (white powder, 73 mg, 57%) was obtained using (1H-benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (125 mg
  • Example 72 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 52 according to the same procedure as in Example 3 (85 mg, A crude compound (93 mg) of (R) -1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-amine was synthesized from 0.253 mmol), and (1S, 2S) -2- (1H) was synthesized.
  • Example 73 (1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-yl)) Pyrrolidine-3-yl) cyclopropane-1-carboxyamide (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (21 mg, 0.090 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and Using (1S, 2S) -2- (1-cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (33 mg, 0.135 mmol) synthesized in Reference Example 54-2.
  • Example 74 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluoroquinoline-2-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide Tert-Butyl (R)-(1- (6-fluoroquinoline-2-yl) pyrrolidine-3-yl) carbamate (39 mg, 0.118 mmol) synthesized in Reference Example 53 according to the same procedure as in Example 3.
  • Example 75 (1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(3- (trifluoromethyl) phenyl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate (105 mg, 0.319 mmol) synthesized in Reference Example 77 according to the same procedure as in Example 3.
  • Example 76 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (5-bromopyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide (R)-(1- (5-bromopyridin-3-yl) pyrrolidine-3-yl) tert-butylcarbamate (71 mg, 0.209 mmol) synthesized in Reference Example 55 according to the same procedure as in Example 3.
  • Example 77 (R) -2- (quinoline-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 88 mg, 100%) was obtained using 6-quinoline acetic acid (49 mg, 0.259 mmol).
  • Example 78 (R) -2- (1H-indole-3-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 87 mg, 100%) was obtained using 3-indoleacetic acid (45 mg, 0.259 mmol).
  • Example 79 (R) -2- (quinoline-7-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide hydrochloride (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (99 mg, 0.427 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1.
  • Example 80 (R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) oxazole-2-yl) pyrrolidine-3-yl) acetamide 2- (4-Cyclopropylphenyl) acetic acid (43 mg, 0.176 mmol) and 2-bromo-4- (trifluoromethyl) -1,3 synthesized in Reference Example 33-2 according to the same procedure as in Example 27. -Oxazole (38 mg, 0.176 mmol) was used to give the title compound (white powder, 61 mg, 92%).
  • Example 81 (R) -2- (1-Methyl-5- (trifluoromethyl) -1H-pyrazole-3-yl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 -Il) acetamide
  • R -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (35 mg, 0.151 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1.
  • the title compound (white powder, 62 mg, 98%) was obtained using 2- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-3-yl) acetic acid (33 mg, 0.159 mmol).
  • Example 82 (R) -2- (6- (Trifluoromethyl) Pyridine-3-yl) -N- (1- (5- (Trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (20 mg, 0.0865 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 27 mg, 74%) was obtained using 2- (6- (trifluoromethyl) pyridine-3-yl) acetic acid (20 mg, 0.0952 mmol).
  • Example 83 (R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide-2,2-d 2 (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (34 mg, 0.145 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 34 mg, 57%) was obtained using 2- (4- (trifluoromethyl) phenyl) acetic acid-2,2-d 2 (30 mg, 0.145 mmol) synthesized in Reference Example 56. ..
  • Example 84 (R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-bromophenyl) -N- (1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Reference Example 57 according to the same procedure as in Example 9 -Il) Acetamide (88 mg, 0.205 mmol) and 3,3-difluoropyrrolidine hydrochloride (35 mg, 0.247 mmol) were used to give the title compound (pale yellow powder, 22 mg, 24%).
  • Example 85 (R) -2- (1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (25 mg, 0.108 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (pale yellow amorphous, 35 mg, 84%) was obtained using 2- (1H-indole-6-yl) acetic acid (23 mg, 0.130 mmol).
  • Example 86 2-(4-((2R, 6S) -2,6-dimethylmorpholino) phenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Acetamide (R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (50 mg, 0.117 mmol) and cis-2,6-dimethylmorpholine (16 mg, 0.140 mmol) were used to give the title compound (white powder, 12 mg, 22%).
  • Example 87 (R) -2- (4- (Pyrrolidine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (50 mg, 0.117 mmol) and pyrrolidine (12 ⁇ L, 0.140 mmol) were used to give the title compound (white crystals, 8 mg, 16%).
  • Example 88 (R) -2- (4-((2-Methoxyethyl) (methyl) amino) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (50 mg, 0.117 mmol) and N- (2-methoxyethyl) methylamine (15 ⁇ L, 0.140 mmol) were used to give the title compound (white amorphous, 2.5 mg, 5%).
  • Example 90 2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide 1- (5- (trifluoromethyl) pyridine-3-yl) azetidine-3-amine (15 mg, 0.0691 mmol) and 2- (1H) synthesized in Reference Example 58-2 according to the same procedure as in Example 1. The title compound (white crystals, 20 mg, 75%) was obtained using -indole-6-yl) acetic acid (15 mg, 0.0829 mmol).
  • Example 91 (R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (12 mg, 0.0529 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 14 mg, 63%) was obtained using 2- (1-methyl-1H-indole-6-yl) acetic acid (10 mg, 0.0529 mmol).
  • Example 92 (R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (12 mg, 0.0529 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 9 mg, 41%) was obtained using 2- (1-methyl-1H-indole-6-yl) acetic acid (10 mg, 0.0529 mmol).
  • Example 95 (R) -2- (4- (4-Acetylpiperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4- (piperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) synthesized in Example 94) After dissolving acetamide (45 mg, 0.104 mmol) and triethylamine (36 ⁇ L, 0.104 mmol) in chloroform (2 mL), acetic anhydride (12 ⁇ L, 0.125 mmol) was added under ice-cooling, and the mixture was stirred at room temperature.
  • Example 99 Trans-2- (3,5-dichlorophenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.130 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. Diastereomer A (TLC (ethyl acetate) above spot, white powder, 25 mg) with trans-2- (3,5-dichlorophenyl) cyclopropane-1-carboxylic acid (33 mg, 0.143 mmol).
  • TLC ethyl acetate
  • Example 100 Trans-2- (4-bromophenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.130 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1.
  • Example 101 (R) -2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide
  • Ethyl 2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) ethyl acetate (16 mg, 0.0524 mmol) synthesized in Reference Example 60 was added to methanol (1 mL) and water.
  • Example 102 (R) -2- (4- (4-oxopiperidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -N- (1- (5- (trifluoro)) synthesized in Example 101
  • Methyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide (17 mg, 0.032 mmol) is dissolved in ethanol (1.0 mL), 2N hydrochloric acid (1.0 mL) is added, and the mixture is heated under reflux overnight under a nitrogen atmosphere.
  • Example 103 2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide (3-Amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) methanol (51 mg, 0.195 mmol) synthesized in Reference Example 61-2 and Reference Example 33-2.
  • the synthesized 2- (4-cyclopropylphenyl) acetic acid 34 mg, 0.195 mmol
  • DMT-MM 80 mg, 0.293 mmol
  • Example 104 Acetic acid (3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methyl 2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) synthesized in Example 103 according to the same procedure as in Example 95. ) Pyrrolidine-3-yl) acetamide (10 mg, 0.0238 mmol) was used to give the title compound (colorless oil, 10 mg, 91%).
  • Example 105 2- (4-Cyclopropylphenyl) -N- (3- (methoxymethyl) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • Example 106 Trans-2- (4-cyclopropylphenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and the same procedure as in Example 1 and Top spot, white powder, 37 mg in the title compound diastereomeric A (TLC (ethyl acetate)) with trans-2- (4-cyclopropylphenyl) cyclopropane-1-carboxylic acid (59 mg, 0.294 mmol).
  • TLC ethyl acetate
  • Example 107 Trans-2- (3,4-difluorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1.
  • Example 108 Trans-2- (4-chlorophenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and the same procedure as in Example 1 and The above spot, white powder, 39 mg, 35 in the title compound diastereomer A (TLC (ethyl acetate)) with trans-2- (4-chlorophenyl) cyclopropane-1-carboxylic acid (58 mg, 0.294 mmol).
  • TLC ethyl acetate
  • Example 109 2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-4-yl) acetamide 2- (4-Isopropylphenyl) -N- (piperidine-4-yl) acetamide (100 mg, 0.384 mmol) and 3-bromo-5- (tri) synthesized in Reference Example 62 according to the same procedure as in Example 9. The title compound (pale yellow crystals, 62 mg, 39%) was obtained using fluoromethyl) pyridine (104 mg, 0.461 mmol).
  • Example 110 (R) -2- (4-Isopropylphenyl) -N- (1- (6-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (296 mg, 1.20 mmol) and 5-bromo-synthesized in Reference Example 63 according to the same procedure as in Example 9.
  • the title compound (pale yellow crystals, 292 mg, 57%) was obtained using 2-methoxy-3- (trifluoromethyl) pyridine (369 mg, 1.44 mmol).
  • Example 111 (R) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (95 mg, 0.386 mmol) and 2-chloro- synthesized in Reference Example 63 according to the same procedure as in Example 27. The title compound (white crystals, 125 mg, 82%) was obtained using 5- (trifluoromethyl) pyrimidine (77 mg, 0.424 mmol).
  • Example 112 (R) -2- (4-Isopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.406 mmol) and 2-bromo- synthesized in Reference Example 63 according to the same procedure as in Example 9. The title compound (pale yellow crystals, 77 mg, 47%) was obtained using 4- (trifluoromethyl) thiazole (113 mg, 0.487 mmol).
  • Example 113 (R) -2- (4-Isopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.406 mmol) and 5-bromo-synthesized in Reference Example 63 according to the same procedure as in Example 9. The title compound (white crystals, 93 mg, 58%) was obtained using 2- (trifluoromethyl) pyridine (110 mg, 0.487 mmol).
  • Example 114 (S) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (S) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (99 mg, 0.428 mmol) synthesized in Reference Example 64-2 and the same procedure as in Example 1 and The title compound (white crystals, 144 mg, 86%) was obtained using 2- (4-isopropylphenyl) acetic acid (92 mg, 0.514 mmol).
  • Example 115 (R) -2- (4- (trifluoromethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (10 mg, 0.0432 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 9 mg, 46%) was obtained using 2- (4- (trifluoromethoxy) phenyl) acetic acid (11 mg, 0.0519 mmol).
  • Example 116 (R) -2- (4- (2,2,2-trifluoroethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (10 mg, 0.0432 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 21 mg, 99%) was obtained using 2- (4- (2,2,2-trifluoroethoxy) phenyl) acetic acid (12 mg, 0.0519 mmol).
  • Example 117 2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide N- (azetidine-) from tert-butyl 3- (2- (4-isopropylphenyl) acetamide) azetidine-1-carboxylate (964 mg, 2.90 mmol) synthesized in Reference Example 65 according to the same procedure as in Example 36.
  • the title compound (white crystals, 55 mg, 34%) was obtained using crude (100 mg) of (4-isopropylphenyl) acetamide and 5-bromo-2- (trifluoromethyl) pyridine (118 mg, 0.52 mmol). ..
  • Example 119 (R) -2- (3,5-dichlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 83 mg, 76%) was obtained using 2- (3,5-dichlorophenyl) acetic acid (64 mg, 0.31 mmol).
  • Example 120 (R) -2- (3-Chloro-5-fluorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 70 mg, 67%) was obtained using 2- (3-chloro-5-fluorophenyl) acetic acid (58 mg, 0.31 mmol).
  • Example 121 (R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.18 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 89 mg, 100%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (51 mg, 0.29 mmol) synthesized in Reference Example 33-2.
  • Example 122 (R) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) thiophen-2-yl) pyrrolidine-3-yl) acetamide
  • R -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.41 mmol) and 2-bromo- synthesized in Reference Example 63 according to the same procedure as in Example 9.
  • the title compound (white crystals, 49 mg, 30%) was obtained using 5- (trifluoromethyl) thiophene (114 mg, 0.49 mmol).
  • Example 124 (R) -2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 89 mg, 100%) was obtained using 2- (1H-indole-6-yl) acetic acid (53 mg, 0.26 mmol).
  • Example 128 (R) -2- (4-Cyclopropylphenyl) -N- (1- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.40 mmol) and 3 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. The title compound (white crystals, 46 mg, 27%) was obtained using -bromo-2-methoxy-5- (trifluoromethyl) pyridine (123 mg, 0.48 mmol).
  • Example 129 (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide Tert-Butyl (R)-(1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-yl) carbamate synthesized in Reference Example 66 according to the same procedure as in Example 3 (100 mg, A crude compound (70 mg) of (R) -1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine was synthesized from 0.29 mmol) to obtain (R) -1-(.
  • Example 130 (R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyridine-3-yl) piperidine-3-yl) carbamate synthesized in Reference Example 72 according to the same procedure as in Example 3 (400 mg, A crude compound (280 mg) of (R) -1- (6- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine was synthesized from 1.16 mmol) to obtain (R) -1-(.
  • Example 132 (R) -2- (4- (3-methylpyrazine-2-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (10 mg, 0.048 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 14 mg, 62%) was obtained using 2- (4- (3-methylpyrazine-2-yl) phenyl) acetic acid (10 mg, 0.044 mmol).
  • Example 133 (R) -2- (4- (4-Methyloxazole-5-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (6 mg, 0.024 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 8.6 mg, 100%) was obtained using 2- (4- (4-methyloxazole-5-yl) phenyl) acetic acid (4 mg, 0.020 mmol).
  • Example 134 (R) -3- (3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-yl) -5- (trifluoromethyl) pyridine 1-oxide (3R) -3- (2- (4) -Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine 1-oxide (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 1 (85 mg, 0) .22 mmol) was dissolved in dichloromethane (3.0 mL), m-CPBA (purity 65%, 58 mg, 0.22 mmol) was added, and the mixture was stirred overnight at room temperature.
  • dichloromethane 3.0 mL
  • m-CPBA
  • Example 135 (R) -2- (4-Cyclopropylphenyl) -2-methyl-N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (25 mg, 0.11 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 45 mg, 94%) was obtained using 2- (4-cyclopropylphenyl) -2-methylpropanoic acid (23 mg, 0.11 mmol).
  • Example 137 2-Amino-2- (4-cyclopropylphenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (1- (4-Cyclopropylphenyl) -2-oxo-2-(((R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) synthesized in Reference Example 67 ) Trifluoroacetic acid (0.50 mL) was added to diastereomeric A (15 mg, 0.030 mmol) of tert-butyl carbamate (amino) ethyl) under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
  • Example 138 2- (4-Cyclopropylphenyl) -2- (dimethylamino) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide hydrochloride (1- (4-Cyclopropylphenyl) -2-oxo-2-(((R) -1- (5- (trifluoromethyl) pyridine-) synthesized in Reference Example 67 according to the same procedure as in Example 137.
  • Example 139 (R) -2- (1-methyl-1H-indole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (13 mg, 0.058 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 6 mg, 26%) was obtained using 2- (1-methyl-1H-indole-5-yl) acetic acid (10 mg, 0.053 mmol).
  • Example 140 (R) -2- (2,4-bis (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 56 mg, 89%) was obtained using 2- (2,4-bis (trifluoromethyl) phenyl) acetic acid (44 mg, 0.16 mmol).
  • Example 141 (R) -2- (2-Fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 59 mg, 100%) was obtained using 2- (2-fluoro-4- (trifluoromethyl) phenyl) acetic acid (36 mg, 0.16 mmol).
  • Example 142 (R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 36 mg, 56%) was obtained using 2- (1-methyl-1H-indazole-5-yl) acetic acid (32 mg, 0.16 mmol).
  • Example 143 (R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide According to the same procedure as in Example 1, (R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (31 mg, 0.13 mmol) synthesized in Reference Example 12-2 and The title compound (white crystals, 35 mg, 66%) was obtained using 2- (1-methyl-1H-indazole-5-yl) acetic acid (32 mg, 0.16 mmol).
  • Example 144 (R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 35 mg, 67%) was obtained using 2- (1-methyl-1H-indazole-5-yl) acetic acid (32 mg, 0.16 mmol).
  • Example 145 (R) -2- (4- (2,2-dimethylmorpholino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
  • R -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il)
  • Acetamide (40 mg, 0.093 mmol) and 2,2-dimethylmorpholine (21 mg, 0.19 mmol) were used to give the title compound (yellow amorphous, 2.1 mg, 5%).
  • Example 146 (R) -2- (4- (1H-pyrazole-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 171 (40 mg, 0.
  • Example 148 (R) -2- (4-Cyclopropylphenyl) -N- (3-methyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R)-(3-Methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 68 according to the same procedure as in Example 3. Obtained by synthesizing a crude compound (20 mg) of (R) -3-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine from butyl (47 mg, 0.23 mmol).
  • Example 150 2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide
  • Example 151 (R) -2- (benzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 26 mg, 52%) was obtained using 2- (benzo [d] oxazole-5-yl) acetic acid (35 mg, 0.16 mmol).
  • Example 152 (R) -2- (benzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow crystals, 33 mg, 65%) was obtained using 2- (benzo [d] oxazole-5-yl) acetic acid (35 mg, 0.16 mmol).
  • Example 153 (R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow crystals, 48 mg, 89%) was obtained using 2- (2-methylbenzo [d] oxazole-5-yl) acetic acid (35 mg, 0.16 mmol) synthesized above.
  • Example 154 (R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 53 mg, 100%) was obtained using 2- (2-methylbenzo [d] oxazole-5-yl) acetic acid (31 mg, 0.16 mmol).
  • a 1N aqueous hydrochloric acid solution (2.4 mL, 2.4 mmol) was added to the reaction solution under an ice bath, and the mixture was distilled off under reduced pressure.
  • a crude (white crystals, 84 mg) of 5-azabicyclo [2.2.2] octane-5-yl) phenyl) acetic acid was obtained.
  • Example 156 2-(4-(((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) -N-((R) -1- (6- (trifluoro)) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide 2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) acetic acid synthesized in Reference Example 70 according to the same procedure as in Example 155.
  • Example 157 (R) -2- (benzo [d] thiazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 33 mg, 61%) was obtained using 2- (benzo [d] thiazole-6-yl) acetic acid (31 mg, 0.16 mmol).
  • Example 158 (R) -2- (benzo [d] thiazole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 20 mg, 36%) was obtained using 2- (benzo [d] thiazole-6-yl) acetic acid (31 mg, 0.16 mmol).
  • Example 159 (R) -2- (1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 59 mg, 57%) was obtained using 2- (1H-indazole-5-yl) acetic acid (56 mg, 0.32 mmol).
  • Example 160 (R) -2- (1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 The title compound (white crystals, 55 mg, 53%) was obtained using 2- (1H-indazole-5-yl) acetic acid (56 mg, 0.32 mmol).
  • Example 161 2- (4-Cyclopropylphenyl) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide (3- (Trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 71 according to the same method as in Example 3. Obtained by synthesizing a crude compound (58 mg) of 3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine from butyl (145 mg, 0.36 mmol).
  • Example 162 N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide (3- (Trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 71 according to the same method as in Example 3. A crude compound (58 mg) of 3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from butyl (145 mg, 0.36 mmol).
  • Example 163 (R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 30 mg, 57%) was obtained using 2- (1H-benzo [d] [1,2,3] triazole-5-yl) acetic acid (28 mg, 0.16 mmol).
  • Example 164 (R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 The title compound (white crystals, 20 mg, 37%) was obtained using 2- (1H-benzo [d] [1,2,3] triazole-5-yl) acetic acid (28 mg, 0.16 mmol).
  • ethyl 4-bromophenylacetate 109 mg, 0.45 mmol
  • 2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride 91 mg, 0.67 mmol.
  • Example 166 2- (4- (2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (44 mg, 0.19 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 165.
  • Example 168 (R) -2- (1-Methyl-1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide
  • R -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1
  • the title compound (white crystals, 8 mg, 13%) was obtained using 2- (1-methyl-1H-benzo [d] [1,2,3] triazole-5-yl) acetic acid (30 mg, 0.16 mmol). It was.
  • Example 170 2- (4-Cyclopropylphenyl) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) azetidine-3-yl) acetamide N- (azetidine-3-yl) -2- (4-cyclopropylphenyl) acetamide (40 mg, 0.17 mmol) and 4-bromo-1 synthesized in Reference Example 75-2 according to the same procedure as in Example 9. -Fluoro-2- (trifluoromethyl) benzene (29 ⁇ L, 0.21 mmol) was used to give the title compound (pale yellow solid, 27 mg, 38%).
  • Example 171 (R) -2- (4-Bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (52 mg, 0.22 mmol) synthesized in Reference Example 1-2 and the same procedure as in Example 1 and The title compound (white solid, 100 mg, 100%) was obtained using 2- (4-bromophenyl) acetic acid (60 mg, 0.28 mmol).
  • Example 173 (R) -N- (1- (5-bromothiazole-2-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide (R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 172. , 5-Dibromothiazole (58 mg, 0.24 mmol) was used to give the title compound (pale yellow solid, 26 mg, 32%).
  • Example 175 (R) -2- (4-Cyclopropylphenyl) -N- (1- (3-methoxyphenyl) pyrrolidine-3-yl) acetamide (R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (244 mg, 1.0 mmol) and 1 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. -Bromo-3-methoxybenzene (152 ⁇ L, 1.2 mmol) was used to give the title compound (white solid, 203 mg, 58%).
  • Example 176 (R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (43 mg, 0.10 mmol) and 3,3-difluoropyrrolidine hydrochloride (17 mg, 0.12 mmol) were used to give the title compound (white solid, 11 mg, 24%).
  • Example 177 Ethyl (R) -2- (3- (3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-yl) phenoxy) -2-methylpropanoate (R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide synthesized in Reference Example 74-2 and reference (98 mg, 0.40 mmol) according to the same procedure as in Example 9. Ethyl 2- (3-bromophenoxy) -2-methylpropanoate (138 mg, 0.48 mmol) synthesized in Example 76 was used to give the title compound (white solid, 43 mg, 24%).
  • Example 178 (R) -2- (4-Cyclopropylphenyl) -N- (1- (3-hydroxyphenyl) pyrrolidine-3-yl) acetamide
  • Pyridine hydrochloride 35 mg, 0.10 mmol
  • to (R) -2- (4-cyclopropylphenyl) -N- (1- (3-methoxyphenyl) pyrrolidine-3-yl) acetamide synthesized in Example 175 500 mg was added and heated at 150 ° C. for 3 hours. Saturated sodium hydrogen carbonate was added to the reaction solution allowed to cool to room temperature, and the mixture was extracted with ethyl acetate.
  • Example 180 (R) -2- (4-Cyclopropylphenyl) -N- (1- (4,6-dimethoxypyrimidine-2-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 172. -Chloro-4,6-dimethoxypyridine (44 mg, 0.24 mmol) was used to give the title compound (white solid, 56 mg, 73%).
  • Example 181 (R) -2- (4-morpholinophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (86 mg, 0.20 mmol) and morpholine (35 ⁇ L, 0.40 mmol) were used to give the title compound (white solid, 12 mg, 13%).
  • Example 182 (R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) pyridin-2-yl) pyrrolidine-3-yl) acetamide (R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 172. -Chloro-4- (trifluoromethyl) pyridine (44 mg, 0.24 mmol) was used to give the title compound (white solid, 40 mg, 51%).
  • Example 185 2- (4- (Trifluoromethyl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide Tert-Butyl (149 mg, 0.40 mmol) of (R) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-1-carbamic acid synthesized in Reference Example 73-1 was added to DMF (2 mL). Sodium hydride (60% oil, 24 mg, 0.60 mmol) and methyl iodide (37 ⁇ L, 0.60 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
  • Example 186 (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide Tert-Butyl (R)-(1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-yl) carbamate synthesized in Reference Example 66 according to the same procedure as in Example 3 (76 mg, A crude compound (166 mg) of (R) -1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine was synthesized from 0.219 mmol) to synthesize (1S, 2S) -2- (1H).
  • Example 188 Pharmacological test 1 T-type calcium inhibitory effect (test method) (1) Construction of human Cav3.2 channel constant expression cells A sequence in which the HindIII site and the kozak sequence (GCCACC) are added to the 5'side of the human Cav3.2 channel ORF (Open Reading Frame) gene and the KpnI site is added to the 3'side. It was incorporated into pcDNA3.1 (+) (Thermo Fisher Scientific # V790-20) and introduced into HEK293 cells (ATCC No. CRL-1573) according to the FuGENE® HD Transfection Reagent (Promega # E2311) protocol.
  • GCCACC HindIII site and the kozak sequence
  • KpnI site Open Reading Frame
  • a buffer 140 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 0.5 mM CaCl 2 , 10 mM Glucose, 10 mM HEPES, pH 7.3
  • B buffer 137.9 mM Choline-Cl, 4.1 mM KCl, 1 mM MgCl 2 , 0.5 mM CaCl 2 , 10 mM Glucose, 10 mM HEPES, pH 7.3
  • Test results The test results are shown in Tables 1 to 3. As a result, it was found that all the compounds of the examples tested this time had an inhibitory effect on the Cav3.2 channel.
  • Example 189 Pharmacological test 2 CFA-induced rheumatoid arthritis model (test method) Using a 7-week-old male C57BL / 6J mouse (Jackson Laboratory), the effect on rheumatoid arthritis was examined using the latency of the escape reaction (Paw Withdrawal Latency: PWL) as an index. Model mice using CFA are said to resemble clinical symptoms in human rheumatoid arthritis in that they are inflamed and painful. The experiment was carried out with 5 to 7 animals per group. The CFA was purchased from Sigma-Aldrich, and the control (control) was Phosphate Buffered Saline (PBS).
  • PBS Phosphate Buffered Saline
  • Compound A The compound of Example 144 (hereinafter referred to as "Compound A”) was suspended in a 1% aqueous solution of methyl cellulose (MC) as an administration solution.
  • MC methyl cellulose
  • a 20 ⁇ L CFA solution was subcutaneously injected into the sole of the hind limb of the mouse to induce thermal hyperalgesia.
  • the mice were fasted for 90 minutes or longer, acclimatized for an additional hour, and then the drug (30 mg / kg compound A) was orally administered.
  • Heat hyperalgesia 0.5, 1, 2, 3, and 4 hours after administration was evaluated by measuring the latency of the escape response in mice with a Hargreaves device (Ugo basele SRL). As a control group, the vehicle was orally administered.
  • the PWL data was analyzed by two-way ANOVA, and then a significant difference test was performed by Dunnett's test. The significance level was 5% (comparison with the control group). Statistical calculations were performed using GraphPad Prism 7.04 (GraphPad Software, Inc.), and the data were shown with mean values and standard errors. (Test results) The results are shown in FIG. The PWL was shortened by the administration of CFA as compared with the Sham group (PBS solution was administered at the time of CFA injection and 1% MC solution was administered at the time of drug administration), and thus CFA induced hyperalgesia. Can be understood.
  • the compound of the present invention has an inhibitory effect on Cav3.2 channel and can be used as a drug for the treatment or prevention of rheumatoid arthritis.

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Abstract

Provided is a medicinal drug for treating or preventing rheumatoid arthritis. As a medicinal drug for treating or preventing rheumatoid arthritis, the present invention uses, as an active ingredient, a compound that has an effect of blocking the T-type calcium channel (Cav3.2 channel) and that is represented by any one of general formulae (I)-(VI), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof.

Description

関節リウマチを治療するためのＴ型カルシウムチャネル阻害剤の使用Use of T-type calcium channel inhibitors to treat rheumatoid arthritis
　本発明は関節リウマチの予防または治療に有用なＣａｖ３．２チャネル阻害剤及びその使用に関する。 The present invention relates to a Cav3.2 channel inhibitor useful for the prevention or treatment of rheumatoid arthritis and its use.
　関節リウマチ（ｒｈｅｕｍａｔｏｉｄ　ａｒｔｈｒｉｔｉｓ：ＲＡ）は、慢性的に経過する関節炎を主病変とする膠原病の一疾患であり、関節の腫れと痛みが進行すると、しばしば関節の破壊をきたす。罹患率は全人口の約１％となっており、わが国において、男女比は１：３～４で女性に有意に多く、好発年齢は３０～５０歳代での発症が多くなっている。 Rheumatoid arthritis (RA) is a disease of collagen disease whose main lesion is chronic arthritis, and when joint swelling and pain progress, it often causes joint destruction. The morbidity rate is about 1% of the total population, and in Japan, the male-female ratio is 1: 3-4, which is significantly higher in females, and the predominant age is more common in the 30s to 50s.
　関節リウマチの治療に用いられる薬物としては、対症療法に分類される非ステロイド性抗炎症薬（ＮＳＡＩＤ）（例えば、ジクロフェナク、イブプロフェン、セレコキシブ等）、コルチコステロイド（例えば、プレドニゾロン等）、原因療法に分類される非生物学的疾患修飾性抗リウマチ薬（ＤＭＡＲＤＳ）（例えば、メトトレキサート、サラゾスルファピリジン、アザチオプリン、シクロスポリン等）、生物学的ＤＭＡＲＤＳ（例えば、インフリキシマブ、エタネルセプト、アダリムマブ、トシリズマブ等）が挙げられる。 Drugs used to treat rheumatoid arthritis include non-steroidal anti-inflammatory drugs (NSAIDs) classified as symptomatic therapies (eg, diclofenac, ibprofen, selecoxib, etc.), corticosteroids (eg, prednisolone, etc.), and causative therapies. Classified non-biological disease-modifying anti-rheumatic drugs (DMARD S ) (eg, methotrexate, salazosulfapyridine, azathiopurine, cyclosporin, etc.), biological DMARD S (eg, infliximab, etanercept, adalimumab, tosirizumab, etc.) Can be mentioned.
　ＮＳＡＩＤは、関節の腫れを軽減し、痛みを緩和することでＲＡの症状を治療するが、損傷の進行は妨げない。ＮＳＡＩＤはその薬理作用から切り離されない副作用として、胃を損傷する可能性がある。
　コルチコステロイドは、ＲＡ炎症と症状を抑える強力な効果のある薬である。副作用のリスクがあるので最小限の投与量で使用するために、関節内に直接注射することが好ましい。
　ＤＭＡＲＤＳは、ＲＡの進行を遅らせることができるが、効果が出るまで数週間ないし数カ月かかる。免疫抑制作用を有するＤＭＡＲＤＳは、関節に隣接する骨の損傷を軽減することができる一方、免疫抑制の結果、感染症や特定のがんの発生リスクが高まる。また、生物学的ＤＭＡＲＤＳは薬価が非常に高い。 NSAIDs treat RA symptoms by reducing joint swelling and pain, but do not prevent the progression of damage. NSAIDs can damage the stomach as a side effect that is inseparable from their pharmacological effects.
Corticosteroids are powerful drugs that reduce RA inflammation and symptoms. Due to the risk of side effects, direct injection into the joint is preferred for use at minimal doses.
DMARD S can slow the progression of RA, but it can take weeks or months to be effective. While DMARD S , which has an immunosuppressive effect, can reduce damage to bones adjacent to joints, immunosuppression increases the risk of developing infections and certain cancers. In addition, biological DMARD S has a very high drug price.
　一方、痛みに関して、Ｃａｖ３．２ノックアウトマウスでは、炎症性疼痛に関与するといわれているホルマリンテスト２ｎｄ　Ｐｈａｓｅの疼痛関連様行動が有意に減少することが報告されている（非特許文献１）。また、カラゲニン誘発炎症性疼痛モデル動物において、カラゲニンを投与した同肢側のＤＲＧにおいてＣａｖ３．１及びＣａｖ３．３の発現が変化しないにも関わらずＣａｖ３．２チャネルの発現が増加すること、またＴ型カルシウムチャネル遮断薬のｍｉｂｅｆｒａｄｉｌ及びＮＮＣ　５５－０３９６の足蹠内投与によって鎮痛作用が認められることが報告されている（非特許文献２）。 On the other hand, regarding pain, it has been reported that in Cav3.2 knockout mice, the pain-related behavior of the formalin test 2nd Phase, which is said to be involved in inflammatory pain, is significantly reduced (Non-Patent Document 1). In addition, in carrageenan-induced inflammatory pain model animals, the expression of Cav3.2 channel was increased even though the expression of Cav3.1 and Cav3.3 was not changed in the DRG on the same limb side to which carrageenin was administered, and T. It has been reported that an analgesic effect is observed by intrafoot administration of mibefradil and NNC 55-0396, which are type calcium channel blockers (Non-Patent Document 2).
　本発明の１つの課題は、ヒトを含む哺乳動物に有用な関節リウマチの治療又は予防用の医薬を提供することである。 One object of the present invention is to provide a medicine for treating or preventing rheumatoid arthritis useful for mammals including humans.
　本発明者らは、アミド結合を有する環状アミン化合物が、Ｔ型カルシウムチャネル、特にＣａｖ３．２チャネルに対して優れた阻害作用を有することを見いだした。そして、当該Ｃａｖ３．２チャネル阻害剤を用いることにより、関節リウマチの予防または治療を達成できることを見出し、本発明を完成するに至った。 The present inventors have found that a cyclic amine compound having an amide bond has an excellent inhibitory effect on T-type calcium channels, particularly Cav3.2 channels. Then, they have found that the prevention or treatment of rheumatoid arthritis can be achieved by using the Cav3.2 channel inhibitor, and have completed the present invention.
  すなわち本発明は以下の（１）～（７６）を提供する。
（１）　次の一般式（Ｉ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000018
（式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接する環状アミンの窒素原子と結合し、
　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＸと結合し、
　Ｒ１及びＲ２は、同一又は異なっていても良く、水素原子、ハロゲン原子、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基を表すか、
　又は、Ｒ１、Ｒ２及びＲ１とＲ２が結合する炭素原子が一緒になって、３～５員のシクロアルキル基を形成しても良く、
　Ｒ３は、水素原子、ハロゲン原子、カルボキシル基、シアノ基、カルバモイル基、Ｃ１－８アルキル基、Ｃ１－８アルコキシカルボニル基、Ｃ１－８アルコキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アシルオキシ基で置換されたＣ１－８アルキル基を表すか、
　又は、Ｒ２及びＲ３が一緒になって、メチレン又はエチレンを形成しても良く、
Ｘは、
Figure JPOXMLDOC01-appb-C000019
 又は
Figure JPOXMLDOC01-appb-C000020
を表し、
ここで、波線は結合位置を表し、
　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
又はＲ４、Ｒ５及びＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良く、
　ｎ及びｍは、同一又は異なっていても良く、０または１で、
　ｐは１、２を表す。
　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシ基で置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。）
（２）　Ｘが、
Figure JPOXMLDOC01-appb-C000021
である上記（１）に記載の医薬。
（３）　Ａ１が置換基を有しても良いフェニルである上記（１）又は（２）に記載の医薬。
（４）　Ａ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である上記（１）又は（２）に記載の医薬。
（５）　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン又はピリダジンである上記（４）に記載の医薬。
（６）　Ａ１のヘテロアリール環がピリジンである上記（４）に記載の医薬。
（７）　Ａ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である上記（１）又は（２）に記載の医薬。
（８）　Ａ１のヘテロ縮合環がキノリン、ベンゾ［ｄ］チアゾールである上記（７）に記載の医薬。
（９）　Ｂ１が置換基を有しても良いフェニルである上記（１）～（８）のいずれかに記載の医薬。
（１０）　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である上記（１）～（８）のいずれかに記載の医薬。
（１１）　Ｂ１のヘテロアリール環が、ピリジンである上記（１０）に記載の医薬。
（１２）　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い６員のヘテロアリール環であるとき、該置換基は４位（パラ位）で置換している上記（９）～（１１）のいずれかに記載の医薬。
（１３）　Ｂ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である上記（１）～（８）のいずれかに記載の医薬。
（１４）　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである上記（１３）に記載の医薬。
（１５）　Ｂ１のヘテロ縮合環が、インダゾールである上記（１３）に記載の医薬。
（１６）　ｎが１で、ｍが０である上記（１）～（１５）のいずれかに記載の医薬。
（１７）　ｐが１である上記（１）～（１６）のいずれかに記載の医薬。
（１８）　Ｒ１及びＲ２が水素原子である上記（１）～（１７）のいずれかに記載の医薬。
（１９）　Ｒ３が水素原子である上記（１）～（１８）のいずれかに記載の医薬。
（２０）　次の一般式（ＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000022
（式中、Ｄ，Ｅ，Ｆ，Ｇ及びＪは、何れか２つがＮで他が同一又は異なっても良いＣＲか、或いは何れか１つがＮで他が同一又は異なっても良いＣＲか、全てが同一又は異なっても良いＣＲである。
　ここで、Ｒは、水素原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基を表す。
　Ｒａ１、Ｒａ２、Ｒｂ１及びＲｂ２は、同一又は異なっても良い水素原子、ハロゲン原子、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基を表すか、
　又は、Ｒａ１、Ｒａ２及びＲａ１とＲａ２が結合する炭素原子が一緒になって、或いはＲｂ１、Ｒｂ２及びＲｂ１とＲｂ２が結合する炭素原子が一緒になって、３～５員のシクロアルキル基を形成しても良く、
　ｓは０、１、２を表し、
　ｔは１、２を表す。
　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＸと結合し、
　Ｘは、
Figure JPOXMLDOC01-appb-C000023
 又は
Figure JPOXMLDOC01-appb-C000024
を表し、
ここで、波線は結合位置を表し、
　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
又はＲ４、Ｒ５とＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良い。
　そして、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。
（２１）　次の一般式（ＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000025
（式中、Ｄ，Ｅ，Ｆ，Ｇ及びＪは、何れか２つがＮで他が同一又は異なっても良いＣＲか、或いは何れか１つがＮで他が同一又は異なっても良いＣＲか、全てが同一又は異なっても良いＣＲである。
　ここで、Ｒは、水素原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基を表す。
　Ｒａ１、Ｒａ２、Ｒｂ１及びＲｂ２は、同一又は異なっても良い水素原子、ハロゲン原子、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基を表すか、
　又は、Ｒａ１、Ｒａ２及びＲａ１とＲａ２が結合する炭素原子が一緒になって、或いはＲｂ１、Ｒｂ２及びＲｂ１とＲｂ２が結合する炭素原子が一緒になって、３～５員のシクロアルキル基を形成しても良く、
　ｓは０、１、２を表し、
　ｔは１、２を表す。
　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＸと結合し、
　Ｘは、
Figure JPOXMLDOC01-appb-C000026
 又は
Figure JPOXMLDOC01-appb-C000027
を表し、
ここで、波線は結合位置を表し、
　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
又はＲ４、Ｒ５とＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良い。
　そして、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。
　但し、Ｄ～Ｊからなる６員環が、置換基を有していても良いフェニル又は置換基を有していても良いピリダジンで、Ｘが、
Figure JPOXMLDOC01-appb-C000028
の時、Ｂ１は、前記の置換基を有していてもよいヘテロ縮合環である。）
（２２）　Ｘが、
Figure JPOXMLDOC01-appb-C000029
である上記（２０）又は（２１）に記載の医薬。
（２３）　ＤとＪが共にＣＨである上記（２０）～（２２）のいずれかに記載の医薬。
（２４）　Ｄ、Ｅ、Ｆ、Ｇ及びＪの何れか１つがＮで、他がＣＲである上記（２０）～（２２）のいずれかに記載の医薬。
（２５）　Ｄ、Ｅ、Ｆ及びＪが同一又は異なっても良いＣＲで、ＧがＮである上記（２０）～（２２）のいずれかに記載の医薬。
（２６）　Ｂ１が置換基を有しても良いフェニルである上記（２０）～（２５）のいずれかに記載の医薬。
（２７）　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である上記（２０）～（２５）のいずれかに記載の医薬。
（２８）　Ｂ１のヘテロアリール環が、ピリジンである上記（２７）に記載の医薬。
（２９）　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い６員のヘテロアリール環であるとき、該置換基は４位（パラ位）で置換している上記（２６）～（２８）のいずれかに記載の医薬。
（３０）　Ｂ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である上記（２０）～（２５）のいずれかに記載の医薬。
（３１）　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである上記（３０）に記載の医薬。
（３２）　Ｂａのヘテロ縮合環が、インダゾールである上記（３０）に記載の医薬。
（３３）　ｓが１である上記（２０）～（３２）のいずれかに記載の医薬。
（３４）　ｔが１である上記（２０）～（３３）のいずれかに記載の医薬。
（３５）　Ｒａ１、Ｒａ２、Ｒｂ１及びＲｂ２が水素原子である上記（２０）～（３４）のいずれかに記載の医薬。
（３６）　次の一般式（ＩＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000030
（式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するピロリジンの窒素原子と結合し、
　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＣ（Ｒ４）（Ｒ５）と結合する。
　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
又はＲ４、Ｒ５と及びＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良く、
　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。
（３７）　次の一般式（ＩＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000031
（式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するピロリジンの窒素原子と結合し、
　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＣ（Ｒ４）（Ｒ５）と結合する。
　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
又はＲ４、Ｒ５及びＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良く、
　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。
　但し、Ａ１が、置換基を有していても良いフェニル、置換基を有していても良いピリダジン及び置換基を有していても良いキナゾリンの時、Ｂ１は、前記の置換基を有していても良いヘテロ縮合環である。）
（３８）　Ａ１が置換基を有しても良いフェニルである上記（３６）又は（３７）に記載の医薬。
（３９）　Ａ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である上記（３６）又は（３７）に記載の医薬。
（４０）　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン、ピリダジンである上記（３９）に記載の医薬。
（４１）　Ａ１のヘテロアリール環がピリジンである上記（３９）に記載の医薬。
（４２）　Ａ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である上記（３６）又は（３７）に記載の医薬。
（４３）　Ａ１のヘテロ縮合環がキノリン、ベンゾ［ｄ］チアゾールである上記（４２）に記載の医薬。
（４４）　Ｂ１が置換基を有しても良いフェニルである上記（３６）～（４３）のいずれかに記載の医薬。
（４５）　Ｂ１が置換基を有していても良いフェニル、又は置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である上記（３６）～（４３）のいずれかに記載の医薬。
（４６）　Ｂ１のヘテロアリール環が、ピリジンである上記（４５）に記載の医薬。
（４７）　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い６員のヘテロアリール環であるとき、該置換基は４位（パラ位）で置換している上記（４４）～（４６）のいずれかに記載の医薬。
（４８）　Ｂ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である上記（３６）～（４３）のいずれかに記載の医薬。
（４９）　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである上記（４８）に記載の医薬。
（５０）　Ｂ１のヘテロ縮合環が、インダゾールである上記（４８）に記載の医薬。
（５１）　Ｒ４及びＲ５が共に水素原子である上記（３６）～（５０）のいずれかに記載の医薬。
（５２）　次の一般式（ＩＶ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000032
（式中、Ｒ６，Ｒ７及びＲ８は、同一又は異なって、水素原子、ハロゲン原子、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基を表し、
　Ｒ９は、１～３個のハロゲン原子で置換されたＣ１－８アルキル、ｔ－ブチル又はシクロプロピルを表し、
そして、ｒは０、１、２を表す。）
（５３）　Ｒ６，Ｒ７及びＲ８が、異なって、水素原子、ハロゲン原子、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、Ｃ１－８アルコキシ基である上記（５２）に記載の医薬。
（５４）　Ｒ９がトリフルオロメチル又はシクロプロピルである上記（５２）～（５３）のいずれかに記載の医薬。
（５５）　ｒが１である上記（５２）～（５４）のいずれかに記載の医薬。
（５６）　次の一般式（Ｖ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000033
（式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するピロリジンの窒素原子と結合し
　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するシクロプロピルと結合する。
　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、３～５員のシクロアルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピペリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキソ－８－アザスピロ［４．５］デカンー８－イル、２－オキソ－６－アザスピロ［３．３］ヘプタンー６－イル、３－オキソー８－アザビシクロ［３．２．１］オクタンー８－イル、２－オキソー５－アザビシクロ［２．２．２］オクタンー５－イル、２－オキソ－５－アザビシクロ［２．２．１］ヘプタンー５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。）
（５７）　Ａ１が置換基を有しても良いフェニルである上記（５６）に記載の医薬。
（５８）　Ａ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である上記（５６）に記載の医薬。
（５９）　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン、ピリダジンである上記（５８）に記載の医薬。
（６０）　Ａ１のヘテロアリール環がピリジンである上記（５８）に記載の医薬。
（６１）　Ａ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である上記（５６）に記載の医薬。
（６２）　Ａ１のヘテロ縮合環がキノリン、ベンゾ［ｄ］チアゾールである上記（６１）に記載の医薬。
（６３）　Ｂ１が置換基を有しても良いフェニルである上記（５６）～（６２）のいずれかに記載の医薬。
（６４）　Ｂ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である上記（５６）～（６２）のいずれかに記載の医薬。
（６５）　Ｂ１のヘテロアリール環が、ピリジンである上記（６３）に記載の医薬。
（６６）　Ｂ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である上記（５６）～（６２）のいずれかに記載の医薬。
（６７）　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである上記（６６）に記載の医薬。
（６８）　Ｂ１のヘテロ縮合環が、ベンゾ［ｄ］オキサゾールである上記（６６）に記載の医薬。
（６９）　次の一般式（ＶＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
Figure JPOXMLDOC01-appb-C000034
（式中、Ａ１は、置換基を有していても良いフェニル、又は環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、ここで、該ヘテロアリール環、該ヘテロ縮合環、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接する環状アミンの窒素原子と結合し
　Ｂ２は、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環と、ベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するメチレン基と結合する。
　そして、上記Ａ１のフェニル及び上記Ａ１のヘテロアリール環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
　上記Ｂ２のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、３～５員のシクロアルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
　ここで、上記Ｂ２のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピペリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキソ－８－アザスピロ［４．５］デカン－８－イル、２－オキソ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキソ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキソー５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキソ－５－アザビシクロ［２．２．１］ヘプタンー５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良く、
　ｕは０、１、２を表す。）
（７０）　Ａ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である上記（６９）に記載の医薬。
（７１）　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン、ピリダジンである上記（７０）に記載の医薬。
（７２）　Ａ１のヘテロアリール環がピリジンである上記（７０）に記載の医薬。
（７３）　（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（５－（トリフルオロメチル）ピリジン－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－ヒドロキシ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（５－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（６－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（４－（トリフルオロメチル）チアゾール－２－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｒ，５Ｓ）－５－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（（１Ｓ，５Ｒ）－３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（（１Ｒ，５Ｓ）－３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－イル）アセトアミド、
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピラジン－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－Ｎ－（１－（６－シアノ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
（Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
（Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
（Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸、
（Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸、
（Ｒ）－２－（１Ｈ－インダゾール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、（Ｒ）－２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
（Ｓ）－２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－メチル－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（２－ヒドロキシプロパン－２－イル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（８－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－６－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボキシアミド、
（Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボキシアミド、
（Ｒ）－２－（４－ヒドロキシフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（１，１－ジオキサイドチオモルホリノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－１－（４－クロロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（Ｒ）－２－（４－ブロモフェニル）－２－ヒドロキシ－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－（４－ブロモフェニル）－２－ヒドロキシ－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリメチルシリル）フェニル）アセトアミド、
（Ｒ）－２－（４－（２－ヒドロキシ－２－メチルプロポキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－フルオロ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（ジメチルアミノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－ニトロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
（Ｒ）－２－（３－フルオロ－４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－アミノフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－１－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（Ｒ）－２－（４－アセトアミドフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－Ｎ－（３－シアノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
（Ｓ）－Ｎ－（３－シアノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
（Ｒ）－３－（２－（１Ｈ－インドール－６－イル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
（Ｓ）－３－（２－（１Ｈ－インドール－６－イル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
（Ｒ）－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
（Ｓ）－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
３－（２－（４－モルホリノフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
（Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－エチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－エチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（５，６－ジフルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（Ｒ）－２－（４－（２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｓ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｓ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－Ｎ－（（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）－２－（キナゾリン－２－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－（メチルスルホニル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－シアノフェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（２－（トリフルオロメチル）ピリジン－４－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－インドール－３－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（１Ｈ－インドール－３－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（ｔｅｒｔ－ブチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリダジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－フルオロキノリン－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－ブロモピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（Ｒ）－２－（キノリン－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１Ｈ－インドール－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（キノリン－７－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）オキサゾール－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（６－（トリフルオロメチル）ピリジン－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド－２，２－ｄ２、
（Ｒ）－２－（４－（３，３－ジフルオロピロリジン－１－イル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリノ）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（ピロリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（（２－メトキシエチル）（メチル）アミノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－インドール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（ピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（４－アセチルピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（２－オキソピペリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（６－クロロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（１Ｓ，２Ｓ）－２－（３，５－ジクロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（３，５－ジクロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（４－ブロモフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（４－ブロモフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（Ｒ）－２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（４－オキソピペリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（ヒドロキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（ヒドロキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－酢酸（３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）メチル、
（Ｓ）－酢酸（３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）メチル、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（メトキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（メトキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（１Ｓ，２Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（３，４－ジフルオロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（３，４－ジフルオロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｓ，２Ｓ）－２－（４－クロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（１Ｒ，２Ｒ）－２－（４－クロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－４－イル）アセトアミド、
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（トリフルオロメトキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（２，２，２－トリフルオロエトキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
２－（４－イソプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
（Ｒ）－２－（３，５－ジクロロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（３－クロロ－５－フルオロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）チオフェン－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（２，２，２－トリフルオロエトキシ）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（２，２，２－トリフルオロエトキシ）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（２，２，２－トリフルオロエトキシ）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（２－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（２－ヒドロキシプロパン－２－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（３－メチルピラジン－２－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（４－メチルオキサゾール－５－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）－５－（トリフルオロメチル）ピリジン　１－オキシド、
（３Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン　１－オキシド、
（Ｒ）－２－（４－シクロプロピルフェニル）－２－メチル－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－フルオロ－５－（トリフルオロメチル）フェニル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－２－（ジメチルアミノ）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｓ）－２－（４－シクロプロピルフェニル）－２－（ジメチルアミノ）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－インドール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（２，４－ビス（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（２－フルオロ－４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（２，２－ジメチルモルホリノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（１Ｈ－ピラゾール－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－Ｎ－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－モルホリノフェニル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（ベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（ベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（ベンゾ［ｄ］チアゾール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（ベンゾ［ｄ］チアゾール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１Ｈ－インダゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１Ｈ－インダゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド、
（Ｓ）－Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド、
（Ｒ）－２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（（１Ｒ，４Ｒ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（（１Ｒ，４Ｒ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）フェニル）アゼチジン－３－イル）アセトアミド、
２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）アゼチジン－３－イル）アセトアミド、
（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－Ｎ－（１－（５－ブロモチアゾール－２－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－メトキシフェニル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（３，３－ジフルオロピロリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）フェノキシ）－２－メチルプロパン酸エチル、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－ヒドロキシフェニル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４，６－ジメトキシピリミジン－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
（Ｒ）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド、
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
（Ｓ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
（Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド及び
（Ｒ）－２－（１－メチル－１Ｈ－インドール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
から選択される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
（７４）　関節リウマチの予防又は治療のための医薬を製造するための、上記（１）～（７３）のいずれかに記載の化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物の使用。
（７５）　関節リウマチの予防又は治療のために使用される上記（１）～（７３）のいずれかに記載の化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物。
（７６）　ヒトにおける関節リウマチを処置する方法であって、前記方法が有効量の上記（１）～（７３）のいずれかに記載の化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を、それを必要とする対象に投与する工程を含む方法。 That is, the present invention provides the following (1) to (76).
(1) The active ingredient contains a compound represented by the following general formula (I), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000018
(In the formula, A 1 Is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents and is attached to the nitrogen atoms of adjacent cyclic amines via the carbon atoms that make up these rings.
B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents, and bonds to adjacent Xs via the carbon atoms that make up these rings,
R 1 And R 2 May be the same or different, hydrogen atom, halogen atom, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Represents an alkyl group
Or R 1 , R 2 And R 1 And R 2 The carbon atoms to which the bonds are attached may be combined to form a 3- to 5-membered cycloalkyl group.
R 3 Is a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group, C. 1-8 Alkyl group, C 1-8 Alkoxycarbonyl group, C 1-8 C substituted with an alkoxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with alkyl group and acyloxy group 1-8 Represents an alkyl group
Or R 2 And R 3 May be combined to form methylene or ethylene,
X is
Figure JPOXMLDOC01-appb-C000019
Or
Figure JPOXMLDOC01-appb-C000020
Represents
Here, the wavy line represents the coupling position and
R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group
Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the bond is attached.
n and m may be the same or different, 0 or 1,
p represents 1 and 2.
And the above A 1 Phenyl, A above 1 Heteroaryl ring and A above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and
B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 C substituted with an alkoxy group 1-8 Alkyl) amino group, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or halogen atom as a substituent, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 4 to 6 consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the alkoxy groups. It is selected from the member heteroaryl rings and
Here, B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 The cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C 1-8 It may be substituted with an alkyl group, a halogen atom, or an acyl group. )
(2) X is
Figure JPOXMLDOC01-appb-C000021
The pharmaceutical according to (1) above.
(3) A 1 The pharmaceutical according to (1) or (2) above, wherein is a phenyl which may have a substituent.
(4) A 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent. The medicament according to the above (1) or (2), which is a 4- to 6-membered heteroaryl ring composed of atoms.
(5) A 1 The medicament according to (4) above, wherein the heteroaryl ring of is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine or pyridazine.
(6) A 1 The medicament according to (4) above, wherein the heteroaryl ring of the above is pyridine.
(7) A 1 A 4- to 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to (1) or (2) above, which is a heterofused ring with a benzene ring.
(8) A 1 The medicament according to (7) above, wherein the heterocondensation ring of the above is quinoline or benzo [d] thiazole.
(9) B 1 The medicament according to any one of (1) to (8) above, wherein is a phenyl which may have a substituent.
(10) B 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent. The medicament according to any one of (1) to (8) above, which is a 5- or 6-membered heteroaryl ring composed of atoms.
(11) B 1 The medicament according to the above (10), wherein the heteroaryl ring of the above is pyridine.
(12) B 1 When is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position) above (9). )-(11).
(13) B 1 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to any one of (1) to (8) above, which is a heterofused ring with a benzene ring.
(14) B 1 The pharmaceutical according to (13) above, wherein the heterocondensation ring of the above is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
(15) B 1 The medicament according to the above (13), wherein the heterocondensation ring of the above is indazole.
(16) The medicament according to any one of (1) to (15) above, wherein n is 1 and m is 0.
(17) The medicament according to any one of (1) to (16) above, wherein p is 1.
(18) R 1 And R 2 The pharmaceutical according to any one of (1) to (17) above, wherein is a hydrogen atom.
(19) R 3 The pharmaceutical according to any one of (1) to (18) above, wherein is a hydrogen atom.
(20) The active ingredient comprises a compound represented by the following general formula (II), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000022
(In the formula, D, E, F, G and J are CRs in which any two are N and the other may be the same or different, or any one is N and the other may be the same or different. All are CRs that may be the same or different.
Here, R is a hydrogen atom, C. 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 Represents an alkoxy group.
R a1 , R a2 , R b1 And R b2 May be the same or different hydrogen atom, halogen atom, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Represents an alkyl group
Or R a1 , R a2 And R a1 And R a2 The carbon atoms to which are bonded together, or R b1 , R b2 And R b1 And R b2 The carbon atoms to which the bonds are attached may be combined to form a 3- to 5-membered cycloalkyl group.
s represents 0, 1, 2 and
t represents 1 and 2.
B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents, and bonds to adjacent Xs via the carbon atoms that make up these rings,
X is
Figure JPOXMLDOC01-appb-C000023
Or
Figure JPOXMLDOC01-appb-C000024
Represents
Here, the wavy line represents the coupling position and
R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group
Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the is bonded.
And the above B 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino group, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or halogen atom as a substituent, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 4 to 6 consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the alkoxy groups. It is selected from the member heteroaryl rings and
Here, B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 The cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C 1-8 It may be substituted with an alkyl group, a halogen atom, or an acyl group.
(21) The active ingredient comprises a compound represented by the following general formula (II), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000025
(In the formula, D, E, F, G and J are CRs in which any two are N and the other may be the same or different, or any one is N and the other may be the same or different. All are CRs that may be the same or different.
Here, R is a hydrogen atom, C. 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 Represents an alkoxy group.
R a1 , R a2 , R b1 And R b2 May be the same or different hydrogen atom, halogen atom, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Represents an alkyl group
Or R a1 , R a2 And R a1 And R a2 The carbon atoms to which are bonded together, or R b1 , R b2 And R b1 And R b2 The carbon atoms to which the bonds are attached may be combined to form a 3- to 5-membered cycloalkyl group.
s represents 0, 1, 2 and
t represents 1 and 2.
B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents, and bonds to adjacent Xs via the carbon atoms that make up these rings,
X is
Figure JPOXMLDOC01-appb-C000026
Or
Figure JPOXMLDOC01-appb-C000027
Represents
Here, the wavy line represents the coupling position and
R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group
Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the is bonded.
And the above B 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino group, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or halogen atom as a substituent, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 4 to 6 consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the alkoxy groups. It is selected from the member heteroaryl rings and
Here, B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 The cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C 1-8 It may be substituted with an alkyl group, a halogen atom, or an acyl group.
However, the 6-membered ring composed of D to J is phenyl which may have a substituent or pyridazine which may have a substituent, and X is
Figure JPOXMLDOC01-appb-C000028
At that time, B 1 Is a heterofused ring which may have the above-mentioned substituent. )
(22) X is
Figure JPOXMLDOC01-appb-C000029
The medicament according to the above (20) or (21).
(23) The medicament according to any one of (20) to (22) above, wherein both D and J are CH.
(24) The medicament according to any one of (20) to (22) above, wherein any one of D, E, F, G and J is N and the other is CR.
(25) The medicament according to any one of (20) to (22) above, wherein D, E, F and J are CRs which may be the same or different and G is N.
(26) B 1 The medicament according to any one of (20) to (25) above, wherein is a phenyl which may have a substituent.
(27) B 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent. The medicament according to any one of (20) to (25) above, which is a 5- or 6-membered heteroaryl ring composed of atoms.
(28) B 1 The medicament according to the above (27), wherein the heteroaryl ring of the above is pyridine.
(29) B 1 When is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position) above (26). )-(28).
(30) B 1 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to any one of (20) to (25) above, which is a heterofused ring with a benzene ring.
(31) B 1 The medicament according to the above (30), wherein the heterocondensation ring of the above is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
(32) B a The medicament according to the above (30), wherein the heterocondensation ring of the above is indazole.
(33) The medicament according to any one of (20) to (32) above, wherein s is 1.
(34) The medicament according to any one of (20) to (33) above, wherein t is 1.
(35) R a1 , R a2 , R b1 And R b2 The medicament according to any one of (20) to (34) above, wherein is a hydrogen atom.
(36) The active ingredient comprises a compound represented by the following general formula (III), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000030
(In the formula, A 1 Is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterofused ring May have substituents and is attached to the nitrogen atom of the adjacent pyrrolidine via the carbon atoms that make up these rings.
B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents, and adjacent C (R) via the carbon atoms that make up these rings. 4 ) (R 5 ).
R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group
Or R 4 , R 5 And and R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the bond is attached.
And the above A 1 Phenyl, A above 1 Heteroaryl ring and A above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and
B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino group, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or halogen atom as a substituent, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 4 to 6 consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the alkoxy groups. It is selected from the member heteroaryl rings and
Here, B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 The cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C 1-8 It may be substituted with an alkyl group, a halogen atom, or an acyl group.
(37) The active ingredient comprises a compound represented by the following general formula (III), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000031
(In the formula, A 1 Is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterofused ring May have substituents and is attached to the nitrogen atom of the adjacent pyrrolidine via the carbon atoms that make up these rings.
B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents, and adjacent C (R) via the carbon atoms that make up these rings. 4 ) (R 5 ).
R 4 And R 5 May be the same or different, hydrogen atom, deuterium, hydroxy group, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Represents a dialkylamino group
Or R 4 , R 5 And R 4 And R 5 May form a 3- to 5-membered cycloalkyl group together with the carbon atom to which the bond is attached.
And the above A 1 Phenyl, A above 1 Heteroaryl ring and A above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and
B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino group, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or halogen atom as a substituent, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 4 to 6 consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the alkoxy groups. It is selected from the member heteroaryl rings and
Here, B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 The cyclic amino group of the substituent which the heterofused ring of Heptane may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 3-oxa-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C 1-8 It may be substituted with an alkyl group, a halogen atom, or an acyl group.
However, A 1 However, when phenyl may have a substituent, pyridazine which may have a substituent, and quinazoline which may have a substituent, B 1 Is a heterocondensed ring which may have the above-mentioned substituent. )
(38) A 1 The medicament according to (36) or (37) above, wherein is a phenyl which may have a substituent.
(39) A 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms that may have a substituent. The medicament according to (36) or (37) above, which is a 4- to 6-membered heteroaryl ring composed of atoms.
(40) A 1 The medicament according to (39) above, wherein the heteroaryl ring of the above is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
(41) A 1 The medicament according to (39) above, wherein the heteroaryl ring of the above is pyridine.
(42) A 1 A 4- to 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to (36) or (37) above, which is a heterofused ring with a benzene ring.
(43) A 1 The medicament according to (42) above, wherein the heterocondensation ring of the above is quinoline or benzo [d] thiazole.
(44) B 1 The medicament according to any one of (36) to (43) above, wherein is a phenyl which may have a substituent.
(45) B 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms that may have a substituent. The medicament according to any one of (36) to (43) above, which is a 5- or 6-membered heteroaryl ring comprising.
(46) B 1 The medicament according to (45) above, wherein the heteroaryl ring of the above is pyridine.
(47) B 1 When is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position) above (44). )-(46).
(48) B 1 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to any one of (36) to (43) above, which is a heterofused ring with a benzene ring.
(49) B 1 The medicament according to the above (48), wherein the heterocondensation ring of the above is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
(50) B 1 The medicament according to the above (48), wherein the heterocondensation ring of the above is indazole.
(51) R 4 And R 5 The pharmaceutical according to any one of (36) to (50) above, wherein both are hydrogen atoms.
(52) The active ingredient comprises a compound represented by the following general formula (IV), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000032
(In the formula, R 6 , R 7 And R 8 Are the same or different, hydrogen atom, halogen atom, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkoxy group, hydroxy group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 Represents an alkoxy group
R 9 Is C substituted with 1 to 3 halogen atoms 1-8 Represents alkyl, t-butyl or cyclopropyl,
And r represents 0, 1, 2. )
(53) R 6 , R 7 And R 8 But differently, hydrogen atom, halogen atom, C 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C 1-8 The medicament according to (52) above, which is an alkoxy group.
(54) R 9 The medicament according to any one of (52) to (53) above, wherein is trifluoromethyl or cyclopropyl.
(55) The medicament according to any one of (52) to (54) above, wherein r is 1.
(56) The active ingredient comprises a compound represented by the following general formula (V), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000033
(In the formula, A 1 Is a 4- to 6-membered hetero consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents and is attached to the nitrogen atom of the adjacent pyrrolidine via the carbon atoms that make up these rings.
B 1 Is a 5- or 6-membered hetero consisting of 1 to 3 heteroatoms of the same or different and carbon atoms selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may have a substituent. Represents an aryl ring, or a heteroaryl ring composed of a heteroaryl ring and a benzene ring, or a heterocondensed ring composed of a 6-membered heteroaryl ring composed of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the heterocondensed ring are represented. May have substituents and binds to adjacent cyclopropyls via the carbon atoms that make up these rings.
And the above A 1 Phenyl, A above 1 Heteroaryl ring and A above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and
B above 1 Phenyl, B above 1 Heteroaryl ring and B above 1 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, 3-5 member cycloalkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or halogen atom as a substituent, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 4 to 6 consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the alkoxy groups. It is selected from the member heteroaryl rings and
Here, B above 1 Phenyl, B above 1 The cyclic amino group of the substituent which the heteroaryl ring of B1 and the heterocondensation ring of B1 may have is pyrrolidino, piperidino, piperazino, 2 or 3-oxopiperidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1 -Dioxidethiomorpholino, 1,4-dioxo-8-azaspiro [4.5] decan-8-yl, 2-oxo-6-azaspiro [3.3] heptane-6-yl, 3-oxo-8-azabicyclo [3] .2.1] Octane-8-yl, 2-oxo-5-azabicyclo [2.2.2] octane-5-yl, 2-oxo-5-azabicyclo [2.2.1] heptane-5-yl, selected from Such a cyclic amino group further comprises C 1-8 It may be substituted with an alkyl group, a halogen atom, or an acyl group. )
(57) A 1 The medicament according to (56) above, wherein is a phenyl which may have a substituent.
(58) A 1 Is a 4- to 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to (56) above.
(59) A 1 The medicament according to the above (58), wherein the heteroaryl ring is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
(60) A 1 The medicament according to (58) above, wherein the heteroaryl ring of the above is pyridine.
(61) A 1 A 4- to 6-membered heteroaryl ring and benzene consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to (56) above, which is a heterofused ring with a ring.
(62) A 1 The medicament according to the above (61), wherein the heterocondensation ring of the above is quinoline or benzo [d] thiazole.
(63) B 1 The medicament according to any one of (56) to (62) above, wherein is a phenyl which may have a substituent.
(64) B 1 Is a 5- or 6-membered heteroaryl ring composed of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to any one of (56) to (62) above.
(65) B 1 The medicament according to (63) above, wherein the heteroaryl ring is pyridine.
(66) B 1 Is a 5- or 6-membered heteroaryl ring and benzene consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms which may have substituents. The medicament according to any one of (56) to (62) above, which is a heterofused ring with a ring.
(67) B 1 The medicament according to the above (66), wherein the heterocondensation ring of the above is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
(68) B 1 The medicament according to (66) above, wherein the heterocondensation ring of the above is benzo [d] oxazole.
(69) The active ingredient comprises a compound represented by the following general formula (VI), a tautomer or stereoisomer of the compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. A drug for the treatment or prevention of rheumatoid arthritis.
Figure JPOXMLDOC01-appb-C000034
(In the formula, A 1 Is a phenyl that may have a substituent, or a 4- to 6-membered ring-constituting atom consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms. It may have a heteroaryl ring, the heteroaryl ring, the heterofused ring, a substituent, and is bonded to the nitrogen atom of an adjacent cyclic amine via a carbon atom constituting these rings.
B 2 Is a 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, and a benzene ring or 1 to 2 atoms. Represents a heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of a nitrogen atom and a carbon atom, wherein the heterocondensed ring may have a substituent, and the carbon atom constituting these rings may be used. It binds to an adjacent methylene group via.
And the above A 1 Phenyl and A above 1 As a substituent that the heteroaryl ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, C 1-8 Alkylsulfonyl group, C 1-8 C substituted with an alkoxycarbonyl group 1-8 It is selected from alkoxy groups and
B above 2 As a substituent that the heterocondensation ring of the above may have, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 C substituted with an alkoxy group and a hydroxy group 1-8 C substituted with alkyl group and hydroxy group 1-8 Alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, 3-5 member cycloalkyl group, amino group, C 1-8 Alkylamino group, C 2-12 Dialkylamino group, (C 1-8 Alkyl) (C 1-8 Alkoxy substituted C 1-8 Alkyl) amino, tri (C) 1-8 Alkyl) silyl group, acylamino group, (N-acyl) (NC) 1-8 Alkyl) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or halogen atom as a substituent, C 1-8 Alkyl group, C 1-8 Alkoxy group, C substituted with 1 to 3 halogen atoms 1-8 Alkyl group, C substituted with 1 to 3 halogen atoms 1-8 4 to 6 consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the alkoxy groups. It is selected from the member heteroaryl rings and
Here, B above 2 Cyclic amino groups of substituents that the heterofused ring of Heptane may have are pyrrolidino, piperidino, piperazino, 2 or 3-oxopiperidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1 , 4-Dioxo-8-azaspiro [4.5] decane-8-yl, 2-oxo-6-azaspiro [3.3] heptane-6-yl, 3-oxo-8-azabicyclo [3.2.1] ] Octane-8-yl, 2-oxo-5-azabicyclo [2.2.2] octane-5-yl, 2-oxo-5-azabicyclo [2.2.1] heptane-5-yl selected from such a ring The amino group is further C 1-8 It may be substituted with an alkyl group, a halogen atom, or an acyl group.
u represents 0, 1, and 2. )
(70) A 1 Is a phenyl that may have a substituent, or the same or different 1 to 3 heteroatoms and carbon selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms which may have a substituent. The medicament according to (69) above, which is a 4- to 6-membered heteroaryl ring composed of atoms.
(71) A 1 The medicament according to the above (70), wherein the heteroaryl ring of the above is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
(72) A 1 The medicament according to (70) above, wherein the heteroaryl ring of the above is pyridine.
(73) (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (5- (trifluoromethyl) pyridin-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-isopropylphenyl) -N- (1- (2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-hydroxy-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (5- (5- (trifluoromethyl) pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (5- (6- (trifluoromethyl) Pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (5- (4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide,
2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
2- (4-Cyclopropylphenyl) -N-((1S, 5R) -3- (5- (trifluoromethyl) pyridin-3-yl) -3-azabicyclo [3.1.0] hexane-1- Il) acetamide,
2- (4-Cyclopropylphenyl) -N-((1R, 5S) -3- (5- (trifluoromethyl) pyridine-3-yl) -3-azabicyclo [3.1.0] hexane-1- Il) acetamide,
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-yl) acetamide,
(R) -N- (1- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
Methyl (R) -3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate,
(S) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate methyl,
(R) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylic acid,
(S) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylic acid,
(R) -2- (1H-indazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide, (R) -2- (4-) Isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) propanamide,
(S) -2- (4-isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6-methyl-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (2-hydroxypropan-2-yl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (8- (trifluoromethyl) imidazole [1,2-a] pyridin-6-yl) pyrrolidine-3-yl) acetamide,
(R) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxyamide,
(S) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxyamide,
(R) -2- (4-Hydroxyphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (1,1-dioxidethiomorpholino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -1- (4-chlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide,
(R) -2- (4-Bromophenyl) -2-hydroxy-N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(S) -2- (4-Bromophenyl) -2-hydroxy-N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -N- (1- (5- (trifluoromethyl) Pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trimethylsilyl) phenyl) acetamide,
(R) -2- (4- (2-Hydroxy-2-methylpropoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-fluoro-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (dimethylamino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-nitrophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(S) -2- (4-isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
(R) -2- (3-Fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-aminophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -1- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide,
(R) -2- (4-acetamide phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -N- (3-cyano-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
(S) -N- (3-cyano-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
(R) -3- (2- (1H-indole-6-yl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylate methyl,
(S) -3- (2- (1H-indole-6-yl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylate methyl,
Methyl (R) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate,
(S) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate methyl,
(1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
(R) -2- (4-morpholinophenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide,
Methyl 3- (2- (4-morpholinophenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate,
(R) -2- (4-morpholinophenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (3-ethyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(S) -2- (4-Cyclopropylphenyl) -N- (3-ethyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine- 3-Il) Cyclopropane-1-carboxyamide,
(R) -2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide,
(1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
(1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
(1R, 2R) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
(1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
(1R, 2R) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
(1R, 2R) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyrimidine-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) -2- (quinazoline-2-yl) cyclopropane-1- Carboxamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(3- (methylsulfonyl) phenyl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (3-cyanophenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide ,
(1S, 2S) -2- (5-cyano-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-yl) Cyclopropane-1-carboxyamide,
(1R, 2R) -2- (5-cyano-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-yl) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyridin-4-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1R, 2R) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) piperidine-3-yl) cyclopropane- 1-carboxyamide,
(1S, 2S) -2- (1H-indole-3-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
(1R, 2R) -2- (1H-indole-3-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-Il) Cyclopropan-1-carboxyamide, (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (tert-) Butyl) thiazole-2-yl) pyrrolidine-3-yl) cyclopropan-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluoroquinoline-2-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
(1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1- (3- (trifluoromethyl) phenyl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (5-bromopyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
(R) -2- (quinoline-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1H-indole-3-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (quinoline-7-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) oxazole-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1-Methyl-5- (trifluoromethyl) -1H-pyrazole-3-yl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 -Il) acetamide,
(R) -2- (6- (trifluoromethyl) pyridin-3-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide-2,2-d2,
(R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide ,
(R) -2- (1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
2-(4-((2R, 6S) -2,6-dimethylmorpholino) phenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Acetamide,
(R) -2- (4- (Pyrrolidine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-((2-Methoxyethyl) (methyl) amino) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide ,
2- (4- (Trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
(R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (4-Methylpiperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (piperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (4-Acetylpiperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (2-oxopiperidine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (6-chlorobenzo [d] oxazole-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (benzo [d] oxazole-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(1S, 2S) -2- (3,5-dichlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
(1R, 2R) -2- (3,5-dichlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
(1S, 2S) -2- (4-bromophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxy Amide,
(1R, 2R) -2- (4-bromophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxy Amide,
(R) -2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (4-oxopiperidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
(S) -2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
(R) -Acetic acid (3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methyl,
(S) -Acetic acid (3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methyl,
(R) -2- (4-Cyclopropylphenyl) -N- (3- (methoxymethyl) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(S) -2- (4-Cyclopropylphenyl) -N- (3- (methoxymethyl) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(1S, 2S) -2- (4-Cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
(1R, 2R) -2- (4-Cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
(1S, 2S) -2- (3,4-difluorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide,
(1R, 2R) -2- (3,4-difluorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide,
(1S, 2S) -2- (4-chlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide ,
(1R, 2R) -2- (4-chlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide ,
2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-4-yl) acetamide,
(R) -2- (4-isopropylphenyl) -N- (1- (6-methoxy-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide, (R) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-isopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-isopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(S) -2- (4-isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (trifluoromethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (2,2,2-trifluoroethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
2- (4-Isopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
(R) -2- (3,5-dichlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (3-Chloro-5-fluorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-isopropylphenyl) -N- (1- (5- (trifluoromethyl) thiophen-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (2,2,2-trifluoroethoxy) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (2,2,2-trifluoroethoxy) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (2,2,2-trifluoroethoxy) pyridin-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide,
(R) -2- (4- (2-Hydroxypropane-2-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (3-methylpyrazine-2-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (4-Methyloxazole-5-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -3- (3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-yl) -5- (trifluoromethyl) pyridine 1-oxide,
(3R) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine 1-oxide,
(R) -2- (4-Cyclopropylphenyl) -2-methyl-N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (3-fluoro-5- (trifluoromethyl) phenyl) pyrrolidine-3-yl) acetamide,
(R) -2-amino-2- (4-cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(S) -2-amino-2- (4-cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -2- (dimethylamino) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) Acetamide,
(S) -2- (4-Cyclopropylphenyl) -2- (dimethylamino) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) Acetamide,
(R) -2- (1-methyl-1H-indole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (2,4-bis (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (2-fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1-methyl-1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1-methyl-1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (2,2-dimethylmorpholino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (1H-pyrazole-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -N- (3-Methyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-morpholinophenyl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (3-methyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-3) Il) pyrrolidine-3-yl) acetamide,
2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide,
(R) -2- (benzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (benzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) -N-((R) -1-(5- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
2-(4-(((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) -N-((R) -1- (6- (trifluoro)) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
(R) -2- (benzo [d] thiazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (benzo [d] thiazole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
2- (4-Cyclopropylphenyl) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
(R) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) Acetamide,
(S) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) Acetamide,
(R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide,
(R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide,
2-(4-((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(5- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(5- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
2-(4-((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(6- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(6- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
(R) -2- (1-Methyl-1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) Pyrrolidine-3-yl) acetamide,
(R) -2- (1-Methyl-1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide,
2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) phenyl) azetidine-3-yl) acetamide,
2- (4-Cyclopropylphenyl) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) azetidine-3-yl) acetamide,
(R) -2- (4-Bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) acetamide,
(R) -N- (1- (5-bromothiazole-2-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (3-methoxyphenyl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide ,
(R) -2- (3- (3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-yl) phenoxy) -2-methylpropanoate ethyl,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (3-hydroxyphenyl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4,6-dimethoxypyrimidine-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-morpholinophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) pyridin-2-yl) pyrrolidine-3-yl) acetamide,
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
(R) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide,
(R) -2- (4- (trifluoromethyl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
(S) -2- (4- (trifluoromethyl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide,
(R) -2- (1H-indole-6-yl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide and
(R) -2- (1-methyl-1H-indole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
A drug for the treatment or prevention of rheumatoid arthritis, which comprises a compound selected from the above, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. ..
(74) The compound according to any one of (1) to (73) above, a tautomer of the compound, a stereoisomer, or a pharmacy thereof for producing a drug for preventing or treating rheumatoid arthritis. Use of locally acceptable salts or solvates thereof.
(75) The compound according to any one of (1) to (73) above, which is used for the prevention or treatment of rheumatoid arthritis, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable thereof. Salts or solvates thereof.
(76) A method for treating rheumatoid arthritis in humans, wherein the method is an effective amount of the compound according to any one of (1) to (73) above, a tautomer, a stereoisomer, or a stereoisomer of the compound. A method comprising the step of administering the pharmaceutically acceptable salt or solvate thereof to a subject in need thereof.
　本発明化合物は、Ｃａｖ３．２チャネルを阻害し、関節リウマチに伴う痛みの軽減作用を有する。 The compound of the present invention inhibits the Cav3.2 channel and has a pain-relieving effect associated with rheumatoid arthritis.
ＣＦＡ誘発関節リウマチモデルのPWLに対する化合物Aの効果を示す。 ｔｗｏ－ｗａｙ　ＡＮＯＶＡで解析後 、Ｂｏｎｆｅｒｒｏｎｉ　ｔｅｓｔにより有意差検定を行った。＊：ｐ＜０．０５ ｖｓ ビヒクルThe effect of Compound A on PWL in the CFA-induced rheumatoid arthritis model is shown. After analysis by two-way ANOVA, a significant difference test was performed by Bonferroni test. * : P <0.05 vs vehicle
　次に本発明をさらに詳細に説明する。
　本願明細書において、Ｃ１－８アルキル基としては、メチル基、エチル基、プロピル基、ｉｓｏ－プロピル基、ブチル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ｉｓｏ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基又はヘキシル基等の直鎖、分枝鎖又は環状のアルキル基が挙げられる。
　１～３個のハロゲン原子で置換されたＣ１－８アルキル基としては、１～３個のフッ素原子、塩素原子若しくは臭素原子等のハロゲン原子により置換されたメチル基、エチル基、プロピル基、ｉｓｏ－プロピル基、ブチル基又はｔｅｒｔ－ブチル基等が挙げられ、好ましくはトリフルオロメチル基、クロロメチル基、２－クロロエチル基、２－ブロモエチル基又は２－フルオロエチル基等が挙げられる。
　Ｃ１－８アルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、ｉｓｏ－プロポキシ基、ブトキシ基、ｉｓｏ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペンチルオキシ基又はヘキシルオキシ基等が挙げられる。
　１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基としては、１～３個のフッ素原子、塩素原子若しくは臭素原子等のハロゲン原子により置換されたメトキシ基、エトキシ基、プロポキシ基、ｉｓｏ－プロポキシ基、ブトキシ基又はｔｅｒｔ－ブトキシ基等が挙げられ、好ましくはトリフルオロメトキシ基、クロロメトキシ基、２－クロロエトキシ基、２－ブロモエトキシ基、２－フルオロエトキシ基、又は２，２，２－トリフルオロエトキシ基等が挙げられる。
　ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、又はヨウ素原子等が挙げられる。
　Ｃ１－８アルコキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基、ブトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基等が挙げられる。
　アシル基としては、好ましくは、炭素数１～７個のアシル基が挙げられ、更に好ましくは、アセチル基、プロピオニル基、ベンゾイル基等が挙げられる。
　ヒドロキシ基で置換されたＣ１－８アルキル基としては、ヒドロキシメチル基、２－ヒドロキシプロパン－２－イル基等が挙げられる。
　アシルオキシ基で置換されたＣ１－８アルキル基としては、アセチルオキシメチル基等が挙げられる。
　ヒドロキシ基で置換されたＣ１－８アルコキシ基としては、２－ヒドロキシエトキシ基等が挙げられる。
　Ｃ１－８アルキルスルホニル基としては、メタンスルホニル基等が挙がられる。
　（Ｃ１－８アルコキシ基で置換されたＣ１－８アルキル）アミノ基としては、（２-メトキシエチル）アミノ基等が挙げられる。
　３～５員のシクロアルキル基としては、シクロプロピル基、シクロブチル基等が挙げられる。
　Ｃ１－８アルキルアミノ基としては、エチルアミノ基等が挙がられる。
　Ｃ２－１２ジアルキルアミノ基としてはジメチルアミノ基、ジエチルアミノ基等が挙げられる。
　（Ｃ１－８アルキル）（Ｃ１－８アルコキシ基で置換されたＣ１－８アルキル）アミノ基としては、Ｎ－エチル－Ｎ－（２-メトキシエチル）アミノ基等が挙げられる。
　トリ（Ｃ１－８アルキル）シリル基としては、トリメチルシリル基、トリエチルシリル基等が挙げられる。
　アシルアミノ基としては、アセチルアミノ基等が挙げられる。
　（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基としては、（Ｎ－アセチル）（Ｎ－エチル）アミノ基等が挙げられる。
　３～６員の環状エーテルとしては、ＴＨＦ、オキセタン等が挙げられる。
　Ｃ１－８アルコキシ基で置換されたＣ１－８アルキル基としては、メトキシ基、エトキシ基、プロポキシ基、ｉｓｏ－プロポキシ基、ブトキシ基、ｉｓｏ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペンチルオキシ基又はヘキシルオキシ基等の炭素数１～６のアルコキシ基で置換されたメチル基、エチル基、プロピル基、ｉｓｏ－プロピル基、ブチル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ｉｓｏ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基又はヘキシル基等の直鎖、分枝鎖又は環状のアルキル基が挙げられる。
　Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基としては、エトキシカルボニルで置換されたイソプロピルオキシ基等が挙げられる。 Next, the present invention will be described in more detail.
In the specification of the present application, the C 1-8 alkyl group includes a methyl group, an ethyl group, a propyl group, an iso-propyl group, a butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an iso-butyl group and a tert-butyl group. , A straight-chain, branched or cyclic alkyl group such as a pentyl group or a hexyl group.
Examples of the C 1-8 alkyl group substituted with 1 to 3 halogen atoms include methyl group, ethyl group, and propyl group substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom and bromine atom. Examples thereof include an iso-propyl group, a butyl group and a tert-butyl group, and preferably a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group and the like.
Examples of the C 1-8 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso-butoxy group, a tert-butoxy group, a pentyloxy group or a hexyloxy group.
Examples of the C 1-8 alkoxy group substituted with 1 to 3 halogen atoms include a methoxy group, an ethoxy group, and a propoxy group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, or a bromine atom. Examples thereof include iso-propoxy group, butoxy group, tert-butoxy group and the like, preferably a trifluoromethoxy group, a chloromethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, a 2-fluoroethoxy group, or 2,2. , 2-Trifluoroethoxy group and the like.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
Examples of the C 1-8 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group and the like.
The acyl group preferably includes an acyl group having 1 to 7 carbon atoms, and more preferably an acetyl group, a propionyl group, a benzoyl group and the like.
Examples of the C 1-8 alkyl group substituted with a hydroxy group include a hydroxymethyl group and a 2-hydroxypropan-2-yl group.
Examples of the C 1-8 alkyl group substituted with the acyloxy group include an acetyloxymethyl group.
Examples of the C 1-8 alkoxy group substituted with a hydroxy group include a 2-hydroxyethoxy group and the like.
Examples of the C 1-8 alkylsulfonyl group include a methanesulfonyl group.
The amino group (C 1-8 C 1-8 alkyl substituted with an alkoxy group), and (2-methoxyethyl) amino group and the like.
Examples of the 3- to 5-membered cycloalkyl group include a cyclopropyl group and a cyclobutyl group.
Examples of the C 1-8 alkylamino group include an ethylamino group.
Examples of the C 2-12 dialkylamino group include a dimethylamino group and a diethylamino group.
The (C 1-8 alkyl) amino group (C 1-8 C 1-8 alkyl substituted with an alkoxy group), such as N- ethyl-N-(2-methoxyethyl) amino group.
Examples of the tri (C 1-8 alkyl) silyl group include a trimethylsilyl group and a triethylsilyl group.
Examples of the acylamino group include an acetylamino group.
Examples of the (N-acyl) ( NC 1-8 alkyl) amino group include a (N-acetyl) (N-ethyl) amino group.
Examples of the 3- to 6-membered cyclic ether include THF, oxetane and the like.
Examples of the C 1-8 alkyl group substituted with the C 1-8 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso-butoxy group, a tert-butoxy group, a pentyloxy group or Methyl group, ethyl group, propyl group, iso-propyl group, butyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, iso-butyl group, tert substituted with alkoxy group having 1 to 6 carbon atoms such as hexyloxy group. -Includes straight-chain, branched or cyclic alkyl groups such as butyl, pentyl or hexyl groups.
Examples of the C 1-8 alkoxy group substituted with the C 1-8 alkoxycarbonyl group include an isopropyloxy group substituted with ethoxycarbonyl and the like.
　「互変異性体」としては、ケト－エノール及びイミン－エナミン異性化のようなプロトンの移動による相互変換を含む。
　「立体異性体」は、同一の化学構造を有するが、原子又は基の空間配置の点で異なる化合物を指す。例えば、シス・トランス異性体や光学活性体、ラセミ体等の立体異性体が存在する場合もあるが、何れも本発明に含まれ、更にはエナンチオマーやジアステレオマーの混合物も本発明に含まれる。
　また、本発明化合物には、後記実施例１３４にあるようなピリジンが、ピリジン　１－オキシドである化合物や、ピロリジン　１－オキシド、ピペリジン　１－オキシドである化合物等も含まれる。 "Tautomers" include interconversion by proton transfer, such as keto-enol and imine-enamine isomerization.
"Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of atoms or groups. For example, stereoisomers such as cis-trans isomers, optically active isomers, and racemates may be present, but all of them are included in the present invention, and a mixture of enantiomers and diastereomers is also included in the present invention. ..
In addition, the compound of the present invention also includes a compound in which pyridine is pyridine 1-oxide, as described in Example 134 below, and a compound in which pyrrolidine 1-oxide and piperidine 1-oxide are used.
　上記一般式（Ｉ）で表される化合物の「薬理学的に許容される塩」としては、酸付加塩として、例えば、塩酸、硫酸、硝酸、リン酸などの鉱酸塩、ギ酸、酢酸、クエン酸、酒石酸、メタンスルホン酸、ｐ－トルエンスルホン酸、シュウ酸、リンゴ酸などの有機酸塩などを用いることができるが、これらに限定されることはない。また、塩基付加塩として、例えば、リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩、若しくはカルシウム塩などの無機塩基との塩、アンモニウム塩、又はトリエチルアミン塩若しくはエタノールアミン塩などの有機塩基との付加塩などを挙げることができるが、これらに限定されることはない。 Examples of the "pharmaceutically acceptable salt" of the compound represented by the above general formula (I) include acid addition salts such as mineral acid salts such as hydrochloric acid, sulfuric acid, nitrate and phosphoric acid, formic acid and acetic acid. Organic acid salts such as citric acid, tartrate acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, and malic acid can be used, but are not limited thereto. Further, as the base addition salt, for example, a salt with an inorganic base such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, or a calcium salt, an ammonium salt, or an addition salt with an organic base such as a triethylamine salt or an ethanolamine salt. However, it is not limited to these.
　「溶媒和物」とは、本発明化合物と化学量論量の１つ以上の薬学的に許容し得る溶媒分子とを含む分子複合体の形態を意味し、溶媒分子としては、エタノール等のアルコールや水が挙げられる。溶媒分子が水の場合は水和物と呼ぶこともあり、水和物としては、１水和物、２水和物等を挙げることができる。 The "solvate" means the form of a molecular complex containing the compound of the present invention and one or more pharmaceutically acceptable solvent molecules of a chemical quantity, and the solvent molecule is an alcohol such as ethanol. And water. When the solvent molecule is water, it may be called a hydrate, and examples of the hydrate include monohydrate and dihydrate.
　また本発明化合物には、プロドラッグや安定同位体で置換された誘導体も含まれる。同位体の例としては、それぞれ２Ｈ、３Ｈ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、および３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、および塩素が包含される。 The compounds of the present invention also include prodrugs and derivatives substituted with stable isotopes. Examples of isotopes include hydrogen, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Includes carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine.
　「関節リウマチの治療又は予防」には、疾患を完治させる場合のみならず、関節リウマチに伴う腫れや痛み等の少なくとも一つの病状を軽減させる場合や、当該病状の悪化を阻止する場合なども含まれる。 "Treatment or prevention of rheumatoid arthritis" includes not only the case of completely curing the disease, but also the case of alleviating at least one medical condition such as swelling and pain associated with rheumatoid arthritis, and the case of preventing the exacerbation of the medical condition. Is done.
  本発明の化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を医薬として用いる場合、それ自体あるいは適宜の医薬上許容される担体と混合し製剤化することができる。ここで、医薬上許容される担体としては、希釈剤、結合剤、賦形剤、滑沢剤、崩壊剤、湿潤剤、乳化剤、界面活性剤、酸化防止剤、防腐剤、着色剤、矯味剤及び矯臭剤等を挙げることができる。 When a compound of the present invention, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof is used as a drug, it may be used as a drug itself or as an appropriate pharmaceutically acceptable carrier. It can be mixed and formulated. Here, pharmaceutically acceptable carriers include diluents, binders, excipients, lubricants, disintegrants, wetting agents, emulsifiers, surfactants, antioxidants, preservatives, colorants, and flavoring agents. And odorants and the like.
　剤型としては、散剤、顆粒剤、錠剤、カプセル剤のような経口剤、点眼剤、点鼻剤、塗布剤、貼付剤、噴霧剤、ゲル剤、クリーム剤のような外用剤、注射剤等の形態を挙げることができ、経口的又は非経口的に投与することができる。 Dosage forms include oral preparations such as powders, granules, tablets and capsules, eye drops, nasal drops, coating agents, patches, sprays, gels, external preparations such as creams, injections, etc. It can be administered orally or parenterally.
　本発明の医薬の投与量は、特に限定されず、年齢、性別、体重、症状、治療効果、投与方法、物質や塩の種類、薬剤に対する感受性、治療効果等に応じて適宜増減することができるが、通常、成人に対して、経口剤の場合は、一回につき、０．０１ｍｇから１０００ｍｇ、好ましくは０．１ｍｇから５００ｍｇ、さらに好ましくは０．１ｍｇから３００ｍｇの範囲で一日１回から６回で投与されるか、外用剤の場合は、一回につき、０．０１ｍｇから２０００ｍｇ、好ましくは０．０５ｍｇから１０００ｍｇ、さらに好ましくは０．１ｍｇから５００ｍｇの範囲で一日１回から６回で使用されるか、注射剤の場合は、一回につき、０．００１ｍｇから１０００ｍｇ、好ましくは０．１ｍｇから１００ｍｇ、さらに好ましくは０．１ｍｇから５０ｍｇの範囲で一日１回から６回で使用される。 The dose of the medicament of the present invention is not particularly limited, and can be appropriately increased or decreased according to age, sex, body weight, symptoms, therapeutic effect, administration method, type of substance or salt, sensitivity to drug, therapeutic effect, and the like. However, for adults, in the case of oral preparations, the dose is 0.01 mg to 1000 mg, preferably 0.1 mg to 500 mg, and more preferably 0.1 mg to 300 mg once a day to 6 times. It is administered in batches, or in the case of external preparations, in the range of 0.01 mg to 2000 mg, preferably 0.05 mg to 1000 mg, and more preferably 0.1 mg to 500 mg, once to 6 times a day. It is used, or in the case of injections, it is used 1 to 6 times a day in the range of 0.001 mg to 1000 mg, preferably 0.1 mg to 100 mg, more preferably 0.1 mg to 50 mg at a time. To.
一般合成法
　本発明の化合物は、市販の化合物を原料として、公知の方法あるいは以下に記載した方法を用いて製造することができる。公知の方法としては、第５版　実験化学講座（丸善出版）、新編　ヘテロ環化合物（講談社）、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（Ｗｉｌｅｙ）等に記載された方法がある。
　本製造法を用いて製造される化合物によっては、製造の各段階において、官能基の保護あるいは脱保護、転化あるいは導入が効果的な場合がある。このような場合は、記載された製造方法の操作あるいは順序に限らず、公知の方法を用いて適切な操作あるいは順序を適用することができる。
　本発明化合物のプロドラッグは、製造の各段階においてアミド化、エステル化、アルキル化等、公知の方法を適用することで製造することができる。
　本製造方法を用いて製造される化合物によっては、各種の塩、水和物、結晶多形を含有することがある。また、光学異性体、幾何異性体あるいは互変異生体が存在し得る場合、特に限定しない場合においては、いずれかの比率の混合物を含有することがある。これらの異性体の混合物は、公知の方法により分離することができる。 General Synthesis Method The compound of the present invention can be produced using a commercially available compound as a raw material by a known method or the method described below. Known methods include the methods described in the 5th Edition Experimental Chemistry Course (Maruzen Publishing), New Heterocyclic Compounds (Kodansha), Protective Groups in Organic Synthesis (Wiley), and the like.
Depending on the compound produced by this production method, protection or deprotection, conversion or introduction of a functional group may be effective at each stage of production. In such a case, not only the operation or order of the described manufacturing method but also a known method can be used to apply an appropriate operation or order.
The prodrug of the compound of the present invention can be produced by applying known methods such as amidation, esterification, and alkylation at each stage of production.
Some compounds produced using this production method may contain various salts, hydrates and polymorphs. Further, when optical isomers, geometric isomers or tautomer organisms can be present, and when not particularly limited, they may contain a mixture in any ratio. Mixtures of these isomers can be separated by known methods.
　以下に本発明の化合物の製造方法について記載するが、本発明の化合物の製造方法は、下記の方法に何ら限定されるものではない。 The method for producing the compound of the present invention will be described below, but the method for producing the compound of the present invention is not limited to the following method.
　本明細書では以下の略号を用いることがある。
Ｍ：モル濃度、Ｎ：規定、ＭＳ：マススペクトル、［Ｍ＋Ｈ］＋：プロトン化分子イオンピーク、［Ｍ＋Ｎａ］＋：ナトリウムイオン付加分子イオンピーク、［Ｍ－Ｈ］－：脱プロトン化分子イオンピーク、ＣＤＣｌ３：重クロロホルム、ＤＭＳＯ－ｄ６：重ジメチルスルホキシド、ＣＤ３ＯＤ：重メタノール、１Ｈ　ＮＭＲ：プロトン核磁気共鳴、Ｍｅ：メチル基、Ｅｔ：エチル基、ｔ－Ｂｕ：ｔｅｒｔ－ブチル基、ＣＮ：シアノ基、ＣＦ３：トリフルオロメチル基、Ｔｓ：ｐ－トルエンスルホニル基、Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル基、ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド、ＴＨＦ：テトラヒドロフラン、ＤＭＥ：１，２－ジメトキシエタン、ＨＡＴＵ：Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロフォスフェート、ＨＯＢＴ：１－ヒドロキシベンゾトリアゾール、ＷＳＣ：１－エチル－３－（ジメチルアミノプロピル）カルボジイミド、ＤＭＴ－ＭＭ：４－（４，６－ジメトキシ－１，３，５，－トリアジン－２－イル）－４－メチルモルホリニウムクロリド、ＤＭＡＰ：Ｎ，Ｎ－ジメチル－４－アミノピリジン、ＤＩＢＡＬ－Ｈ：水素化ジイソブチルアルミニウム、Ｌ－セレクトライド：水素化トリ（ｓｅｃ－ブチル）ホウ素リチウム、ＤＩＰＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン、ＢＩＮＡＰ：２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル、ＤＭＳＯ：ジメチルスルホキシド、ＦＢＳ：牛胎児血清、ＤＭＥＭ：ダルベッコ変法イーグル培地、ＣＯ２：二酸化炭素、ＮａＣｌ：塩化ナトリウム、ＫＣｌ：塩化カリウム、ＭｇＣｌ２：塩化マグネシウム、ＣａＣｌ２：塩化カルシウム、ＣｓＣｌ：塩化セシウム、ＣｓＦ：フッ化セシウム、ＨＥＰＥＳ：４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸、ＥＧＴＡ：グリコールエーテルジアミン４酢酸 The following abbreviations may be used herein.
M: Mol concentration, N: Normal, MS: Mass spectrum, [M + H] + : Protonized molecular ion peak, [M + Na] + : Sodium ion-added molecular ion peak, [MH] - : Deprotonized molecular ion peak , CDCl 3 : Heavy chloroform, DMSO-d 6 : Heavy dimethyl sulfoxide, CD 3 OD: Heavy methanol, 1 H NMR: Proton nuclear magnetic resonance, Me: Methyl group, Et: Ethyl group, t-Bu: tert-butyl group , CN: cyano group, CF 3 : trifluoromethyl group, Ts: p-toluenesulfonyl group, Boc: tert-butoxycarbonyl group, DMF: N, N-dimethylformamide, THF: tetrahydrofuran, DME: 1,2-dimethoxy Ethan, HATU: O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate, HOBT: 1-hydroxybenzotriazole, WSC: 1-ethyl -3- (Dimethylaminopropyl) Carbodiimide, DMT-MM: 4- (4,6-dimethoxy-1,3,5-yl) -4-methylmorpholinium chloride, DMAP: N, N -Dimethyl-4-aminopyridine, DIBAL-H: hydride diisobutylaluminum, L-selectride: tri (sec-butyl) boron lithium hydride, DIPEA: N, N-diisopropylethylamine, BINAP: 2,2'-bis (Diphenylphosphino) -1,1'-binaphthyl, DMSO: dimethyl sulfoxide, FBS: bovine fetal serum, DMEM: modified Dalbecco eagle medium, CO 2 : carbon dioxide, NaCl: sodium chloride, KCl: potassium chloride, MgCl 2 : Magnesium chloride, CaCl 2 : Calcium chloride, CsCl: Cesium chloride, CsF: Cesium fluoride, HEPES: 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid, EGTA: Glycol etherdiamine tetraacetic acid
　一般式（Ｚ）で表される化合物の製造方法を以下に記載する。 The method for producing the compound represented by the general formula (Z) is described below.
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　一般式中、ＡＺは、例えば、上記一般式（Ｉ）で表される化合物中のＡ１、又は上記一般式（ＩＩ）で表される化合物中の
Figure JPOXMLDOC01-appb-C000036
 を表し、 In the formula, A Z, for example, A 1 in the compound represented by the general formula (I), or a compound represented by the general formula (II)
Figure JPOXMLDOC01-appb-C000036
 Represents
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
は、例えば、上記一般式（Ｉ）で表される化合物中の
Figure JPOXMLDOC01-appb-C000038
 Is, for example, in the compound represented by the above general formula (I).
Figure JPOXMLDOC01-appb-C000038
又は、上記一般式（ＩＩ）で表される化合物中の
Figure JPOXMLDOC01-appb-C000039
 Alternatively, in the compound represented by the above general formula (II)
Figure JPOXMLDOC01-appb-C000039
を表し、
　Ｘは、一般式（Ｉ）で表される化合物若しくは上記一般式（ＩＩ）で表される化合物中の、 Represents
X is a compound represented by the general formula (I) or a compound represented by the above general formula (II).
Figure JPOXMLDOC01-appb-C000040
 又は
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000040
Or
Figure JPOXMLDOC01-appb-C000041
を表し、
　そして、ＢＺは、例えば、一般式（Ｉ）で表される化合物中のＢ１又は上記一般式（ＶＩ）で表される化合物中のＢ2を表す。
　一般式（ＩＩＩ）～（ＶＩ）等で表される化合物も同様にして製造することができる。 Represents
Then, B Z represents, for example, B 1 in the compound represented by the general formula (I) or B 2 in the compound represented by the general formula (VI).
Compounds represented by the general formulas (III) to (VI) and the like can also be produced in the same manner.
化合物（Ｚ）の製造法
　上記化合物（Ｚ）は、例えば以下に示す方法によって製造することができる。 Method for Producing Compound (Z) The compound (Z) can be produced, for example, by the method shown below.
（製造法１）
Figure JPOXMLDOC01-appb-C000042
 ［式中の記号は前記と同義とする。］ (Manufacturing method 1)
Figure JPOXMLDOC01-appb-C000042
 [The symbols in the formula have the same meaning as above. ]
　化合物（Ｚ）は、化合物（Ｚ－Ａ）と化合物（Ｚ－Ｂ）をＤＭＦ等の適切な溶媒中、ＨＡＴＵあるいはＷＳＣ等の縮合剤、必要に応じてＨＯＢＴあるいはＤＭＡＰ等の添加剤、必要に応じてトリエチルアミン、ＤＩＰＥＡ等の塩基の存在下、０℃～１００℃で反応させることにより製造することができる。
　また、化合物（Ｚ－Ａ）に対して、化合物（Ｚ－Ｂ）に対応するカルボン酸クロライドあるいはカルボン酸無水物をテトラヒドロフランなどの適切な溶媒中、必要であればトリエチルアミン、ＤＩＰＥＡ、ピリジン等の塩基の存在下０℃～１００℃で反応させることにより製造することができる。
　その他にもＣｈｒｉｓｔｉａｎ　Ａ．Ｇ．Ｎ．　Ｍｏｎｔａｌｂｅｔｔｉ，　ｅｔ　ａｌ，Ｔｅｔｒａｈｅｄｒｏｎ，　６１（４６），　２００５，　１０８２７－１０８５２．に記載されている、あるいはそれに準ずる縮合反応を用いて、化合物（Ｚ－Ａ）および化合物（Ｚ－Ｂ）、あるいはそれぞれに準ずる化合物から製造することができる。 Compound (Z) is prepared by combining compound (ZA) and compound (ZB) in a suitable solvent such as DMF, a condensing agent such as HATU or WSC, and optionally an additive such as HOBT or DMAP, if necessary. It can be produced by reacting at 0 ° C. to 100 ° C. in the presence of a base such as triethylamine or DIPEA.
Further, for compound (ZA), a carboxylic acid chloride or carboxylic acid anhydride corresponding to compound (ZB) is placed in a suitable solvent such as tetrahydrofuran, and if necessary, a base such as triethylamine, DIPEA or pyridine. It can be produced by reacting at 0 ° C to 100 ° C in the presence of.
In addition, Christian A. G. N. Montalbetti, et al, Tetrahedron, 61 (46), 2005, 10827-10852. It can be produced from the compound (ZA) and the compound (ZB), or a compound equivalent thereto, by using the condensation reaction described in the above or the equivalent thereof.
　化合物（Ｚ－Ａ）は、例えば以下に示す方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000043
 ［式中、Ｐｒｇは保護基を意味し、脱保護反応によって水素に変換可能な任意の官能基を示す。その他の記号は、前記と同義とする。］ Compound (ZA) can be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000043
 [In the formula, Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction. Other symbols have the same meaning as described above. ]
　化合物（Ｚ－Ａ）は、化合物（Ｚ－Ｃ）をメタノール等の適切な溶媒中、あるいは無溶媒中、塩化水素あるいはトリフルオロ酢酸等の酸を－１０℃～１００℃で反応させることで製造することができる。
　また、化合物（Ｚ－Ａ）は、化合物（Ｚ－Ｃ）をメタノール等の適切な溶媒中０℃～１００℃で、パラジウム炭素あるいは水酸化パラジウム等の触媒を用いた水素添加反応により製造することができる。
　その他にも、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（Ｗｉｌｅｙ）等に記載されている、あるいはそれに準ずる保護基の脱保護反応を用いて、化合物（Ｚ－Ｃ）あるいはそれに準ずる化合物から製造することができる。 Compound (ZA) is produced by reacting compound (ZA) in a suitable solvent such as methanol or in the absence of a solvent with an acid such as hydrogen chloride or trifluoroacetic acid at −10 ° C. to 100 ° C. can do.
Further, the compound (ZA) is produced by hydrogenating the compound (ZC) in a suitable solvent such as methanol at 0 ° C to 100 ° C using a catalyst such as palladium carbon or palladium hydroxide. Can be done.
In addition, it can be produced from compound (ZC) or a compound equivalent thereto by using a deprotection reaction of a protecting group described in Protective Groups in Organic Synthesis (Wiley) or the like, or equivalent thereto.
　化合物（Ｚ－Ｃ）は、例えば以下に示す方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000044
 ［式中、Ｐｒｇは保護基を意味し、脱保護反応によって水素に変換可能な任意の官能基を示す。Ｌｖは脱離基を示す。その他の記号は、前記と同義とする。］ Compound (ZC) can be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000044
 [In the formula, Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction. Lv indicates a leaving group. Other symbols have the same meaning as described above. ]
　化合物（Ｚ－Ｃ）は、化合物（Ｚ－Ｄ）と化合物（Ｚ－Ｅ）をＤＭＦ等の適切な溶媒中、トリス（ジベンジリデンアセトン）ジパラジウム、ヨウ化銅等の金属触媒、必要に応じてＢＩＮＡＰ、エチレンジアミン等の配位子、必要に応じてトリエチルアミン、ＤＩＰＥＡ等の塩基の存在下、０℃～２００℃で反応させることにより製造することができる。脱離基は、ハロゲンやトシル基等の適切な官能基を用いる。
　その他にも、化合物（Ｚ－Ｃ）は、化合物（Ｚ－Ｄ）と化合物（Ｚ－Ｅ）をＤＭＦ等の適切な溶媒中、水素化ナトリウム、炭酸セシウム等の塩基の存在下、０℃～２００℃で反応させることにより製造することができる。
　また、これらに準ずる反応を用いて、化合物（Ｚ－Ｄ）および化合物（Ｚ－Ｅ）、あるいはそれぞれに準ずる化合物から製造することができる。 Compound (ZC) is prepared by mixing compound (ZD) and compound (ZE) in a suitable solvent such as DMF, a metal catalyst such as tris (dibenzylideneacetone) dipalladium, copper iodide, if necessary. It can be produced by reacting at 0 ° C. to 200 ° C. in the presence of a ligand such as BINAP or ethylenediamine and, if necessary, a base such as triethylamine or DIPEA. As the leaving group, an appropriate functional group such as a halogen or a tosyl group is used.
In addition, compound (ZC) is prepared by mixing compound (ZD) and compound (ZE) from 0 ° C. in a suitable solvent such as DMF in the presence of a base such as sodium hydride or cesium carbonate. It can be produced by reacting at 200 ° C.
In addition, it can be produced from compound (ZD) and compound (ZE), or a compound equivalent to each, by using a reaction similar thereto.
　化合物（Ｚ－Ｄ）は、市販品あるいは市販品から公知の方法によって製造することができる。例えば公知の特許文献ＷＯ２０１４／１５９９６９、ＷＯ２０１２／１５４２７４、ＷＯ２０１７／１９０６０９あるいはＷＯ２０１６／０２７１９５等に記載されている、あるいはそれらに準じる合成法に従って、適切な出発原料から公知の方法を組み合わせることにより製造することができる。 Compound (ZD) can be produced from a commercially available product or a commercially available product by a known method. For example, it is produced by combining known methods from appropriate starting materials according to a synthetic method described in, for example, known patent documents WO2014 / 1599969, WO2012 / 154274, WO2017 / 190609 or WO2016 / 027195, etc. Can be done.
　化合物（Ｚ－Ｅ）は、市販品あるいは市販品から公知の方法によって製造することができる。例えば公知の学術文献Ｃｏｔｔｅｔ　Ｆａｂｒｉｃｅ，　ｅｔ　ａｌ，　Ｅｕｒ．　Ｊ．　Ｏｒｇ．　Ｃｈｅｍ．　（２），　２００２，　３２７－３３０．や公知の特許文献ＷＯ２０１３／０８８４０４やＷＯ２０１０／０６４７０７等に記載されている、あるいはそれらに準じた合成法に従って、適切な出発原料から公知の方法を組み合わせることにより製造することができる。 The compound (ZE) can be produced from a commercially available product or a commercially available product by a known method. For example, the well-known academic literature Cottet Fabrice, et al, Euro. J. Org. Chem. (2), 2002, 327-330. , And known patent documents WO2013 / 088404, WO2010 / 064707, etc., or by combining known methods from appropriate starting materials according to a synthetic method similar thereto.
　化合物（Ｚ－Ｂ）は、例えば以下に示す方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000045
 ［式中、Ｐｒｇは保護基を意味し、脱保護反応によって水素に変換可能な任意の官能基を示す。その他の記号は、前記と同義とする。］ Compound (ZB) can be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000045
 [In the formula, Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction. Other symbols have the same meaning as described above. ]
　化合物（Ｚ－Ｂ）は、水とメタノールあるいはテトラヒドロフランとの混合溶媒等の適切な溶媒中、水酸化リチウムあるいは水酸化ナトリウム等の塩基と０℃～１００℃で反応させることで化合物（Ｚ－Ｆ）から製造することができる。
　その他にも、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（Ｗｉｌｅｙ）等に記載されている、あるいはそれに準ずる保護基の脱保護反応を用いて、化合物（Ｚ－Ｆ）あるいはそれに準ずる化合物から製造することができる。 Compound (Z-B) is prepared by reacting compound (Z-F) with a base such as lithium hydroxide or sodium hydroxide at 0 ° C. to 100 ° C. in a suitable solvent such as a mixed solvent of water and methanol or tetrahydrofuran. ) Can be manufactured.
In addition, it can be produced from compound (ZF) or a compound equivalent thereto by using a deprotection reaction of a protecting group described in Protective Groups in Organic Synthesis (Wiley) or the like, or equivalent thereto.
　化合物（Ｚ－Ｆ）は、市販品あるいは市販品から公知の方法によって製造することができる。例えば公知の特許文献ＷＯ２０１７／１２２７５４、ＷＯ２０１３／０２６９１４ＷＯ２０１５／０７３５２８や学術文献Ｒａｄｏｓｌａｗ　Ｌａｕｆｅｒ，　Ｂｉｏｏｒｇ．　Ｍｅｄ．　Ｃｈｅｍ，　２２（１７），　２０１４，　４９６８－４９９７．等に記載されている、あるいはそれらに準じる合成法に従って、適切な出発原料から公知の方法を組み合わせることにより製造することができる。 The compound (ZF) can be produced from a commercially available product or a commercially available product by a known method. For example, known patent documents WO2017 / 122754, WO2013 / 026914 WO2015 / 073528, and academic documents Radoslaw Laufer, Bioorg. Med. Chem, 22 (17), 2014, 4968-4997. It can be produced by combining known methods from appropriate starting materials according to the synthetic methods described in, etc., or similar thereto.
　また、化合物（Ｚ－Ｂ）は、市販品あるいは市販品から公知の方法によって製造することができる。例えば公知の特許文献ＷＯ２０１３／１４４２９５、ＷＯ２０１４／０１０７４８あるいはＷＯ２００８／１２５３３７等に記載されている、あるいはそれらに準じる合成法に従って、適切な出発原料から公知の方法を組み合わせることにより製造することができる。 Further, the compound (ZB) can be produced from a commercially available product or a commercially available product by a known method. For example, it can be produced by combining known methods from appropriate starting materials according to a synthetic method described in known patent documents WO2013 / 144295, WO2014 / 01748, WO2008 / 125337, etc., or similar thereto.
（製造法２）
Figure JPOXMLDOC01-appb-C000046
 ［式中、Ｌｖは脱離基を示す。その他の記号は、前記と同義とする。］ (Manufacturing method 2)
Figure JPOXMLDOC01-appb-C000046
 [In the formula, Lv indicates a leaving group. Other symbols have the same meaning as described above. ]
　本発明の化合物（Ｚ）は、化合物（Ｚ－Ｅ）と化合物（Ｚ－Ｇ）をＤＭＦ等の適切な溶媒中、トリス（ジベンジリデンアセトン）ジパラジウム、ヨウ化銅等の金属触媒、必要に応じてＢＩＮＡＰ、エチレンジアミン等の配位子、必要に応じてトリエチルアミン、ＤＩＰＥＡ等の塩基の存在下、０℃～２００℃で反応させることにより製造することができる。脱離基は、ハロゲンやトシル基等の適切な官能基を用いる。
　その他にも、化合物（Ｚ）は、化合物（Ｚ－Ｅ）と化合物（Ｚ－Ｇ）をＤＭＦ等の適切な溶媒中、水素化ナトリウム、炭酸セシウム等の塩基の存在下、０℃～２００℃で反応させることにより製造することができる。
　また、これらに準ずる反応を用いて、化合物（Ｚ－Ｅ）および化合物（Ｇ－Ｇ）、あるいはそれぞれに準ずる化合物から製造することができる。 The compound (Z) of the present invention comprises compound (ZE) and compound (ZG) in a suitable solvent such as DMF, and a metal catalyst such as tris (dibenzylideneacetone) dipalladium or copper iodide, if necessary. It can be produced by reacting at 0 ° C. to 200 ° C. in the presence of a ligand such as BINAP or ethylenediamine and, if necessary, a base such as triethylamine or DIPEA. As the leaving group, an appropriate functional group such as a halogen or a tosyl group is used.
In addition, compound (Z) is prepared by mixing compound (ZE) and compound (ZG) at 0 ° C to 200 ° C in a suitable solvent such as DMF in the presence of a base such as sodium hydride or cesium carbonate. It can be produced by reacting with.
In addition, it can be produced from compound (ZE) and compound (GG), or a compound equivalent to each, by using a reaction similar thereto.
　化合物（Ｚ－Ｇ）は、例えば以下に示す方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000047
 ［式中、Ｐｒｇは保護基を意味し、脱保護反応によって水素に変換可能な任意の官能基を示す。その他の記号は、前記と同義とする。］ Compound (ZG) can be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000047
 [In the formula, Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction. Other symbols have the same meaning as described above. ]
　化合物（Ｚ－Ｇ）は、化合物（Ｚ－Ｈ）をメタノールあるいはクロロホルムのような適切な溶媒中、あるいは無溶媒中、塩酸あるいはトリフルオロ酢酸等の酸と－１０℃～１００℃で反応させることで製造することができる。
　また、化合物（Ｚ－Ｇ）は、化合物（Ｚ－Ｈ）をメタノールあるいはＴＨＦ等の適切な溶媒中０℃～１００℃で、パラジウム炭素あるいは水酸化パラジウム等の触媒を用いた水素添加反応により製造することができる。
　その他にも、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（Ｗｉｌｅｙ）等に記載されている、あるいはそれに準ずる保護基の脱保護反応を用いて、化合物（Ｚ－Ｈ）またはそれに準ずる化合物から製造することができる。 Compound (ZG) is prepared by reacting compound (ZH) with an acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol or chloroform or in the absence of a solvent at −10 ° C. to 100 ° C. Can be manufactured in.
In addition, compound (ZG) is produced by hydrogenating compound (ZH) in a suitable solvent such as methanol or THF at 0 ° C to 100 ° C using a catalyst such as palladium carbon or palladium hydroxide. can do.
In addition, it can be produced from compound (ZH) or a compound equivalent thereto by using a deprotection reaction of a protecting group described in Protective Groups in Organic Synthesis (Wiley) or the like, or equivalent thereto.
　化合物（Ｚ－Ｈ）は、例えば以下に示す方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000048
 ［式中、Ｐｒｇは保護基を意味し、脱保護反応によって水素に変換可能な任意の官能基を示す。その他の記号は、前記と同義とする。］ Compound (ZH) can be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000048
 [In the formula, Prg means a protecting group and represents any functional group that can be converted to hydrogen by a deprotection reaction. Other symbols have the same meaning as described above. ]
　化合物（Ｚ－Ｈ）は、化合物（Ｚ－Ｂ）と化合物（Ｚ－Ｉ）をＤＭＦ等の適切な溶媒中、ＨＡＴＵあるいはＷＳＣ等の縮合剤、必要に応じてＨＯＢＴあるいはＤＭＡＰ等の添加剤、必要に応じてトリエチルアミン、ＤＩＰＥＡ等の塩基の存在下、０℃～１００℃で反応させることにより製造することができる。
　また、化合物（Ｚ－Ｉ）に対して、化合物（Ｚ－Ｂ）に対応するカルボン酸クロライドあるいはカルボン酸無水物をテトラヒドロフランなどの適切な溶媒中、必要であればトリエチルアミン、ＤＩＰＥＡ、ピリジン等の塩基の存在下０℃～１００℃で反応させることにより製造することができる。
　その他にもＣｈｒｉｓｔｉａｎ　Ａ．Ｇ．Ｎ．　Ｍｏｎｔａｌｂｅｔｔｉ，　ｅｔ　ａｌ．，Ｔｅｔｒａｈｅｄｒｏｎ，　６１（４６），　２００５，　１０８２７－１０８５２．に記載されている、あるいはそれに準ずる縮合反応を用いて、化合物（Ｚ－Ｂ）および化合物（Ｚ－Ｉ）、あるいはそれぞれに準ずる化合物から製造することができる。 Compound (ZH) is a condensing agent such as HATU or WSC, and optionally an additive such as HOBT or DMAP, in a suitable solvent such as DMF or the compound (ZB) and the compound (ZI). If necessary, it can be produced by reacting at 0 ° C to 100 ° C in the presence of a base such as triethylamine or DIPEA.
Further, for compound (Z-I), a carboxylic acid chloride or carboxylic acid anhydride corresponding to compound (Z-B) is placed in a suitable solvent such as tetrahydrofuran, and if necessary, a base such as triethylamine, DIPEA or pyridine. It can be produced by reacting at 0 ° C to 100 ° C in the presence of.
In addition, Christian A. G. N. Montalbetti, et al. , Tetrahedron, 61 (46), 2005, 10827-10852. It can be produced from the compound (ZB) and the compound (ZI), or a compound equivalent thereto, by using the condensation reaction described in the above or the equivalent thereof.
　化合物（Ｚ－Ｉ）は、市販品あるいは市販品から公知の方法によって製造することができる。例えば公知の特許文献ＷＯ２０１６／１００１５４、ＷＯ２０１２／１２５８９３、ＷＯ２００８／０１３１３０や学術文献Ｋｙｏｊｉ　Ｔｏｍｉｔａ　ｅｔ　ａｌ．，　Ｊ．　Ｍｅｄ．　Ｃｈｅｍ．，　４５（２５），　２００２，　５５６４－５５７５．等に記載されている、あるいはそれらに準じる合成法に従って、適切な出発原料から公知の方法を組み合わせることにより製造することができる。 Compound (Z-I) can be produced from a commercially available product or a commercially available product by a known method. For example, known patent documents WO2016 / 100154, WO2012 / 125893, WO2008 / 013130 and academic literature Kyoji Tomita et al. , J. Med. Chem. , 45 (25), 2002, 5564-5575. It can be produced by combining known methods from appropriate starting materials according to the synthetic methods described in, etc., or similar thereto.
  以下、実施例により本発明を具体的に説明する。ただし、本発明はこれらの実施例のみに限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to Examples. However, the present invention is not limited to these examples.
　参考例および実施例で使用したカラム、ＰＬＣ及びＴＬＣは、特に記載がない限り、シリカゲルあるいはＮＨシリカゲルのいずれか、または両方を用いた。合成した化合物の分析には、１Ｈ　ＮＭＲ（４００ＭＨｚ）、大気圧イオン化高分解能飛行時間型質量分析計（ＥＳＩ）、その他の適切な分析法を用いた。
　参考例及び実施例化合物名は、ケンブリッジソフト社製ＣｈｅｍＤｒａｗ　ｖｅｒ．　１３、１４または１５のいずれかを用いて描画した構造式を同ソフトウェア搭載の命名アルゴリズムによって変換した名称を基に命名した。 Unless otherwise specified, the columns, PLCs and TLCs used in Reference Examples and Examples used either silica gel or NH silica gel, or both. 1 H NMR (400 MHz), atmospheric pressure ionization high resolution time-of-flight mass spectrometer (ESI), and other suitable analytical methods were used to analyze the synthesized compounds.
Reference examples and example compound names are ChemDraw ver. The structural formula drawn using any of 13, 14 or 15 was named based on the name converted by the naming algorithm installed in the software.
参考例１－１
（Ｒ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000049
 ３－ブロモ－５－（トリフルオロメチル）ピリジン（２３０ｍｇ，１．０２ｍｍｏｌ）、（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１９０ｍｇ，１．０２ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（９３ｍｇ，０．１０ｍｍｏｌ）、ＢＩＮＡＰ（６７ｍｇ，０．２２ｍｍｏｌ）及びナトリウムｔｅｒｔ－ブトキシド（１９６ｍｇ，２．０４ｍｍｏｌ）をトルエン（４．０ｍＬ）に懸濁し、窒素気流下８５℃で３時間撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（白色アモルファス，１１６ｍｇ，３４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４０（ｂｒ　ｓ，１Ｈ），４．６９（ｂｒ　ｓ，１Ｈ），６．９－７．０（ｍ，１Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）． Reference example 1-1
(R)-(1- (5- (Trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000049
 3-Bromo-5- (trifluoromethyl) pyridine (230 mg, 1.02 mmol), (R) -pyrrolidine-3-ylcarbamate tert-butyl (190 mg, 1.02 mmol), tris (dibenzylideneacetone) dipalladium (0) (93 mg, 0.10 mmol), BINAP (67 mg, 0.22 mmol) and sodium tert-butoxide (196 mg, 2.04 mmol) were suspended in toluene (4.0 mL) at 85 ° C. for 3 hours under a nitrogen stream. Stirred. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (white amorphous, 116 mg, 34%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.23 (Dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.40 (br s, 1H), 4.69 (br s, 1H), 6.9-7.0 (m, 1H), 8.12 (d, 1H, J = 3Hz), 8.21 (s, 1H).
参考例１－２
（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000050
参考例１－１で合成した（Ｒ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１１６ｍｇ，０．３５ｍｍｏｌ）に氷冷下でトリフルオロ酢酸（２．０ｍＬ）を加え、室温で１時間撹拌した。氷冷下、反応液に飽和炭酸水素ナトリウム水溶液及び酢酸エチルを加えてしばらく撹拌した後、有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して表題化合物（茶色油状物，６０ｍｇ，７４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．０８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，２Ｈ），３．７－３．９（ｍ，１Ｈ），６．９２（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），８．１１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１７（ｓ，１Ｈ）．２Ｈ分観測できず Reference example 1-2
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000050
Ice-cooled to tert-butyl (R)-(1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate (116 mg, 0.35 mmol) synthesized in Reference Example 1-1. Trifluoroacetic acid (2.0 mL) was added below and stirred at room temperature for 1 hour. Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was stirred for a while. Then, the organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure to obtain the title compound ( A brown oil, 60 mg, 74%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.08 (dd, 1H, J = 4, 10Hz), 3.3-3.5 (m, 1H), 3.5-3.6 (m, 2H), 3.7-3.9 (m, 1H), 6.92 (dd, 1H, J = 2,2 Hz), 8.11 (d, 1H, J = 3 Hz), 8.17 (s, 1H). Cannot observe for 2 hours
参考例２
（Ｒ）－（１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000051
参考例１－１と同様の手法に従い、５－ブロモ－２－（トリフルオロメチル）ピリミジン（９４０ｍｇ，４．１４ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（９５０ｍｇ，５．１０ｍｍｏｌ）を用いて表題化合物（白色粉末，４１ｍｇ，３．０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．２８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３－４．５（ｍ，１Ｈ），４．６８（ｂｒ　ｓ，１Ｈ），８．１０（ｓ，２Ｈ）． Reference example 2
(R)-(1- (2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000051
5. Following the same procedure as in Reference Example 1-1, 5-bromo-2- (trifluoromethyl) pyrimidine (940 mg, 4.14 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (950 mg, 5. 10 mmol) was used to give the title compound (white powder, 41 mg, 3.0%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.28 (Dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.70 (dd, 1H, J = 6,10Hz), 4.3-4.5 (m, 1H), 4.68 (br s, 1H), 8.10 (s, 2H).
参考例３
（（３Ｓ，４Ｓ）－４－ヒドロキシ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000052
３－ブロモ－５－（トリフルオロメチル）ピリジン（１３４ｍｇ，０．５９ｍｍｏｌ）、（（３Ｓ，４Ｓ）－４－ヒドロキシピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１００ｍｇ，０．４９ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（４５ｍｇ，０．０５ｍｍｏｌ）、ＸａｎｔＰｈｏｓ（５７ｍｇ，０．１０ｍｍｏｌ）及び炭酸カリウム（１３７ｍｇ，０．９９ｍｍｏｌ）をトルエン（５．０ｍＬ）に懸濁し、窒素気流下８５℃で１６時間撹拌した。室温まで放冷した反応液に酢酸エチルを加え、セライトで不溶物をろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製し表題化合物（白色結晶，１０６ｍｇ，６２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４７（ｓ，９Ｈ），３．２４（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．７－３．９（ｍ，２Ｈ），４．１－４．２（ｍ，１Ｈ），４．４－４．５（ｍ，１Ｈ），４．７６（ｂｒ　ｓ，１Ｈ），６．９４（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２４（ｓ，１Ｈ）． Reference example 3
((3S, 4S) -4-hydroxy-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000052
3-Bromo-5- (trifluoromethyl) pyridine (134 mg, 0.59 mmol), ((3S, 4S) -4-hydroxypyrrolidin-3-yl) tert-butyl carbamate (100 mg, 0.49 mmol), tris (Dibenzylideneacetone) Dipalladium (0) (45 mg, 0.05 mmol), Xantphos (57 mg, 0.10 mmol) and potassium carbonate (137 mg, 0.99 mmol) were suspended in toluene (5.0 mL) under a nitrogen stream. The mixture was stirred at 85 ° C. for 16 hours. Ethyl acetate was added to the reaction solution allowed to cool to room temperature, the insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (white crystals, 106 mg, 62%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.47 (s, 9H), 3.24 (dd, 1H, J = 5,10 Hz), 3.3-3.4 (m, 2H), 3 .7-3.9 (m, 2H), 4.1-4.2 (m, 1H), 4.4-4.5 (m, 1H), 4.76 (br s, 1H), 6. 94 (dd, 1H, J = 2.2Hz), 8.12 (d, 1H, J = 3Hz), 8.24 (s, 1H).
参考例４
（Ｒ）－（５－（５－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000053
３－ブロモ－５－（トリフルオロメチル）ピリジン（３８３ｍｇ，１．７０ｍｍｏｌ）、（Ｒ）－（５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル（３００ｍｇ，１．４１ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（９３ｍｇ，０．１０ｍｍｏｌ）、ＸａｎｔＰｈｏｓ（１６４ｍｇ，０．２８ｍｍｏｌ）及びナトリウムｔｅｒｔ－ブトキシド（２７２ｍｇ，２．８３ｍｍｏｌ）をトルエン（１４ｍＬ）に懸濁し、窒素気流下８５℃で１６時間撹拌した。室温まで放冷した反応液に酢酸エチルを加え、セライトで不溶物をろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（黄色結晶，３３６ｍｇ，６７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．７－０．８（ｍ，２Ｈ），０．８－１．０（ｍ，２Ｈ），１．４４（ｓ，９Ｈ），３．１０（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．５－３．６（ｍ，１Ｈ），３．６３（ｄ，１Ｈ，Ｊ＝９Ｈｚ），３．７－３．８（ｍ，１Ｈ），３．８－３．９（ｍ，１Ｈ），４．７８（ｂｒ　ｓ，１Ｈ），６．９－７．０（ｍ，１Ｈ），８．０９（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）． Reference example 4
(R)-(5- (5- (trifluoromethyl) Pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) tert-butyl carbamate
Figure JPOXMLDOC01-appb-C000053
3-Bromo-5- (trifluoromethyl) pyridine (383 mg, 1.70 mmol), (R)-(5-azaspiro [2.4] heptane-7-yl) tert-butylcarbamate (300 mg, 1.41 mmol) ), Tris (dibenzylideneacetone) dipalladium (0) (93 mg, 0.10 mmol), Xantphos (164 mg, 0.28 mmol) and sodium tert-butoxide (272 mg, 2.83 mmol) were suspended in toluene (14 mL). The mixture was stirred at 85 ° C. under a nitrogen stream for 16 hours. Ethyl acetate was added to the reaction solution allowed to cool to room temperature, the insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (yellow crystals, 336 mg, 67%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.7-0.8 (m, 2H), 0.8-1.0 (m, 2H), 1.44 (s, 9H), 3.10 (D, 1H, J = 10Hz), 3.5-3.6 (m, 1H), 3.63 (d, 1H, J = 9Hz), 3.7-3.8 (m, 1H), 3 8.-3.9 (m, 1H), 4.78 (br s, 1H), 6.9-7.0 (m, 1H), 8.09 (d, 1H, J = 3Hz), 8. 21 (s, 1H).
参考例５
（Ｒ）－（５－（６－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000054
参考例４と同様の手法に従い、（Ｒ）－（５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル（２００ｍｇ，０．９４ｍｍｏｌ）及び５－ブロモ－２－（トリフルオロメチル）ピリジン（２５５ｍｇ，１．１３ｍｍｏｌ）を用いて表題化合物（黄色結晶，２７１ｍｇ，８０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．７－０．８（ｍ，２Ｈ），０．８－１．０（ｍ，２Ｈ），１．４４（ｓ，９Ｈ），３．１１（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．５－３．６（ｍ，１Ｈ），３．６３（ｄ，１Ｈ，Ｊ＝９Ｈｚ），３．７－３．８（ｍ，１Ｈ），３．８－３．９（ｍ，１Ｈ），４．７６（ｂｒ　ｓ，１Ｈ），６．８０（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４９（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９８（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 5
(R)-(5- (6- (trifluoromethyl) Pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) tert-butyl carbamate
Figure JPOXMLDOC01-appb-C000054
Following the same procedure as in Reference Example 4, tert-butyl (R)-(5-azaspiro [2.4] heptane-7-yl) carbamic acid (200 mg, 0.94 mmol) and 5-bromo-2- (trifluoro) The title compound (yellow crystals, 271 mg, 80%) was obtained using methyl) pyridine (255 mg, 1.13 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.7-0.8 (m, 2H), 0.8-1.0 (m, 2H), 1.44 (s, 9H), 3.11 (D, 1H, J = 10Hz), 3.5-3.6 (m, 1H), 3.63 (d, 1H, J = 9Hz), 3.7-3.8 (m, 1H), 3 .8-3.9 (m, 1H), 4.76 (br s, 1H), 6.80 (dd, 1H, J = 3.9Hz), 7.49 (d, 1H, J = 9Hz), 7.98 (d, 1H, J = 3Hz).
参考例６
（Ｒ）－（５－（４－（トリフルオロメチル）チアゾール－２－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000055
参考例４と同様の手法に従い、（Ｒ）－（５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル（２００ｍｇ，０．９４ｍｍｏｌ）及び２－ブロモ－４－（トリフルオロメチル）チアゾール（２５５ｍｇ，１．１０ｍｍｏｌ）を用いて表題化合物（黄色結晶，１９２ｍｇ，５６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．８－１．０（ｍ，２Ｈ），１．４４（ｓ，９Ｈ），３．３２（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．５７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），３．７４（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），３．８－３．９（ｍ，２Ｈ），４．７７（ｂｒ　ｓ，１Ｈ），６．９３（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ）． Reference example 6
(R)-(5- (4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptane-7-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000055
Following the same procedure as in Reference Example 4, tert-butyl (R)-(5-azaspiro [2.4] heptane-7-yl) carbamate (200 mg, 0.94 mmol) and 2-bromo-4- (trifluoro) The title compound (yellow crystals, 192 mg, 56%) was obtained using methyl) thiazole (255 mg, 1.10 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.8-1.0 (m, 2H), 1.44 (s, 9H), 3.32 (D, 1H, J = 10Hz), 3.57 (d, 1H, J = 8Hz), 3.74 (d, 1H, J = 11Hz), 3.8-3.9 (m, 2H), 4 .77 (br s, 1H), 6.93 (d, 1H, J = 0.8Hz).
参考例７－１
（２Ｓ，４Ｒ）－４－（２－（４－シクロプロピルフェニル）アセトアミド）－２－メチルピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000056
（２Ｓ，４Ｒ）－４－アミノ－２－メチルピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（２５０ｍｇ，１．２５ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（２６４ｍｇ，１．５０ｍｍｏｌ）をＤＭＦ（１３ｍＬ）に溶解した後、ＤＩＰＥＡ（６９１μＬ，４．０１ｍｍｏｌ）及びＨＡＴＵ（５７０ｍｇ，１．５０ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（無色油状物，３６５ｍｇ，８２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．１－１．２（ｍ，３Ｈ），１．４３（ｓ，９Ｈ），１．７－１．９（ｍ，３Ｈ），３．０－３．１（ｍ，１Ｈ），３．５１（ｓ，２Ｈ），３．５－３．７（ｍ，１Ｈ），３．７－４．０（ｍ，１Ｈ），４．４－４．６（ｍ，１Ｈ），５．３１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１０（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 7-1
(2S, 4R) -4- (2- (4-cyclopropylphenyl) acetamide) -2-methylpyrrolidine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000056
(2S, 4R) tert-butyl (250 mg, 1.25 mmol) -4-amino-2-methylpyrrolidin-1-carboxylate and 2- (4-cyclopropylphenyl) acetic acid (264 mg) synthesized in Reference Example 33-2. , 1.50 mmol) was dissolved in DMF (13 mL), DIPEA (691 μL, 4.01 mmol) and HATU (570 mg, 1.50 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (colorless oil, 365 mg, 82%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.1-1.2 (m, 3H) , 1.43 (s, 9H), 1.7-1.9 (m, 3H), 3.0-3.1 (m, 1H), 3.51 (s, 2H), 3.5-3 .7 (m, 1H), 3.7-4.0 (m, 1H), 4.4-4.6 (m, 1H), 5.31 (d, 1H, J = 7Hz), 7.04 (D, 2H, J = 8Hz), 7.10 (d, 2H, J = 8Hz).
参考例７－２
２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｒ，５Ｓ）－５－メチルピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000057
参考例７－１で合成した（２Ｓ，４Ｒ）－４－（２－（４－シクロプロピルフェニル）アセトアミド）－２－メチルピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（３６５ｍｇ，１．０２ｍｍｏｌ）に氷冷下で２Ｎ塩酸メタノール溶液（１５ｍＬ）を加えて室温で２時間撹拌した後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－４０％）により精製し表題化合物（白色結晶，２７０ｍｇ，１０３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．１３（ｄ，３Ｈ，Ｊ＝６Ｈｚ），１．５－１．７（ｍ，３Ｈ），１．８－１．９（ｍ，１Ｈ），２．５１（ｄｄ，１Ｈ，Ｊ＝５，１２Ｈｚ），３．１－３．２（ｍ，１Ｈ），３．３８（ｄｄ，１Ｈ，Ｊ＝７，１２Ｈｚ），３．５０（ｓ，２Ｈ），４．３－４．５（ｍ，１Ｈ），５．５０（ｂｒ　ｓ，１Ｈ），７．０５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 7-2
2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methylpyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000057
Ice on tert-butyl (2S, 4R) -4- (2- (4-cyclopropylphenyl) acetamide) -2-methylpyrrolidin-1-carboxylate (365 mg, 1.02 mmol) synthesized in Reference Example 7-1. A 2N hydrochloric acid-methanol solution (15 mL) was added under cooling, and the mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-40%) to give the title compound (white crystals, 270 mg, 103%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.13 (d, 3H, J = 6 Hz) , 1.5-1.7 (m, 3H), 1.8-1.9 (m, 1H), 2.51 (dd, 1H, J = 5,12Hz), 3.1-3.2 ( m, 1H), 3.38 (dd, 1H, J = 7,12Hz), 3.50 (s, 2H), 4.3-4.5 (m, 1H), 5.50 (br s, 1H) ), 7.05 (d, 2H, J = 8Hz), 7.12 (d, 2H, J = 8Hz).
参考例８
（３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000058
参考例４と同様の手法に従い、（３－アザビシクロ［３．１．０］ヘキサン－１－イル）カルバミン酸ｔｅｒｔ－ブチル（２５０ｍｇ，１．２６ｍｍｏｌ）及び３－ブロモ－５－（トリフルオロメチル）ピリジン（３４２ｍｇ，１．５１ｍｍｏｌ）を用いて表題化合物（無色油状物，１０３ｍｇ，２３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．１－１．２（ｍ，１Ｈ），１．２－１．３（ｍ，１Ｈ），１．４６（ｓ，９Ｈ），１．８－２．０（ｍ，１Ｈ），３．４－３．７（ｍ，３Ｈ），３．７５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），５．１３（ｂｒ　ｓ，１Ｈ），６．９３（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），８．０９（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２０（ｓ，１Ｈ）． Reference example 8
(3- (5- (Trifluoromethyl) Pyridine-3-yl) -3-azabicyclo [3.1.0] Hexane-1-yl) tert-butyl carbamate
Figure JPOXMLDOC01-appb-C000058
Following the same procedure as in Reference Example 4, tert-butyl (3-azabicyclo [3.1.0] hexane-1-yl) carbamic acid (250 mg, 1.26 mmol) and 3-bromo-5- (trifluoromethyl) The title compound (colorless oil, 103 mg, 23%) was obtained using pyridine (342 mg, 1.51 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.1-1.2 (m, 1H), 1.2-1.3 (m, 1H), 1.46 (s, 9H), 1.8 -2.0 (m, 1H), 3.4-3.7 (m, 3H), 3.75 (d, 1H, J = 8Hz), 5.13 (br s, 1H), 6.93 ( dd, 1H, J = 2.2Hz), 8.09 (d, 1H, J = 2Hz), 8.20 (s, 1H).
参考例９
（Ｒ）－（１－（６－（トリフルオロメチル）ピラジン－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000059
（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（２５０ｍｇ，１．３４ｍｍｏｌ）をＤＭＦ（１３ｍＬ）に溶解した後、２－クロロ－６－（トリフルオロメチル）ピラジン（２９４ｍｇ，１．６１ｍｍｏｌ）及び炭酸カリウム（３７１ｍｇ，２．６８ｍｍｏｌ）を加えて１２０℃で２０時間撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（白色結晶，２９２ｍｇ，６５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．４３（ｄｄ，１Ｈ，Ｊ＝４，１１Ｈｚ），３．５－３．７（ｍ，２Ｈ），３．８２（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．３９（ｂｒ　ｓ，１Ｈ），４．７４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），８．０３（ｓ，１Ｈ），８．１４（ｓ，１Ｈ）． Reference example 9
(R)-(1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000059
After dissolving tert-butyl (R) -pyrrolidine-3-ylcarbamic acid (250 mg, 1.34 mmol) in DMF (13 mL), 2-chloro-6- (trifluoromethyl) pyrazine (294 mg, 1.61 mmol) And potassium carbonate (371 mg, 2.68 mmol) were added, and the mixture was stirred at 120 ° C. for 20 hours. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with a mixed solution of chloroform and methanol. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (white crystals, 292 mg, 65%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.43 (Dd, 1H, J = 4,11Hz), 3.5-3.7 (m, 2H), 3.82 (dd, 1H, J = 6,11Hz), 4.39 (br s, 1H), 4.74 (d, 1H, J = 7Hz), 8.03 (s, 1H), 8.14 (s, 1H).
参考例１０
（Ｒ）－（１－（６－シアノ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000060
参考例４と同様の手法に従い、（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（２００ｍｇ，１．０７ｍｍｏｌ）及び５－ブロモ－３－（トリフルオロメチル）ピコリノニトリル（３２３ｍｇ，１．２９ｍｍｏｌ）を用いて表題化合物（黄色油状物，１３９ｍｇ，３０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．３３（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７－３．８（ｍ，１Ｈ），４．３－４．５（ｍ，１Ｈ），４．８４（ｂｒ　ｓ，１Ｈ），６．９５（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 10
(R)-(1- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000060
Following the same procedure as in Reference Example 4, tert-butyl (R) -pyrrolidine-3-ylcarbamate (200 mg, 1.07 mmol) and 5-bromo-3- (trifluoromethyl) picorinonitrile (323 mg, 1. 29 mmol) was used to give the title compound (yellow oil, 139 mg, 30%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 2.0-2.2 (m, 1H), 2.3-2.5 (m, 1H), 3.33 (Dd, 1H, J = 5,10Hz), 3.4-3.6 (m, 2H), 3.7-3.8 (m, 1H), 4.3-4.5 (m, 1H) , 4.84 (br s, 1H), 6.95 (d, 1H, J = 3Hz), 8.07 (d, 1H, J = 3Hz).
参考例１１－１
１－ベンジル－３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000061
参考例７－１と同様の手法に従い、３－（アザニル）－１－ベンジルピロリジン－３－カルボン酸メチル（２５０ｍｇ，１．０７ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（２２６ｍｇ，１．２８ｍｍｏｌ）用いて表題化合物（白色結晶，３６２ｍｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．５－２．７（ｍ，１Ｈ），２．７５（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），２．７９（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），２．８－２．９（ｍ，１Ｈ），３．５０（ｓ，２Ｈ），３．５４（ｄ，１Ｈ，Ｊ＝１３Ｈｚ），３．６２（ｄ，１Ｈ，Ｊ＝１３Ｈｚ），３．７０（ｓ，３Ｈ），６．０３（ｂｒ　ｓ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），７．２－７．３（ｍ，５Ｈ）． Reference example 11-1
Methyl 1-benzyl-3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000061
Methyl 3- (azanyl) -1-benzylpyrrolidine-3-carboxylate (250 mg, 1.07 mmol) and 2- (4-cyclopropyl) synthesized in Reference Example 33-2 according to the same procedure as in Reference Example 7-1. The title compound (white crystals, 362 mg, 86%) was obtained using phenyl) acetic acid (226 mg, 1.28 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.4-2.5 (m, 1H), 2.5-2.7 (m, 1H), 2.75 (d, 1H, J = 10Hz), 2.79 (d, 1H, J = 10Hz), 2.8-2.9 (m, 1H), 3.50 (s, 2H), 3.54 (d, 1H, J = 13Hz), 3.62 (d, 1H, J = 13Hz) , 3.70 (s, 3H), 6.03 (br s, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 7.2 7.3 (m, 5H).
参考例１１－２
３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000062
参考例１１－１で合成した１－ベンジル－３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－３－カルボン酸メチル（３６２ｍｇ，０．９２ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、パラジウム炭素（３６ｍｇ）を加えて水素気流下４時間室温で撹拌した。不溶物をろ過後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－４０％）により精製し表題化合物（９４ｍｇ，３４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．０－２．２（ｍ，２Ｈ），２．２－２．３（ｍ，１Ｈ），２．９－３．０（ｍ，１Ｈ），３．１０（ｄ，１Ｈ，Ｊ＝１２Ｈｚ），３．１－３．２（ｍ，１Ｈ），３．３３（ｄ，１Ｈ，Ｊ＝１２Ｈｚ），３．５１（ｓ，２Ｈ），３．７３（ｓ，３Ｈ），６．３５（ｂｒ　ｓ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ）． Reference example 11-2
Methyl 3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000062
Methyl 1-benzyl-3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-3-carboxylate (362 mg, 0.92 mmol) synthesized in Reference Example 11-1 was dissolved in methanol (20 mL) and palladium was added. Carbon (36 mg) was added and stirred at room temperature for 4 hours under a hydrogen stream. After filtering the insoluble material, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-40%) to give the title compound (94 mg, 34%). Obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.0-2.2 (m, 2H), 2.2-2.3 (m, 1H), 2.9-3.0 (m, 1H), 3.10 (d, 1H, J = 12Hz), 3.1-3.2 (m, 1H), 3.33 (d, 1H, J = 12Hz), 3.51 (s, 2H), 3.73 (s, 3H), 6.35 (Br s, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H).
参考例１２－１
（Ｒ）－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000063
参考例９と同様の手法に従い、２－ブロモ－４－（トリフルオロメチル）チアゾール（５４０ｍｇ，２．３３ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５２０ｍｇ，２．７９ｍｍｏｌ）を用いて表題化合物（白色結晶，７０６ｍｇ，９０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．３５（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．５－３．７（ｍ，２Ｈ），３．７５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３８（ｂｒ　ｓ，１Ｈ），４．６８（ｂｒ　ｓ，１Ｈ），６．９２（ｄ，１Ｈ，Ｊ＝０．７Ｈｚ）． Reference example 12-1
(R)-(1- (4- (Trifluoromethyl) Thiazole-2-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000063
Following the same procedure as in Reference Example 9, 2-bromo-4- (trifluoromethyl) thiazole (540 mg, 2.33 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (520 mg, 2.79 mmol). The title compound (white crystals, 706 mg, 90%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.35 (Dd, 1H, J = 4,10Hz), 3.5-3.7 (m, 2H), 3.75 (dd, 1H, J = 6,10Hz), 4.38 (br s, 1H), 4.68 (br s, 1H), 6.92 (d, 1H, J = 0.7Hz).
参考例１２－２
（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000064
参考例７－２と同様の手法に従い、参考例１２－１で合成した（Ｒ）－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（７０６ｍｇ，２．０９ｍｍｏｌ）を用いて表題化合物（白色結晶，４８０ｍｇ，９７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．３４（ｂｒ　ｓ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．５－３．６（ｍ，１Ｈ），３．６－３．７（ｍ，２Ｈ），３．７－３．９（ｍ，１Ｈ），６．９０（ｂｒ　ｓ，１Ｈ）． Reference example 12-2
(R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000064
(R)-(1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 12-1 according to the same method as in Reference Example 7-2. Butyl (706 mg, 2.09 mmol) was used to give the title compound (white crystals, 480 mg, 97%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.34 (br s, 2H), 1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3. 23 (dd, 1H, J = 4,10Hz), 3.5-3.6 (m, 1H), 3.6-3.7 (m, 2H), 3.7-3.9 (m, 1H) ), 6.90 (br s, 1H).
参考例１３
（Ｒ）－（１－（６－メチル－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000065
参考例４と同様の手法に従い、５－ブロモ－２－メチル－３－（トリフルオロメチル）ピリジン（３１０ｍｇ，１．２９ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（２８９ｍｇ，１．５５ｍｍｏｌ）を用いて表題化合物（白色結晶，２２ｍｇ，４．９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．５－２．６（ｍ，３Ｈ），３．２０（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．４（ｍ，１Ｈ），３．４－３．５（ｍ，１Ｈ），３．６１（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４０（ｂｒ　ｓ，１Ｈ），４．７０（ｂｒ　ｓ，１Ｈ），７．００（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．９８（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 13
(R)-(1- (6-Methyl-5- (trifluoromethyl) Pyridine-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000065
Following the same procedure as in Reference Example 4, 5-bromo-2-methyl-3- (trifluoromethyl) pyridine (310 mg, 1.29 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (289 mg, 1.55 mmol) was used to give the title compound (white crystals, 22 mg, 4.9%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 2.5 -2.6 (m, 3H), 3.20 (dd, 1H, J = 4,10Hz), 3.3-3.4 (m, 1H), 3.4-3.5 (m, 1H) , 3.61 (dd, 1H, J = 6,10Hz), 4.40 (br s, 1H), 4.70 (br s, 1H), 7.00 (d, 1H, J = 3Hz), 7 .98 (d, 1H, J = 3Hz).
参考例１４－１
（Ｒ）－（１－（５－（２－ヒドロキシプロパン－２－イル）ピリジン－３－イル）ピロリジン－３－イル）－カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000066
参考例３と同様の手法に従い、２－（５－ブロモピリジン－３－イル）プロパン－２－オール（２１０ｍｇ，０．９７ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（２１７ｍｇ，１．１７ｍｍｏｌ）を用いて表題化合物（茶色アモルファス，１８７ｍｇ，６０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．５８（ｓ，６Ｈ），１．９－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．８０（ｂｒ　ｓ，１Ｈ），３．１７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．４（ｍ，１Ｈ），３．４－３．５（ｍ，１Ｈ），３．５６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３６（ｂｒ　ｓ，１Ｈ），４．９６（ｂｒ　ｓ，１Ｈ），６．９９（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．７８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．０１（ｄ，１Ｈ，Ｊ＝２Ｈｚ）． Reference example 14-1
(R)-(1- (5- (2-Hydroxypropane-2-yl) pyridin-3-yl) pyrrolidine-3-yl) -tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000066
Following the same procedure as in Reference Example 3, 2- (5-bromopyridin-3-yl) propan-2-ol (210 mg, 0.97 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (217 mg). , 1.17 mmol) was used to give the title compound (brown amorphous, 187 mg, 60%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.58 (s, 6H), 1.9-2.0 (m, 1H), 2.2-2.4 (M, 1H), 2.80 (br s, 1H), 3.17 (dd, 1H, J = 4,10Hz), 3.3-3.4 (m, 1H), 3.4-3. 5 (m, 1H), 3.56 (dd, 1H, J = 6,10Hz), 4.36 (br s, 1H), 4.96 (br s, 1H), 6.99 (dd, 1H, J = 2.2Hz), 7.78 (d, 1H, J = 3Hz), 8.01 (d, 1H, J = 2Hz).
参考例１４－２
（Ｒ）－２－（５－（３－アミノピロリジン－１－イル）ピリジン－３－イル）プロパン－２－オール
Figure JPOXMLDOC01-appb-C000067
参考例７－２と同様の手法に従い、参考例１４－１で合成した（Ｒ）－（１－（５－（２－ヒドロキシプロパン－２－イル）ピリジン－３－イル）ピロリジン－３－イル）－カルバミン酸ｔｅｒｔ－ブチル（１８７ｍｇ，０．５８ｍｍｏｌ）を用いて表題化合物（茶色油状物，１１４ｍｇ，８８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５９（ｓ，６Ｈ），１．７－１．９（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．０３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．４（ｍ，１Ｈ），３．４－３．６（ｍ，４Ｈ），３．７－３．８（ｍ，１Ｈ），６．９９（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．８０（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．００（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．１Ｈ分観測できず Reference example 14-2
(R) -2- (5- (3-Aminopyrrolidine-1-yl) Pyridine-3-yl) Propane-2-ol
Figure JPOXMLDOC01-appb-C000067
(R)-(1- (5- (2-Hydroxypropane-2-yl) pyridin-3-yl) pyrrolidine-3-yl synthesized in Reference Example 14-1 according to the same method as in Reference Example 7-2. )-Butyl carbamic acid (187 mg, 0.58 mmol) was used to give the title compound (brown oil, 114 mg, 88%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.59 (s, 6H), 1.7-1.9 (m, 1H), 2.1-2.3 (m, 1H), 3.03 (Dd, 1H, J = 4,10Hz), 3.3-3.4 (m, 1H), 3.4-3.6 (m, 4H), 3.7-3.8 (m, 1H) , 6.99 (dd, 1H, J = 2.2Hz), 7.80 (d, 1H, J = 3Hz), 8.00 (d, 1H, J = 2Hz). Cannot observe for 1H
参考例１５
（Ｒ）－（１－（８－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－６－イル）ピロリジン－３－イル）－カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000068
参考例４と同様の手法に従い、６－ブロモ－８－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン（２５０ｍｇ，０．９４ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（２１１ｍｇ，１．１３ｍｍｏｌ）を用いて表題化合物（茶色油状物，９０ｍｇ，２６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１７（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ），３．２－３．４（ｍ，１Ｈ），３．４－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），４．４０（ｂｒ　ｓ，１Ｈ），４．７９（ｂｒ　ｓ，１Ｈ），７．１９（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ），７．４０（ｄ，１Ｈ，Ｊ＝１Ｈｚ），７．５６（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ），７．６４（ｄ，１Ｈ，Ｊ＝１Ｈｚ）． Reference example 15
(R)-(1- (8- (trifluoromethyl) imidazole [1,2-a] pyridin-6-yl) pyrrolidine-3-yl) -tert-butyl carbamate
Figure JPOXMLDOC01-appb-C000068
Following the same procedure as in Reference Example 4, 6-bromo-8- (trifluoromethyl) imidazole [1,2-a] pyridine (250 mg, 0.94 mmol) and (R) -pyrrolidine-3-ylcarbamic acid tert- Butyl (211 mg, 1.13 mmol) was used to give the title compound (brown oil, 90 mg, 26%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.17 (Dd, 1H, J = 4.9Hz), 3.2-3.4 (m, 1H), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H) , 4.40 (br s, 1H), 4.79 (br s, 1H), 7.19 (d, 1H, J = 0.8Hz), 7.40 (d, 1H, J = 1Hz), 7 .56 (d, 1H, J = 0.8Hz), 7.64 (d, 1H, J = 1Hz).
参考例１６
２－（４－（１，１－ジオキサイドチオモルホリノ）フェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000069
参考例３と同様の手法に従い、２－（４－ブロモフェニル）酢酸エチル（３００ｍｇ，１．２３ｍｍｏｌ）及び１，１－ジオキサイドチオモルホリン（３３４ｍｇ，２．４７ｍｍｏｌ）を用いて表題化合物（淡黄色油状物，３０ｍｇ，８．２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２６（ｔ，３Ｈ，Ｊ＝７Ｈｚ），３．０－３．１（ｍ，４Ｈ），３．５４（ｓ，２Ｈ），３．８－３．９（ｍ，４Ｈ），４．１２（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，２Ｈ），７．２－７．３（ｍ，２Ｈ）． Reference example 16
2- (4- (1,1-dioxidethiomorpholino) phenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000069
Following the same procedure as in Reference Example 3, the title compound (pale yellow) with 2- (4-bromophenyl) ethyl acetate (300 mg, 1.23 mmol) and 1,1-dioxidethiomorpholine (334 mg, 2.47 mmol). An oil, 30 mg, 8.2%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.26 (t, 3H, J = 7 Hz), 3.0-3.1 (m, 4H), 3.54 (s, 2H), 3.8 -3.9 (m, 4H), 4.12 (q, 2H, J = 7Hz), 6.8-6.9 (m, 2H), 7.2-7.3 (m, 2H).
参考例１７
２－（４－（トリメチルシリル）フェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000070
窒素雰囲気下、マグネシウム（１６８ｍｇ，６．９８ｍｍｏｌ）及びＴＨＦ（１．０ｍＬ）を加えた丸底フラスコに少量のヨウ素を加え、次いでＴＨＦ（３．４ｍＬ）に溶解した２－（４－ブロモフェニル）酢酸エチル（５００ｍｇ，２．０６ｍｍｏｌ）を加えて３０分間加熱還流した。反応液を室温まで放冷し、クロロトリメチルシラン（５２０μＬ，４．１１ｍｍｏｌ）を加えて２時間加熱還流した。室温まで放冷した反応液に飽和塩化アンモニウム水溶液を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（無色油状物，３０ｍｇ，６．２％）を得た。
１Ｈ　ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）：δ＝０．２５（ｓ，９Ｈ），１．２４（ｔ，３Ｈ，Ｊ＝７Ｈｚ），３．５９（ｓ，２Ｈ），４．１０（ｑ，２Ｈ，Ｊ＝７Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，２Ｈ）． Reference example 17
2- (4- (Trimethylsilyl) phenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000070
Under a nitrogen atmosphere, a small amount of iodine was added to a round bottom flask containing magnesium (168 mg, 6.98 mmol) and THF (1.0 mL), and then 2- (4-bromophenyl) dissolved in THF (3.4 mL). Ethyl acetate (500 mg, 2.06 mmol) was added and the mixture was heated under reflux for 30 minutes. The reaction mixture was allowed to cool to room temperature, chlorotrimethylsilane (520 μL, 4.11 mmol) was added, and the mixture was heated under reflux for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (colorless oil, 30 mg, 6.2%).
1 1 H NMR (CD 3 OD, 400 MHz): δ = 0.25 (s, 9H), 1.24 (t, 3H, J = 7 Hz), 3.59 (s, 2H), 4.10 (q, 2H, J = 7Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 2H).
参考例１８
（３Ｓ，４Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－４－フルオロピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000071
参考例７－１と同様の手法に従い、（３Ｓ，４Ｓ）－３－アミノ－４－フルオロピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（２５０ｍｇ，１．２２ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（２５９ｍｇ，１．４７ｍｍｏｌ）を用いて表題化合物（黄色粉末，３６９ｍｇ，８３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．４５（ｓ，９Ｈ），１．８－１．９（ｍ，１Ｈ），３．１－３．７（ｍ，６Ｈ），４．４３（ｂｒ　ｓ，１Ｈ），４．８－５．１（ｍ，１Ｈ），５．３２（ｂｒ　ｓ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ）． Reference example 18
(3S, 4S) -3- (2- (4-cyclopropylphenyl) acetamide) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000071
Synthesized with tert-butyl (3S, 4S) -3-amino-4-fluoropyrrolidine-1-carboxylate (250 mg, 1.22 mmol) and Reference Example 33-2 according to the same procedure as in Reference Example 7-1 2 -(4-Cyclopropylphenyl) acetic acid (259 mg, 1.47 mmol) was used to give the title compound (yellow powder, 369 mg, 83%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.45 (s, 9H), 1.8 -1.9 (m, 1H), 3.1-3.7 (m, 6H), 4.43 (br s, 1H), 4.8-5.1 (m, 1H), 5.32 ( br s, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H).
参考例１９
３－シアノ－３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000072
参考例７－１と同様の手法に従い、３－アミノ－３－シアノピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（３００ｍｇ，１．４２ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（３００ｍｇ，１．７０ｍｍｏｌ）を用いて表題化合物（黄色油状物，４５４ｍｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．４４（ｓ，９Ｈ），１．８－１．９（ｍ，１Ｈ），２．２－２．６（ｍ，２Ｈ），３．３－３．４（ｍ，１Ｈ），３．４－３．６（ｍ，４Ｈ），３．９－４．０（ｍ，１Ｈ），６．３－６．４（ｍ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１０（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 19
3-Cyano-3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000072
Following the same procedure as in Reference Example 7-1, tert-butyl 3-amino-3-cyanopyrrolidine-1-carboxylate (300 mg, 1.42 mmol) and 2- (4-cyclopropyl) synthesized in Reference Example 33-2. The title compound (yellow oil, 454 mg, 86%) was obtained using phenyl) acetic acid (300 mg, 1.70 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.44 (s, 9H), 1.8 -1.9 (m, 1H), 2.2-2.6 (m, 2H), 3.3-3.4 (m, 1H), 3.4-3.6 (m, 4H), 3 .9-4.0 (m, 1H), 6.3-6.4 (m, 1H), 7.04 (d, 2H, J = 8Hz), 7.10 (d, 2H, J = 8Hz) ..
参考例２０－１
１－ベンジル－３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000073
３－アミノ－１－ベンジルピロリジン－３－カルボン酸メチル（５００ｍｇ，２．１３ｍｍｏｌ）、ＤＩＰＥＡ（７８８μＬ，４．５７ｍｍｏｌ）及びＢｏｃ無水物（９３１ｍｇ，４．２７ｍｍｏｌ）をクロロホルム（２１ｍＬ）に溶解して室温で１６時間撹拌した。反応液に水を加えてしばらく撹拌した後、クロロホルムで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（無色油状物，５２２ｍｇ，７３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４２（ｓ，９Ｈ），１．９－２．０（ｍ，１Ｈ），２．５－２．７（ｍ，２Ｈ），２．７－３．０（ｍ，３Ｈ），３．６１（ｄ，１Ｈ，Ｊ＝１３Ｈｚ），３．６８（ｄ，１Ｈ，Ｊ＝１３Ｈｚ），３．７４（ｓ，３Ｈ），５．１２（ｂｒ　ｓ，１Ｈ），７．２－７．４（ｍ，５Ｈ）． Reference example 20-1
Methyl 1-benzyl-3-((tert-butoxycarbonyl) amino) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000073
Methyl 3-amino-1-benzylpyrrolidine-3-carboxylate (500 mg, 2.13 mmol), DIPEA (788 μL, 4.57 mmol) and Boc anhydride (931 mg, 4.27 mmol) are dissolved in chloroform (21 mL). The mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, the mixture was stirred for a while, and then extracted with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (colorless oil, 522 mg, 73%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.42 (s, 9H), 1.9-2.0 (m, 1H), 2.5-2.7 (m, 2H), 2.7 -3.0 (m, 3H), 3.61 (d, 1H, J = 13Hz), 3.68 (d, 1H, J = 13Hz), 3.74 (s, 3H), 5.12 (br) s, 1H), 7.2-7.4 (m, 5H).
参考例２０－２
３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000074
参考例１１－２と同様の手法に従い、実施例２０－１で合成した１－ベンジル－３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）ピロリジン－３－カルボン酸メチル（５２２ｍｇ，１．５６ｍｍｏｌ）を用いて３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）ピロリジン－３－カルボン酸メチルの粗体（無色油状物，４０２ｍｇ）を得た。参考例４と同様の手法に従い、得られた３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）ピロリジン－３－カルボン酸メチルの粗体（４０２ｍｇ）及び（３－ブロモ－５－（トリフルオロメチル）ピリジン（４２３ｍｇ，１．８７ｍｍｏｌ）を用いて表題化合物（３４ｍｇ，５．８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），２．３－２．５（ｍ，１Ｈ），２．５－２．６（ｍ，１Ｈ），３．５－３．６（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７９（ｓ，３Ｈ），４．０１（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），５．１７（ｂｒ　ｓ，１Ｈ），６．９－７．０（ｍ，１Ｈ），８．１１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）． Reference example 20-2
Methyl 3-((tert-butoxycarbonyl) amino) -1-(5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000074
Methyl 1-benzyl-3-((tert-butoxycarbonyl) amino) pyrrolidine-3-carboxylate (522 mg, 1.56 mmol) synthesized in Example 20-1 was used in the same manner as in Reference Example 11-2. A crude product of methyl 3-((tert-butoxycarbonyl) amino) pyrrolidine-3-carboxylate (colorless oil, 402 mg) was obtained. Following the same procedure as in Reference Example 4, the obtained crude product of methyl 3-((tert-butoxycarbonyl) amino) pyrrolidine-3-carboxylate (402 mg) and (3-bromo-5- (trifluoromethyl) pyridine (423 mg, 1.87 mmol) was used to give the title compound (34 mg, 5.8%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 2.3-2.5 (m, 1H), 2.5-2.6 (m, 1H), 3.5 -3.6 (m, 2H), 3.6-3.7 (m, 1H), 3.79 (s, 3H), 4.01 (d, 1H, J = 10Hz), 5.17 (br s, 1H), 6.9-7.0 (m, 1H), 8.11 (d, 1H, J = 3Hz), 8.22 (s, 1H).
参考例２１－１
３－シアノ－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000075
参考例７－１と同様の手法に従い、３－アミノ－３－シアノピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（３００ｍｇ，１．４２ｍｍｏｌ）及び２－（４－（トリフルオロメチル）フェニル）酢酸（３４８ｍｇ，１．７０ｍｍｏｌ）を用いて表題化合物（白色粉末，３５２ｍｇ，６２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），２．２－２．６（ｍ，２Ｈ），３．３－３．７（ｍ，３Ｈ），３．６８（ｓ，２Ｈ），３．９－４．１（ｍ，１Ｈ），５．７－５．８（ｍ，１Ｈ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６４（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 21-1
3-Cyano-3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000075
Following the same procedure as in Reference Example 7-1, tert-butyl 3-amino-3-cyanopyrrolidine-1-carboxylate (300 mg, 1.42 mmol) and 2- (4- (trifluoromethyl) phenyl) acetic acid (348 mg). , 1.70 mmol) was used to give the title compound (white powder, 352 mg, 62%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 2.2-2.6 (m, 2H), 3.3-3.7 (m, 3H), 3.68 (S, 2H), 3.9-4.1 (m, 1H), 5.7-5.8 (m, 1H), 7.40 (d, 2H, J = 8Hz), 7.64 (d) , 2H, J = 8Hz).
参考例２１－２
３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000076
参考例７－２と同様の手法に従い、参考例２１－１で合成した３－シアノ－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（３５２ｍｇ，０．８９ｍｍｏｌ）を用いて表題化合物（白色粉末，２１３ｍｇ，７３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，２Ｈ），３．０－３．１（ｍ，１Ｈ），３．１４（ｄ，１Ｈ，Ｊ＝１２Ｈｚ），３．１－３．２（ｍ，１Ｈ），３．３５（ｄ，１Ｈ，Ｊ＝１２Ｈｚ），３．６１（ｓ，２Ｈ），３．７５（ｓ，３Ｈ），６．５２（ｂｒ　ｓ，１Ｈ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 21-2
Methyl 3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000076
Following the same procedure as in Reference Example 7-2, tert-butyl 3-cyano-3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-1-carboxylate synthesized in Reference Example 21-1 ( The title compound (white powder, 213 mg, 73%) was obtained using 352 mg (0.89 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 1H), 2.2-2.4 (m, 2H), 3.0-3.1 (m, 1H) , 3.14 (d, 1H, J = 12Hz), 3.1-3.2 (m, 1H), 3.35 (d, 1H, J = 12Hz), 3.61 (s, 2H), 3 .75 (s, 3H), 6.52 (br s, 1H), 7.40 (d, 2H, J = 8Hz), 7.61 (d, 2H, J = 8Hz).
参考例２２－１
（１Ｓ，２Ｓ）－シクロプロパン－１，２－ジカルボン酸ジメチル
Figure JPOXMLDOC01-appb-C000077
（１Ｓ，２Ｓ）－シクロプロパン－１，２－ジカルボン酸（２．０ｇ，１５．４ｍｍｏｌ）をメタノール（３０ｍＬ）に溶解し、塩化チオニル（２．７９ｍＬ，３８．４ｍｍｏｌ）及び少量のＤＭＦを加えて室温で４時間撹拌した後、減圧下溶媒を留去した。得られた残渣に水及び酢酸エチルを加えてしばらく撹拌した後、分離した有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。不溶物をろ過後、減圧下溶媒を留去して表題化合物（茶色油状物，２．０９ｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），２．１－２．２（ｍ，２Ｈ），３．７１（ｓ，６Ｈ）． Reference example 22-1
Dimethyl (1S, 2S) -Cyclopropane-1,2-dicarboxylic Acid
Figure JPOXMLDOC01-appb-C000077
(1S, 2S) -cyclopropane-1,2-dicarboxylic acid (2.0 g, 15.4 mmol) is dissolved in methanol (30 mL), thionyl chloride (2.79 mL, 38.4 mmol) and a small amount of DMF are added. After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the mixture was stirred for a while, and then the separated organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After filtering the insoluble material, the solvent was distilled off under reduced pressure to obtain the title compound (brown oil, 2.09 g, 86%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.5 (m, 2H), 2.1-2.2 (m, 2H), 3.71 (s, 6H).
参考例２２－２
（１Ｓ，２Ｓ）－２－（メトキシカルボニル）シクロプロパン－１－カルボン酸
Figure JPOXMLDOC01-appb-C000078
参考例２２－１で合成した（１Ｓ，２Ｓ）－シクロプロパン－１，２－ジカルボン酸ジメチル（２．０９ｇ，１３．２ｍｍｏｌ）をメタノール（１３ｍＬ）及び水（２．０ｍＬ）に溶解し、２Ｎ水酸化ナトリウム水溶液（６．２８ｍＬ）を加えて室温で１６時間撹拌した後、減圧下溶媒を留去した。得られた残渣に水を加えてクロロホルムで洗浄し、２Ｎ塩酸水溶液を加えて水層のｐＨを２～３とした後、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して表題化合物（茶色油状物，１．４５ｇ，７６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．６（ｍ，２Ｈ），２．１－２．２（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．７２（ｓ，３Ｈ）．１Ｈ分観測できず Reference example 22-2
(1S, 2S) -2- (methoxycarbonyl) cyclopropane-1-carboxylic acid
Figure JPOXMLDOC01-appb-C000078
Dimethyl (2.09 g, 13.2 mmol) of (1S, 2S) -cyclopropane-1,2-dicarboxylic acid synthesized in Reference Example 22-1 was dissolved in methanol (13 mL) and water (2.0 mL) and 2N. An aqueous sodium hydroxide solution (6.28 mL) was added, and the mixture was stirred at room temperature for 16 hours, and then the solvent was distilled off under reduced pressure. Water was added to the obtained residue, the mixture was washed with chloroform, a 2N hydrochloric acid aqueous solution was added to adjust the pH of the aqueous layer to 2-3, and the mixture was extracted with a mixed solution of chloroform and methanol. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (brown oil, 1.45 g, 76%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.6 (m, 2H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H) , 3.72 (s, 3H). Cannot observe for 1H
参考例２２－３
（１Ｓ，２Ｓ）－２－（（２－ブロモ－４－フルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000079
参考例７－１と同様の手法に従い、参考例２２－２で合成した（１Ｓ，２Ｓ）－２－（メトキシカルボニル）シクロプロパン－１－カルボン酸（３６３ｍｇ，２．５２ｍｍｏｌ）及び２－ブロモ－４－フルオロアニリン（５７４ｍｇ，３．０２ｍｍｏｌ）を用いて表題化合物（５１５ｍｇ，６５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，１Ｈ），１．５－１．６（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．７５（ｓ，３Ｈ），７．０５（ｄｄｄ，１Ｈ，Ｊ＝６，８，９Ｈｚ），７．３１（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．７６（ｂｒ　ｓ，１Ｈ），８．２８（ｄｄ，１Ｈ，Ｊ＝６，９Ｈｚ）． Reference example 22-3
Methyl (1S, 2S) -2-((2-bromo-4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000079
(1S, 2S) -2- (methoxycarbonyl) cyclopropane-1-carboxylic acid (363 mg, 2.52 mmol) and 2-bromo- synthesized in Reference Example 22-2 according to the same method as in Reference Example 7-1. The title compound (515 mg, 65%) was obtained using 4-fluoroaniline (574 mg, 3.02 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H) , 2.2-2.3 (m, 1H), 3.75 (s, 3H), 7.05 (ddd, 1H, J = 6,8,9Hz), 7.31 (dd, 1H, J = 3.8Hz), 7.76 (br s, 1H), 8.28 (dd, 1H, J = 6.9Hz).
参考例２２－４
（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000080
参考例２２－３で合成した（１Ｓ，２Ｓ）－２－（（２－ブロモ－４－フルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル（５１５ｍｇ，１．６３ｍｍｏｌ）、ヨウ化銅（Ｉ）（３１ｍｇ，０．１６ｍｍｏｌ）、１，１０－フェナントロリン（５９ｍｇ，０．３３ｍｍｏｌ）及び炭酸セシウム（７９６ｍｇ，２．４４ｍｍｏｌ）をＤＭＥ（５．０ｍＬ）に懸濁し、窒素気流下で１６時間加熱還流した。室温まで放冷した反応液をセライトでろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（淡黄色結晶，２２６ｍｇ，５９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．８（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．７５（ｓ，３Ｈ），７．０－７．１（ｍ，１Ｈ），７．１９（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．５５（ｄｄ，１Ｈ，Ｊ＝５，９Ｈｚ）． Reference example 22-4
Methyl (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000080
Methyl (1S, 2S) -2-((2-bromo-4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate (515 mg, 1.63 mmol) synthesized in Reference Example 22-3, copper iodide (I) ) (31 mg, 0.16 mmol), 1,10-phenanthroline (59 mg, 0.33 mmol) and cesium carbonate (796 mg, 2.44 mmol) in DME (5.0 mL), heated and refluxed under a nitrogen stream for 16 hours. did. The reaction solution allowed to cool to room temperature was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (pale yellow crystals, 226 mg, 59%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H) , 3.75 (s, 3H), 7.0-7.1 (m, 1H), 7.19 (dd, 1H, J = 2.8Hz), 7.55 (dd, 1H, J = 5, 9Hz).
参考例２３－１
２－（４－モルホリノフェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000081
２－（４－ブロモフェニル）酢酸エチル（１．２８ｇ，５．２７ｍｍｏｌ）、モルホリン（９１７μＬ，１０．５ｍｍｏｌ）、酢酸パラジウム（１１８ｍｇ，０．５３ｍｍｏｌ）、ｔｅｒｔ－ブチルＸＰｈｏｓ（４４７ｍｇ，１．０５ｍｍｏｌ）及び炭酸セシウム（３．４３ｇ，１０．５ｍｍｏｌ）をトルエン（２５ｍＬ）に懸濁し、窒素気流下１１０℃で１６時間撹拌した。室温まで放冷した反応液をセライトでろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（黄色結晶，７６０ｍｇ，５８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２５（ｔ，３Ｈ，Ｊ＝７Ｈｚ），３．１－３．２（ｍ，４Ｈ），３．５３（ｓ，２Ｈ），３．８－３．９（ｍ，４Ｈ），４．１４（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ）． Reference example 23-1
2- (4-morpholinophenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000081
2- (4-Bromophenyl) ethyl acetate (1.28 g, 5.27 mmol), morpholine (917 μL, 10.5 mmol), palladium acetate (118 mg, 0.53 mmol), tert-butyl XPhos (447 mg, 1.05 mmol) And cesium carbonate (3.43 g, 10.5 mmol) was suspended in toluene (25 mL) and stirred at 110 ° C. for 16 hours under a nitrogen stream. The reaction solution allowed to cool to room temperature was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (yellow crystals, 760 mg, 58%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.25 (t, 3H, J = 7 Hz), 3.1-3.2 (m, 4H), 3.53 (s, 2H), 3.8 -3.9 (m, 4H), 4.14 (q, 2H, J = 7Hz), 6.8-6.9 (m, 2H), 7.1-7.2 (m, 2H).
参考例２３－２
２－（４－モルホリノフェニル）酢酸
Figure JPOXMLDOC01-appb-C000082
参考例２３－１で合成した２－（４－モルホリノフェニル）酢酸エチル（７６０ｍｇ，３．０５ｍｍｏｌ）をメタノール（５．０ｍＬ）に溶解し、２Ｎ水酸化ナトリウム水溶液（４．６ｍＬ）を加えて室温で１６時間撹拌し、減圧下溶媒を留去した。得られた残渣に水を加えてクロロホルムで洗浄し、２Ｎ塩酸水溶液を加えて中和した後、減圧下溶媒を留去した。得られた残渣にクロロホルム及びメタノールの混液を加えてしばらく撹拌し、不溶物をろ過後、減圧下溶媒を留去して表題化合物の粗体（白色粉末，７３３ｍｇ）を得た。
１Ｈ　ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）：δ＝３．０－３．１（ｍ，４Ｈ），３．３８（ｓ，２Ｈ），３．８－３．９（ｍ，４Ｈ），６．８－６．９（ｍ，２Ｈ），７．２－７．３（ｍ，２Ｈ）．１Ｈ分観測できず Reference example 23-2
2- (4-morpholinophenyl) acetic acid
Figure JPOXMLDOC01-appb-C000082
Ethyl 2- (4-morpholinophenyl) acetate (760 mg, 3.05 mmol) synthesized in Reference Example 23-1 is dissolved in methanol (5.0 mL), and a 2N sodium hydroxide aqueous solution (4.6 mL) is added to room temperature. The mixture was stirred for 16 hours and the solvent was distilled off under reduced pressure. Water was added to the obtained residue, the mixture was washed with chloroform, neutralized by adding a 2N aqueous hydrochloric acid solution, and then the solvent was distilled off under reduced pressure. A mixed solution of chloroform and methanol was added to the obtained residue, and the mixture was stirred for a while, the insoluble material was filtered, and the solvent was distilled off under reduced pressure to obtain a crude product (white powder, 733 mg) of the title compound.
1 1 H NMR (CD 3 OD, 400 MHz): δ = 3.0-3.1 (m, 4H), 3.38 (s, 2H), 3.8-3.9 (m, 4H), 6. 8-6.9 (m, 2H), 7.2-7.3 (m, 2H). Cannot observe for 1H
参考例２４
３－（２－（４－シクロプロピルフェニル）アセトアミド）－３－エチルピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000083
参考例７－１と同様の手法に従い、３－アミノ－３－エチルピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（５００ｍｇ，２．３３ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（４９３ｍｇ，２．８０ｍｍｏｌ）を用いて表題化合物（白色結晶，７８２ｍｇ，９０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．７－０．８（ｍ，３Ｈ），０．９－１．０（ｍ，２Ｈ），１．４４（ｓ，９Ｈ），１．５－２．５（ｍ，５Ｈ），３．１－３．６（ｍ，６Ｈ），５．１４（ｄ，１Ｈ，Ｊ＝１４Ｈｚ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ）． Reference example 24
3- (2- (4-Cyclopropylphenyl) acetamide) -3-ethylpyrrolidine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000083
Following the same procedure as in Reference Example 7-1, tert-butyl 3-amino-3-ethylpyrrolidine-1-carboxylate (500 mg, 2.33 mmol) and 2- (4-cyclopropyl) synthesized in Reference Example 33-2. The title compound (white crystals, 782 mg, 90%) was obtained using phenyl) acetic acid (493 mg, 2.80 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.7-0.8 (m, 3H), 0.9-1.0 (m, 2H) , 1.44 (s, 9H), 1.5-2.5 (m, 5H), 3.1-3.6 (m, 6H), 5.14 (d, 1H, J = 14Hz), 7 .0-7.1 (m, 2H), 7.1-7.2 (m, 2H).
参考例２５－１
（１Ｓ，２Ｓ）－２－（（２－ブロモフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000084
参考例２２－１と同様の手法に従い、（１Ｓ，２Ｓ）－シクロプロパン－１，２－ジカルボン酸（５００ｍｇ，３．８４ｍｍｏｌ）を用いて（１Ｓ，２Ｓ）－シクロプロパン－１，２－ジカルボン酸ジメチルの粗体（茶色油状物，６９５ｍｇ）を得た。参考例２２－２と同様の手法に従い、得られた（１Ｓ，２Ｓ）－シクロプロパン－１，２－ジカルボン酸ジメチルの粗体（６９５ｍｇ）を用いて（１Ｓ，２Ｓ）－２－（メトキシカルボニル）シクロプロパン－１－カルボン酸（４２７ｍｇ，７７％）を得た。参考例７－１と同様の手法に従い、得られた（１Ｓ，２Ｓ）－２－（メトキシカルボニル）シクロプロパン－１－カルボン酸（４２７ｍｇ，２．９６ｍｍｏｌ）及び２－ブロモアニリン（６１２ｍｇ，３．５６ｍｍｏｌ）を用いて表題化合物（黄色粉末，３９７ｍｇ，４５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，１Ｈ），１．５－１．６（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．７４（ｓ，３Ｈ），６．９－７．０（ｍ，１Ｈ），７．２－７．３（ｍ，１Ｈ），７．５４（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．９３（ｂｒ　ｓ，１Ｈ），８．３０（ｄ，１Ｈ，Ｊ＝８Ｈｚ）． Reference example 25-1
Methyl (1S, 2S) -2-((2-bromophenyl) carbamoyl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000084
Following the same procedure as in Reference Example 22-1, (1S, 2S) -cyclopropane-1,2-dicarboxylic acid was used with (1S, 2S) -cyclopropane-1,2-dicarboxylic acid (500 mg, 3.84 mmol). A crude body of dimethyl acid (brown oil, 695 mg) was obtained. According to the same method as in Reference Example 22-2, (1S, 2S) -2- (methoxycarbonyl) using the obtained crude product (695 mg) of dimethyl (1S, 2S) -cyclopropane-1,2-dicarboxylic acid. ) Cyclopropane-1-carboxylic acid (427 mg, 77%) was obtained. According to the same procedure as in Reference Example 7-1, the obtained (1S, 2S) -2- (methoxycarbonyl) cyclopropane-1-carboxylic acid (427 mg, 2.96 mmol) and 2-bromoaniline (612 mg, 3. 56 mmol) was used to give the title compound (yellow powder, 397 mg, 45%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H) , 2.2-2.3 (m, 1H), 3.74 (s, 3H), 6.9-7.0 (m, 1H), 7.2-7.3 (m, 1H), 7 .54 (dd, 1H, J = 1.8Hz), 7.93 (br s, 1H), 8.30 (d, 1H, J = 8Hz).
参考例２５－２
（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000085
参考例２２－４と同様の手法に従い、参考例２５－１で合成した（１Ｓ，２Ｓ）－２－（（２－ブロモフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル（３９７ｍｇ，１．３３ｍｍｏｌ）を用いて表題化合物（９５ｍｇ，３３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．８（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．７５（ｓ，３Ｈ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，１Ｈ），７．６－７．７（ｍ，１Ｈ）． Reference example 25-2
Methyl (1S, 2S) -2- (benzo [d] oxazole-2-yl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000085
Methyl (1S, 2S) -2-((2-bromophenyl) carbamoyl) cyclopropane-1-carboxylate (397 mg, 1.33 mmol) synthesized in Reference Example 25-1 according to the same procedure as in Reference Example 22-4. ) Was used to obtain the title compound (95 mg, 33%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H) , 3.75 (s, 3H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H).
参考例２６－１
（１Ｓ，２Ｓ）－２－（（２－ブロモ－４，５－ジフルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000086
参考例７－１と同様の手法に従い、参考例２２－２で合成した（１Ｓ，２Ｓ）－２－（メトキシカルボニル）シクロプロパン－１－カルボン酸（３４４ｍｇ，２．３９ｍｍｏｌ）及び２－ブロモ－４，５－ジフルオロアニリン（５９６ｍｇ，２．８７ｍｍｏｌ）を用いて表題化合物（３１３ｍｇ，３９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．６（ｍ，２Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．７５（ｓ，３Ｈ），７．３－７．４（ｍ，１Ｈ），７．７９（ｂｒ　ｓ，１Ｈ），８．３－８．４（ｍ，１Ｈ）． Reference example 26-1
Methyl (1S, 2S) -2-((2-bromo-4,5-difluorophenyl) carbamoyl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000086
(1S, 2S) -2- (methoxycarbonyl) cyclopropane-1-carboxylic acid (344 mg, 2.39 mmol) and 2-bromo- synthesized in Reference Example 22-2 according to the same method as in Reference Example 7-1. The title compound (313 mg, 39%) was obtained using 4,5-difluoroaniline (596 mg, 2.87 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.6 (m, 2H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H) , 3.75 (s, 3H), 7.3-7.4 (m, 1H), 7.79 (br s, 1H), 8.3-8.4 (m, 1H).
参考例２６－２
（１Ｓ，２Ｓ）－２－（５，６－ジフルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000087
参考例２２－４と同様の手法に従い、参考例２６－１で合成した（１Ｓ，２Ｓ）－２－（（２－ブロモ－４，５－ジフルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル（３１３ｍｇ，０．９４ｍｍｏｌ）を用いて表題化合物（淡黄色油状物，６８ｍｇ，２９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．８（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．７５（ｓ，３Ｈ），７．３－７．４（ｍ，１Ｈ），７．４－７．５（ｍ，１Ｈ）． Reference example 26-2
Methyl (1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000087
Methyl (1S, 2S) -2-((2-bromo-4,5-difluorophenyl) carbamoyl) cyclopropane-1-carboxylate synthesized in Reference Example 26-1 according to the same procedure as in Reference Example 22-4. (313 mg, 0.94 mmol) was used to give the title compound (pale yellow oil, 68 mg, 29%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H) , 3.75 (s, 3H), 7.3-7.4 (m, 1H), 7.4-7.5 (m, 1H).
参考例２７
２－（４－（２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル）フェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000088
２－（４－ブロモフェニル）酢酸エチル（１．０ｇ，４．１１ｍｍｏｌ）、２－オキサ－６－アザスピロ［３．３］ヘプタン（８１６ｍｇ，８．２３ｍｍｏｌ）、酢酸パラジウム（９２ｍｇ，０．４１ｍｍｏｌ）、ＸＰｈｏｓ（２７０ｍｇ，０．５７ｍｍｏｌ）及び炭酸セシウム（２．６８ｇ，８．２３ｍｍｏｌ）をトルエン（３０ｍＬ）に懸濁し、窒素気流下１１０℃で１６時間撹拌した。室温まで放冷した後セライトで不溶物をろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（無色油状物，１．２６ｇ，１１７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２４（ｔ，３Ｈ，Ｊ＝７Ｈｚ），３．５０（ｓ，２Ｈ），４．０１（ｂｒ　ｓ，４Ｈ），４．１３（ｑ，２Ｈ，Ｊ＝７Ｈｚ），４．８３（ｂｒ　ｓ，４Ｈ），６．４－６．５（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ）． Reference example 27
2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000088
2- (4-Bromophenyl) ethyl acetate (1.0 g, 4.11 mmol), 2-oxa-6-azaspiro [3.3] heptane (816 mg, 8.23 mmol), palladium acetate (92 mg, 0.41 mmol) , XPhos (270 mg, 0.57 mmol) and cesium carbonate (2.68 g, 8.23 mmol) were suspended in toluene (30 mL) and stirred at 110 ° C. for 16 hours under a nitrogen stream. After allowing to cool to room temperature, the insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (colorless oil, 1.26 g, 117%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.24 (t, 3H, J = 7 Hz), 3.50 (s, 2H), 4.01 (br s, 4H), 4.13 (q, 2H, J = 7Hz), 4.83 (br s, 4H), 6.4-6.5 (m, 2H), 7.1-7.2 (m, 2H).
参考例２８－１
（１Ｓ，２Ｓ）－２－（（２－ブロモ－５－フルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000089
参考例２２－２で合成した（１Ｓ，２Ｓ）－２－（メトキシカルボニル）シクロプロパン－１－カルボン酸（２９４ｍｇ，２．０４ｍｍｏｌ）及び２－ブロモ－５－フルオロアニリン（４６５ｍｇ，２．４５ｍｍｏｌ）をＤＭＦ（１５ｍＬ）に溶解した後、ＤＩＰＥＡ（１．１３ｍＬ，６．５６ｍｍｏｌ）及びＨＡＴＵ（９３１ｍｇ，２．４５ｍｍｏｌ）を加えて５０℃で１６時間撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（象牙色粉末，２１０ｍｇ，３３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，１Ｈ），１．５－１．６（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．７４（ｓ，３Ｈ），６．７３（ｄｄｄ，１Ｈ，Ｊ＝３，８，９Ｈｚ），７．４９（ｄｄ，１Ｈ，Ｊ＝６，９Ｈｚ），７．９５（ｂｒ　ｓ，１Ｈ），８．２１（ｄｄ，１Ｈ，Ｊ＝２，１１Ｈｚ）． Reference example 28-1
Methyl (1S, 2S) -2-((2-bromo-5-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000089
(1S, 2S) -2- (methoxycarbonyl) cyclopropane-1-carboxylic acid (294 mg, 2.04 mmol) and 2-bromo-5-fluoroaniline (465 mg, 2.45 mmol) synthesized in Reference Example 22-2. Was dissolved in DMF (15 mL), DIPEA (1.13 mL, 6.56 mmol) and HATU (931 mg, 2.45 mmol) were added, and the mixture was stirred at 50 ° C. for 16 hours. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (ivory powder, 210 mg, 33%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H), 2.1-2.2 (m, 1H) , 2.3-2.4 (m, 1H), 3.74 (s, 3H), 6.73 (ddd, 1H, J = 3,8,9Hz), 7.49 (dd, 1H, J = 6.9Hz), 7.95 (br s, 1H), 8.21 (dd, 1H, J = 2,11Hz).
参考例２８－２
（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000090
参考例２２－４と同様の手法に従い、参考例２８－１で合成した（１Ｓ，２Ｓ）－２－（（２－ブロモ－５－フルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸メチル（２１０ｍｇ，０．６６ｍｍｏｌ）を用いて表題化合物（象牙色粉末，４７ｍｇ，３０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．８（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．７５（ｓ，３Ｈ），７．０－７．１（ｍ，１Ｈ），７．３１（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．３８（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ）． Reference example 28-2
Methyl (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000090
Methyl (1S, 2S) -2-((2-bromo-5-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate (210 mg) synthesized in Reference Example 28-1 according to the same procedure as in Reference Example 22-4. , 0.66 mmol) was used to give the title compound (ivory powder, 47 mg, 30%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H), 2.7-2.8 (m, 1H) , 3.75 (s, 3H), 7.0-7.1 (m, 1H), 7.31 (dd, 1H, J = 2.8Hz), 7.38 (dd, 1H, J = 4, 9Hz).
参考例２９－１
トランス－２－（エトキシカルボニル）シクロプロパン－１－カルボン酸
Figure JPOXMLDOC01-appb-C000091
参考例２２－２と同様の手法に従い、トランス－シクロプロパン－１，２－ジカルボン酸ジエチル（７．３ｇ，３９．２ｍｍｏｌ）を用いて表題化合物（白色結晶，５．９１ｇ，９５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２８（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．４－１．６（ｍ，２Ｈ），２．１－２．３（ｍ，２Ｈ），４．１６（ｑ，２Ｈ，Ｊ＝７Ｈｚ）．１Ｈ分観測できず Reference example 29-1
Trans-2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid
Figure JPOXMLDOC01-appb-C000091
The title compound (white crystals, 5.91 g, 95%) was obtained using diethyl trans-cyclopropane-1,2-dicarboxylic acid (7.3 g, 39.2 mmol) according to the same procedure as in Reference Example 22-2. It was.
1 1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.28 (t, 3H, J = 7 Hz), 1.4-1.6 (m, 2H), 2.1-23 (m, 2H) , 4.16 (q, 2H, J = 7Hz). Cannot observe for 1H
参考例２９－２
トランス－２－（（２－ブロモフェニル）カルバモイル）シクロプロパン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000092
参考例２８－１と同様の手法に従い、参考例２９－１で合成したトランス－２－（エトキシカルボニル）シクロプロパン－１－カルボン酸（２．０ｇ，１２．６ｍｍｏｌ）及び２－ブロモアニリン（２．６１ｇ，１５．２ｍｍｏｌ）を用いて表題化合物（白色粉末，３．４２ｇ，８７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．３０（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．４－１．５（ｍ，１Ｈ），１．５－１．６（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），４．１９（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，１Ｈ），７．２－７．３（ｍ，１Ｈ），７．５５（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．９０（ｂｒ　ｓ，１Ｈ），８．３３（ｄ，１Ｈ，Ｊ＝８Ｈｚ）． Reference example 29-2
Ethyl trans-2-((2-bromophenyl) carbamoyl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000092
Trans-2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid (2.0 g, 12.6 mmol) and 2-bromoaniline (2) synthesized in Reference Example 29-1 according to the same method as in Reference Example 28-1. The title compound (white powder, 3.42 g, 87%) was obtained using .61 g, 15.2 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.30 (t, 3H, J = 7 Hz), 1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H) , 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 4.19 (q, 2H, J = 7Hz), 6.9-7.0 (m, 1H), 7.2-7.3 (m, 1H), 7.55 (dd, 1H, J = 1.8Hz), 7.90 (br s, 1H), 8.33 (d, 1H, J) = 8Hz).
参考例２９－３
トランス－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000093
参考例２２－４と同様の手法に従い、参考例２９－２で合成したトランス－２－（（２－ブロモフェニル）カルバモイル）シクロプロパン－１－カルボン酸エチル（３．４２ｇ，１１．０ｍｍｏｌ）を用いて表題化合物（淡黄色油状物，１．２２ｇ，４８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２９（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．７－１．８（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），４．２０（ｑ，２Ｈ，Ｊ＝７Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，１Ｈ），７．６－７．７（ｍ，１Ｈ）． Reference example 29-3
Ethyl trans-2- (benzo [d] oxazole-2-yl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000093
Ethyl trans-2-((2-bromophenyl) carbamoyl) cyclopropane-1-carboxylate (3.42 g, 11.0 mmol) synthesized in Reference Example 29-2 was prepared in the same manner as in Reference Example 22-4. The title compound (pale yellow oil, 1.22 g, 48%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.29 (t, 3H, J = 7 Hz), 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H) , 2.7-2.8 (m, 1H), 4.20 (q, 2H, J = 7Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H).
参考例３０－１
（１Ｓ，２Ｓ）－２－（エトキシカルボニル）シクロプロパン－１－カルボン酸
Figure JPOXMLDOC01-appb-C000094
（１Ｓ，２Ｓ）－シクロプロパン－１，２－ジカルボン酸（２．５ｇ，１９．２ｍｍｏｌ）をエタノール（３８ｍＬ）に溶解し、塩化チオニル（３．４８ｍＬ，４８．０ｍｍｏｌ）及び少量のＤＭＦを加えて室温で４時間撹拌した後、減圧下溶媒を留去した。得られた残渣に水及び酢酸エチルを加えてしばらく撹拌した後、分離した有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。不溶物をろ過後、減圧下溶媒を留去して（１Ｓ，２Ｓ）－２－（エトキシカルボニル）シクロプロパン－１－カルボン酸の粗体（淡象牙色油状物，３．６６ｇ）を得た。
参考例２２－２と同様の手法に従い、得られた（１Ｓ，２Ｓ）－２－（エトキシカルボニル）シクロプロパン－１－カルボン酸の粗体（３．６６ｇ）を用いて表題化合物（黄色油状物，２．３１ｇ，７６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２８（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．４－１．６（ｍ，２Ｈ），２．１－２．３（ｍ，２Ｈ），４．１６（ｑ，２Ｈ，Ｊ＝７Ｈｚ）．１Ｈ分観測できず Reference example 30-1
(1S, 2S) -2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid
Figure JPOXMLDOC01-appb-C000094
(1S, 2S) -cyclopropane-1,2-dicarboxylic acid (2.5 g, 19.2 mmol) is dissolved in ethanol (38 mL), thionyl chloride (3.48 mL, 48.0 mmol) and a small amount of DMF are added. After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the mixture was stirred for a while, and then the separated organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After filtering the insoluble material, the solvent was distilled off under reduced pressure to obtain a crude product of (1S, 2S) -2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid (pale ivory oil, 3.66 g). ..
Following the same procedure as in Reference Example 22-2, the title compound (yellow oil) was used with the obtained crude product (3.66 g) of (1S, 2S) -2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid. , 2.31 g, 76%).
1 1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.28 (t, 3H, J = 7 Hz), 1.4-1.6 (m, 2H), 2.1-23 (m, 2H) , 4.16 (q, 2H, J = 7Hz). Cannot observe for 1H
参考例３０－２
（１Ｓ，２Ｓ）－２－（（２－ブロモ－５－フルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000095
参考例２８－１と同様の手法に従い、参考例３０－１で合成した（１Ｓ，２Ｓ）－２－（エトキシカルボニル）シクロプロパン－１－カルボン酸（５００ｍｇ，３．１６ｍｍｏｌ）及び２－ブロモアニリン（７２１ｍｇ，３．７９ｍｍｏｌ）を用いて表題化合物（象牙色粉末，５３０ｇ，５１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．３（ｍ，３Ｈ），１．４－１．５（ｍ，１Ｈ），１．５－１．６（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），４．１９（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．７－６．８（ｍ，１Ｈ），７．４９（ｄｄ，１Ｈ，Ｊ＝６，８Ｈｚ），７．９３（ｂｒ　ｓ，１Ｈ），８．２３（ｄｄ，１Ｈ，Ｊ＝３，１１Ｈｚ）． Reference example 30-2
Ethyl (1S, 2S) -2-((2-bromo-5-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000095
(1S, 2S) -2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid (500 mg, 3.16 mmol) and 2-bromoaniline synthesized in Reference Example 30-1 according to the same procedure as in Reference Example 28-1. (721 mg, 3.79 mmol) was used to give the title compound (ivory powder, 530 g, 51%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.3 (m, 3H), 1.4-1.5 (m, 1H), 1.5-1.6 (m, 1H) , 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 4.19 (q, 2H, J = 7Hz), 6.7-6.8 (m, 1H), 7.49 (dd, 1H, J = 6.8Hz), 7.93 (br s, 1H), 8.23 (dd, 1H, J = 3,11Hz).
参考例３０－３
（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000096
参考例２２－４と同様の手法に従い、参考例３０－２で合成した（１Ｓ，２Ｓ）－２－（（２－ブロモ－５－フルオロフェニル）カルバモイル）シクロプロパン－１－カルボン酸エチル（５３０ｍｇ，１．６１ｍｍｏｌ）を用いて表題化合物（茶色油状物，１４１ｍｇ，３５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２９（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．７－１．８（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），４．２０（ｑ，２Ｈ，Ｊ＝７Ｈｚ），７．０２（ｄｄｄ，１Ｈ，Ｊ＝２，９，９Ｈｚ），７．３１（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．３８（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ）． Reference example 30-3
Ethyl (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000096
Ethyl (1S, 2S) -2-((2-bromo-5-fluorophenyl) carbamoyl) cyclopropane-1-carboxylate (530 mg) synthesized in Reference Example 30-2 according to the same method as in Reference Example 22-4. , 1.61 mmol) was used to give the title compound (brown oil, 141 mg, 35%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.29 (t, 3H, J = 7 Hz), 1.7-1.8 (m, 2H), 2.4-2.5 (m, 1H) , 2.7-2.8 (m, 1H), 4.20 (q, 2H, J = 7Hz), 7.02 (ddd, 1H, J = 2,9,9Hz), 7.31 (dd, dd, 1H, J = 3.8Hz), 7.38 (dd, 1H, J = 4.9Hz).
参考例３１－１
２－（５－（トリフルオロメチル）ピリジン－２－イル）マロン酸ジメチル
Figure JPOXMLDOC01-appb-C000097
２－クロロ－５－（トリフルオロメチル）ピリジン（５．００ｇ，２７．５ｍｍｏｌ）、マロン酸ジメチル（５．４６ｇ，４１．３ｍｍｏｌ）及び炭酸セシウム（１８．０ｇ，５５．１ｍｍｏｌ）をジメチルスルホキシド（１０．０ｍＬ）に溶解し、窒素気流下１１０℃で終夜撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：２５－７５％）により精製し表題化合物（黄色油状物，２．４６ｇ，３２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝３．８１（ｓ，６Ｈ），５．０５（ｓ，１Ｈ），７．６７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．８４（ｓ，１Ｈ）． Reference example 31-1
2- (5- (Trifluoromethyl) Pyridine-2-yl) Dimethyl malonate
Figure JPOXMLDOC01-appb-C000097
2-Chloro-5- (trifluoromethyl) pyridine (5.00 g, 27.5 mmol), dimethyl malonate (5.46 g, 41.3 mmol) and cesium carbonate (18.0 g, 55.1 mmol) in dimethyl sulfoxide (18.0 g, 55.1 mmol) It was dissolved in 10.0 mL) and stirred overnight at 110 ° C. under a nitrogen stream. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 25-75%) to give the title compound (yellow oil, 2.46 g, 32%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 3.81 (s, 6H), 5.05 (s, 1H), 7.67 (d, 1H, J = 8Hz), 7.97 (d, 1H) , J = 8Hz), 8.84 (s, 1H).
参考例３１－２
２－（５－（トリフルオロメチル）ピリジン－２－イル）酢酸
Figure JPOXMLDOC01-appb-C000098
参考例３１－１で合成した２－（５－（トリフルオロメチル）ピリジン－２－イル）マロン酸ジメチル（７９０ｍｇ，２．８５ｍｍｏｌ）をメタノール（１８ｍＬ）に溶解し、２Ｎ水酸化ナトリウム水溶液（３．６ｍＬ）を加えて５０℃で終夜撹拌した。室温まで放冷した反応液に２Ｎ塩酸水溶液（３．５ｍＬ）を加えて水層のｐＨを６～７とした後、減圧下溶媒を留去して塩化ナトリウムを含む表題化合物（淡黄色結晶，８６４ｍｇ）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝３．８５（ｓ，２Ｈ），７．６０（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．１５（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），８．８６（ｓ，１Ｈ）．１Ｈ分観測できず Reference example 31-2
2- (5- (trifluoromethyl) pyridin-2-yl) acetic acid
Figure JPOXMLDOC01-appb-C000098
Dimethyl 2- (5- (trifluoromethyl) pyridine-2-yl) malonate (790 mg, 2.85 mmol) synthesized in Reference Example 31-1 was dissolved in methanol (18 mL) and dissolved in 2N sodium hydroxide aqueous solution (3). .6 mL) was added and stirred at 50 ° C. overnight. A 2N hydrochloric acid aqueous solution (3.5 mL) was added to the reaction solution allowed to cool to room temperature to adjust the pH of the aqueous layer to 6 to 7, and then the solvent was distilled off under reduced pressure to obtain the title compound containing sodium chloride (pale yellow crystals, 864 mg) was obtained.
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 3.85 (s, 2H), 7.60 (d, 1H, J = 8 Hz), 8.15 (dd, 1H, J = 2.8 Hz) , 8.86 (s, 1H). Cannot observe for 1H
参考例３２－１
（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000099
参考例４と同様の手法に従い、５－ブロモ－２－（トリフルオロメチル）ピリジン（２．５５ｇ，１１．３ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１．５０ｇ，７．４９ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，２．２０ｇ，８９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２－３．３（ｍ，１Ｈ），３．３－３．６（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．３－４．５（ｍ，１Ｈ），４．６－４．８（ｍ，１Ｈ），６．８２（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４８（ｄ，１Ｈ，Ｊ＝９Ｈｚ），８．０１（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 32-1
(R)-(1- (6- (Trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000099
Following the same procedure as in Reference Example 4, 5-bromo-2- (trifluoromethyl) pyridine (2.55 g, 11.3 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (1.50 g, 7.49 mmol) was used to give the title compound (pale yellow amorphous, 2.20 g, 89%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.2 -3.3 (m, 1H), 3.3-3.6 (m, 2H), 3.6-3.7 (m, 1H), 4.3-4.5 (m, 1H), 4 .6-4.8 (m, 1H), 6.82 (dd, 1H, J = 3,9Hz), 7.48 (d, 1H, J = 9Hz), 8.01 (d, 1H, J = 3Hz).
参考例３２－２
（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000100
参考例１－２と同様の手法に従い、参考例３２－１で合成した（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（２．２０ｇ，６．６４ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，１．５０ｇ，９７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４０（ｂｒ　ｓ，２Ｈ），１．８－２．０（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．３－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，２Ｈ），３．７－３．９（ｍ，１Ｈ），６．８０（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），８．００（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 32-2
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000100
(R)-(1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 32-1 according to the same method as in Reference Example 1-2. The title compound (pale yellow crystals, 1.50 g, 97%) was obtained using butyl (2.20 g, 6.64 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.40 (br s, 2H), 1.8-2.0 (m, 1H), 2.2-2.3 (m, 1H), 3. 0-3.1 (m, 1H), 3.3-3.5 (m, 1H), 3.5-3.6 (m, 2H), 3.7-3.9 (m, 1H), 6.80 (dd, 1H, J = 3,9Hz), 7.47 (d, 1H, J = 9Hz), 8.00 (d, 1H, J = 3Hz).
参考例３３－１
２－（４－シクロプロピルフェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000101
４－ブロモフェニル酢酸エチル（６．０ｇ，２４．７ｍｍｏｌ）、シクロプロピルボロン酸（２．７６ｇ，３２．１ｍｍｏｌ）、酢酸パラジウム（２７６ｍｇ，１．２３ｍｍｏｌ）、トリシクロヘキシルホスフィン（０．６Ｍトルエン溶液，４．２ｍＬ，２．４６ｍｍｏｌ）及びリン酸カリウム一水和物（１９．９ｇ，８６．４ｍｍｏｌ）をトルエン（６０．０ｍＬ）及び水（３．０ｍＬ）に懸濁し、窒素気流下１００℃で１６時間撹拌した。室温まで放冷した反応液をセライトパッドでろ過後、ろ液の溶媒を減圧下留去した。得られた残渣を酢酸エチルで希釈し、有機層を炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－３０％）により精製し表題化合物（黄色油状物，４．９０ｇ，９７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．２４（ｔ，３Ｈ，Ｊ＝８Ｈｚ），１．８－１．９（ｍ，１Ｈ），３．５２（ｓ，２Ｈ），４．１２（ｑ，２Ｈ，Ｊ＝８Ｈｚ），７．０１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１５（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 33-1
2- (4-Cyclopropylphenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000101
4-Bromophenyl ethyl acetate (6.0 g, 24.7 mmol), cyclopropylboronic acid (2.76 g, 32.1 mmol), palladium acetate (276 mg, 1.23 mmol), tricyclohexylphosphine (0.6 M toluene solution, 4.2 mL, 2.46 mmol) and potassium phosphate monohydrate (19.9 g, 86.4 mmol) were suspended in toluene (60.0 mL) and water (3.0 mL) and 16 at 100 ° C. under a nitrogen stream. Stirred for hours. The reaction solution allowed to cool to room temperature was filtered through a Celite pad, and the solvent of the filtrate was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-30%) to give the title compound (yellow oil, 4.90 g, 97%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.24 (t, 3H, J = 8 Hz) , 1.8-1.9 (m, 1H), 3.52 (s, 2H), 4.12 (q, 2H, J = 8Hz), 7.01 (d, 2H, J = 8Hz), 7 .15 (d, 2H, J = 8Hz).
参考例３３－２
２－（４－シクロプロピルフェニル）酢酸
Figure JPOXMLDOC01-appb-C000102
参考例２２－２と同様の手法に従い、参考例３３－１で合成した２－（４－シクロプロピルフェニル）酢酸エチル（４．９０ｇ，２４．０ｍｍｏｌ）を用いて表題化合物（白色結晶，３．８０ｇ，９０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），３．６０（ｓ，２Ｈ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１６（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．１Ｈ分観測できず Reference example 33-2
2- (4-Cyclopropylphenyl) acetic acid
Figure JPOXMLDOC01-appb-C000102
Following the same procedure as in Reference Example 22-2, the title compound (white crystals, 3.) was used with ethyl 2- (4-cyclopropylphenyl) acetate (4.90 g, 24.0 mmol) synthesized in Reference Example 33-1. 80 g, 90%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 1H) , 3.60 (s, 2H), 7.03 (d, 2H, J = 8Hz), 7.16 (d, 2H, J = 8Hz). Cannot observe for 1H
参考例３４
（Ｒ）－（１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000103
参考例１－１と同様の手法に従い、１－ブロモ－４－（トリフルオロメチル）ベンゼン（２６０ｍｇ，１．６１ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（２００ｍｇ，１．０７ｍｍｏｌ）を用いて表題化合物（淡黄色シロップ，２７３ｍｇ，７７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２０（ｄｄ，１Ｈ，Ｊ＝３，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６２（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３８（ｂｒ　ｓ，１Ｈ），４．６９（ｂｒ　ｓ，１Ｈ），６．５５（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．４５（ｄ，２Ｈ，Ｊ＝９Ｈｚ）． Reference example 34
(R)-(1- (4- (Trifluoromethyl) phenyl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000103
Following the same procedure as in Reference Example 1-1, 1-bromo-4- (trifluoromethyl) benzene (260 mg, 1.61 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (200 mg, 1. 07 mmol) was used to give the title compound (pale yellow syrup, 273 mg, 77%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.20 (Dd, 1H, J = 3,10Hz), 3.3-3.5 (m, 2H), 3.62 (dd, 1H, J = 6,10Hz), 4.38 (br s, 1H), 4.69 (br s, 1H), 6.55 (d, 2H, J = 9Hz), 7.45 (d, 2H, J = 9Hz).
参考例３５
（Ｓ）－（１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000104
参考例１－１と同様の手法に従い、１－ブロモ－４－（トリフルオロメチル）ベンゼン（２６０ｍｇ，１．６１ｍｍｏｌ）及び（Ｓ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（２００ｍｇ，１．０７ｍｍｏｌ）を用いて表題化合物（淡黄色固体，２３６ｍｇ，６７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２０（ｄｄ，１Ｈ，Ｊ＝３，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６２（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３７（ｂｒ　ｓ，１Ｈ），４．６９（ｂｒ　ｓ，１Ｈ），６．５５（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．４５（ｄ，２Ｈ，Ｊ＝９Ｈｚ）． Reference example 35
(S)-(1- (4- (Trifluoromethyl) phenyl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000104
Following the same procedure as in Reference Example 1-1, 1-bromo-4- (trifluoromethyl) benzene (260 mg, 1.61 mmol) and tert-butyl (S) -pyrrolidine-3-ylcarbamate (200 mg, 1. 07 mmol) was used to give the title compound (pale yellow solid, 236 mg, 67%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.20 (Dd, 1H, J = 3,10Hz), 3.3-3.5 (m, 2H), 3.62 (dd, 1H, J = 6,10Hz), 4.37 (br s, 1H), 4.69 (br s, 1H), 6.55 (d, 2H, J = 9Hz), 7.45 (d, 2H, J = 9Hz).
参考例３６
（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000105
参考例１－１と同様の手法に従い、５－ブロモ－２－（トリフルオロメチル）ピリジン（６７ｍｇ，０．２９ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２７ｍｍｏｌ）を用いて表題化合物（淡黄色固体，５３ｍｇ，５９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４０（ｂｒ　ｓ，１Ｈ），４．８１（ｂｒ　ｓ，１Ｈ），６．８２（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９９（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 36
(R)-(1- (6- (Trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000105
Following the same procedure as in Reference Example 1-1, 5-bromo-2- (trifluoromethyl) pyridine (67 mg, 0.29 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (50 mg, 0. 27 mmol) was used to give the title compound (pale yellow solid, 53 mg, 59%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.23 (Dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.40 (br s, 1H), 4.81 (br s, 1H), 6.82 (dd, 1H, J = 3,9Hz), 7.47 (d, 1H, J = 9Hz), 7.99 (d, 1H, J = 3Hz) ..
参考例３７
（Ｓ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000106
 参考例１－１と同様の手法に従い、５－ブロモ－２－（トリフルオロメチル）ピリジン（６７ｍｇ，０．２９ｍｍｏｌ）及び（Ｓ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２７ｍｍｏｌ）を用いて表題化合物（淡黄色固体，５９ｍｇ，６６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２４　（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４０（ｂｒ　ｓ，１Ｈ），４．８９（ｂｒ　ｓ，１Ｈ），６．８２（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９９（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 37
(S)-(1- (6- (Trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000106
 Following the same procedure as in Reference Example 1-1, 5-bromo-2- (trifluoromethyl) pyridine (67 mg, 0.29 mmol) and tert-butyl (S) -pyrrolidine-3-ylcarbamate (50 mg, 0. 27 mmol) was used to give the title compound (pale yellow solid, 59 mg, 66%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.24 (Dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.40 (br s, 1H), 4.89 (br s, 1H), 6.82 (dd, 1H, J = 3,9Hz), 7.47 (d, 1H, J = 9Hz), 7.99 (d, 1H, J = 3Hz) ..
参考例３８－１
（Ｒ）－（１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000107
 参考例９と同様の手法に従い、２－クロロ－５－（トリフルオロメチル）ピリミジン（４９ｍｇ，０．２７ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２７ｍｍｏｌ）を用いて表題化合物（白色固体，８６ｍｇ，９７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．５０（ｄｄ，１Ｈ，Ｊ＝５，１２Ｈｚ），３．６－３．８（ｍ，２Ｈ），３．８８（ｄｄ，１Ｈ，Ｊ＝６，１２Ｈｚ），４．３６（ｂｒ　ｓ，１Ｈ），４．７３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），８．５０（ｓ，２Ｈ）． Reference example 38-1
(R)-(1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000107
 Following the same procedure as in Reference Example 9, 2-chloro-5- (trifluoromethyl) pyrimidine (49 mg, 0.27 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (50 mg, 0.27 mmol). Was used to give the title compound (white solid, 86 mg, 97%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.50 (Dd, 1H, J = 5,12Hz), 3.6-3.8 (m, 2H), 3.88 (dd, 1H, J = 6,12Hz), 4.36 (br s, 1H), 4.73 (d, 1H, J = 7Hz), 8.50 (s, 2H).
参考例３８－２
（Ｒ）－１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000108
 参考例１－２と同様の手法に従い、参考例３８－１で合成した（Ｒ）－（１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（８６ｍｇ，０．２６ｍｍｏｌ）を用いて表題化合物（白色固体，４５ｍｇ，７５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．３－３．４（ｍ，１Ｈ），３．６－３．９（ｍ，４Ｈ），８．５０（ｓ，２Ｈ）．２Ｈ分観測できず Reference example 38-2
(R) -1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000108
 (R)-(1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 38-1 according to the same method as in Reference Example 1-2. The title compound (white solid, 45 mg, 75%) was obtained using butyl (86 mg, 0.26 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.1-2.3 (m, 1H), 3.3-3.4 (m, 1H) , 3.6-3.9 (m, 4H), 8.50 (s, 2H). Cannot observe for 2 hours
参考例３９
（Ｒ）－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000109
 参考例１－１と同様の手法に従い、４－ブロモ－１－フルオロ－２－（トリフルオロメチル）ベンゼン（１４４ｍｇ，０．５９ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１００ｍｇ，０．５４ｍｍｏｌ）を用いて表題化合物（淡黄色固体，１１２ｍｇ，６０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１５（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ），３．２－３．５（ｍ，２Ｈ），３．５５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３７（ｂｒ　ｓ，１Ｈ），４．７９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．５－６．６（ｍ，２Ｈ），７．０４（ｔ，１Ｈ，Ｊ＝１０Ｈｚ）． Reference example 39
(R)-(1- (4-Fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000109
 Following the same procedure as in Reference Example 1-1, 4-bromo-1-fluoro-2- (trifluoromethyl) benzene (144 mg, 0.59 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (tert-butyl (R) -pyrrolidine-3-ylcarbamate) ( The title compound (pale yellow solid, 112 mg, 60%) was obtained using 100 mg (0.54 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.15 (Dd, 1H, J = 4.9Hz), 3.2-3.5 (m, 2H), 3.55 (dd, 1H, J = 6,10Hz), 4.37 (br s, 1H), 4.79 (d, 1H, J = 7Hz), 6.5-6.6 (m, 2H), 7.04 (t, 1H, J = 10Hz).
参考例４０－１
（１Ｓ，２Ｓ）－２－（（２－ホルミルフェニル）カルバモイル）シクロプロパン－１－カルボン酸（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシル
Figure JPOXMLDOC01-appb-C000110
 参考例２８－１と同様の手法に従い、（１Ｓ，２Ｓ）－２－（（（（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシル）オキシ）カルボニル）シクロプロパン－１－カルボン酸（１．１７ｇ，４．３５ｍｍｏｌ）及び２－アミノベンズアルデヒド（９８８ｍｇ，８．１２ｍｍｏｌ）を用いて表題化合物の粗体を得た。 Reference example 40-1
(1S, 2S) -2-((2-formylphenyl) carbamoyl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl
Figure JPOXMLDOC01-appb-C000110
 According to the same method as in Reference Example 28-1, (1S, 2S) -2-((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) cyclopropane-1-carboxylic acid A crude of the title compound was obtained using (1.17 g, 4.35 mmol) and 2-aminobenzaldehyde (988 mg, 8.12 mmol).
参考例４０－２
（１Ｓ，２Ｓ）－２－（キナゾリン－２－イル）シクロプロパン－１－カルボン酸（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシル
Figure JPOXMLDOC01-appb-C000111
 参考例４０－１で合成した（１Ｓ，２Ｓ）－２－（（２－ホルミルフェニル）カルバモイル）シクロプロパン－１－カルボン酸（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシルの粗体、酢酸アンモニウムをトルエン中１２０℃で１０時間加熱還流した。室温まで放冷し反応液に炭酸水素ナトリウムを加えしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：１０－５０％）により精製し表題化合物（２７７ｍｇ，１８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．７６（ｄ，３Ｈ，Ｊ＝７Ｈｚ），０．８０（ｄ，３Ｈ，Ｊ＝７Ｈｚ），０．８－２．１（ｍ，１２Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），２．９－３．０（ｍ，１Ｈ），４．６－４．８（ｍ，１Ｈ），７．５８（ｄｄｄ，１Ｈ，Ｊ＝１，７，７Ｈｚ），７．８－８．０（ｍ，３Ｈ），９．２７（ｓ，１Ｈ）． Reference example 40-2
(1S, 2S) -2- (quinazoline-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl
Figure JPOXMLDOC01-appb-C000111
 Crude of (1S, 2S) -2-((2-formylphenyl) carbamoyl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl synthesized in Reference Example 40-1 The body, ammonium acetate, was heated to reflux in toluene at 120 ° C. for 10 hours. After allowing to cool to room temperature, sodium hydrogen carbonate was added to the reaction solution, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 10-50%) to give the title compound (277 mg, 18%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.76 (d, 3H, J = 7 Hz), 0.80 (d, 3H, J = 7 Hz), 0.8-2.1 (m, 12H) , 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 2.9-3.0 (m, 1H), 4.6-4.8 (m, 1H), 7.58 (ddd, 1H, J = 1,7,7Hz), 7.8-8.0 (m, 3H), 9.27 (s, 1H).
参考例４０－３
（１Ｓ，２Ｓ）－２－（キナゾリン－２－イル）シクロプロパン－１－カルボン酸
Figure JPOXMLDOC01-appb-C000112
 参考例４０－２で合成した（１Ｓ，２Ｓ）－２－（キナゾリン－２－イル）シクロプロパン－１－カルボン酸（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシル（２７７ｍｇ，０．７９ｍｍｏｌ）をイソプロパノール（２．１ｍＬ）及び水（１７０μＬ）に溶解し、水酸化ナトリウム（６３ｍｇ，１．５７ｍｍｏｌ）を加えて８０℃で２５時間撹拌した後、減圧下溶媒を留去した。得られた残渣に３Ｎ塩酸及び水を加えて酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、酢酸エチル及びヘキサンを用いて析出させた固体をろ取し表題化合物（淡黄色固体，７３ｍｇ，４３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．８－２．９（ｍ，１Ｈ），７．６７（ｄｄｄ，１Ｈ，Ｊ＝１，７，７Ｈｚ），７．９１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．９７（ｄｄｄ，１Ｈ，Ｊ＝１，７，７Ｈｚ），８．０３（ｄｄ，１Ｈ，Ｊ＝１，７Ｈｚ），９．３９（ｓ，１Ｈ）．１Ｈ分観測できず Reference example 40-3
(1S, 2S) -2- (quinazoline-2-yl) cyclopropane-1-carboxylic acid
Figure JPOXMLDOC01-appb-C000112
 (1S, 2S) -2- (quinazoline-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl (277 mg, 0) synthesized in Reference Example 40-2 .79 mmol) was dissolved in isopropanol (2.1 mL) and water (170 μL), sodium hydroxide (63 mg, 1.57 mmol) was added, and the mixture was stirred at 80 ° C. for 25 hours, and then the solvent was distilled off under reduced pressure. 3N Hydrochloric acid and water were added to the obtained residue, and the mixture was extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and the solid precipitated with ethyl acetate and hexane was collected by filtration to give the title compound (pale yellow solid, 73 mg, 43%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.9 (m, 1H), 2.3-2.4 (m, 1H) , 2.8-2.9 (m, 1H), 7.67 (ddd, 1H, J = 1,7,7Hz), 7.91 (d, 1H, J = 7Hz), 7.97 (ddd, 1H, J = 1,7,7Hz), 8.03 (dd, 1H, J = 1,7Hz), 9.39 (s, 1H). Cannot observe for 1H
参考例４１－１
（Ｒ）－（１－（３－（メチルスルホニル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000113
 参考例１－１と同様の手法に従い、１－ブロモ－３－（メチルスルホニル）ベンゼン（６３ｍｇ，０．２７ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２７ｍｍｏｌ）を用いて表題化合物（淡黄色オイル，５７ｍｇ，６２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０４（ｓ，３Ｈ），３．２１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３４（ｂｒ　ｓ，１Ｈ），４．７８（ｂｒ　ｓ，１Ｈ），６．７５（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．０２（ｔ，１Ｈ，Ｊ＝２Ｈｚ），７．２０（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．３８（ｔ，１Ｈ，Ｊ＝８Ｈｚ）． Reference example 41-1
(R)-(1- (3- (Methylsulfonyl) phenyl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000113
 Following the same procedure as in Reference Example 1-1, 1-bromo-3- (methylsulfonyl) benzene (63 mg, 0.27 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (50 mg, 0.27 mmol) ) Was used to obtain the title compound (pale yellow oil, 57 mg, 62%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.04 (S, 3H), 3.21 (dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.63 (dd, 1H, J = 6,10Hz), 4 .34 (br s, 1H), 4.78 (br s, 1H), 6.75 (dd, 1H, J = 2.8Hz), 7.02 (t, 1H, J = 2Hz), 7.20 (D, 1H, J = 8Hz), 7.38 (t, 1H, J = 8Hz).
参考例４１－２
（Ｒ）－１－（３－（メチルスルホニル）フェニル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000114
 参考例１－２と同様の手法に従い、参考例４１－１で合成した（Ｒ）－（１－（３－（メチルスルホニル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（５７ｍｇ，０．１７ｍｍｏｌ）を用いて表題化合物（淡黄色オイル，１２ｍｇ，３０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．０４（ｓ，３Ｈ），３．７８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．３－３．６（ｍ，３Ｈ），３．７７（ｑｕｉｎ，１Ｈ，Ｊ＝６Ｈｚ），６．７４（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．０２（ｔ，１Ｈ，Ｊ＝２Ｈｚ），７．１７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．３７（ｔ，１Ｈ，Ｊ＝８Ｈｚ）．２Ｈ分観測できず Reference example 41-2
(R) -1- (3- (Methylsulfonyl) phenyl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000114
 Tert-Butyl (R)-(1- (3- (methylsulfonyl) phenyl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 41-1 according to the same method as in Reference Example 1-2 (57 mg, 0) .17 mmol) was used to give the title compound (pale yellow oil, 12 mg, 30%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.04 (s, 3H), 3.78 (Dd, 1H, J = 6,10Hz), 3.3-3.6 (m, 3H), 3.77 (quin, 1H, J = 6Hz), 6.74 (dd, 1H, J = 2, 8Hz), 7.02 (t, 1H, J = 2Hz), 7.17 (d, 1H, J = 8Hz), 7.37 (t, 1H, J = 8Hz). Cannot observe for 2 hours
参考例４２－１
（Ｒ）－（１－（３－シアノフェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000115
 参考例１－１と同様の手法に従い、３－ブロモベンゾニトリル（５４ｍｇ，０．３０ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２７ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，５７ｍｇ，７４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１６（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３７（ｂｒ　ｓ，１Ｈ），４．７６（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．７－６．８（ｍ，２Ｈ），６．９４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．２－７．３（ｍ，１Ｈ）． Reference example 42-1
(R)-(1- (3-Cyanophenyl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000115
 Following the same procedure as in Reference Example 1-1, the title compound was used with 3-bromobenzonitrile (54 mg, 0.30 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (50 mg, 0.27 mmol). (Pale yellow amorphous, 57 mg, 74%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.16 (Dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.57 (dd, 1H, J = 6,10Hz), 4.37 (br s, 1H), 4.76 (d, 1H, J = 6Hz), 6.7-6.8 (m, 2H), 6.94 (d, 1H, J = 7Hz), 7.2-7.3 (m, 1H) ).
参考例４２－２
（Ｒ）－３－（３－アミノピロリジン－１－イル）ベンゾニトリル
Figure JPOXMLDOC01-appb-C000116
 参考例１－２と同様の手法に従い、参考例４２－１で合成した（Ｒ）－（１－（３－シアノフェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（５７ｍｇ，０．２０ｍｍｏｌ）を用いて表題化合物（淡黄色オイル，３２ｍｇ，８５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝５，９Ｈｚ），３．２－３．６（ｍ，３Ｈ），３．７６（ｑｕｉｎ，１Ｈ，Ｊ＝６Ｈｚ），６．６－６．８（ｍ，２Ｈ），６．９１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．２－７．３（ｍ，１Ｈ）．２Ｈ分観測できず Reference example 42-2
(R) -3- (3-aminopyrrolidine-1-yl) benzonitrile
Figure JPOXMLDOC01-appb-C000116
 Tert-Butyl (R)-(1- (3-cyanophenyl) pyrrolidine-3-yl) carbamate (57 mg, 0.20 mmol) synthesized in Reference Example 42-1 according to the same method as in Reference Example 1-2. Was used to give the title compound (pale yellow oil, 32 mg, 85%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.11 (dd, 1H, J = 5, 9Hz), 3.2-3.6 (m, 3H), 3.76 (quin, 1H, J = 6Hz), 6.6-6.8 (m, 2H), 6.91 (d, 1H, J = 7Hz), 7.2-7.3 (m, 1H). Cannot observe for 2 hours
参考例４３－１
トランス－２－（（２－アミノ－５－シアノフェニル）カルバモイル）シクロプロパン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000117
 参考例７－１と同様の手法に従い、トランス－２－（エトキシカルボニル）シクロプロパン－１－カルボン酸（１００ｍｇ，０．６３ｍｍｏｌ）及び３，４－ジアミノベンゾニトリル（１０１ｍｇ，０．７６ｍｍｏｌ）を用いて表題化合物の粗体を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２７（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．３－１．６（ｍ，２Ｈ），２．１－２．４（ｍ，２Ｈ），４．１５（ｑ，２Ｈ，Ｊ＝７Ｈｚ），４．７５（ｂｒ　ｓ，２Ｈ），６．７２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．７２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．２２（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．５７（ｄ，１Ｈ，Ｊ＝２Ｈｚ）． Reference example 43-1
Ethyl trans-2-((2-amino-5-cyanophenyl) carbamoyl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000117
 Trans-2- (ethoxycarbonyl) cyclopropane-1-carboxylic acid (100 mg, 0.63 mmol) and 3,4-diaminobenzonitrile (101 mg, 0.76 mmol) were used in the same manner as in Reference Example 7-1. The crude product of the title compound was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.27 (t, 3H, J = 7 Hz), 1.3-1.6 (m, 2H), 2.1-2.4 (m, 2H) , 4.15 (q, 2H, J = 7Hz), 4.75 (br s, 2H), 6.72 (d, 1H, J = 8Hz), 6.72 (d, 1H, J = 8Hz), 7.22 (dd, 1H, J = 2.8Hz), 7.57 (d, 1H, J = 2Hz).
参考例４３－２
トランス－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000118
 参考例４３－１で合成したトランス－２－（（２－アミノ－５－シアノフェニル）カルバモイル）シクロプロパン－１－カルボン酸エチルの粗体を酢酸中８５℃で５時間加熱した後、室温まで放冷し減圧下溶媒を留去した。炭酸水素ナトリウム水溶液を加えしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル）（濃度勾配：４０－８０％）により精製し表題化合物（微褐色アモルファス，１４２ｍｇ，８８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２７（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．７－１．９（ｍ，２Ｈ），２．４－２．６（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），４．１５（ｑ，２Ｈ，Ｊ＝７Ｈｚ），７．４－８．０（ｍ，２Ｈ），７．４９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１１．５８（ｂｒ　ｓ，１Ｈ）． Reference example 43-2
Ethyl trans-2- (5-cyano-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylate
Figure JPOXMLDOC01-appb-C000118
 A crude product of ethyl trans-2-((2-amino-5-cyanophenyl) carbamoyl) cyclopropane-1-carboxylate synthesized in Reference Example 43-1 was heated in acetic acid at 85 ° C. for 5 hours and then brought to room temperature. The mixture was allowed to cool and the solvent was distilled off under reduced pressure. An aqueous sodium hydrogen carbonate solution was added, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) (concentration gradient: 40-80%) to give the title compound (slight brown amorphous, 142 mg, 88%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.27 (t, 3H, J = 7 Hz), 1.7-1.9 (m, 2H), 2.4-2.6 (m, 1H) , 2.7-2.8 (m, 1H), 4.15 (q, 2H, J = 7Hz), 7.4-8.0 (m, 2H), 7.49 (d, 1H, J = 7 Hz), 11.58 (br s, 1H).
参考例４３－３
トランス－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸
Figure JPOXMLDOC01-appb-C000119
 参考例４３－２で合成したトランス－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸エチル（１４２ｍｇ，０．５６ｍｍｏｌ）をメタノール（６ｍＬ）及び水（１ｍＬ）に溶解し水酸化リチウム一水和物（４７ｍｇ，１．１１ｍｍｏｌ）を加えて室温で撹拌した後、減圧下溶媒を留去した。得られた残渣に３Ｎ塩酸を加えて減圧下溶媒を留去した。酢酸エチル及びヘキサンを用いて析出させた固体をろ取し表題化合物（８５ｍｇ，６７％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），２．６－２．８（ｍ，１Ｈ），７．５２（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．６１（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．８７（ｓ，１Ｈ）．２Ｈ分観測できず Reference example 43-3
Trans-2- (5-cyano-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid
Figure JPOXMLDOC01-appb-C000119
 Trans-2- (5-cyano-1H-benzo [d] imidazol-2-yl) cyclopropan-1-carboxylate ethyl (142 mg, 0.56 mmol) synthesized in Reference Example 43-2 was added to methanol (6 mL) and It was dissolved in water (1 mL), lithium hydroxide monohydrate (47 mg, 1.11 mmol) was added, and the mixture was stirred at room temperature, and then the solvent was distilled off under reduced pressure. 3N Hydrochloric acid was added to the obtained residue, and the solvent was distilled off under reduced pressure. The solid precipitated with ethyl acetate and hexane was collected by filtration to give the title compound (85 mg, 67%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.6-1.8 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 7.52 (dd, 1H, J = 1.8Hz), 7.61 (d, 1H, J = 8Hz), 7.87 (s, 1H). Cannot observe for 2 hours
参考例４４
（Ｒ）－（１－（２－（トリフルオロメチル）ピリジン－４－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000120
 参考例９と同様の手法に従い、４－クロロ－２－（トリフルオロメチル）ピリジン（４９ｍｇ，０．２７ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２７ｍｍｏｌ）を用いて表題化合物（白色アモルファス）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３８（ｂｒ　ｓ，１Ｈ），４．８－５．１（ｍ，１Ｈ），６．４６（ｄｄ，１Ｈ，Ｊ＝２，６Ｈｚ），６．７２（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２８（ｄ，１Ｈ，Ｊ＝６Ｈｚ）． Reference example 44
(R)-(1- (2- (Trifluoromethyl) Pyridine-4-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000120
 Following the same procedure as in Reference Example 9, 4-chloro-2- (trifluoromethyl) pyridine (49 mg, 0.27 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (50 mg, 0.27 mmol). Was used to obtain the title compound (white amorphous).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.24 (Dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.66 (dd, 1H, J = 6,10Hz), 4.38 (br s, 1H), 4.8-5.1 (m, 1H), 6.46 (dd, 1H, J = 2.6Hz), 6.72 (d, 1H, J = 2Hz), 8.28 (d, 1H, J) = 6Hz).
参考例４５－１
（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000121
 参考例１－１と同様の手法に従い、５－ブロモ－２－（トリフルオロメチル）ピリジン（６２ｍｇ，０．２７ｍｍｏｌ）及び（Ｒ）－ピペリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２５ｍｍｏｌ）を用いて表題化合物（微褐色固体，７２ｍｇ，８４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－２．０（ｍ，４Ｈ），１．４６（ｓ，９Ｈ），２．９－４．０（ｍ，５Ｈ），４．５－４．９（ｍ，１Ｈ），７．３３（ｓ，１Ｈ），８．３１（ｓ，１Ｈ），８．４６（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 45-1
(R)-(1- (6- (trifluoromethyl) Pyridine-3-yl) Piperidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000121
 Following the same procedure as in Reference Example 1-1, 5-bromo-2- (trifluoromethyl) pyridine (62 mg, 0.27 mmol) and tert-butyl (R) -piperidine-3-ylcarbamate (50 mg, 0. 25 mmol) was used to give the title compound (light brown solid, 72 mg, 84%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-2.0 (m, 4H), 1.46 (s, 9H), 2.9-4.0 (m, 5H), 4.5 -4.9 (m, 1H), 7.33 (s, 1H), 8.31 (s, 1H), 8.46 (d, 1H, J = 3Hz).
参考例４５－２
（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－アミン
Figure JPOXMLDOC01-appb-C000122
 参考例１－２と同様の手法に従い、参考例４５－１で合成した（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（７２ｍｇ，０．２１ｍｍｏｌ）を用いて表題化合物（微褐色シロップ，５０ｍｇ，９７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．４（ｍ，１Ｈ），１．６－１．８（ｍ，１Ｈ），１．８－２．１（ｍ，２Ｈ），２．６８（ｄｄ，１Ｈ，Ｊ＝９，１２Ｈｚ），２．８－３．１（ｍ，２Ｈ），３．５－３．６（ｍ，１Ｈ），３．６－３．７（ｍ，１Ｈ），７．３２（ｓ，１Ｈ），８．２８（ｄ，１Ｈ，Ｊ＝１Ｈｚ），８．４５（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．２Ｈ分観測できず Reference example 45-2
(R) -1- (6- (trifluoromethyl) Pyridine-3-yl) Piperidine-3-amine
Figure JPOXMLDOC01-appb-C000122
 (R)-(1- (6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) carbamic acid tert- synthesized in Reference Example 45-1 according to the same method as in Reference Example 1-2. The title compound (light brown syrup, 50 mg, 97%) was obtained using butyl (72 mg, 0.21 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.4 (m, 1H), 1.6-1.8 (m, 1H), 1.8-2.1 (m, 2H) , 2.68 (dd, 1H, J = 9,12Hz), 2.8-3.1 (m, 2H), 3.5-3.6 (m, 1H), 3.6-3.7 ( m, 1H), 7.32 (s, 1H), 8.28 (d, 1H, J = 1Hz), 8.45 (d, 1H, J = 3Hz). Cannot observe for 2 hours
参考例４６－１
２－クロロ－４－（トリフルオロメチル）チアゾール
Figure JPOXMLDOC01-appb-C000123
 ４－（トリフルオロメチル）チアゾール－２－アミン（１００ｍｇ，０．６０ｍｍｏｌ）及び塩化銅（II）（９６ｍｇ，０．７１ｍｍｏｌ）をアセトニトリル（８ｍＬ）に懸濁させ、亜硝酸ｔｅｒｔ－ブチル（９２ｍｇ，０．８９ｍｍｏｌ）を加えて室温１時間撹拌した。反応液を氷冷した１Ｎ塩酸に加えジエチルエーテルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下（７００ｍｂａｒ）、３０℃で溶媒を留去し表題化合物の粗体を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝７．６９（ｓ，１Ｈ）． Reference example 46-1
2-Chloro-4- (trifluoromethyl) thiazole
Figure JPOXMLDOC01-appb-C000123
 4- (Trifluoromethyl) thiazole-2-amine (100 mg, 0.60 mmol) and copper (II) chloride (96 mg, 0.71 mmol) were suspended in acetonitrile (8 mL) and tert-butyl nitrite (92 mg, 92 mg, 0.89 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to ice-cooled 1N hydrochloric acid and extracted with diethyl ether. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and then the solvent was distilled off at 30 ° C. under reduced pressure (700 mbar) to obtain a crude product of the title compound.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 7.69 (s, 1H).
参考例４６－２
（Ｒ）－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000124
 （Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１１１ｍｇ，０．６０ｍｍｏｌ）、参考例４６－１で合成した２－クロロ－４－（トリフルオロメチル）チアゾールの粗体及び炭酸カリウム（９９ｍｇ，０．７２ｍｍｏｌ）をアセトニトリル（８ｍＬ）に溶解した後、６０℃で１７時間撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル）（濃度勾配：１０－６０％）により精製し表題化合物（淡黄色固体，１４７ｍｇ，７３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．３５（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．５－３．７（ｍ，２Ｈ），３．７５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３８（ｂｒ　ｓ，１Ｈ），４．８２（ｂｒ　ｓ，１Ｈ），６．９２（ｓ，１Ｈ）． Reference example 46-2
(R)-(1- (4- (Trifluoromethyl) Thiazole-2-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000124
 (R) -Pyrrolidine-3-ylcarbamate tert-butyl (111 mg, 0.60 mmol), crude of 2-chloro-4- (trifluoromethyl) thiazole synthesized in Reference Example 46-1 and potassium carbonate (99 mg) , 0.72 mmol) was dissolved in acetonitrile (8 mL) and then stirred at 60 ° C. for 17 hours. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) (concentration gradient: 10-60%) to give the title compound (pale yellow solid, 147 mg, 73%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.35 (Dd, 1H, J = 4,10Hz), 3.5-3.7 (m, 2H), 3.75 (dd, 1H, J = 6,10Hz), 4.38 (br s, 1H), 4.82 (br s, 1H), 6.92 (s, 1H).
参考例４６－３
（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000125
 参考例１－２と同様の手法に従い、参考例４６－２で合成した（Ｒ）－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１４７ｍｇ，０．４４ｍｍｏｌ）を用いて表題化合物（淡黄色シロップ，９４ｍｇ，９１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，１Ｈ），３．６－３．７（ｍ，２Ｈ），３．７－３．９（ｍ，１Ｈ），６．９０（ｄ，１Ｈ，Ｊ＝１Ｈｚ）．２Ｈ分観測できず Reference example 46-3
(R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000125
 (R)-(1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 46-2 according to the same method as in Reference Example 1-2. Butyl (147 mg, 0.44 mmol) was used to give the title compound (pale yellow syrup, 94 mg, 91%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.3 (m, 1H), 3.23 (dd, 1H, J = 4, 10Hz), 3.4-3.6 (m, 1H), 3.6-3.7 (m, 2H), 3.7-3.9 (m, 1H), 6.90 (d, 1H, J = 1Hz). Cannot observe for 2 hours
参考例４７－１
（Ｒ）－（１－（４－（トリフルオロメチル）フェニル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000126
 参考例１－１と同様の手法に従い、１－ブロモ－４－（トリフルオロメチル）ベンゼン（６２ｍｇ，０．２７ｍｍｏｌ）及び（Ｒ）－ピペリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２５ｍｍｏｌ）を用いて表題化合物（淡黄色固体，５９ｍｇ，６８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．９（ｍ，１３Ｈ），２．８－３．９（ｍ，５Ｈ），４．４－４．９（ｍ，１Ｈ），６．９４（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．４６（ｄ，２Ｈ，Ｊ＝９Ｈｚ）． Reference example 47-1
(R)-(1- (4- (Trifluoromethyl) phenyl) piperidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000126
 Following the same procedure as in Reference Example 1-1, 1-bromo-4- (trifluoromethyl) benzene (62 mg, 0.27 mmol) and tert-butyl (R) -piperidine-3-ylcarbamate (50 mg, 0. 25 mmol) was used to give the title compound (pale yellow solid, 59 mg, 68%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.9 (m, 13H), 2.8-3.9 (m, 5H), 4.4-4.9 (m, 1H) , 6.94 (d, 2H, J = 9Hz), 7.46 (d, 2H, J = 9Hz).
参考例４７－２
（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピペリジン－３－アミン
Figure JPOXMLDOC01-appb-C000127
 参考例１－２と同様の手法に従い、参考例４７－１で合成した（Ｒ）－（１－（４－（トリフルオロメチル）フェニル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（５９ｍｇ，０．１７ｍｍｏｌ）を用いて表題化合物（微褐色シロップ，４２ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．４（ｍ，１Ｈ），１．６－１．９（ｍ，２Ｈ），１．９－２．１（ｍ，１Ｈ），２．６７（ｄｄ，１Ｈ，Ｊ＝９，１２Ｈｚ），２．８－３．０（ｍ，２Ｈ），３．５４（ｄｔ，１Ｈ，Ｊ＝４，１２Ｈｚ），３．６－３．７（ｍ，１Ｈ），６．９２（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．４５（ｄ，２Ｈ，Ｊ＝９Ｈｚ）．２Ｈ分観測できず Reference example 47.2
(R) -1- (4- (trifluoromethyl) phenyl) piperidine-3-amine
Figure JPOXMLDOC01-appb-C000127
 Tert-butyl (R)-(1- (4- (trifluoromethyl) phenyl) piperidin-3-yl) carbamate synthesized in Reference Example 47-1 according to the same procedure as in Reference Example 1-2 (59 mg, 0.17 mmol) was used to give the title compound (light brown syrup, 42 mg, 100%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.4 (m, 1H), 1.6-1.9 (m, 2H), 1.9-2.1 (m, 1H) , 2.67 (dd, 1H, J = 9,12Hz), 2.8-3.0 (m, 2H), 3.54 (dt, 1H, J = 4,12Hz), 3.6-3. 7 (m, 1H), 6.92 (d, 2H, J = 9Hz), 7.45 (d, 2H, J = 9Hz). Cannot observe for 2 hours
参考例４８－１
（Ｒ）－（１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000128
 参考例１－１と同様の手法に従い、５－ブロモ－２－メトキシ－３－（トリフルオロメチル）ピリジン（１５１ｍｇ，０．５９ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１００ｍｇ，０．５４ｍｍｏｌ）を用いて表題化合物（淡黄色固体，２６ｍｇ，１３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１５（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ），３．２９（ｄｔ，１Ｈ，Ｊ＝６，９Ｈｚ），３．３－３．５（ｍ，１Ｈ），３．５３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．９６（ｓ，３Ｈ），４．３８（ｂｒ　ｓ，１Ｈ），４．７５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．６２（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 48-1
(R)-(1- (6-Methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000128
 Following the same procedure as in Reference Example 1-1, 5-bromo-2-methoxy-3- (trifluoromethyl) pyridine (151 mg, 0.59 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (tert-butyl (R) -pyrrolidine-3-ylcarbamate). The title compound (pale yellow solid, 26 mg, 13%) was obtained using 100 mg (0.54 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.15 (Dd, 1H, J = 4.9Hz), 3.29 (dt, 1H, J = 6.9Hz), 3.3-3.5 (m, 1H), 3.53 (dd, 1H, J = 6,10Hz), 3.96 (s, 3H), 4.38 (br s, 1H), 4.75 (d, 1H, J = 7Hz), 7.12 (d, 1H, J = 3Hz), 7.62 (d, 1H, J = 3Hz).
参考例４８－２
（Ｒ）－１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000129
 参考例１－２と同様の手法に従い、参考例４８－１で合成した（Ｒ）－（１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（２６ｍｇ，０．０７ｍｍｏｌ）を用いて表題化合物（淡黄色シロップ，１８ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．９（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．０１（ｄｄ，１Ｈ，Ｊ＝５，９Ｈｚ），３．３０（ｄｔ，１Ｈ，Ｊ＝６，８Ｈｚ），３．４－３．５（ｍ，２Ｈ），３．７６（ｑｕｉｎ，１Ｈ，Ｊ＝６Ｈｚ），３．９６（ｓ，３Ｈ），７．１１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．６２（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．２Ｈ分観測できず Reference example 48-2
(R) -1- (6-Methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000129
 (R)-(1- (6-methoxy-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) synthesized in Reference Example 48-1 according to the same method as in Reference Example 1-2) The title compound (pale yellow syrup, 18 mg, 100%) was obtained using tert-butyl carbamate (26 mg, 0.07 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.9 (m, 1H), 2.2-2.3 (m, 1H), 3.01 (dd, 1H, J = 5, 9Hz), 3.30 (dt, 1H, J = 6.8Hz), 3.4-3.5 (m, 2H), 3.76 (quin, 1H, J = 6Hz), 3.96 (s, 3H), 7.11 (d, 1H, J = 3Hz), 7.62 (d, 1H, J = 3Hz). Cannot observe for 2 hours
参考例４９－１
（Ｒ）－（１－（４－（ｔｅｒｔ－ブチル）チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000130
 参考例９と同様の手法に従い、２－ブロモ－４－（ｔｅｒｔ－ブチル）チアゾール（１００ｍｇ，０．４５ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１２７ｍｇ，０．６８ｍｍｏｌ）を用いて表題化合物（無色オイル，１０３ｍｇ，７０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２７（ｓ，９Ｈ），１．４５（ｓ，９Ｈ），１．９－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．３１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ）），３．７１（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．３５（ｂｒ　ｓ，１Ｈ），４．７４（ｂｒ　ｓ，１Ｈ），６．０６（ｓ，１Ｈ）． Reference example 49-1
(R)-(1- (4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000130
 Following the same procedure as in Reference Example 9, 2-bromo-4- (tert-butyl) thiazole (100 mg, 0.45 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (127 mg, 0.68 mmol). Was used to give the title compound (colorless oil, 103 mg, 70%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.27 (s, 9H), 1.45 (s, 9H), 1.9-2.0 (m, 1H), 2.2-2.4 (M, 1H), 3.31 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H)), 3.71 (dd, 1H, J = 6,11Hz), 4.35 (br s, 1H), 4.74 (br s, 1H), 6.06 (s, 1H).
参考例４９－２
（Ｒ）－１－（４－（ｔｅｒｔ－ブチル）チアゾール－２－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000131
 参考例１－２と同様の手法に従い、参考例４９－１で合成した（Ｒ）－（１－（４－（ｔｅｒｔ－ブチル）チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１０３ｍｇ，０．３２ｍｍｏｌ）を用いて表題化合物（無色オイル，６５ｍｇ，９１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２７（ｓ，９Ｈ），１．７－１．９（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．１７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．８（ｍ，４Ｈ），６．０４（ｓ，１Ｈ）．２Ｈ分観測できず Reference example 49-2
(R) -1- (4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000131
 (R)-(1- (4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 49-1 according to the same method as in Reference Example 1-2. The title compound (colorless oil, 65 mg, 91%) was obtained using butyl (103 mg, 0.32 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.27 (s, 9H), 1.7-1.9 (m, 1H), 2.1-2.3 (m, 1H), 3.17 (Dd, 1H, J = 4,10 Hz), 3.4-3.8 (m, 4H), 6.04 (s, 1H). Cannot observe for 2 hours
参考例５０
（Ｒ）－（１－（６－（トリフルオロメチル）ピリダジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000132
参考例９と同様の手法に従い、３－クロロ－６－（トリフルオロメチル）ピリダジン（６０ｍｇ，０．３２２ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５９ｍｇ，０．３２２ｍｍｏｌ）を用いて表題化合物（白色粉末，９０ｍｇ，８４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．４－４．０（ｍ，４Ｈ），４．４１（ｂｒ　ｓ，１Ｈ），４．７１（ｂｒ　ｓ，１Ｈ），６．６７（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），７．４８（ｄ，１Ｈ，Ｊ＝１０Ｈｚ）． Reference example 50
(R)-(1- (6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000132
Following the same procedure as in Reference Example 9, 3-chloro-6- (trifluoromethyl) pyridazine (60 mg, 0.322 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (59 mg, 0.322 mmol) Was used to give the title compound (white powder, 90 mg, 84%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.4 -4.0 (m, 4H), 4.41 (br s, 1H), 4.71 (br s, 1H), 6.67 (d, 1H, J = 10Hz), 7.48 (d, 1H) , J = 10Hz).
参考例５１
（Ｒ）－（１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000133
参考例１－１と同様の手法に従い、５－ブロモ－２－（トリフルオロメチル）ピリミジン（１３４ｍｇ，０．５９１ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１００ｍｇ，０．５３７ｍｍｏｌ）を用いて表題化合物（黄色粉末，１２９ｍｇ，７２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．２８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４２（ｂｒ　ｓ，１Ｈ），４．６９（ｂｒ　ｓ，１Ｈ），８．１０（ｓ，２Ｈ）． Reference example 51
(R)-(1- (2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000133
Following the same procedure as in Reference Example 1-1, 5-bromo-2- (trifluoromethyl) pyrimidine (134 mg, 0.591 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (100 mg, 0. 537 mmol) was used to give the title compound (yellow powder, 129 mg, 72%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.28 (Dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.70 (dd, 1H, J = 6,10Hz), 4.42 (br s, 1H), 4.69 (br s, 1H), 8.10 (s, 2H).
参考例５２
（Ｒ）－（１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000134
（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２６８ｍｍｏｌ）及び２－クロロ－６－フルオロベンゾチアゾール（５８ｍｇ，０．３０９ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解した後、炭酸セシウム（１０１ｍｇ，０．３０９ｍｍｏｌ）を加えて１００℃で２時間撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：２５－４０％）により精製し表題化合物（淡黄色粉末，８５ｍｇ，９４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．４４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．６－３．８（ｍ，２Ｈ），３．８３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４１（ｂｒ　ｓ，１Ｈ），４．７０（ｂｒ　ｓ，１Ｈ），７．０２（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．３２（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．５０（ｄｄ，１Ｈ，Ｊ＝５，９Ｈｚ）． Reference example 52
(R)-(1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000134
After dissolving tert-butyl (R) -pyrrolidine-3-ylcarbamic acid (50 mg, 0.268 mmol) and 2-chloro-6-fluorobenzothiazole (58 mg, 0.309 mmol) in DMF (1 mL), cesium carbonate (101 mg, 0.309 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 25-40%) to give the title compound (pale yellow powder, 85 mg, 94%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.44 (Dd, 1H, J = 4,10Hz), 3.6-3.8 (m, 2H), 3.83 (dd, 1H, J = 6,10Hz), 4.41 (br s, 1H), 4.70 (br s, 1H), 7.02 (dd, 1H, J = 3.9Hz), 7.32 (dd, 1H, J = 3.8Hz), 7.50 (dd, 1H, J = 5,9 Hz).
参考例５３
（Ｒ）－（１－（６－フルオロキノリン－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000135
（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５０ｍｇ，０．２６８ｍｍｏｌ）及び２－クロロ－６－フルオロキノリン（５４ｍｇ，０．２９５ｍｍｏｌ）をトルエン（１．５ｍＬ）及び水（１５０μＬ）に溶解した後、炭酸カリウム（４４ｍｇ，０．３２２ｍｍｏｌ）を加えて窒素雰囲気下、終夜加熱還流した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：２０－３２％）により精製し表題化合物（白色粉末，３９ｍｇ，４４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．５１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．６－３．８（ｍ，２Ｈ），３．８７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３９（ｂｒ　ｓ，１Ｈ），４．７３（ｂｒ　ｓ，１Ｈ），６．７５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．２－７．４（ｍ，２Ｈ），７．６７（ｄｄ，１Ｈ，Ｊ＝６，９Ｈｚ），７．８２（ｄ，１Ｈ，Ｊ＝９Ｈｚ）． Reference example 53
(R)-(1- (6-Fluoroquinoline-2-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000135
Add tert-butyl (R) -pyrrolidine-3-ylcarbamic acid (50 mg, 0.268 mmol) and 2-chloro-6-fluoroquinoline (54 mg, 0.295 mmol) to toluene (1.5 mL) and water (150 μL). After dissolution, potassium carbonate (44 mg, 0.322 mmol) was added, and the mixture was heated under reflux overnight under a nitrogen atmosphere. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 20-32%) to give the title compound (white powder, 39 mg, 44%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.51 (Dd, 1H, J = 4,10Hz), 3.6-3.8 (m, 2H), 3.87 (dd, 1H, J = 6,10Hz), 4.39 (br s, 1H), 4.73 (br s, 1H), 6.75 (d, 1H, J = 9Hz), 7.2-7.4 (m, 2H), 7.67 (dd, 1H, J = 6,9Hz) , 7.82 (d, 1H, J = 9Hz).
参考例５４－１
（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシル
Figure JPOXMLDOC01-appb-C000136
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシル（４０８ｍｇ，１．１ｍｍｏｌ）、シクロプロピルボロン酸（１８４ｍｇ，２．１ｍｍｏｌ）及び炭酸ナトリウム（２２７ｍｇ，２．１ｍｍｏｌ）をトルエン（４ｍＬ）に溶解した後、トルエン（７ｍＬ）に懸濁させた酢酸銅（ＩＩ）一水和物　（２１４ｍｇ，１．１ｍｍｏｌ）及び２，２’－ビピリジル（１６７ｍｇ，１．１ｍｍｏｌ）を加えて７０℃で終夜撹拌した。反応液に飽和塩化アンモニウム水溶液と水を加え、酢酸エチルで抽出した。分離した有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル）（濃度勾配：１０％－２５％）により精製し表題化合物（無色油状物，２７０ｍｇ，６６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．８０（ｄ，３Ｈ，Ｊ＝７Ｈｚ），０．９－１．５（ｍ，１５Ｈ），１．６－２．１（ｍ，６Ｈ），２．３２（ｄｄｄ，１Ｈ，Ｊ＝４，６，９Ｈｚ），２．８７（ｄｄｄ，１Ｈ，Ｊ＝４，６，９Ｈｚ），３．３０（ｄｄｄ，１Ｈ，Ｊ＝４，７，１１Ｈｚ），４．７３（ｔｄ，１Ｈ，Ｊ＝４，１１Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４－７．７（ｍ，２Ｈ）． Reference example 54-1
(1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl
Figure JPOXMLDOC01-appb-C000136
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl (408 mg, 1.1 mmol) ), Cyclopropylboronic acid (184 mg, 2.1 mmol) and sodium carbonate (227 mg, 2.1 mmol) were dissolved in toluene (4 mL) and then suspended in toluene (7 mL) for monohydration of cupric acetate (II). The product (214 mg, 1.1 mmol) and 2,2'-bipyridyl (167 mg, 1.1 mmol) were added, and the mixture was stirred at 70 ° C. overnight. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) (concentration gradient: 10% -25%) to give the title compound (colorless oil, 270 mg, 66%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.80 (d, 3H, J = 7 Hz), 0.9-1.5 (m, 15H), 1.6-2.1 (m, 6H) , 2.32 (ddd, 1H, J = 4,6,9Hz), 2.87 (ddd, 1H, J = 4,6,9Hz), 3.30 (ddd, 1H, J = 4,7,11Hz) ), 4.73 (td, 1H, J = 4,11Hz), 7.2-7.3 (m, 2H), 7.4-7.7 (m, 2H).
参考例５４－２
（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸
Figure JPOXMLDOC01-appb-C000137
参考例５４－１で合成した（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（１Ｒ，２Ｓ，５Ｒ）－２－イソプロピル－５－メチルシクロヘキシル（２７０ｍｇ，０．７０９ｍｍｏｌ）をイソプロパノール（２ｍＬ）及び水（１５０μＬ）に懸濁した後、水酸化ナトリウム（５７ｍｇ，１．４２ｍｍｏｌ）を加え８０℃で５時間撹拌した。溶媒を減圧下留去した後、得られた残渣に０．２規定水酸化ナトリウム水溶液（２０ｍＬ）を加え、ジエチルエーテルで２回洗浄した。水層に１規定塩酸（１５ｍＬ）を加え酸性とした後、溶媒を留去することで得られた残渣にトルエン及び水を加え懸濁させた。得られた固体をろ取して室温で減圧乾燥し表題化合物（白色粉末，４８ｍｇ，２８％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．１－１．４（ｍ，４Ｈ），１．７１（ｑｕｉｎ，１Ｈ，Ｊ＝５Ｈｚ），１．８－１．９（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），２．９３（ｄｄｄ，１Ｈ，Ｊ＝４，６，９Ｈｚ），３．５－３．７（ｍ，１Ｈ），７．４４（ｑｕｉｎ，２Ｈ，Ｊ＝８Ｈｚ），７．６７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．７７（ｄ，１Ｈ，Ｊ＝８Ｈｚ）．１Ｈ分観測できず Reference example 54-2
(1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid
Figure JPOXMLDOC01-appb-C000137
(1S, 2S) -2- (1-cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (1R, 2S, 5R) -2 synthesized in Reference Example 54-1 -Isopropyl-5-methylcyclohexyl (270 mg, 0.709 mmol) was suspended in isopropanol (2 mL) and water (150 μL), sodium hydroxide (57 mg, 1.42 mmol) was added, and the mixture was stirred at 80 ° C. for 5 hours. After distilling off the solvent under reduced pressure, a 0.2N aqueous sodium hydroxide solution (20 mL) was added to the obtained residue, and the mixture was washed twice with diethyl ether. After adding 1N hydrochloric acid (15 mL) to the aqueous layer to make it acidic, toluene and water were added to the residue obtained by distilling off the solvent and suspended. The obtained solid was collected by filtration and dried under reduced pressure at room temperature to give the title compound (white powder, 48 mg, 28%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.1-1.4 (m, 4H), 1.71 (quin, 1H, J = 5 Hz), 1.8-1.9 (m, 1H), 2.3-2.5 (m, 1H), 2.93 (ddd, 1H, J = 4,6,9Hz), 3.5-3.7 (m, 1H), 7.44 ( quin, 2H, J = 8Hz), 7.67 (d, 1H, J = 8Hz), 7.77 (d, 1H, J = 8Hz). Cannot observe for 1H
参考例５５
（Ｒ）－（１－（５－ブロモピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000138
参考例１－１と同様の手法に従い、３，５－ジブロモピリジン（１７８ｍｇ，０．７５１ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（４７ｍｇ，０．２５２ｍｍｏｌ）を用いて表題化合物（白色粉末，７１ｍｇ，８３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３８（ｂｒ　ｓ，１Ｈ），４．６８（ｂｒ　ｓ，１Ｈ），６．９５（ｔ，１Ｈ，Ｊ＝２Ｈｚ），７．７８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．８０（ｄ，１Ｈ，Ｊ＝２Ｈｚ）． Reference example 55
(R)-(1- (5-Bromopyridine-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000138
Following the same procedure as in Reference Example 1-1, the title was used with 3,5-dibromopyridine (178 mg, 0.751 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (47 mg, 0.252 mmol). A compound (white powder, 71 mg, 83%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.17 (Dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.59 (dd, 1H, J = 6,10Hz), 4.38 (br s, 1H), 4.68 (br s, 1H), 6.95 (t, 1H, J = 2Hz), 7.78 (d, 1H, J = 3Hz), 8.80 (d, 1H, J = 2Hz).
参考例５６
２－（４－（トリフルオロメチル）フェニル）酢酸－２，２－ｄ２
Figure JPOXMLDOC01-appb-C000139
４－（トリフルオロメチル）フェニル酢酸（５０ｍｇ，０．２４５ｍｍｏｌ）を重水（１ｍＬ）に溶解した後、４０％重水酸化ナトリウム溶液（０．５ｍＬ，７．００ｍｍｏｌ）を加えて窒素雰囲気下、終夜加熱還流した。室温まで放冷した反応液に重水を加えてジエチルエーテルで洗浄後、水層に３Ｎ塩酸を加え酸性とし、ジエチルエーテルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をクロロホルムに懸濁させ、不溶物をろ過後、減圧下溶媒を留去し表題化合物（白色粉末，３０ｍｇ，５９％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝７．４３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．５９（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．１Ｈ分観測できず Reference example 56
2- (4- (trifluoromethyl) phenyl) acetic acid-2,2-d 2
Figure JPOXMLDOC01-appb-C000139
After dissolving 4- (trifluoromethyl) phenylacetic acid (50 mg, 0.245 mmol) in heavy water (1 mL), add 40% sodium oxide solution (0.5 mL, 7.00 mmol) and heat overnight under a nitrogen atmosphere. Refluxed. Heavy water was added to the reaction solution allowed to cool to room temperature, washed with diethyl ether, 3N hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted with diethyl ether. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in chloroform, the insoluble material was filtered, and the solvent was evaporated under reduced pressure to give the title compound (white powder, 30 mg, 59%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 7.43 (d, 2H, J = 8 Hz), 7.59 (d, 2H, J = 8 Hz). Cannot observe for 1H
参考例５７
（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000140
参考例７－１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２１６ｍｍｏｌ）及び４－ブロモフェニル酢酸（５６ｍｇ，０．２５９ｍｍｏｌ）用いて表題化合物（淡黄色粉末，８８ｍｇ，９５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１６（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５２（ｂｒ　ｓ，１Ｈ），６．８０（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．１４（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．４－７．５（ｍ，３Ｈ），７．９８（ｄ，１Ｈ，Ｊ＝３Ｈｚ）． Reference example 57
(R) -2- (4-Bromophenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000140
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 32-2 according to the same method as in Reference Example 7-1. ) And 4-bromophenylacetic acid (56 mg, 0.259 mmol) to give the title compound (pale yellow powder, 88 mg, 95%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.16 (dd, 1H, J = 4, 10Hz), 3.3-3.5 (m, 2H), 3.53 (s, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.52 (br s, 1H), 6.80 (dd, 1H, J = 3.9Hz), 7.14 (d, 2H, J = 9Hz), 7.4-7.5 (m) , 3H), 7.98 (d, 1H, J = 3Hz).
参考例５８－１
（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000141
参考例４と同様の手法に従い、３－ブロモ－５－（トリフルオロメチル）ピリジン（３９０ｍｇ，１．７３ｍｍｏｌ）及びアゼチジン－３－イルカルバミン酸ｔｅｒｔ－ブチル塩酸塩（３００ｍｇ，１．４４ｍｍｏｌ）用いて表題化合物（淡黄色粉末，１１２ｍｇ，２５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），３．７６（ｄｄ，２Ｈ，Ｊ＝６，８Ｈｚ），４．３２（ｔ，２Ｈ，Ｊ＝７Ｈｚ），４．６９（ｂｒ　ｓ，１Ｈ），４．９９（ｂｒ　ｓ，１Ｈ），６．８６（ｓ，１Ｈ），７．９９（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２７（ｓ，１Ｈ）． Reference example 58-1
(1- (5- (Trifluoromethyl) Pyridine-3-yl) Azetidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000141
Following the same procedure as in Reference Example 4, 3-bromo-5- (trifluoromethyl) pyridine (390 mg, 1.73 mmol) and azetidine-3-ylcarbamic acid tert-butyl hydrochloride (300 mg, 1.44 mmol) were used. The title compound (pale yellow powder, 112 mg, 25%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 3.76 (dd, 2H, J = 6.8 Hz), 4.32 (t, 2H, J = 7 Hz), 4 .69 (br s, 1H), 4.99 (br s, 1H), 6.86 (s, 1H), 7.99 (d, 1H, J = 3Hz), 8.27 (s, 1H).
参考例５８－２
１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－アミン
Figure JPOXMLDOC01-appb-C000142
参考例１－２と同様の手法に従い、参考例５８－１で合成した（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１１２ｍｇ，０．３５３ｍｍｏｌ）用いて表題化合物（白色粉末，６０ｍｇ，７９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝３．５９（ｄｄ，２Ｈ，Ｊ＝６，８Ｈｚ），４．０－４．１（ｍ，１Ｈ），４．２７（ｔ，２Ｈ，Ｊ＝７Ｈｚ），６．８５（ｔ，１Ｈ，Ｊ＝２Ｈｚ），７．９９（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２４（ｓ，１Ｈ）．２Ｈ分観測できず Reference example 58-2
1- (5- (trifluoromethyl) Pyridine-3-yl) Azetidine-3-amine
Figure JPOXMLDOC01-appb-C000142
Tert-Butyl carbamic acid (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) synthesized in Reference Example 58-1 according to the same procedure as in Reference Example 1-2 (112 mg, 0.353 mmol) was used to give the title compound (white powder, 60 mg, 79%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 3.59 (dd, 2H, J = 6.8 Hz), 4.0-4.1 (m, 1H), 4.27 (t, 2H, J = 7Hz), 6.85 (t, 1H, J = 2Hz), 7.99 (d, 1H, J = 3Hz), 8.24 (s, 1H). Cannot observe for 2 hours
参考例５９
（Ｒ）－４－（４－（２－オキソ－２－（（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アミノ）エチル）フェニル）ピペラジン－１－カルボン酸ベンジル
Figure JPOXMLDOC01-appb-C000143
参考例７－１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（８０ｍｇ，０．３４６ｍｍｏｌ）及び２－（４－（４－（（ベンジルオキシ）カルボニル）ピペラジン－１－イル）フェニル）酢酸（１３５ｍｇ，０．３８１ｍｍｏｌ）用いて表題化合物（黄色粉末，１７６ｍｇ，９０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，５Ｈ），３．３７（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５１（ｓ，２Ｈ），３．６－３．７（ｍ，５Ｈ），４．５－４．７（ｍ，１Ｈ），５．１６（ｓ，２Ｈ），５．５３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，３Ｈ），７．１４（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．３－７．４（ｍ，５Ｈ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）． Reference example 59
(R) -4- (4- (2-oxo-2-((1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) amino) ethyl) phenyl) piperazin-1- Benzyl carboxylate
Figure JPOXMLDOC01-appb-C000143
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (80 mg, 0.346 mmol) synthesized in Reference Example 1-2 according to the same method as in Reference Example 7-1. ) And 2- (4- (4-((benzyloxy) carbonyl) piperazin-1-yl) phenyl) acetic acid (135 mg, 0.381 mmol) were used to give the title compound (yellow powder, 176 mg, 90%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 5H) , 3.37 (t, 2H, J = 7Hz), 3.51 (s, 2H), 3.6-3.7 (m, 5H), 4.5-4.7 (m, 1H), 5 .16 (s, 2H), 5.53 (d, 1H, J = 7Hz), 6.8-6.9 (m, 3H), 7.14 (d, 2H, J = 9Hz), 7.3 -7.4 (m, 5H), 8.07 (d, 1H, J = 3Hz), 8.20 (s, 1H).
参考例６０
２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000144
参考例２３－１と同様の手法に従い、２－（４－ブロモフェニル）酢酸エチル（３００ｍｇ，１．２３ｍｍｏｌ）及び４－ピペリドンエチレンケタール（３１７μＬ，２．４６ｍｍｏｌ）用いて表題化合物（黄色油状物，１６ｍｇ，４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２５（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．８４（ｔ，４Ｈ，Ｊ＝６Ｈｚ），３．３１（ｔ，４Ｈ，Ｊ＝６Ｈｚ），３．５２（ｓ，２Ｈ），３．９９（ｓ，４Ｈ），４．１４（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．９０（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．１６（ｄ，２Ｈ，Ｊ＝９Ｈｚ）． Reference example 60
2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000144
Following the same procedure as in Reference Example 23-1, the title compound (yellow oil) was used with 2- (4-bromophenyl) ethyl acetate (300 mg, 1.23 mmol) and 4-piperidone ethylene ketal (317 μL, 2.46 mmol). , 16 mg, 4%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.25 (t, 3H, J = 7 Hz), 1.84 (t, 4H, J = 6 Hz), 3.31 (t, 4H, J = 6 Hz) , 3.52 (s, 2H), 3.99 (s, 4H), 4.14 (q, 2H, J = 7Hz), 6.90 (d, 2H, J = 9Hz), 7.16 (d) , 2H, J = 9Hz).
参考例６１－１
７－（５－（トリフルオロメチル）ピリジン－３－イル）－３－オキサ－１，７－ジアザスピロ［４．４］ノナン－２－オン
Figure JPOXMLDOC01-appb-C000145
参考例１－１と同様の手法に従い、３－ブロモ－５－（トリフルオロメチル）ピリジン（１６２ｍｇ，０．７１７ｍｍｏｌ）及びＮ－（３－（ヒドロキシメチル）ピロリジン－３－イル）カルバミン酸ベンジル（１８９ｍｇ，０．７５３ｍｍｏｌ）用いて表題化合物（白色粉末，１０６ｍｇ，５１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．２－２．５（ｍ，２Ｈ），３．４－３．６（ｍ，４Ｈ），４．４１（ｄ，１Ｈ，Ｊ＝９Ｈｚ），４．４５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），５．５７（ｓ，１Ｈ），６．９７（ｔ，１Ｈ，Ｊ＝２Ｈｚ），８．１４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２９（ｓ，１Ｈ）． Reference example 61-1
7- (5- (trifluoromethyl) Pyridine-3-yl) -3-oxa-1,7-diazaspiro [4.4] nonane-2-one
Figure JPOXMLDOC01-appb-C000145
According to the same procedure as in Reference Example 1-1, 3-bromo-5- (trifluoromethyl) pyridine (162 mg, 0.717 mmol) and N- (3- (hydroxymethyl) pyrrolidine-3-yl) carbamate benzyl ( The title compound (white powder, 106 mg, 51%) was obtained using 189 mg, 0.753 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.2-2.5 (m, 2H), 3.4-3.6 (m, 4H), 4.41 (d, 1H, J = 9Hz) , 4.45 (d, 1H, J = 9Hz), 5.57 (s, 1H), 6.97 (t, 1H, J = 2Hz), 8.14 (d, 1H, J = 3Hz), 8 .29 (s, 1H).
参考例６１－２
（３－アミノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）メタノール
Figure JPOXMLDOC01-appb-C000146
参考例６１－１で合成した７－（５－（トリフルオロメチル）ピリジン－３－イル）－３－オキサ－１，７－ジアザスピロ［４．４］ノナン－２－オン（９５ｍｇ，０．３３１ｍｍｏｌ）をエタノール（４ｍＬ）及び水（１ｍＬ）に溶解し、水酸化リチウム一水和物（２７８ｍｇ，６．６１ｍｍｏｌ）を加えて窒素雰囲気下、終夜加熱還流した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去し表題化合物（黄色粉末，８６ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），３．１９（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．４－３．７（ｍ，５Ｈ），６．９３（ｔ，１Ｈ，Ｊ＝２Ｈｚ），８．１１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．３Ｈ分観測できず Reference example 61-2
(3-Amino-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methanol
Figure JPOXMLDOC01-appb-C000146
7- (5- (trifluoromethyl) pyridine-3-yl) -3-oxa-1,7-diazaspiro [4.4] nonane-2-one (95 mg, 0.331 mmol) synthesized in Reference Example 61-1 ) Was dissolved in ethanol (4 mL) and water (1 mL), lithium hydroxide monohydrate (278 mg, 6.61 mmol) was added, and the mixture was heated under reflux overnight under a nitrogen atmosphere. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was evaporated under reduced pressure to give the title compound (yellow powder, 86 mg, 100%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.1-2.2 (m, 1H), 3.19 (d, 1H, J = 10 Hz) , 3.4-3.7 (m, 5H), 6.93 (t, 1H, J = 2Hz), 8.11 (d, 1H, J = 3Hz), 8.20 (s, 1H). Cannot observe for 3 hours
参考例６２
２－（４－イソプロピルフェニル）－Ｎ－（ピペリジン－４－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000147
４－アミノ－１－ｔｅｒｔ－ブトキシカルボニルピペリジン（１．００ｇ，４．５４ｍｍｏｌ）及び２－（４－イソプロピルフェニル）酢酸（０．９７１ｇ，５．４５ｍｍｏｌ）をＤＭＦ（１３ｍＬ）に溶解した後、ＤＩＰＥＡ（２．３ｍＬ，１３．６ｍｍｏｌ）及びＨＡＴＵ（２．４２ｇ，６．３６ｍｍｏｌ）を加えて室温で終夜撹拌した。反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去し４－（２－（４－イソプロピルフェニル）アセトアミド）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルの粗体（茶褐色油状物，２．４５ｇ）を得た。参考例１－２と同様の手法に従い、得られた４－（２－（４－イソプロピルフェニル）アセトアミド）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルの粗体（２．４５ｇ）を用いて表題化合物（黄土色結晶，０．９１１ｇ，７７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．１－１．３（ｍ，９Ｈ），１．８－１．９（ｍ，２Ｈ），２．６５（ｔｄ，２Ｈ，Ｊ＝３，１２Ｈｚ），２．８－３．０（ｍ，３Ｈ），３．５２（ｓ，２Ｈ），３．８－４．０（ｍ，１Ｈ），５．２４（ｄ，１Ｈ，Ｊ＝６Ｈｚ），７．１－７．３（ｍ，４Ｈ）． Reference example 62
2- (4-Isopropylphenyl) -N- (piperidine-4-yl) acetamide
Figure JPOXMLDOC01-appb-C000147
After dissolving 4-amino-1-tert-butoxycarbonylpiperidine (1.00 g, 4.54 mmol) and 2- (4-isopropylphenyl) acetic acid (0.971 g, 5.45 mmol) in DMF (13 mL), DIPEA (2.3 mL, 13.6 mmol) and HATU (2.42 g, 6.36 mmol) were added and stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, the insoluble matter is filtered, and the solvent is distilled off under reduced pressure to remove 4- (2- (4-isopropylphenyl) acetamide) piperidin-1-carboxylic acid. A crude product of tert-butyl acid (brown oil, 2.45 g) was obtained. The title compound (2.45 g) was used as a crude product (2.45 g) of the obtained tert-butyl 4- (2- (4-isopropylphenyl) acetamide) piperidine-1-carboxylate according to the same procedure as in Reference Example 1-2. Ocher crystals, 0.911 g, 77%) were obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.1-1.3 (m, 9H), 1.8-1.9 (m, 2H), 2.65 (td, 2H, J = 3, 12Hz), 2.8-3.0 (m, 3H), 3.52 (s, 2H), 3.8-4.0 (m, 1H), 5.24 (d, 1H, J = 6Hz) , 7.1-7.3 (m, 4H).
参考例６３
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000148
参考例６２と同様の手法に従い、（３Ｒ）－（＋）－１－（ｔｅｒｔ－ブトキシカルボニル）－３－アミノピロリジン（２．００ｇ，１０．７ｍｍｏｌ）及び２－（４－イソプロピルフェニル）酢酸（２．３０ｇ，１２．９ｍｍｏｌ）を用いて（Ｒ）－３－（２－（４－イソプロピルフェニル）アセトアミド）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチルの粗体（４．２５ｇ）を合成後、表題化合物（淡桃色結晶，２．２２ｇ，８４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２５（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．４－１．５（ｍ，１Ｈ），２．０－２．２（ｍ，１Ｈ），２．６５（ｄｄ，１Ｈ，Ｊ＝４，１１Ｈｚ），２．８－３．０（ｍ，３Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝７，１１Ｈｚ），３．５１（ｓ，２Ｈ），４．３－４．４（ｍ，１Ｈ），５．５５（ｂｒ　ｓ，１Ｈ），７．１６（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．１Ｈ分観測できず Reference example 63
(R) -2- (4-Isopropylphenyl) -N- (pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000148
Following the same procedure as in Reference Example 62, (3R)-(+)-1- (tert-butoxycarbonyl) -3-aminopyrrolidine (2.00 g, 10.7 mmol) and 2- (4-isopropylphenyl) acetic acid ( After synthesizing a crude product (4.25 g) of tert-butyl (R) -3- (2- (4-isopropylphenyl) acetamide) pyrrolidine-1-carboxylate using 2.30 g, 12.9 mmol), the title A compound (pale pink crystal, 2.22 g, 84%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.25 (d, 6H, J = 7 Hz), 1.4-1.5 (m, 1H), 2.0-2.2 (m, 1H) , 2.65 (dd, 1H, J = 4,11Hz), 2.8-3.0 (m, 3H), 3.11 (dd, 1H, J = 7,11Hz), 3.51 (s, 2H), 4.3-4.4 (m, 1H), 5.55 (br s, 1H), 7.16 (d, 2H, J = 8Hz), 7.21 (d, 2H, J = 8Hz) ). Cannot observe for 1H
参考例６４－１
（Ｓ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000149
参考例４と同様の手法に従い、（Ｓ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（５００ｍｇ，２．６８ｍｍｏｌ）及び５－ブロモ－２－（トリフルオロメチル）ピリジン（７２８ｍｇ，３．２２ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，１８５ｍｇ，２０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４０（ｂｒ　ｓ，１Ｈ），４．７１（ｂｒ　ｓ，１Ｈ），６．９４（ｓ，１Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）． Reference example 64-1
(S)-(1- (5- (Trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000149
Following the same procedure as in Reference Example 4, tert-butyl (S) -pyrrolidine-3-ylcarbamate (500 mg, 2.68 mmol) and 5-bromo-2- (trifluoromethyl) pyridine (728 mg, 3.22 mmol). The title compound (pale yellow crystals, 185 mg, 20%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.23 (Dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.40 (br s, 1H), 4.71 (br s, 1H), 6.94 (s, 1H), 8.12 (d, 1H, J = 3Hz), 8.21 (s, 1H).
参考例６４－２
（Ｓ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン
Figure JPOXMLDOC01-appb-C000150
参考例１－２と同様の手法に従い、参考例６４－１で合成した（Ｓ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１８４ｍｇ，０．５５５ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，１００ｍｇ，７７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０８（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．６（ｍ，３Ｈ），３．８１（ｑｕｉｎ，１Ｈ，Ｊ＝６Ｈｚ）６．９２（ｓ，１Ｈ），８．１１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１７（ｓ，１Ｈ）．２Ｈ分観測できず Reference example 64-2
(S) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine
Figure JPOXMLDOC01-appb-C000150
(S)-(1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 64-1 according to the same method as in Reference Example 1-2. The title compound (pale yellow crystals, 100 mg, 77%) was obtained using butyl (184 mg, 0.555 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.08 (dd, 1H, J = 5, 10Hz), 3.3-3.6 (m, 3H), 3.81 (quin, 1H, J = 6Hz) 6.92 (s, 1H), 8.11 (d, 1H, J = 3Hz), 8.17 (s, 1H). Cannot observe for 2 hours
参考例６５
３－（２－（４－イソプロピルフェニル）アセトアミド）アゼチジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000151
参考例７－１と同様の手法に従い、３－アミノアゼチジン－１－カルボン酸ｔｅｒｔ－ブチル（５００ｍｇ，２．９０ｍｍｏｌ）及び２－（４－イソプロピルフェニル）酢酸（６２４ｍｇ，３．５０ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，９６４ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２６（ｄ，６Ｈ，Ｊ＝７Ｈｚ），２．８－３．０（ｍ，１Ｈ），３．５４（ｓ，２Ｈ），３．５－３．７（ｍ，２Ｈ），４．２－４．４（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），６．６－６．８（ｍ，１Ｈ），７．１５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２３（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 65
3- (2- (4-isopropylphenyl) acetamide) azetidine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000151
Following the same procedure as in Reference Example 7-1, tert-butyl 3-aminoazetidine-1-carboxylate (500 mg, 2.90 mmol) and 2- (4-isopropylphenyl) acetic acid (624 mg, 3.50 mmol) were used. The title compound (pale yellow amorphous, 964 mg, 100%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.26 (d, 6H, J = 7 Hz), 2.8-3.0 (m, 1H), 3.54 (s, 2H), 3.5 -3.7 (m, 2H), 4.2-4.4 (m, 2H), 4.5-4.7 (m, 1H), 6.6-6.8 (m, 1H), 7 .15 (d, 2H, J = 8Hz), 7.23 (d, 2H, J = 8Hz).
参考例６６
（Ｒ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000152
参考例４と同様の手法に従い、３－ブロモ－５－（トリフルオロメチル）ピリジン（４０７ｍｇ，１．８０ｍｍｏｌ）及び（Ｒ）－３－（ｔｅｒｔ－ブトキシカルボニルアミノ）ピペリジン（３００ｍｇ，１．５０ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，１００ｍｇ，２０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．６－１．８（ｍ，１Ｈ），１．８－２．０（ｍ，２Ｈ），２．９－３．２（ｍ，２Ｈ），３．２－３．４（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），３．８－３．９（ｍ，１Ｈ），４．７－４．８（ｍ，１Ｈ），７．３３（ｓ，１Ｈ），８．３２（ｓ，１Ｈ），８．４６（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．１Ｈ分観測できず Reference example 66
(R)-(1- (5- (trifluoromethyl) Pyridine-3-yl) Piperidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000152
Following the same procedure as in Reference Example 4, 3-bromo-5- (trifluoromethyl) pyridine (407 mg, 1.80 mmol) and (R) -3- (tert-butoxycarbonylamino) piperidine (300 mg, 1.50 mmol). The title compound (yellow amorphous, 100 mg, 20%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.6-1.8 (m, 1H), 1.8-2.0 (m, 2H), 2.9 -3.2 (m, 2H), 3.2-3.4 (m, 1H), 3.5-3.6 (m, 1H), 3.8-3.9 (m, 1H), 4 .7-4.8 (m, 1H), 7.33 (s, 1H), 8.32 (s, 1H), 8.46 (d, 1H, J = 2Hz). Cannot observe for 1H
参考例６７
（１－（４－シクロプロピルフェニル）－２－オキソ－２－（（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アミノ）エチル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000153
参考例７－１と同様の手法に従い、（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１５０ｍｇ，０．６５ｍｍｏｌ）及び２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－２－（４－シクロプロピルフェニル）酢酸（１８９ｍｇ，０．６５ｍｍｏｌ）を用いて表題化合物をそれぞれ（ジアステレオマーＡ：ＴＬＣ（酢酸エチル：ヘプタン＝１：１）においてＲｆ値＝０．２，黄色アモルファス，１５ｍｇ，５％，ジアステレオマーＢ：ＴＬＣ（酢酸エチル：ヘプタン＝１：１）においてＲｆ値＝０．１８，黄色アモルファス，１５ｍｇ，５％，ジアステレオマー混合物：２９０ｍｇ，８８％）得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．３９（ｓ，９Ｈ），１．８－１．９（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．５－３．６（ｍ，１Ｈ），４．５－４．７（ｍ，１Ｈ），５．０－５．１（ｍ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．２－６．３（ｍ，１Ｈ），６．８３（ｓ，１Ｈ），７．００（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．００（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１４（ｓ，１Ｈ）．
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．４０（ｓ，９Ｈ）１．８－２．０（ｍ，２Ｈ），２．２－２．３（ｍ，１Ｈ），３．２－３．４（ｍ，３Ｈ），３．６－３．７（ｍ，１Ｈ），４．６－４．７（ｍ，１Ｈ），５．０－５．１（ｍ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．２－６．３（ｍ，１Ｈ），６．８５（ｓ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１２（ｓ，１Ｈ）． Reference example 67
(1- (4-Cyclopropylphenyl) -2-oxo-2-(((R) -1-(5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) amino) ethyl) carbamate Tert-Butyl acid
Figure JPOXMLDOC01-appb-C000153
Following the same procedure as in Reference Example 7-1, (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (150 mg, 0.65 mmol) and 2-((tert-) Rf values in each of the title compounds (diastereomer A: TLC (ethyl acetate: heptane = 1: 1)) using butoxycarbonyl) amino) -2- (4-cyclopropylphenyl) acetic acid (189 mg, 0.65 mmol). = 0.2, yellow amorphous, 15 mg, 5%, diastereomer B: Rf value = 0.18 at TLC (ethyl acetate: heptan = 1: 1), yellow amorphous, 15 mg, 5%, diastereomer mixture: 290 mg, 88%) was obtained.
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.39 (s, 9H), 1.8 -1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3 .3-3.5 (m, 2H), 3.5-3.6 (m, 1H), 4.5-4.7 (m, 1H), 5.0-5.1 (m, 1H) , 5.5-5.7 (m, 1H), 6.2-6.3 (m, 1H), 6.83 (s, 1H), 7.00 (d, 2H, J = 8Hz), 7 .19 (d, 2H, J = 8Hz), 8.00 (d, 1H, J = 3Hz), 8.14 (s, 1H).
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.40 (s, 9H) 1.8- 2.0 (m, 2H), 2.2-2.3 (m, 1H), 3.2-3.4 (m, 3H), 3.6-3.7 (m, 1H), 4. 6-4.7 (m, 1H), 5.0-5.1 (m, 1H), 5.5-5.7 (m, 1H), 6.2-6.3 (m, 1H), 6.85 (s, 1H), 7.04 (d, 2H, J = 8Hz), 7.22 (d, 2H, J = 8Hz), 8.01 (d, 1H, J = 3Hz), 8. 12 (s, 1H).
参考例６８
（Ｒ）－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000154
参考例４と同様の手法に従い、３－ブロモ－５－（トリフルオロメチル）ピリジン（７９ｍｇ，０．２３ｍｍｏｌ）及び（Ｒ）－（３－メチルピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（４７ｍｇ，０．２３ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，５０ｍｇ，６３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．５４（ｓ，３Ｈ），１．９－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．３－３．５（ｍ，３Ｈ），３．５－３．６（ｍ，１Ｈ），４．６６（ｂｒ　ｓ，１Ｈ），６．９２（ｓ，１Ｈ），８．１０（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ）． Reference example 68
(R)-(3-Methyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000154
Following the same procedure as in Reference Example 4, 3-bromo-5- (trifluoromethyl) pyridine (79 mg, 0.23 mmol) and (R)-(3-methylpyrrolidine-3-yl) carbamate tert-butyl (47 mg) , 0.23 mmol) was used to give the title compound (yellow amorphous, 50 mg, 63%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.54 (s, 3H), 1.9-2.1 (m, 1H), 2.3-2.5 (M, 1H), 3.3-3.5 (m, 3H), 3.5-3.6 (m, 1H), 4.66 (br s, 1H), 6.92 (s, 1H) , 8.10 (d, 1H, J = 3Hz), 8.19 (s, 1H).
参考例６９
２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000155
参考例２７と同様の手法に従い、４－ブロモフェニル酢酸エチル（１０９ｍｇ，０．４５ｍｍｏｌ）及び３－オキサ－８－アザビシクロ［３．２．１］オクタン塩酸塩（１００ｍｇ，０．６７ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，８７ｍｇ，７０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２５（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．９－２．１（ｍ，４Ｈ），３．５１（ｓ，２Ｈ），３．４－３．６（ｍ，２Ｈ），３．９１（ｄ，２Ｈ，Ｊ＝１０Ｈｚ），４．０－４．１（ｍ，２Ｈ），４．１４（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．７４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１５（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 69
2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000155
Following the same procedure as in Reference Example 27, using ethyl 4-bromophenylacetate (109 mg, 0.45 mmol) and 3-oxa-8-azabicyclo [3.2.1] octane hydrochloride (100 mg, 0.67 mmol). The title compound (pale yellow amorphous, 87 mg, 70%) was obtained.
1 1 H NMR (CDCl 3,400 MHz): δ = 1.25 (t, 3H, J = 7 Hz), 1.9-2.1 (m, 4H), 3.51 (s, 2H), 3.4- 3.6 (m, 2H), 3.91 (d, 2H, J = 10Hz), 4.0-4.1 (m, 2H), 4.14 (q, 2H, J = 7Hz), 6. 74 (d, 2H, J = 8Hz), 7.15 (d, 2H, J = 8Hz).
参考例７０
２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）酢酸エチル
Figure JPOXMLDOC01-appb-C000156
参考例２７と同様の手法に従い、４－ブロモフェニル酢酸エチル（１０９ｍｇ，０．４５ｍｍｏｌ）及び（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタンシュウ酸塩（１０６ｍｇ，０．６７ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，１０９ｍｇ，８８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２５（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．６－１．８（ｍ，１Ｈ），１．８－２．０（ｍ，１Ｈ），２．０－２．３（ｍ，２Ｈ），３．３－３．４（ｍ，１Ｈ），３．５１（ｓ，２Ｈ），３．７－３．９（ｍ，２Ｈ），４．０－４．１（ｍ，２Ｈ），４．１－４．２（ｍ，１Ｈ），４．１３（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．５９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１６（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 70
2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) ethyl acetate
Figure JPOXMLDOC01-appb-C000156
Following the same procedure as in Reference Example 27, ethyl 4-bromophenylacetate (109 mg, 0.45 mmol) and (1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane oxalate (106 mg, 0.67 mmol) was used to give the title compound (pale yellow amorphous, 109 mg, 88%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.25 (t, 3H, J = 7 Hz), 1.6-1.8 (m, 1H), 1.8-2.0 (m, 1H) , 2.0-2.3 (m, 2H), 3.3-3.4 (m, 1H), 3.51 (s, 2H), 3.7-3.9 (m, 2H), 4 0.0-4.1 (m, 2H), 4.1-4.2 (m, 1H), 4.13 (q, 2H, J = 7Hz), 6.59 (d, 2H, J = 8Hz) , 7.16 (d, 2H, J = 8Hz).
参考例７１
３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000157
参考例４と同様の手法に従い、３－ブロモ－５－（トリフルオロメチル）ピリジン（１６０ｍｇ，０．２３ｍｍｏｌ）及び３－（トリフルオロメチル）ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１５０ｍｇ，０．５９ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，１４５ｍｇ，６２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），２．５－２．８（ｍ，２Ｈ），３．５－３．７（ｍ，２Ｈ），３．８－３．９（ｍ，１Ｈ），３．９－４．０（ｍ，１Ｈ），４．８５（ｂｒ　ｓ，１Ｈ），６．９８（ｓ，１Ｈ），８．１４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２６（ｓ，１Ｈ）． Reference example 71
3- (Trifluoromethyl) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000157
Following the same procedure as in Reference Example 4, 3-bromo-5- (trifluoromethyl) pyridine (160 mg, 0.23 mmol) and 3- (trifluoromethyl) pyrrolidine-3-ylcarbamate tert-butyl (150 mg, 0) .59 mmol) was used to give the title compound (yellow amorphous, 145 mg, 62%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 2.5-2.8 (m, 2H), 3.5-3.7 (m, 2H), 3.8 -3.9 (m, 1H), 3.9-4.0 (m, 1H), 4.85 (br s, 1H), 6.98 (s, 1H), 8.14 (d, 1H, J = 3Hz), 8.26 (s, 1H).
参考例７２
（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000158
参考例４と同様の手法に従い、５－ブロモ－２－（トリフルオロメチル）ピリジン（４０７ｍｇ，１．８０ｍｍｏｌ）及び（Ｒ）－３－（ｔｅｒｔ－ブトキシカルボニルアミノ）ピペリジン（３００ｍｇ，１．５０ｍｍｏｌ）を用いて表題化合物（黄色結晶，４００ｍｇ，７７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．６－２．０（ｍ，４Ｈ），２．９－３．１（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，１Ｈ），３．６－３．７（ｍ，１Ｈ），３．７－３．８（ｍ，１Ｈ），４．６５（ｂｒ　ｓ，１Ｈ），７．１７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．４９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），８．３３（ｓ，１Ｈ）． Reference example 72
(R)-(1- (6- (trifluoromethyl) Pyridine-3-yl) Piperidine-3-yl) tert-Butyl Carbamic Acid
Figure JPOXMLDOC01-appb-C000158
Following the same procedure as in Reference Example 4, 5-bromo-2- (trifluoromethyl) pyridine (407 mg, 1.80 mmol) and (R) -3- (tert-butoxycarbonylamino) piperidine (300 mg, 1.50 mmol). Was used to give the title compound (yellow crystals, 400 mg, 77%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.6-2.0 (m, 4H), 2.9-3.1 (m, 1H), 3.1 -3.2 (m, 1H), 3.3-3.5 (m, 1H), 3.6-3.7 (m, 1H), 3.7-3.8 (m, 1H), 4 .65 (br s, 1H), 7.17 (d, 1H, J = 7Hz), 7.49 (d, 1H, J = 7Hz), 8.33 (s, 1H).
参考例７３－１
（Ｒ）－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）ピロリジン－１－カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000159
参考例７－１と同様の手法に従い、（Ｒ）－アミノピロリジン－１－カルバミン酸ｔｅｒｔ－ブチル（１．１１ｇ，６．０ｍｍｏｌ）及び２－（４－（トリフルオロメチル）フェニル）酢酸（１．３５ｇ，６．６ｍｍｏｌ）用いて表題化合物（白色固体，１．９６ｇ，８８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４５（ｓ，９Ｈ），１．６－１．９（ｍ，１Ｈ），２．０－２．２（ｍ，１Ｈ），３．０－３．５（ｍ，３Ｈ），３．５－３．７（ｍ，１Ｈ），３．６０（ｓ，２Ｈ），４．３－４．５（ｍ，１Ｈ），５．５３（ｂｒ　ｓ，１Ｈ），７．３９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 73-1
(R) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-1-carbamic acid tert-butyl
Figure JPOXMLDOC01-appb-C000159
Following the same procedure as in Reference Example 7-1, tert-butyl (R) -aminopyrrolidine-1-carbamic acid (1.11 g, 6.0 mmol) and 2- (4- (trifluoromethyl) phenyl) acetic acid (1). The title compound (white solid, 1.96 g, 88%) was obtained using .35 g, 6.6 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.45 (s, 9H), 1.6-1.9 (m, 1H), 2.0-2.2 (m, 1H), 3.0 -3.5 (m, 3H), 3.5-3.7 (m, 1H), 3.60 (s, 2H), 4.3-4.5 (m, 1H), 5.53 (br) s, 1H), 7.39 (d, 2H, J = 8Hz), 7.61 (d, 2H, J = 8Hz).
参考例７３－２
（Ｒ）－Ｎ－（ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000160
 参考例１－２と同様の手法に従い、参考例７３－１で合成した（Ｒ）－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）ピロリジン－１－カルバミン酸ｔｅｒｔ－ブチル（１．１２ｇ，３．０ｍｍｏｌ）用いて表題化合物（白色固体，６５０ｍｇ，８０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４－１．６（ｍ，１Ｈ），２．０－２．２（ｍ，１Ｈ），２．７１（ｄｄ，１Ｈ，Ｊ＝４，１１Ｈｚ），２．８－３．１（ｍ，２Ｈ），３．１０（ｄｄ，１Ｈ，Ｊ＝７，１２Ｈｚ），３．５７（ｓ，２Ｈ），４．３－４．４（ｍ，１Ｈ），５．６９（ｂｒ　ｓ，１Ｈ），７．３９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６０（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．１Ｈ分観測されず Reference example 73-2
(R) -N- (pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide
Figure JPOXMLDOC01-appb-C000160
 (R) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-1-carbamic acid tert-butyl synthesized in Reference Example 73-1 according to the same method as in Reference Example 1-2 ( The title compound (white solid, 650 mg, 80%) was obtained using 1.12 g, 3.0 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.4-1.6 (m, 1H), 2.0-2.2 (m, 1H), 2.71 (dd, 1H, J = 4, 11Hz), 2.8-3.1 (m, 2H), 3.10 (dd, 1H, J = 7,12Hz), 3.57 (s, 2H), 4.3-4.4 (m, 1H), 5.69 (br s, 1H), 7.39 (d, 2H, J = 8Hz), 7.60 (d, 2H, J = 8Hz). Not observed for 1H
参考例７４－１
（Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000161
参考例７－１と同様の手法に従い、３－アミノピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（１．５ｍＬ，８．２９ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（１．８ｇ，９．９５ｍｍｏｌ）を用いて表題化合物（黄色結晶，２．０ｇ，７０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．４３（ｓ，９Ｈ），１．５－１．７（ｍ，１Ｈ），１．８－１．９（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．９－３．１（ｍ，１Ｈ），３．２－３．５（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．５－３．６（ｍ，１Ｈ），４．３－４．５（ｍ，１Ｈ），５．３－５．５（ｍ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１０（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 74-1
(R) -3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000161
Following the same procedure as in Reference Example 7-1, tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 mL, 8.29 mmol) and 2- (4-cyclopropylphenyl) synthesized in Reference Example 33-2. The title compound (yellow crystals, 2.0 g, 70%) was obtained using acetic acid (1.8 g, 9.95 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.43 (s, 9H), 1.5 -1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.9-3.1 (m, 1H), 3 .2-3.5 (m, 2H), 3.51 (s, 2H), 3.5-3.6 (m, 1H), 4.3-4.5 (m, 1H), 5.3 -5.5 (m, 1H), 7.04 (d, 2H, J = 8Hz), 7.10 (d, 2H, J = 8Hz).
参考例７４－２
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000162
参考例１－２と同様の手法に従い、参考例７４－１で合成した（Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（２．０ｇ，５．８１ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，１．１ｇ，７７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．４－１．５（ｍ，１Ｈ），１．８－１．９（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．６－２．７（ｍ，１Ｈ），２．８－３．０（ｍ，２Ｈ），３．０－３．１（ｍ，１Ｈ），３．４８（ｓ，２Ｈ），４．２－４．４（ｂｒ　ｓ，１Ｈ），５．６２（ｂｒ　ｓ，１Ｈ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 74-2
(R) -2- (4-Cyclopropylphenyl) -N- (pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000162
Tert-Butyl (R) -3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-carboxylate synthesized in Reference Example 74-1 according to the same procedure as in Reference Example 1-2 (2.0 g) , 5.81 mmol) was used to give the title compound (pale yellow crystals, 1.1 g, 77%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.4-1.5 (m, 1H) , 1.8-1.9 (m, 2H), 2.0-2.2 (m, 1H), 2.6-2.7 (m, 1H), 2.8-3.0 (m, 2H), 3.0-3.1 (m, 1H), 3.48 (s, 2H), 4.2-4.4 (br s, 1H), 5.62 (br s, 1H), 7 .03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz).
参考例７５－１
３－（２－（４－シクロプロピルフェニル）アセトアミド）アゼチジン－１－カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000163
参考例７－１と同様の手法に従い、３－アミノアゼチジン－１－カルバミン酸ｔｅｒｔ－ブチル（２７６ｍｇ，１．６ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（３５２ｍｇ，２．０ｍｍｏｌ）用いて表題化合物（白色固体，４３４ｍｇ，８２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．１（ｍ，２Ｈ），１．４１（ｓ，９Ｈ），１．８－２．０（ｍ，１Ｈ），３．５３（ｓ，２Ｈ），３．５８（ｄｄ，２Ｈ，Ｊ＝５，１０Ｈｚ），４．２８（ｔ，２Ｈ，Ｊ＝９Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．７１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．０７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ）． Reference example 75-1
3- (2- (4-Cyclopropylphenyl) acetamide) azetidine-1-carbamic acid tert-butyl
Figure JPOXMLDOC01-appb-C000163
Following the same procedure as in Reference Example 7-1, tert-butyl 3-aminoazetidine-1-carbamic acid (276 mg, 1.6 mmol) and 2- (4-cyclopropylphenyl) acetic acid synthesized in Reference Example 33-2. (352 mg, 2.0 mmol) was used to give the title compound (white solid, 434 mg, 82%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.41 (s, 9H), 1.8 -2.0 (m, 1H), 3.53 (s, 2H), 3.58 (dd, 2H, J = 5,10Hz), 4.28 (t, 2H, J = 9Hz), 4.5 -4.7 (m, 1H), 5.71 (d, 1H, J = 7Hz), 7.07 (d, 2H, J = 8Hz), 7.12 (d, 2H, J = 8Hz).
参考例７５－２
Ｎ－（アゼチジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000164
参考例１－２と同様の手法に従い、参考例７５－１で合成した３－（２－（４－シクロプロピルフェニル）アセトアミド）アゼチジン－１－カルバミン酸ｔｅｒｔ－ブチル（４３１ｍｇ，１．３ｍｍｏｌ）用いて表題化合物（白色固体，８３ｍｇ，２８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．１（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），３．３－３．６（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．８－３．９（ｍ，２Ｈ），４．６－４．８（ｍ，１Ｈ），５．７１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．０６（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１３（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．１Ｈ分観測できず Reference example 75-2
N- (azetidine-3-yl) -2- (4-cyclopropylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000164
Using tert-butyl 3- (2- (4-cyclopropylphenyl) acetamide) azetidine-1-carbamic acid (431 mg, 1.3 mmol) synthesized in Reference Example 75-1 according to the same method as in Reference Example 1-2. The title compound (white solid, 83 mg, 28%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 1H) , 3.3-3.6 (m, 2H), 3.51 (s, 2H), 3.8-3.9 (m, 2H), 4.6-4.8 (m, 1H), 5 .71 (d, 1H, J = 7Hz), 7.06 (d, 2H, J = 8Hz), 7.13 (d, 2H, J = 8Hz). Cannot observe for 1H
参考例７６
２－（３－ブロモフェノキシ）－２－メチルプロパン酸エチル
Figure JPOXMLDOC01-appb-C000165
参考例５２と同様の手法に従い、３－ブロモフェノール（１７３ｍｇ，１．０ｍｍｏｌ）及び２－ブロモ－２－メチルプロパン酸エチル（１９５ｍｇ，１．０ｍｍｏｌ）を用いて表題化合物（白色アモルファス，１４９ｍｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２６（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．６０（ｓ，６Ｈ），４．２４（ｑ，２Ｈ，Ｊ＝７Ｈｚ），６．７－６．８（ｍ，１Ｈ），７．０－７．２（ｍ，３Ｈ）． Reference example 76
Ethyl 2- (3-bromophenoxy) -2-methylpropanoate
Figure JPOXMLDOC01-appb-C000165
Following the same procedure as in Reference Example 52, the title compound (white amorphous, 149 mg, 86) was used with 3-bromophenol (173 mg, 1.0 mmol) and ethyl 2-bromo-2-methylpropanoate (195 mg, 1.0 mmol). %) Was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.26 (t, 3H, J = 7 Hz), 1.60 (s, 6H), 4.24 (q, 2H, J = 7 Hz), 6.7 -6.8 (m, 1H), 7.0-7.2 (m, 3H).
参考例７７
（Ｒ）－（１－（３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000166
参考例１－１と同様の手法に従い、３－ブロモベンゾトリフルオリド（８９μＬ，０．６４４ｍｍｏｌ）及び（Ｒ）－ピロリジン－３－イルカルバミン酸ｔｅｒｔ－ブチル（１００ｍｇ，０．５３７ｍｍｏｌ）を用いて表題化合物（黄色粉末，１０５ｍｇ，５９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．４６（ｓ，９Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１９（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３８（ｂｒ　ｓ，１Ｈ），４．６９（ｂｒ　ｓ，１Ｈ），６．６８（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），６．７３（ｓ，１Ｈ），６．９３（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．３１（ｔ，１Ｈ，Ｊ＝８Ｈｚ）．
Reference example 77
(R)-(1- (3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) tert-butyl carbamic acid
Figure JPOXMLDOC01-appb-C000166
Following the same procedure as in Reference Example 1-1, the title was used with 3-bromobenzotrifluoride (89 μL, 0.644 mmol) and tert-butyl (R) -pyrrolidine-3-ylcarbamate (100 mg, 0.537 mmol). The compound (yellow powder, 105 mg, 59%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.46 (s, 9H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.19 (Dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.60 (dd, 1H, J = 6,10Hz), 4.38 (br s, 1H), 4.69 (br s, 1H), 6.68 (dd, 1H, J = 2.8Hz), 6.73 (s, 1H), 6.93 (d, 1H, J = 8Hz), 7.31 (T, 1H, J = 8Hz).
実施例１
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000167
参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２０ｍｇ，０．０９ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（３０ｍｇ，０．０９ｍｍｏｌ）をＤＭＦ（２．０ｍＬ）に溶解した後、ＤＩＰＥＡ（２９μＬ，０．１７ｍｍｏｌ）及びＨＡＴＵ（３３ｍｇ，０．０９ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（白色粉末，１８ｍｇ，５３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．５４（ｓ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．６０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０６（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：３９０．２０［Ｍ＋Ｈ］＋ Example 1
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000167
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and 2 synthesized in Reference Example 33-2. -(4-Cyclopropylphenyl) acetic acid (30 mg, 0.09 mmol) is dissolved in DMF (2.0 mL), then DIPEA (29 μL, 0.17 mmol) and HATU (33 mg, 0.09 mmol) are added at room temperature. Stirred overnight. Water was added to the reaction mixture, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (white powder, 18 mg, 53%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.11 (dd, 1H, J = 4,10Hz), 3.3-3.4 (m, 2H), 3.54 (s, 2H) , 3.64 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 5.60 (d, 1H, J = 6Hz), 6.8-6.9 ( m, 1H), 7.04 (d, 2H, J = 8Hz), 7.12 (d, 2H, J = 8Hz), 8.06 (d, 1H, J = 2Hz), 8.19 (s, 1H).
MS: 390.20 [M + H] +
実施例２
（Ｒ）－２－（５－（トリフルオロメチル）ピリジン－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000168
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２０ｍｇ，０．０９ｍｍｏｌ）及び参考例３１－２で合成した２－（５－（トリフルオロメチル）ピリジン－２－イル）酢酸の粗体（２６ｍｇ）を用いて表題化合物（白色結晶，１１ｍｇ，３１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，２Ｈ），２．３－２．４（ｍ，１Ｈ），３．２５（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．８１（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），６．９－７．０（ｍ，１Ｈ），７．４－７．５（ｍ，２Ｈ），８．１２（ｂｒ　ｓ，１Ｈ），８．２２（ｂｒ　ｓ，１Ｈ），８．７７（ｓ，１Ｈ）．
ＭＳ：４１９．１５［Ｍ＋Ｈ］＋ Example 2
(R) -2- (5- (trifluoromethyl) pyridin-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000168
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 11 mg, 31%) was obtained using a crude product (26 mg) of 2- (5- (trifluoromethyl) pyridine-2-yl) acetic acid synthesized in Reference Example 31-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 2H), 2.3-2.4 (m, 1H), 3.25 (dd, 1H, J = 4, 10Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 3.81 (s, 2H), 4.6-4.7 (m, 1H), 6.9-7.0 (m, 1H), 7.4-7.5 (m, 2H), 8.12 (br s, 1H), 8.22 (br s, 1H), 8 .77 (s, 1H).
MS: 419.15 [M + H] +
実施例３
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000169
参考例２で合成した（Ｒ）－（１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（４１ｍｇ，０．１２ｍｍｏｌ）に氷冷下でトリフルオロ酢酸（２．０ｍＬ）を加え、室温で３時間撹拌した。氷冷下、反応液に飽和炭酸水素ナトリウム水溶液及び酢酸エチルを加えてしばらく撹拌した後、有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して（Ｒ）－１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－アミンの粗体（淡黄色油状物，１８ｍｇ）を得た。実施例１と同様の手法に従い、得られた（Ｒ）－１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－アミンの粗体（１８ｍｇ）及び２－（４－イソプロピルフェニル）酢酸（２６ｍｇ，０．１５ｍｍｏｌ）を用いて表題化合物（象牙色粉末，１４ｍｇ，２９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２３（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．８－２．９（ｍ，１Ｈ），３．１７（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．４－３．５（ｍ，２Ｈ），３．５６（ｓ，２Ｈ），３．７１（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．５０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），７．１５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０６（ｓ，２Ｈ）．
ＭＳ：３９１．２６［Ｍ－Ｈ］－ Example 3
(R) -2- (4-Isopropylphenyl) -N- (1- (2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000169
To tert-butyl (R)-(1- (2- (trifluoromethyl) pyrimidin-5-yl) pyrrolidine-3-yl) carbamic acid (41 mg, 0.12 mmol) synthesized in Reference Example 2 under ice-cooling. Trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was stirred for a while, the organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure (R). A crude (pale yellow oil, 18 mg) of -1- (2- (trifluoromethyl) pyrimidin-5-yl) pyrrolidine-3-amine was obtained. The crude (18 mg) and 2- (4-isopropyl) of the obtained (R) -1- (2- (trifluoromethyl) pyrimidin-5-yl) pyrrolidine-3-amine obtained according to the same procedure as in Example 1. The title compound (ivory powder, 14 mg, 29%) was obtained using phenyl) acetic acid (26 mg, 0.15 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.23 (d, 6H, J = 7 Hz), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H) , 2.8-2.9 (m, 1H), 3.17 (dd, 1H, J = 5,10Hz), 3.4-3.5 (m, 2H), 3.56 (s, 2H) , 3.71 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 5.50 (d, 1H, J = 6Hz), 7.15 (d, 2H, J = 8Hz), 7.21 (d, 2H, J = 8Hz), 8.06 (s, 2H).
MS: 391.26 [MH] -
実施例４
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000170
実施例３と同様の手法に従い、参考例１－１で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１３０ｍｇ，０．３９ｍｍｏｌ）から（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（１００ｍｇ）を合成し、２－（４－イソプロピルフェニル）酢酸（８５ｍｇ，０．４８ｍｍｏｌ）を用いて表題化合物（白色アモルファス，９０ｍｇ，５８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２２（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．８－２．９（ｍ，１Ｈ），３．１２（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．５５（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．６－４．７（ｍ，１Ｈ），５．７－５．８（ｍ，１Ｈ），６．８７（ｓ，１Ｈ），７．１－７．３（ｍ，４Ｈ），８．０４（ｓ，１Ｈ），８．１７（ｓ，１Ｈ）．　
ＭＳ：３９１．１９［Ｍ－Ｈ］－ Example 4
(R) -2- (4-isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000170
Tert-Butyl (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 1-1 according to the same procedure as in Example 3 (130 mg) , 0.39 mmol) to synthesize a crude (100 mg) of (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine and 2- (4-isopropylphenyl) acetate. (85 mg, 0.48 mmol) was used to give the title compound (white amorphous, 90 mg, 58%).
1 1 H NMR (CDCl 3,400 MHz): δ = 1.22 (d, 6H, J = 7 Hz), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.8-2.9 (m, 1H), 3.12 (dd, 1H, J = 4.9Hz), 3.3-3.4 (m, 2H), 3.55 (s, 2H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5.7-5.8 (m, 1H), 6.87 (s, 1H), 7. 1-7.3 (m, 4H), 8.04 (s, 1H), 8.17 (s, 1H).
MS: 391.19 [MH] -
実施例５
２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－ヒドロキシ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000171
実施例３と同様の手法に従い、参考例３で合成した（（３Ｓ，４Ｓ）－４－ヒドロキシ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１０６ｍｇ，０．３１ｍｍｏｌ）から（３Ｓ，４Ｓ）－４－アミノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－オール（白色結晶）を合成し、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（５４ｍｇ，０．３１ｍｍｏｌ）を用いて表題化合物（白色結晶，１５ｍｇ，１２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．２７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．５６（ｓ，２Ｈ），３．６１（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．０９（ｂｒ　ｓ，１Ｈ），４．３－４．４（ｍ，２Ｈ），５．９７（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），８．０２（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１７（ｓ，１Ｈ）．　
ＭＳ：４０６．１４［Ｍ＋Ｈ］＋ Example 5
2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-hydroxy-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000171
Carbamic acid synthesized in Reference Example 3 ((3S, 4S) -4-hydroxy-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) according to the same procedure as in Example 3. (3S, 4S) -4-amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-ol (white crystals) was synthesized from tert-butyl (106 mg, 0.31 mmol). The title compound (white crystals, 15 mg, 12%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (54 mg, 0.31 mmol) synthesized in Reference Example 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 3.11 (dd, 1H, J = 5,10Hz), 3.27 (dd, 1H, J = 4,10Hz), 3.56 (s, 2H), 3.61 (dd, 1H, J = 6,10Hz), 3.76 (dd, 1H, J = 6,10Hz), 4.09 (br s, 1H), 4.3-4.4 (m, 2H), 5.97 (d, 1H) , J = 6Hz), 6.8-6.9 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.02 (d) , 1H, J = 2Hz), 8.17 (s, 1H).
MS: 406.14 [M + H] +
実施例６
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（５－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000172
実施例３と同様の手法に従い、参考例４で合成した（Ｒ）－（５－（５－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル（１３０ｍｇ，０．３６ｍｍｏｌ）から（Ｒ）－５－（５－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－アミン（白色結晶）を合成し、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（６４ｍｇ，０．３６ｍｍｏｌ）を用いて表題化合物（白色結晶，３０ｍｇ，２０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．５－０．６（ｍ，１Ｈ），０．６－０．７（ｍ，４Ｈ），０．８－０．９（ｍ，１Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），３．０９（ｄ，１Ｈ，Ｊ＝９Ｈｚ），３．３９（ｄｄ，１Ｈ，Ｊ＝２，１０Ｈｚ），３．４５（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．５２（ｄ，２Ｈ，Ｊ＝３Ｈｚ），３．７４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．１－４．２（ｍ，１Ｈ），５．６２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），８．０４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．　
ＭＳ：４１６．１８［Ｍ＋Ｈ］＋ Example 6
(R) -2- (4-Cyclopropylphenyl) -N- (5- (5- (trifluoromethyl) Pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide
Figure JPOXMLDOC01-appb-C000172
(R)-(5-(5- (trifluoromethyl) pyridine-3-yl) -5-azaspiro [2.4] heptan-7-yl) synthesized in Reference Example 4 according to the same method as in Example 3. ) From tert-butyl carbamic acid (130 mg, 0.36 mmol) to (R) -5- (5- (trifluoromethyl) pyridine-3-yl) -5-azaspiro [2.4] heptan-7-amine (white) Crystals) were synthesized, and the title compound (white crystals, 30 mg, 20%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (64 mg, 0.36 mmol) synthesized in Reference Example 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.5-0.6 (m, 1H), 0.6-0.7 (m, 4H), 0.8-0.9 (m, 1H) , 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 3.09 (d, 1H, J = 9Hz), 3.39 (dd, 1H, J = 2,10Hz), 3.45 (d, 1H, J = 10Hz), 3.52 (d, 2H, J = 3Hz), 3.74 (dd, 1H, J = 6,10Hz), 4.1- 4.2 (m, 1H), 5.62 (d, 1H, J = 8Hz), 6.8-6.9 (m, 1H), 7.0-7.1 (m, 2H), 7. 1-7.2 (m, 2H), 8.04 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 416.18 [M + H] +
実施例７
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（６－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000173
参考例５で合成した（Ｒ）－（５－（６－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル（２７１ｍｇ，０．７６ｍｍｏｌ）に氷冷下で２Ｎ塩酸メタノール溶液（１５ｍＬ）を加えて室温で２時間撹拌した後、減圧下溶媒を留去して（Ｒ）－５－（６－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－アミン（１８７ｍｇ）を得た。実施例１と同様の手法に従い、得られた（Ｒ）－５－（６－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－アミン（１８７ｍｇ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（１５４ｍｇ，０．８７ｍｍｏｌ）を用いて表題化合物（白色結晶，２８０ｍｇ，８９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．５－０．７（ｍ，５Ｈ），０．８－０．９（ｍ，１Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），３．１１（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．４０（ｄｄ，１Ｈ，Ｊ＝３，１０Ｈｚ），３．４５（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．５３（ｄ，２Ｈ，Ｊ＝３Ｈｚ），３．７５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．１－４．２（ｍ，１Ｈ），５．５６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．７７（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），７．４８（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９３（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．　
ＭＳ：４１５．１９［Ｍ＋Ｈ］＋ Example 7
(R) -2- (4-Cyclopropylphenyl) -N- (5- (6- (trifluoromethyl) Pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide
Figure JPOXMLDOC01-appb-C000173
Tert-Butyl (R)-(5- (6- (trifluoromethyl) pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) carbamate synthesized in Reference Example 5 (271 mg, A 2N hydrochloric acid-methanol solution (15 mL) was added to 0.76 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. -3-yl) -5-azaspiro [2.4] heptane-7-amine (187 mg) was obtained. Following the same procedure as in Example 1, the obtained (R) -5- (6- (trifluoromethyl) pyridine-3-yl) -5-azaspiro [2.4] heptane-7-amine (187 mg) and The title compound (white crystals, 280 mg, 89%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (154 mg, 0.87 mmol) synthesized in Reference Example 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.5-0.7 (m, 5H), 0.8-0.9 (m, 1H), 0.9-1.0 (m, 2H) , 1.8-1.9 (m, 1H), 3.11 (d, 1H, J = 10Hz), 3.40 (dd, 1H, J = 3,10Hz), 3.45 (d, 1H, J = 10Hz), 3.53 (d, 2H, J = 3Hz), 3.75 (dd, 1H, J = 6,10Hz), 4.1-4.2 (m, 1H), 5.56 ( d, 1H, J = 7Hz), 6.77 (dd, 1H, J = 3.8Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 7.48 (d, 1H, J = 9Hz), 7.93 (d, 1H, J = 3Hz).
MS: 415.19 [M + H] +
実施例８
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（４－（トリフルオロメチル）チアゾール－２－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000174
実施例７と同様の手法に従い、参考例６で合成した（Ｒ）－（５－（４－（トリフルオロメチル）チアゾール－２－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）カルバミン酸ｔｅｒｔ－ブチル（１９２ｍｇ，０．５３ｍｍｏｌ）から（Ｒ）－５－（４－（トリフルオロメチル）チアゾール－２－イル）－５－アザスピロ［２．４］ヘプタン－７－アミン（白色結晶）を合成し、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（１１２ｍｇ，０．６４ｍｍｏｌ）を用いて表題化合物（白色結晶，１７７ｍｇ，７９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．５－０．６（ｍ，１Ｈ），０．６－０．７（ｍ，４Ｈ），０．７－０．８（ｍ，１Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），３．３２（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．４４（ｄｄ，１Ｈ，Ｊ＝２，１０Ｈｚ），３．５２（ｄ，２Ｈ，Ｊ＝２Ｈｚ），３．５６（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．８３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．１－４．２（ｍ，１Ｈ），５．５３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９３（ｄ，１Ｈ，Ｊ＝１Ｈｚ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ）．　
ＭＳ：４２１．１４［Ｍ＋Ｈ］＋ Example 8
(R) -2- (4-Cyclopropylphenyl) -N- (5- (4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide
Figure JPOXMLDOC01-appb-C000174
(R)-(5-(4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptan-7-yl) synthesized in Reference Example 6 according to the same method as in Example 7. ) From tert-butyl carbamic acid (192 mg, 0.53 mmol) to (R) -5- (4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptan-7-amine (white) Crystals) were synthesized, and the title compound (white crystals, 177 mg, 79%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (112 mg, 0.64 mmol) synthesized in Reference Example 33-2.
1 H NMR (CDCl 3 , 400 MHz): δ = 0.5-0.6 (m, 1H), 0.6-0.7 (m, 4H), 0.7-0.8 (m, 1H) , 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H), 3.32 (d, 1H, J = 10Hz), 3.44 (dd, 1H, J = 2,10Hz), 3.52 (d, 2H, J = 2Hz), 3.56 (d, 1H, J = 10Hz), 3.83 (dd, 1H, J = 6,10Hz), 4.1- 4.2 (m, 1H), 5.53 (d, 1H, J = 7Hz), 6.93 (d, 1H, J = 1Hz), 7.0-7.1 (m, 2H), 7. 1-7.2 (m, 2H).
MS: 421.14 [M + H] +
実施例９
２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｒ，５Ｓ）－５－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000175
参考例７－２で合成した２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｒ，５Ｓ）－５－メチルピロリジン－３－イル）アセトアミド（１５０ｍｇ，０．５８ｍｍｏｌ）、３－ブロモ－５－（トリフルオロメチル）ピリジン（１５７ｍｇ，０．７０ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（５３ｍｇ，０．０６ｍｍｏｌ）、ＸａｎｔＰｈｏｓ（６７ｍｇ，０．１２ｍｍｏｌ）及びナトリウムｔｅｒｔ－ブトキシド（１１２ｍｇ，１．１６ｍｍｏｌ）をトルエン（５．８ｍＬ）に懸濁し、窒素気流下８５℃で１６時間撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（白色結晶，４５ｍｇ，１９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．２２（ｄ，３Ｈ，Ｊ＝６Ｈｚ），１．８－２．０（ｍ，２Ｈ），２．０－２．１（ｍ，１Ｈ），２．９３（ｄｄ，１Ｈ，Ｊ＝７，１０Ｈｚ），３．５４（ｓ，２Ｈ），３．８０（ｄｄ，１Ｈ，Ｊ＝８，１０Ｈｚ），３．９－４．０（ｍ，１Ｈ），４．７－４．８（ｍ，１Ｈ），５．４８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．８８（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１７（ｓ，１Ｈ）．
ＭＳ：４０４．１６［Ｍ＋Ｈ］＋ Example 9
2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000175
2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methylpyrrolidin-3-yl) acetamide (150 mg, 0.58 mmol), 3-bromo-5 synthesized in Reference Example 7-2. -(Trifluoromethyl) pyridine (157 mg, 0.70 mmol), tris (dibenzylideneacetone) dipalladium (0) (53 mg, 0.06 mmol), XantPhos (67 mg, 0.12 mmol) and sodium tert-butoxide (112 mg, 1.16 mmol) was suspended in toluene (5.8 mL) and stirred at 85 ° C. for 16 hours under a nitrogen stream. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (white crystals, 45 mg, 19%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.22 (d, 3H, J = 6 Hz) , 1.8-2.0 (m, 2H), 2.0-2.1 (m, 1H), 2.93 (dd, 1H, J = 7,10Hz), 3.54 (s, 2H) , 3.80 (dd, 1H, J = 8,10Hz), 3.9-4.0 (m, 1H), 4.7-4.8 (m, 1H), 5.48 (d, 1H, J = 8Hz), 6.88 (dd, 1H, J = 2.2Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.07 ( d, 1H, J = 3Hz), 8.17 (s, 1H).
MS: 404.16 [M + H] +
実施例１０
２－（４－シクロプロピルフェニル）－Ｎ－（３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000176
実施例７と同様の手法に従い、参考例８で合成した（３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－イル）カルバミン酸ｔｅｒｔ－ブチル（１０３ｍｇ，０．３０ｍｍｏｌ）から３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－アミン（黄色油状物，１２１ｍｇ）を合成し、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（６３ｍｇ，０．３６ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，７３ｍｇ，６１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．８－０．９（ｍ，１Ｈ），０．９－１．１（ｍ，３Ｈ），１．８－２．０（ｍ，２Ｈ），３．３－３．４（ｍ，１Ｈ），３．５－３．６（ｍ，４Ｈ），３．７－３．８（ｍ，１Ｈ），５．８９（ｓ，１Ｈ），６．９０（ｓ，１Ｈ），７．０７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０６（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１８（ｓ，１Ｈ）．
ＭＳ：４０２．１６［Ｍ＋Ｈ］＋ Example 10
2- (4-Cyclopropylphenyl) -N- (3- (5- (trifluoromethyl) pyridine-3-yl) -3-azabicyclo [3.1.0] hexane-1-yl) acetamide
Figure JPOXMLDOC01-appb-C000176
(3- (5- (Trifluoromethyl) pyridine-3-yl) -3-azabicyclo [3.1.0] hexane-1-yl) carbamine synthesized in Reference Example 8 according to the same procedure as in Example 7. From tert-butyl acid (103 mg, 0.30 mmol) to 3- (5- (trifluoromethyl) pyridine-3-yl) -3-azabicyclo [3.1.0] hexane-1-amine (yellow oil, 121 mg) ) Was synthesized, and the title compound (pale yellow amorphous, 73 mg, 61%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (63 mg, 0.36 mmol) synthesized in Reference Example 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.8-0.9 (m, 1H), 0.9-1.1 (m, 3H) , 1.8-2.0 (m, 2H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 4H), 3.7-3.8 (m, 1H), 5.89 (s, 1H), 6.90 (s, 1H), 7.07 (d, 2H, J = 8Hz), 7.13 (d, 2H, J = 8Hz), 8.06 (D, 1H, J = 2Hz), 8.18 (s, 1H).
MS: 402.16 [M + H] +
実施例１１
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピラジン－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000177
実施例７と同様の手法に従い、参考例９で合成した（Ｒ）－（１－（６－（トリフルオロメチル）ピラジン－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１５９ｍｇ，０．４８ｍｍｏｌ）から（Ｒ）－１－（６－（トリフルオロメチル）ピラジン－２－イル）ピロリジン－３－アミンを合成し、２－（４－（トリフルオロメチル）フェニル）酢酸（１１７ｍｇ，０．５７ｍｍｏｌ）を用いて表題化合物（白色粉末，１８７ｍｇ，９４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．３８（ｄｄ，１Ｈ，Ｊ＝４，１１Ｈｚ），３．６－３．７（ｍ，４Ｈ），３．８７（ｄｄ，１Ｈ，Ｊ＝６，１２Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．５３（ｄ，１Ｈ，Ｊ＝６Ｈｚ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０３（ｓ，１Ｈ），８．１７（ｓ，１Ｈ）．
ＭＳ：４１９．１０［Ｍ＋Ｈ］＋ Example 11
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000177
Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 9 according to the same procedure as in Example 7 (159 mg, (R) -1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-amine was synthesized from 0.48 mmol), and 2- (4- (trifluoromethyl) phenyl) acetic acid (117 mg, 0.57 mmol) was used to give the title compound (white powder, 187 mg, 94%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.38 (dd, 1H, J = 4, 11Hz), 3.6-3.7 (m, 4H), 3.87 (dd, 1H, J = 6,12Hz), 4.6-4.7 (m, 1H), 5.53 (d, 1H, J = 6Hz), 7.40 (d, 2H, J = 8Hz), 7.61 (d, 2H, J = 8Hz), 8.03 (s, 1H), 8.17 (s, 1H) ..
MS: 419.10 [M + H] +
実施例１２
（Ｒ）－Ｎ－（１－（６－シアノ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000178
実施例３と同様の手法に従い、参考例１０で合成した（Ｒ）－（１－（６－シアノ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１３９ｍｇ，０．３９ｍｍｏｌ）から（Ｒ）－１－（６－シアノ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンを合成し、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（８２ｍｇ，０．４７ｍｍｏｌ）を用いて表題化合物（白色アモルファス，５２ｍｇ，３２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝８，１０Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７－３．８（ｍ，１Ｈ），４．５－４．７（ｍ，１Ｈ），５．８０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．０２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．００（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：４１３．１５［Ｍ－Ｈ］－ Example 12
(R) -N- (1- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000178
(R)-(1- (6-cyano-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 10 according to the same procedure as in Example 3. (R) -1- (6-cyano-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from butyl (139 mg, 0.39 mmol) and synthesized in Reference Example 33-2. The title compound (white amorphous, 52 mg, 32%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (82 mg, 0.47 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.23 (dd, 1H, J = 8,10Hz), 3.4-3.6 ( m, 4H), 3.7-3.8 (m, 1H), 4.5-4.7 (m, 1H), 5.80 (d, 1H, J = 6Hz), 6.88 (d, 1H, J = 3Hz), 7.02 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 8.00 (d, 1H, J = 2Hz).
MS: 413.15 [MH] -
実施例１３
３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000179
実施例９と同様の手法に従い、参考例１１－２で合成した３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－３－カルボン酸メチル（９４ｍｇ，０．３１ｍｍｏｌ）及び３－ブロモ－５－（トリフルオロメチル）ピリジン（８４ｍｇ，０．３７ｍｍｏｌ）を用いて表題化合物（白色アモルファス，５３ｍｇ，３８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．５－２．６（ｍ，１Ｈ），３．４－３．５（ｍ，２Ｈ），３．５５（ｓ，２Ｈ），３．５－３．６（ｍ，１Ｈ），３．７５（ｓ，３Ｈ），３．９８（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），６．１７（ｓ，１Ｈ），６．８－６．９（ｍ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），８．０５（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４４８．１４［Ｍ＋Ｈ］＋ Example 13
Methyl 3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000179
Methyl 3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-3-carboxylate (94 mg, 0.31 mmol) and 3-bromo- synthesized in Reference Example 11-2 according to the same procedure as in Example 9. The title compound (white amorphous, 53 mg, 38%) was obtained using 5- (trifluoromethyl) pyridine (84 mg, 0.37 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.3-2.4 (m, 1H), 2.5-2.6 (m, 1H), 3.4-3.5 (m, 2H), 3.55 (s, 2H), 3 .5-3.6 (m, 1H), 3.75 (s, 3H), 3.98 (d, 1H, J = 10Hz), 6.17 (s, 1H), 6.8-6.9 (M, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.05 (d, 1H, J = 3Hz), 8.20 (s) , 1H).
MS: 448.14 [M + H] +
実施例１４
３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸
Figure JPOXMLDOC01-appb-C000180
実施例１３で合成した３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル（５０ｍｇ，０．１１ｍｍｏｌ）をＴＨＦ（２．０ｍＬ）に溶解し、２Ｎ水酸化ナトリウム水溶液（２．０ｍＬ）を加えて室温で３時間撹拌した。反応液に１Ｎ塩酸水溶液を加えて中和した後、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－９０％）により精製した後、得られた粉末にメタノール及び水を加えてしばらく撹拌した。析出した粉末をろ過し、１００℃で３時間減圧下乾燥して表題化合物（白色粉末，３８ｍｇ，７９％）を得た。
１Ｈ　ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）：δ＝０．５－０．６（ｍ，２Ｈ），０．８－０．９（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．４－２．６（ｍ，２Ｈ），３．４－３．６（ｍ，４Ｈ），３．６－３．７（ｍ，１Ｈ），３．９－４．０（ｍ，１Ｈ），４．６０（ｂｒ　ｓ，１Ｈ），６．９－７．０（ｍ，２Ｈ），７．０－７．２（ｍ，３Ｈ），８．０－８．１（ｍ，２Ｈ）．１Ｈ分観測できず
ＭＳ：４３４．１６［Ｍ＋Ｈ］＋ Example 14
3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000180
Methyl 3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate (50 mg, 0.11 mmol) synthesized in Example 13. ) Was dissolved in THF (2.0 mL), a 2N aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding a 1N aqueous hydrochloric acid solution, and then extracted with a mixed solution of chloroform and methanol. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-90%), and then methanol and water were added to the obtained powder and stirred for a while. The precipitated powder was filtered and dried at 100 ° C. for 3 hours under reduced pressure to give the title compound (white powder, 38 mg, 79%).
1 1 H NMR (CD 3 OD, 400 MHz): δ = 0.5-0.6 (m, 2H), 0.8-0.9 (m, 2H), 1.8-1.9 (m, 1H) ), 2.4-2.6 (m, 2H), 3.4-3.6 (m, 4H), 3.6-3.7 (m, 1H), 3.9-4.0 (m) , 1H), 4.60 (br s, 1H), 6.9-7.0 (m, 2H), 7.0-7.2 (m, 3H), 8.0-8.1 (m, 2H). Cannot observe for 1H MS: 434.16 [M + H] +
実施例１５
（Ｒ）－２－（１Ｈ－インダゾール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000181
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６６ｍｇ，０．２８ｍｍｏｌ）及び２－（１Ｈ－インダゾール－６－イル）酢酸（５０ｍｇ，０．２８ｍｍｏｌ）を用いて表題化合物（白色粉末，８２ｍｇ，７４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．６３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７０（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．６２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．０４（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．３９（ｓ，１Ｈ），７．７２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．０－８．１（ｍ，２Ｈ），８．１８（ｓ，１Ｈ），１０．１（ｂｒ　ｓ，１Ｈ）．
ＭＳ：３８８．１５［Ｍ－Ｈ］－ Example 15
(R) -2- (1H-indazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000181
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (66 mg, 0.28 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 82 mg, 74%) was obtained using 2- (1H-indazole-6-yl) acetic acid (50 mg, 0.28 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.13 (dd, 1H, J = 4, 10Hz), 3.3-3.4 (m, 2H), 3.63 (dd, 1H, J = 6,10Hz), 3.70 (s, 2H), 4.6-4.7 (m, 1H), 5.62 (d, 1H, J = 7Hz), 6.8-6.9 (m, 1H), 7.04 (dd, 1H, J = 1.8Hz), 7.39 (s, 1H), 7.72 (d, 1H, J = 8Hz), 8.0-8.1 (m, 2H), 8.18 (s, 1H), 10.1 (br s, 1H).
MS: 388.15 [MH] -
実施例１６
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000182
実施例１と同様の手法に従い、参考例１２－２で合成した（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン（３３ｍｇ，０．１４ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（２９ｍｇ，０．１７ｍｍｏｌ）を用いて表題化合物（黄緑色粉末，３０ｍｇ，５５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．４７（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．９２（ｓ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１０（ｄ，２Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：３９４．１４［Ｍ－Ｈ］－ Example 16
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000182
(R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (33 mg, 0.14 mmol) synthesized in Reference Example 12-2 and the same procedure as in Example 1 and The title compound (yellowish green powder, 30 mg, 55%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (29 mg, 0.17 mmol) synthesized in Reference Example 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.23 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 4H), 3.74 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.47 (d, 1H, J = 6Hz), 6.92 (s, 1H), 7.04 (d, 2H, J = 8Hz), 7.10 (d, 2H, J = 2Hz).
MS: 394.14 [MH] -
実施例１７
２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド
Figure JPOXMLDOC01-appb-C000183
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３５ｍｇ，０．１５ｍｍｏｌ）及び２－（４－イソブチルフェニル）プロパン酸（３７ｍｇ，０．１８ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，５０ｍｇ，７９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．８－０．９（ｍ，６Ｈ），１．５１（ｄ，１．５Ｈ，Ｊ＝８Ｈｚ），１．５２（ｄ，１．５Ｈ，Ｊ＝８Ｈｚ），１．８－２．０（ｍ，２Ｈ），２．２－２．３（ｍ，１Ｈ），２．４－２．５（ｍ，２Ｈ），３．０３（ｄｄ，０．５Ｈ，Ｊ＝４，１０Ｈｚ），３．１２（ｄｄ，０．５Ｈ，Ｊ＝４，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．５－３．７（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．６７（ｄ，０．５Ｈ，Ｊ＝７Ｈｚ），５．７０（ｄ，０．５Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），８．０１（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），８．１５（ｓ，１Ｈ）．
ＭＳ：４２０．２０［Ｍ＋Ｈ］＋ Example 17
2- (4-Isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide
Figure JPOXMLDOC01-appb-C000183
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 50 mg, 79%) was obtained using 2- (4-isobutylphenyl) propanoic acid (37 mg, 0.18 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.8-0.9 (m, 6H), 1.51 (d, 1.5H, J = 8Hz), 1.52 (d, 1.5H, J = 8Hz), 1.8-2.0 (m, 2H), 2.2-2.3 (m, 1H), 2.4-2.5 (m, 2H), 3.03 (dd, dd, 0.5H, J = 4,10Hz), 3.12 (dd, 0.5H, J = 4,10Hz), 3.2-3.4 (m, 2H), 3.5-3.7 (m) , 2H), 4.5-4.7 (m, 1H), 5.67 (d, 0.5H, J = 7Hz), 5.70 (d, 0.5H, J = 7Hz), 6.8 -6.9 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.01 (dd, 1H, J = 2.2Hz) , 8.15 (s, 1H).
MS: 420.20 [M + H] +
実施例１８
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－メチル－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000184
実施例７と同様の手法に従い、参考例１３で合成した（Ｒ）－（１－（６－メチル－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（２２ｍｇ，０．０６ｍｍｏｌ）から（Ｒ）－１－（６－メチル－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（白色粉末，２２ｍｇ）を合成し、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（１３ｍｇ，０．０７ｍｍｏｌ）を用いて表題化合物（白色アモルファス，５．９ｍｇ，２３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），２．５７（ｓ，３Ｈ），３．０８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），３．６０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５０（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．９５（ｄ，１Ｈ，Ｊ＝２Ｈｚ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．９３（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：４０４．１６［Ｍ＋Ｈ］＋ Example 18
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6-methyl-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000184
(R)-(1- (6-methyl-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamic acid tert- synthesized in Reference Example 13 according to the same procedure as in Example 7. (R) -1- (6-methyl-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (white powder, 22 mg) was synthesized from butyl (22 mg, 0.06 mmol) and used as a reference example. The title compound (white amorphous, 5.9 mg, 23%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (13 mg, 0.07 mmol) synthesized in 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 2H) , 2.2-2.4 (m, 1H), 2.57 (s, 3H), 3.08 (dd, 1H, J = 4,10Hz), 3.3-3.4 (m, 2H) , 3.53 (s, 2H), 3.60 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.50 (d, 1H, J = 8Hz) , 6.95 (d, 1H, J = 2Hz), 7.04 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 7.93 (d, 1H, J = 2Hz).
MS: 404.16 [M + H] +
実施例１９
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（２－ヒドロキシプロパン－２－イル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000185
実施例１と同様の手法に従い、参考例１４－２で合成した（Ｒ）－２－（５－（３－アミノピロリジン－１－イル）ピリジン－３－イル）プロパン－２－オール（５５ｍｇ，０．１７ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（３６ｍｇ，０．２０ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，８１ｍｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．５９（ｓ，６Ｈ），１．７－１．８（ｍ，１Ｈ），１．８－１．９（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．３－３．４（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），３．６０（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．６１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．８２（ｂｒ　ｓ，１Ｈ），８．０４（ｂｒ　ｓ，１Ｈ）．
ＭＳ：３８０．２０［Ｍ＋Ｈ］＋ Example 19
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (2-hydroxypropan-2-yl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000185
(R) -2- (5- (3-aminopyrrolidine-1-yl) pyridin-3-yl) propan-2-ol (55 mg,) synthesized in Reference Example 14-2 according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 81 mg, 86%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (36 mg, 0.20 mmol) synthesized in Reference Example 33-2 (0.17 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.59 (s, 6H), 1.7 -1.8 (m, 1H), 1.8-1.9 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3 .3-3.4 (m, 2H), 3.53 (s, 2H), 3.60 (dd, 1H, J = 4,10Hz), 4.6-4.7 (m, 1H), 5 .61 (d, 1H, J = 7Hz), 6.9-7.0 (m, 1H), 7.04 (d, 2H, J = 8Hz), 7.12 (d, 2H, J = 8Hz) , 7.82 (br s, 1H), 8.04 (br s, 1H).
MS: 380.20 [M + H] +
実施例２０
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（８－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－６－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000186
実施例７と同様の手法に従い、参考例１５で合成した（Ｒ）－（１－（８－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－６－イル）ピロリジン－３－イル）－カルバミン酸ｔｅｒｔ－ブチル（９０ｍｇ，０．２４ｍｍｏｌ）から（Ｒ）－１－（８－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－６－イル）ピロリジン－３－アミン（５６ｍｇ）を合成し、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（４４ｍｇ，０．２５ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，５８ｍｇ，５６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．３－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．２－３．３（ｍ，１Ｈ），３．３－３．４（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），３．５６（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），６．７０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．０８（ｓ，１Ｈ），７．１５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．５２（ｓ，１Ｈ），７．６０（ｓ，１Ｈ）．１Ｈ分観測できず
ＭＳ：４２９．１６［Ｍ＋Ｈ］＋ Example 20
(R) -2- (4-Cyclopropylphenyl) -N- (1- (8- (trifluoromethyl) imidazole [1,2-a] pyridin-6-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000186
(R)-(1- (1- (8- (trifluoromethyl) imidazo [1,2-a] pyridin-6-yl) pyrrolidine-3-yl) synthesized in Reference Example 15 according to the same method as in Example 7) -Tert-Butylcarbamate (90 mg, 0.24 mmol) to (R) -1- (8- (trifluoromethyl) imidazole [1,2-a] pyridin-6-yl) pyrrolidine-3-amine (56 mg) Was synthesized, and the title compound (yellow amorphous, 58 mg, 56%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (44 mg, 0.25 mmol) synthesized in Reference Example 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.3-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 1H), 3.56 (s, 2H), 4.6-4.7 (m, 1H), 6.70 (d, 1H, J = 6Hz) , 7.04 (d, 2H, J = 8Hz), 7.08 (s, 1H), 7.15 (d, 2H, J = 8Hz), 7.52 (s, 1H), 7.60 (s) , 1H). Cannot observe for 1H MS: 429.16 [M + H] +
実施例２１
３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボキシアミド
Figure JPOXMLDOC01-appb-C000187
実施例１と同様の手法に従い、実施例１４で合成した３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸（１５ｍｇ，０．０４ｍｍｏｌ）及び酢酸アンモニウム（５．３ｍｇ，０．０７ｍｍｏｌ）を用いて表題化合物（白色粉末，１１ｍｇ，７３％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝０．５－０．６（ｍ，２Ｈ），０．８－０．９（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，２Ｈ），３．２－３．５（ｍ，４Ｈ），３．５－３．６（ｍ，１Ｈ），３．８２（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），６．８５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），６．９－７．１（ｍ，３Ｈ），７．１１（ｓ，１Ｈ），７．２９（ｂｒ　ｓ，１Ｈ），８．１－８．２（ｍ，２Ｈ），８．５４（ｓ，１Ｈ）．
ＭＳ：４３１．２０［Ｍ－Ｈ］－ Example 21
3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxyamide
Figure JPOXMLDOC01-appb-C000187
3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3- (5- (trifluoromethyl) pyridine-3-yl) synthesized in Example 14 according to the same procedure as in Example 1. Carboxylic acid (15 mg, 0.04 mmol) and ammonium acetate (5.3 mg, 0.07 mmol) were used to give the title compound (white powder, 11 mg, 73%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 0.5-0.6 (m, 2H), 0.8-0.9 (m, 2H), 1.8-1.9 (m, 1H), 2.3-2.4 (m, 2H), 3.2-3.5 (m, 4H), 3.5-3.6 (m, 1H), 3.82 (d, 1H, J = 10Hz), 6.85 (d, 2H, J = 8Hz), 6.9-7.1 (m, 3H), 7.11 (s, 1H), 7.29 (br s, 1H), 8.1-8.2 (m, 2H), 8.54 (s, 1H).
MS: 431.20 [MH] -
実施例２２
（Ｒ）－２－（４－ヒドロキシフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000188
実施例１と同様の手法に従い、実施例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２００ｍｇ，０．８６ｍｍｏｌ）及び２－（４－ヒドロキシフェニル）酢酸（１５８ｍｇ，１．０４ｍｍｏｌ）を用いて表題化合物（白色アモルファス，２９２ｍｇ，９２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１２（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），５．１８（ｓ，１Ｈ），５．５０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８－６．９（ｍ，２Ｈ），６．９－７．０（ｍ，１Ｈ），７．１－７．２（ｍ，２Ｈ），８．０７（ｄ，２Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：３６６．１１［Ｍ＋Ｈ］＋ Example 22
(R) -2- (4-Hydroxyphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000188
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (200 mg, 0.86 mmol) synthesized in Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 292 mg, 92%) was obtained using 2- (4-hydroxyphenyl) acetic acid (158 mg, 1.04 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.12 (dd, 1H, J = 5, 10Hz), 3.3-3.4 (m, 2H), 3.51 (s, 2H), 3.65 (dd, 1H, J = 6,10Hz), 5.18 (s, 1H), 5 .50 (d, 1H, J = 6Hz), 6.8-6.9 (m, 2H), 6.9-7.0 (m, 1H), 7.1-7.2 (m, 2H) , 8.07 (d, 2H, J = 3Hz), 8.21 (s, 1H).
MS: 366.11 [M + H] +
実施例２３
（Ｒ）－２－（４－（１，１－ジオキサイドチオモルホリノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000189
参考例１６で合成した２－（４－（１，１－ジオキサイドチオモルホリノ）フェニル）酢酸エチル（３０ｍｇ，０．１０ｍｍｏｌ）をＴＨＦ（２．０ｍＬ）に溶解した後、２Ｎ水酸化ナトリウム水溶液（２．０ｍＬ）を加えて５０℃で２０分間撹拌し、減圧下溶媒を留去した。得られた残渣に水及び酢酸エチルを加えてしばらく撹拌した後、分離した水層に１Ｎ塩酸水溶液を加えて中和し、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して２－（４－（１，１－ジオキサイドチオモルホリノ）フェニル）酢酸の粗体（淡黄色結晶）を得た。実施例１と同様の手法に従い、得られた２－（４－（１，１－ジオキサイドチオモルホリノ）フェニル）酢酸の粗体及び参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２３ｍｇ，０．１０ｍｍｏｌ）を用いて表題化合物（白色アモルファス，３０ｍｇ，６１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，４Ｈ），３．１６（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．８－３．９（ｍ，４Ｈ），４．６－４．７（ｍ，１Ｈ），５．５３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．１－７．２（ｍ，２Ｈ），８．０９（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４８１．１８［Ｍ－Ｈ］－ Example 23
(R) -2- (4- (1,1-dioxidethiomorpholino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000189
After dissolving ethyl 2- (4- (1,1-dioxsidethiomorpholino) phenyl) acetate (30 mg, 0.10 mmol) synthesized in Reference Example 16 in THF (2.0 mL), a 2N aqueous sodium hydroxide solution ( 2.0 mL) was added, and the mixture was stirred at 50 ° C. for 20 minutes, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the mixture was stirred for a while, then neutralized by adding a 1N aqueous hydrochloric acid solution to the separated aqueous layer, and extracted with a mixed solution of chloroform and methanol. The separated organic layer is dried over anhydrous sodium sulfate, the insoluble matter is filtered, and the solvent is distilled off under reduced pressure to obtain a crude (pale yellow) of 2- (4- (1,1-dioxidethiomorpholino) phenyl) acetic acid. Crystals) were obtained. According to the same method as in Example 1, the obtained crude product of 2- (4- (1,1-dioxidethiomorpholino) phenyl) acetic acid and (R) -1- (5) synthesized in Reference Example 1-2. -(Trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (23 mg, 0.10 mmol) was used to give the title compound (white amorphous, 30 mg, 61%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.0-3.1 (m, 4H) , 3.16 (dd, 1H, J = 5,10Hz), 3.3-3.5 (m, 2H), 3.51 (s, 2H), 3.67 (dd, 1H, J = 6, 10Hz), 3.8-3.9 (m, 4H), 4.6-4.7 (m, 1H), 5.53 (d, 1H, J = 7Hz), 6.8-7.0 ( m, 3H), 7.1-7.2 (m, 2H), 8.09 (d, 1H, J = 2Hz), 8.21 (s, 1H).
MS: 481.18 [MH] -
実施例２４
（Ｒ）－１－（４－クロロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000190
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２２ｍｍｏｌ）及び１－（４－クロロフェニル）シクロプロパン－１－カルボン酸（５１ｍｇ，０．２６ｍｍｏｌ）を用いて表題化合物（白色アモルファス，７０ｍｇ，７９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．０－１．１（ｍ，２Ｈ），１．６－１．７（ｍ，２Ｈ），１．７－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．２－３．４（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．５－４．６（ｍ，１Ｈ），５．３６（ｄ，１Ｈ，Ｊ＝５Ｈｚ），６．８９（ｓ，１Ｈ），７．２－７．４（ｍ，４Ｈ），８．０５（ｓ，１Ｈ），８．１９（ｓ，１Ｈ）．
ＭＳ：４１０．０７［Ｍ＋Ｈ］＋ Example 24
(R) -1- (4-chlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000190
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 70 mg, 79%) was obtained using 1- (4-chlorophenyl) cyclopropane-1-carboxylic acid (51 mg, 0.26 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.0-1.1 (m, 2H), 1.6-1.7 (m, 2H), 1.7-1.9 (m, 1H) , 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.6-3.7 (m, 1H), 4.5-4.6 (m, 1H), 5.36 (d, 1H, J = 5Hz), 6.89 (s, 1H), 7.2-7.4 (m, 4H) , 8.05 (s, 1H), 8.19 (s, 1H).
MS: 410.07 [M + H] +
実施例２５
２－（４－ブロモフェニル）－２－ヒドロキシ－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000191
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２２ｍｍｏｌ）及び２－（４－ブロモフェニル）－２－ヒドロキシ酢酸（６０ｍｇ，０．２６ｍｍｏｌ）を用いて表題化合物（白色粉末，６８ｍｇ，７１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．９２（ｓ，０．５Ｈ），４．１５（ｓ，０．５Ｈ），４．６－４．７（ｍ，１Ｈ），５．０６（ｓ，１Ｈ），６．８－７．０（ｍ，２Ｈ），７．３１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．９４（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．１２（ｄ，１Ｈ，Ｊ＝４Ｈｚ）．
ＭＳ：４４４．００［Ｍ＋Ｈ］＋ Example 25
2- (4-Bromophenyl) -2-hydroxy-N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000191
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 68 mg, 71%) was obtained using 2- (4-bromophenyl) -2-hydroxyacetic acid (60 mg, 0.26 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H) , 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.92 (s, 0.5H), 4.15 (s, 0.5H), 4 .6-4.7 (m, 1H), 5.06 (s, 1H), 6.8-7.0 (m, 2H), 7.31 (d, 2H, J = 8Hz), 7.49 (D, 2H, J = 8Hz), 7.94 (d, 1H, J = 8Hz), 8.12 (d, 1H, J = 4Hz).
MS: 444.00 [M + H] +
実施例２６
（Ｒ）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリメチルシリル）フェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000192
参考例１７で合成した２－（４－（トリメチルシリル）フェニル）酢酸エチル（３０ｍｇ，０．１３ｍｍｏｌ）をメタノール（２．０ｍＬ）に溶解した後、２Ｎ水酸化ナトリウム水溶液（２．０ｍＬ）を加えて室温で４時間撹拌し、減圧下溶媒を留去した。水を加えて水溶液とした後、酢酸エチルで洗浄し、１Ｎ塩酸水溶液を加えて中和し、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して２－（４－（トリメチルシリル）フェニル）酢酸の粗体を得た。実施例１と同様の手法に従い、得られた２－（４－（トリメチルシリル）フェニル）酢酸の粗体及び参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２９ｍｇ，０．１３ｍｍｏｌ）を用いて表題化合物（無色油状物，６．８ｍｇ，１３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．２６（ｓ，９Ｈ），１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．５８（ｓ，２Ｈ），３．６６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．６５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８９（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，２Ｈ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：４２２．１６［Ｍ＋Ｈ］＋ Example 26
(R) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4- (trimethylsilyl) phenyl) acetamide
Figure JPOXMLDOC01-appb-C000192
After dissolving 2- (4- (trimethylsilyl) phenyl) ethyl acetate (30 mg, 0.13 mmol) synthesized in Reference Example 17 in methanol (2.0 mL), a 2N aqueous sodium hydroxide solution (2.0 mL) was added. The mixture was stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. After adding water to make an aqueous solution, the mixture was washed with ethyl acetate, neutralized by adding a 1N hydrochloric acid aqueous solution, and extracted with a mixed solution of chloroform and methanol. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of 2- (4- (trimethylsilyl) phenyl) acetic acid. The crude product of 2- (4- (trimethylsilyl) phenyl) acetic acid obtained and the (R) -1- (5- (trifluoromethyl) pyridine) synthesized in Reference Example 1-2 according to the same method as in Example 1. The title compound (colorless oil, 6.8 mg, 13%) was obtained using -3-yl) pyrrolidine-3-amine (29 mg, 0.13 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.26 (s, 9H), 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.13 (Dd, 1H, J = 4,10Hz), 3.3-3.4 (m, 2H), 3.58 (s, 2H), 3.66 (dd, 1H, J = 6,10Hz), 4 .6-4.7 (m, 1H), 5.65 (d, 1H, J = 7Hz), 6.89 (dd, 1H, J = 2.2Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 2H), 8.07 (d, 1H, J = 3Hz), 8.19 (s, 1H).
MS: 422.16 [M + H] +
実施例２７
（Ｒ）－２－（４－（２－ヒドロキシ－２－メチルプロポキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000193
実施例２２で合成した（Ｒ）－２－（４－ヒドロキシフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（３０ｍｇ，０．０８ｍｍｏｌ）をＤＭＦ（１．０ｍＬ）に溶解した後、２，２－ジメチルオキシラン（２２μＬ，０．２５ｍｍｏｌ）及び炭酸カリウム（３４ｍｇ，０．２５ｍｍｏｌ）を加えて１１０℃で１６時間撹拌した。室温まで放冷した反応液に水を加えてしばらく撹拌した後、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－４０％）により精製し表題化合物（無色油状物，３．４ｍｇ，９．４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．３５（ｓ，６Ｈ），１．８－１．９（ｍ，１Ｈ），２．２５（ｓ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１２（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７８（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．４８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．８－６．９（ｍ，３Ｈ），７．１－７．２（ｍ，２Ｈ），８．０７（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４３８．１７［Ｍ＋Ｈ］＋ Example 27
(R) -2- (4- (2-Hydroxy-2-methylpropoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000193
(R) -2- (4-Hydroxyphenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 22 (30 mg, 0. 08 mmol) was dissolved in DMF (1.0 mL), 2,2-dimethyloxylane (22 μL, 0.25 mmol) and potassium carbonate (34 mg, 0.25 mmol) were added, and the mixture was stirred at 110 ° C. for 16 hours. Water was added to the reaction solution allowed to cool to room temperature, the mixture was stirred for a while, and then extracted with a mixed solution of chloroform and methanol. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-40%) to give the title compound (colorless oil, 3.4 mg, 9.4%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.35 (s, 6H), 1.8-1.9 (m, 1H), 2.25 (s, 1H), 2.3-2.4 (M, 1H), 3.12 (dd, 1H, J = 5,10Hz), 3.3-3.4 (m, 2H), 3.53 (s, 2H), 3.65 (dd, 1H) , J = 6,10Hz), 3.78 (s, 2H), 4.6-4.7 (m, 1H), 5.48 (d, 1H, J = 8Hz), 6.8-6.9 (M, 3H), 7.1-7.2 (m, 2H), 8.07 (d, 1H, J = 2Hz), 8.21 (s, 1H).
MS: 438.17 [M + H] +
実施例２８
２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－フルオロ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000194
参考例１８で合成した（３Ｓ，４Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－４－フルオロピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（３６９ｍｇ，１．０２ｍｍｏｌ）に氷冷下で２Ｎ塩酸メタノール溶液（１２ｍＬ）を加えて室温で２時間撹拌した後、減圧下溶媒を留去して（２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－フルオロピロリジン－３－イルアセトアミドの粗体（２３０ｍｇ）を得た。得られた２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－フルオロピロリジン－３－イルアセトアミドの粗体（２３０ｍｇ）、３－ブロモ－５－（トリフルオロメチル）ピリジン（２３０ｍｇ，１．０２ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（９２ｍｇ，０．１０ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（１１８ｍｇ，０．２０ｍｍｏｌ）及び炭酸カリウム（２８１ｍｇ，２．０４ｍｍｏｌ）をトルエン（５．８ｍＬ）に懸濁し、窒素気流下８５℃で１６時間撹拌した。室温まで放冷した反応液をセライトでろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（白色アモルファス，２８ｍｇ，６．７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），３．２４（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７－３．８（ｍ，１Ｈ），４．６－４．７（ｍ，１Ｈ），５．１－５．３（ｍ，１Ｈ），５．６－５．７（ｍ，１Ｈ），６．８８（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．０－７．１（ｍ，４Ｈ），８．０４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４０８．１６［Ｍ＋Ｈ］＋ Example 28
2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-fluoro-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000194
(3S, 4S) -3- (2- (4-cyclopropylphenyl) acetamide) -4-fluoropyrrolidin-1-carboxylate tert-butyl (369 mg, 1.02 mmol) synthesized in Reference Example 18 under ice-cooling. After adding a 2N methanol solution of hydrochloric acid (12 mL) and stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure (2- (4-cyclopropylphenyl) -N-((3S, 4S) -4-fluoro). A crude product of pyrrolidine-3-ylacetamide (230 mg) was obtained. The obtained crude product of 2- (4-cyclopropylphenyl) -N-((3S, 4S) -4-fluoropyrrolidin-3-ylacetamide) was obtained. (230 mg), 3-bromo-5- (trifluoromethyl) pyridine (230 mg, 1.02 mmol), tris (dibenzilidenacetone) dipalladium (0) (92 mg, 0.10 mmol), Xantphos (118 mg, 0.20 mmol) ) And potassium carbonate (281 mg, 2.04 mmol) were suspended in toluene (5.8 mL), and the mixture was stirred at 85 ° C. under a nitrogen stream for 16 hours. The reaction solution allowed to cool to room temperature was filtered through Celite, and the solvent was removed under reduced pressure. Distilled off. The obtained residue was purified by silica gel column chromatography (heptan: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (white amorphous, 28 mg, 6.7%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 3.24 (d, 1H, J = 11Hz), 3.4-3.6 (m, 4H), 3.7-3.8 (m, 1H), 4.6-4.7 (m, 1H), 5.1-5.3 (m, 1H), 5.6-5.7 (m, 1H), 6.88 (dd, 1H, J = 2.2Hz), 7.0-7. 1 (m, 4H), 8.04 (d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 408.16 [M + H] +
実施例２９
（Ｒ）－２－（４－（ジメチルアミノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000195
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４６ｍｇ，０．２０ｍｍｏｌ）及び２－（４－（ジメチルアミノ）フェニル）酢酸（４３ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（白色アモルファス，４０ｍｇ，５１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．９４（ｓ，６Ｈ），３．０９（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．４９（ｓ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．６３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．６－６．７（ｍ，２Ｈ），６．８８（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．０－７．１（ｍ，２Ｈ），８．０６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１８（ｓ，１Ｈ）．
ＭＳ：３９３．１６［Ｍ＋Ｈ］＋ Example 29
(R) -2- (4- (dimethylamino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000195
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (46 mg, 0.20 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 40 mg, 51%) was obtained using 2- (4- (dimethylamino) phenyl) acetic acid (43 mg, 0.24 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 2.94 (s, 6H), 3.09 (Dd, 1H, J = 5,10Hz), 3.3-3.4 (m, 2H), 3.49 (s, 2H), 3.64 (dd, 1H, J = 6,10Hz), 4 .6-4.7 (m, 1H), 5.63 (d, 1H, J = 7Hz), 6.6-6.7 (m, 2H), 6.88 (dd, 1H, J = 2, 2Hz), 7.0-7.1 (m, 2H), 8.06 (d, 1H, J = 3Hz), 8.18 (s, 1H).
MS: 393.16 [M + H] +
実施例３０
（Ｒ）－２－（４－ニトロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000196
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１５０ｍｇ，０．６５ｍｍｏｌ）及び２－（４－ニトロフェニル）酢酸（１４１ｍｇ，０．７８ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，２１９ｍｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．２０（ｄｄ，１Ｈ，Ｊ＝３，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．６３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．６７（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），６．５９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．４－７．５（ｍ，２Ｈ），７．９７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１１（ｂｒ　ｓ，１Ｈ），８．１－８．２（ｍ，２Ｈ）．
ＭＳ：３９５．０９［Ｍ＋Ｈ］＋ Example 30
(R) -2- (4-Nitrophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000196
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (150 mg, 0.65 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 219 mg, 86%) was obtained using 2- (4-nitrophenyl) acetic acid (141 mg, 0.78 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.20 (dd, 1H, J = 3, 10Hz), 3.3-3.4 (m, 2H), 3.63 (dd, 1H, J = 6,10Hz), 3.67 (s, 2H), 4.6-4.7 (m, 1H), 6.59 (d, 1H, J = 7Hz), 6.8-6.9 (m, 1H), 7.4-7.5 (m, 2H), 7.97 (d, 1H, J = 3Hz), 8.11 (br s, 1H), 8.1-8.2 (m, 2H).
MS: 395.09 [M + H] +
実施例３１
（Ｓ）－２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド
Figure JPOXMLDOC01-appb-C000197
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１５ｍｇ，０．０６ｍｍｏｌ）及び（Ｓ）－２－（４－イソブチルフェニル）プロパン酸（１６ｍｇ，０．０８ｍｍｏｌ）を用いて表題化合物（白色結晶，２２ｍｇ，８１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．８－０．９（ｍ，６Ｈ），１．５１（ｄ，３Ｈ，Ｊ＝７Ｈｚ），１．８－１．９（ｍ，２Ｈ），２．２－２．３（ｍ，１Ｈ），２．４５（ｄ，２Ｈ，Ｊ＝７Ｈｚ），３．１３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．５－３．６（ｍ，１Ｈ），３．６３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８６（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），８．０３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１６（ｓ，１Ｈ）．
ＭＳ：４１８．２５［Ｍ－Ｈ］－ Example 31
(S) -2- (4-isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide
Figure JPOXMLDOC01-appb-C000197
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (15 mg, 0.06 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 22 mg, 81%) was obtained using (S) -2- (4-isobutylphenyl) propanoic acid (16 mg, 0.08 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.8-0.9 (m, 6H), 1.51 (d, 3H, J = 7Hz), 1.8-1.9 (m, 2H) , 2.2-2.3 (m, 1H), 2.45 (d, 2H, J = 7Hz), 3.13 (dd, 1H, J = 4,10Hz), 3.2-3.4 ( m, 2H), 3.5-3.6 (m, 1H), 3.63 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.59 ( d, 1H, J = 7Hz), 6.86 (dd, 1H, J = 2,2Hz), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 8.03 (d, 1H, J = 3Hz), 8.16 (s, 1H).
MS: 418.25 [MH] -
実施例３２
（Ｒ）－２－（３－フルオロ－４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000198
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２０ｍｇ，０．０９ｍｍｏｌ）及び２－（３－フルオロ－４－（トリフルオロメチル）フェニル）酢酸（２３ｍｇ，０．１０ｍｍｏｌ）を用いて表題化合物（白色アモルファス，２５ｍｇ，６６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．２０（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６０（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），６．２７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８６（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．１６（ｓ，１Ｈ），７．１－７．２（ｍ，１Ｈ），７．５７（ｔ，１Ｈ，Ｊ＝７Ｈｚ），８．０２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１４（ｓ，１Ｈ）．
ＭＳ：４３６．０８［Ｍ＋Ｈ］＋ Example 32
(R) -2- (3-Fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000198
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (20 mg, 0.09 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 25 mg, 66%) was obtained using 2- (3-fluoro-4- (trifluoromethyl) phenyl) acetic acid (23 mg, 0.10 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.20 (dd, 1H, J = 4, 10Hz), 3.3-3.5 (m, 2H), 3.60 (s, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 6.27 (d, 1H, J = 7Hz), 6.86 (dd, 1H, J = 2.2Hz), 7.16 (s, 1H), 7.1-7.2 (m, 1H), 7.57 (t, 1H, J = 7Hz), 8.02 (d, 1H, J = 3Hz), 8.14 (s, 1H).
MS: 436.08 [M + H] +
実施例３３
（Ｒ）－２－（４－アミノフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000199
実施例３０で合成した（Ｒ）－２－（４－ニトロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（２１５ｍｇ，０．５５ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、パラジウム炭素（２０ｍｇ）を加えて水素気流下６時間室温で撹拌した。不溶物をろ過後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－３０％）により精製し表題化合物（白色アモルファス，１９５ｍｇ，９８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１０（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．４８（ｓ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．６９（ｂｒ　ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．５９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．６－６．７（ｍ，２Ｈ），６．８－６．９（ｍ，１Ｈ），７．０－７．１（ｍ，２Ｈ），８．０６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：３６５．１０［Ｍ＋Ｈ］＋ Example 33
(R) -2- (4-Aminophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000199
(R) -2- (4-nitrophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 30 (215 mg, 0. 55 mmol) was dissolved in methanol (20 mL), palladium carbon (20 mg) was added, and the mixture was stirred under a hydrogen stream for 6 hours at room temperature. After filtering the insoluble material, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-30%) and the title compound (white amorphous, 195 mg, 98). %) Was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.10 (dd, 1H, J = 5, 10Hz), 3.3-3.4 (m, 2H), 3.48 (s, 2H), 3.64 (dd, 1H, J = 6,10Hz), 3.69 (br s, 2H), 4.6-4.7 (m, 1H), 5.59 (d, 1H, J = 7Hz), 6.6-6.7 (m, 2H), 6.8-6.9 (m, 1H) ), 7.0-7.1 (m, 2H), 8.06 (d, 1H, J = 3Hz), 8.19 (s, 1H).
MS: 365.10 [M + H] +
実施例３４
（Ｒ）－１－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000200
２－（４－（トリフルオロメチル）フェニル）アセトニトリル（１．００ｇ，５．４０ｍｍｏｌ）をＴＨＦ（８．０ｍＬ）に溶解して－５０℃でしばらく撹拌し、リチウムビス（トリメチルシリル）アミドのＴＨＦ溶液（１．３Ｍ）（４．１５ｍＬ，５．４０ｍｍｏｌ）を加えた後、１－ブロモ－２－クロロエタンを加えた。その後、再びリチウムビス（トリメチルシリル）アミドのＴＨＦ溶液（１．３Ｍ）（４．１５ｍＬ，５．４０ｍｍｏｌ）を加えて３０分間撹拌した後、室温で２時間撹拌した。反応液に水を加えて酢酸エチルで抽出し、分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して１－４－（トリフルオロメチル）フェニル）シクロプロパン－１－カルボニトリルの粗体（淡黄色粉末，２１９ｍｇ）を得た。得られた１－４－（トリフルオロメチル）フェニル）シクロプロパン－１－カルボニトリルの粗体（２１９ｍｇ）をＴＨＦ（３．０ｍＬ）に溶解した後、４Ｎ水酸化ナトリウム水溶液（３．０ｍＬ）を加えて１００℃で１６時間撹拌し、減圧下溶媒を留去した。水を加えて水溶液とした後、酢酸エチルで洗浄し、２Ｎ塩酸水溶液を加えて中和し、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して１－（４－（トリフルオロメチル）フェニル）シクロプロパン－１－カルボン酸の粗体（黄色結晶，４２ｍｇ）を得た。実施例１と同様の手法に従い、得られた１－（４－（トリフルオロメチル）フェニル）シクロプロパン－１－カルボン酸の粗体（４２ｍｇ）及び参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４２ｍｇ，０．１８ｍｍｏｌ）を用いて表題化合物（白色アモルファス，４３ｍｇ，１．８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．０－１．２（ｍ，２Ｈ），１．６－１．７（ｍ，２Ｈ），１．７－１．８（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．０５（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．６（ｍ，１Ｈ），５．２６（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．５３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０－８．１（ｍ，１Ｈ），８．２０（ｓ，１Ｈ）．
ＭＳ：４４４．０７［Ｍ＋Ｈ］＋ Example 34
(R) -1- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000200
2- (4- (Trifluoromethyl) phenyl) acetonitrile (1.00 g, 5.40 mmol) is dissolved in THF (8.0 mL), stirred at −50 ° C. for a while, and a THF solution of lithium bis (trimethylsilyl) amide. After adding (1.3 M) (4.15 mL, 5.40 mmol), 1-bromo-2-chloroethane was added. Then, a THF solution (1.3 M) (4.15 mL, 5.40 mmol) of lithium bis (trimethylsilyl) amide was added again, and the mixture was stirred for 30 minutes and then at room temperature for 2 hours. Water is added to the reaction solution, extracted with ethyl acetate, the separated organic layer is dried over anhydrous sodium sulfate, the insoluble matter is filtered, and the solvent is distilled off under reduced pressure to make 1-4 (trifluoromethyl) phenyl). A crude body of cyclopropan-1-carbonitrile (pale yellow powder, 219 mg) was obtained. After dissolving the obtained crude material (219 mg) of 1-4- (trifluoromethyl) phenyl) cyclopropane-1-carbonitrile in THF (3.0 mL), a 4N aqueous sodium hydroxide solution (3.0 mL) was added. In addition, the mixture was stirred at 100 ° C. for 16 hours, and the solvent was distilled off under reduced pressure. After adding water to make an aqueous solution, the mixture was washed with ethyl acetate, neutralized by adding a 2N hydrochloric acid aqueous solution, and extracted with a mixed solution of chloroform and methanol. The separated organic layer is dried over anhydrous sodium sulfate, the insoluble matter is filtered, and the solvent is distilled off under reduced pressure to obtain a crude product of 1- (4- (trifluoromethyl) phenyl) cyclopropan-1-carboxylic acid (yellow). Crystals (42 mg) were obtained. According to the same method as in Example 1, the obtained crude product of 1- (4- (trifluoromethyl) phenyl) cyclopropane-1-carboxylic acid (42 mg) and (R)-synthesized in Reference Example 1-2. The title compound (white amorphous, 43 mg, 1.8%) was obtained using 1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (42 mg, 0.18 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.0-1.2 (m, 2H), 1.6-1.7 (m, 2H), 1.7-1.8 (m, 1H) , 2.3-2.4 (m, 1H), 3.05 (dd, 1H, J = 5,10Hz), 3.3-3.4 (m, 2H), 3.64 (dd, 1H, J = 6,10Hz), 4.5-4.6 (m, 1H), 5.26 (d, 1H, J = 6Hz), 6.8-6.9 (m, 1H), 7.53 ( d, 2H, J = 8Hz), 7.64 (d, 2H, J = 8Hz), 8.0-8.1 (m, 1H), 8.20 (s, 1H).
MS: 444.07 [M + H] +
実施例３５
（Ｒ）－２－（４－アセトアミドフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000201
実施例３３で合成した（Ｒ）－２－（４－アミノフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（３０ｍｇ，０．０８ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、塩化アセチル（５．９μＬ，０．０８ｍｍｏｌ）及びＤＩＰＥＡ（３０μＬ，０．１６ｍｍｏｌ）を加えて室温で６０時間撹拌した。反応液に水を加えてしばらく撹拌し、分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－４０％）により精製し表題化合物（白色アモルファス，６．０ｍｇ，１８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．１８（ｓ，３Ｈ），２．３－２．４（ｍ，１Ｈ），３．１２（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．５４（ｓ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．６６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．２－７．３（ｍ，２Ｈ），７．２３（ｂｒ　ｓ，１Ｈ），７．４－７．５（ｍ，２Ｈ），８．０５（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１９（ｓ，１Ｈ）
ＭＳ：４０７．１２［Ｍ＋Ｈ］＋ Example 35
(R) -2- (4-acetamide phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000201
(R) -2- (4-Aminophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 33 (30 mg, 0. 08 mmol) was dissolved in chloroform (1.0 mL), acetyl chloride (5.9 μL, 0.08 mmol) and DIPEA (30 μL, 0.16 mmol) were added, and the mixture was stirred at room temperature for 60 hours. Water was added to the reaction solution, and the mixture was stirred for a while. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-40%) to give the title compound (white amorphous, 6.0 mg, 18%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.18 (s, 3H), 2.3-2.4 (m, 1H), 3.12 (Dd, 1H, J = 5,10Hz), 3.3-3.4 (m, 2H), 3.54 (s, 2H), 3.64 (dd, 1H, J = 6,10Hz), 4 .6-4.7 (m, 1H), 5.66 (d, 1H, J = 7Hz), 6.8-6.9 (m, 1H), 7.2-7.3 (m, 2H) , 7.23 (br s, 1H), 7.4-7.5 (m, 2H), 8.05 (d, 1H, J = 2Hz), 8.19 (s, 1H)
MS: 407.12 [M + H] +
実施例３６
Ｎ－（３－シアノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000202
参考例１９で合成した３－シアノ－３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（４５４ｍｇ，１．２３ｍｍｏｌ）に氷冷下でトリフルオロ酢酸（１５ｍＬ）を加え、室温で４時間撹拌した後、減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－８０％）により精製しＮ－（３－シアノピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド（茶色油状物，３６７ｍｇ）を得た。実施例９と同様の手法に従い、得られたＮ－（３－シアノピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド（３６７ｍｇ）及び３－ブロモ－５－（トリフルオロメチル）ピリジン（２７８ｍｇ，１．２３ｍｍｏｌ）を用いて表題化合物（黄色粉末，３０ｍｇ，５．８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．４－２．５（ｍ，１Ｈ），３．４９（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．６７（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．６－３．８（ｍ，４Ｈ），６．９－７．０（ｍ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），８．００（ｂｒ　ｓ，１Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４１５．１３［Ｍ＋Ｈ］＋ Example 36
N- (3-Cyano-1- (5- (trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) -2- (4-Cyclopropylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000202
Trifluoroacetic acid (15 mL) was added to the 3-cyano-3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-carboxylic acid tert-butyl (454 mg, 1.23 mmol) synthesized in Reference Example 19 under ice-cooling. ) Was added, and the mixture was stirred at room temperature for 4 hours, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-80%) and N- ( 3-Cyanopyrrolidin-3-yl) -2- (4-cyclopropylphenyl) acetamide (brown oil, 367 mg) was obtained. N- (3-cyanopyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide (367 mg) and 3-bromo-5- (trifluoromethyl) obtained according to the same procedure as in Example 9. The title compound (yellow powder, 30 mg, 5.8%) was obtained using pyridine (278 mg, 1.23 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.1-2.2 (m, 1H), 2.4-2.5 (m, 1H), 3.49 (d, 1H, J = 10Hz), 3.67 (d, 1H, J = 10Hz), 3.6-3.8 (m, 4H), 6.9-7.0 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 ( m, 2H), 8.00 (br s, 1H), 8.12 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 415.13 [M + H] +
実施例３７
３－（２－（１Ｈ－インドール－６－イル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000203
実施例７と同様の手法に従い、参考例２０－２で合成した３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル（３４ｍｇ，０．０９ｍｍｏｌ）から３－アミノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチルを合成し、２－（１Ｈ－インドール－６－イル）酢酸（１５ｍｇ，０．０９ｍｍｏｌ）を用いて表題化合物（白色粉末，２６ｍｇ，６７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．２－２．３（ｍ，１Ｈ），２．４－２．５（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６１（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．７１（ｓ，２Ｈ），３．７６（ｓ，３Ｈ），４．００（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），５．９４（ｓ，１Ｈ），６．５－６．６（ｍ，１Ｈ），６．８－６．９（ｍ，１Ｈ），６．９８（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．６２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．０６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１６（ｂｒ　ｓ，１Ｈ），８．２２（ｓ，１Ｈ）．
ＭＳ：４４７．１０［Ｍ＋Ｈ］＋ Example 37
3- (2- (1H-indole-6-yl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylate methyl
Figure JPOXMLDOC01-appb-C000203
3-((tert-butoxycarbonyl) amino) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylic synthesized in Reference Example 20-2 according to the same procedure as in Example 7. Methyl 3-amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate was synthesized from methyl acid (34 mg, 0.09 mmol) to synthesize 2- (1H-indole-6-). Il) Acetic acid (15 mg, 0.09 mmol) was used to give the title compound (white powder, 26 mg, 67%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.2-2.3 (m, 1H), 2.4-2.5 (m, 1H), 3.3-3.5 (m, 2H) , 3.61 (d, 1H, J = 10Hz), 3.71 (s, 2H), 3.76 (s, 3H), 4.00 (d, 1H, J = 10Hz), 5.94 (s) , 1H), 6.5-6.6 (m, 1H), 6.8-6.9 (m, 1H), 6.98 (dd, 1H, J = 2.8Hz), 7.2-7 .3 (m, 2H), 7.62 (d, 1H, J = 8Hz), 8.06 (d, 1H, J = 3Hz), 8.16 (br s, 1H), 8.22 (s, 1H).
MS: 447.10 [M + H] +
実施例３８
３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000204
参考例２１－２で合成した３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）ピロリジン－３－カルボン酸メチル（２９４ｍｇ，０．８９ｍｍｏｌ）、３－ブロモ－５－（トリフルオロメチル）ピリジン（３０２ｍｇ，１．３４ｍｍｏｌ）、酢酸パラジウム（２０ｍｇ，０．０９ｍｍｏｌ）、ＸＰｈｏｓ（８５ｍｇ，０．１８ｍｍｏｌ）及び炭酸セシウム（６２８ｍｇ，１．７８ｍｍｏｌ）をトルエン（９．０ｍＬ）に懸濁し、窒素気流下８５℃で６時間撹拌した。室温まで放冷した後セライトで不溶物をろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（白色アモルファス，８．１ｍｇ，１．９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．４－２．５（ｍ，１Ｈ），２．５－２．６（ｍ，１Ｈ），３．４－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，３Ｈ），３．７６（ｓ，３Ｈ），３．９８（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），６．２４（ｓ，１Ｈ），６．９－７．０（ｍ，１Ｈ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４７６．０９［Ｍ＋Ｈ］＋ Example 38
Methyl 3- (2- (4- (trifluoromethyl) phenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000204
Methyl 3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-3-carboxylate (294 mg, 0.89 mmol) synthesized in Reference Example 21-2, 3-bromo-5- (trifluoromethyl) ) Ppyridine (302 mg, 1.34 mmol), palladium acetate (20 mg, 0.09 mmol), XPhos (85 mg, 0.18 mmol) and cesium carbonate (628 mg, 1.78 mmol) suspended in toluene (9.0 mL) and nitrogen. The mixture was stirred at 85 ° C. under an air stream for 6 hours. After allowing to cool to room temperature, the insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (white amorphous, 8.1 mg, 1.9%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.4-2.5 (m, 1H), 2.5-2.6 (m, 1H), 3.4-3.5 (m, 2H) , 3.6-3.7 (m, 3H), 3.76 (s, 3H), 3.98 (d, 1H, J = 11Hz), 6.24 (s, 1H), 6.9-7 .0 (m, 1H), 7.40 (d, 2H, J = 8Hz), 7.61 (d, 2H, J = 8Hz), 8.06 (d, 1H, J = 3Hz), 8.21 (S, 1H).
MS: 476.09 [M + H] +
実施例３９
（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000205
実施例２６と同様の手法に従い、参考例２５－２で合成した（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル（９５ｍｇ，０．４４ｍｍｏｌ）から（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸（白色粉末）を合成し、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１０１ｍｇ，０．４４ｍｍｏｌ）を用いて表題化合物（白色粉末，７２ｍｇ，４０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．８－１．９（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．２－３．３（ｍ，１Ｈ），３．４－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），３．６－３．７（ｍ，１Ｈ），４．７－４．８（ｍ，１Ｈ），６．１８（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．９２（ｓ，１Ｈ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，１Ｈ），７．６－７．７（ｍ，１Ｈ），８．１０（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４１７．１１［Ｍ＋Ｈ］＋ Example 39
(1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000205
Methyl (1S, 2S) -2- (benzo [d] oxazole-2-yl) cyclopropane-1-carboxylate (95 mg, 0.44 mmol) synthesized in Reference Example 25-2 according to the same procedure as in Example 26. ) To (1S, 2S) -2- (benzo [d] oxazole-2-yl) cyclopropane-1-carboxylic acid (white powder) was synthesized, and (R) -1- was synthesized in Reference Example 1-2. The title compound (white powder, 72 mg, 40%) was obtained using (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (101 mg, 0.44 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H) , 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.2-3.3 (m, 1H), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.6-3.7 (m, 1H), 4.7-4.8 ( m, 1H), 6.18 (d, 1H, J = 6Hz), 6.92 (s, 1H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H), 8.10 (d, 1H, J = 2Hz), 8.20 (s, 1H).
MS: 417.11 [M + H] +
実施例４０
（Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000206
実施例１と同様の手法に従い、参考例１２－２で合成した（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン（７０ｍｇ，０．３０ｍｍｏｌ）及び参考例２３－２で合成した２－（４－モルホリノフェニル）酢酸（９８ｍｇ，０．４４ｍｍｏｌ）を用いて表題化合物（白色粉末，６０ｍｇ，４６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，４Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．８－３．９（ｍ，４Ｈ），４．５－４．７（ｍ，１Ｈ），５．４８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８８（ｄ，２Ｈ，Ｊ＝９Ｈｚ），６．９２（ｓ，１Ｈ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：４４１．１０［Ｍ＋Ｈ］＋ Example 40
(R) -2- (4-morpholinophenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000206
(R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (70 mg, 0.30 mmol) synthesized in Reference Example 12-2 and the same procedure as in Example 1 The title compound (white powder, 60 mg, 46%) was obtained using 2- (4-morpholinophenyl) acetic acid (98 mg, 0.44 mmol) synthesized in Reference Example 23-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 4H) , 3.23 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 4H), 3.75 (dd, 1H, J = 6,10Hz), 3.8-3. 9 (m, 4H), 4.5-4.7 (m, 1H), 5.48 (d, 1H, J = 7Hz), 6.88 (d, 2H, J = 9Hz), 6.92 ( s, 1H), 7.12 (d, 2H, J = 8Hz).
MS: 441.10 [M + H] +
実施例４１
３－（２－（４－モルホリノフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル
Figure JPOXMLDOC01-appb-C000207
実施例７と同様の手法に従い、参考例２０－２で合成した３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル（３９ｍｇ，０．１０ｍｍｏｌ）から３－アミノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチルを合成し、参考例２３－２で合成した２－（４－モルホリノフェニル）酢酸（３３ｍｇ，０．１５ｍｍｏｌ）を用いて表題化合物（白色粉末，２１ｍｇ，４３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．３－２．４（ｍ，１Ｈ），２．５－２．６（ｍ，１Ｈ），３．１－３．２（ｍ，４Ｈ），３．４－３．５（ｍ，２Ｈ），３．５３（ｓ，２Ｈ）３．６２（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），３．７６（ｓ，３Ｈ），３．８－３．９（ｍ，４Ｈ），４．００（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），５．９９（ｓ，１Ｈ），６．８－６．９（ｍ，２Ｈ），６．９１（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．１－７．２（ｍ，２Ｈ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４９３．１６［Ｍ＋Ｈ］＋ Example 41
Methyl 3- (2- (4-morpholinophenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000207
3-((tert-butoxycarbonyl) amino) -1-(5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylic acid synthesized in Reference Example 20-2 according to the same procedure as in Example 7. Methyl 3-amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate was synthesized from methyl acid (39 mg, 0.10 mmol), and was synthesized in Reference Example 23-2. -(4-Molholinophenyl) acetic acid (33 mg, 0.15 mmol) was used to give the title compound (white powder, 21 mg, 43%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.3-2.4 (m, 1H), 2.5-2.6 (m, 1H), 3.1-3.2 (m, 4H) , 3.4-3.5 (m, 2H), 3.53 (s, 2H) 3.62 (d, 1H, J = 10Hz), 3.76 (s, 3H), 3.8-3. 9 (m, 4H), 4.00 (d, 1H, J = 10Hz), 5.99 (s, 1H), 6.8-6.9 (m, 2H), 6.91 (dd, 1H, J = 2,2 Hz), 7.1-7.2 (m, 2H), 8.07 (d, 1H, J = 3 Hz), 8.22 (s, 1H).
MS: 493.16 [M + H] +
実施例４２
（Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000208
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（７０ｍｇ，０．３０ｍｍｏｌ）及び参考例２３－２で合成した２－（４－モルホリノフェニル）酢酸（１００ｍｇ，０．４５ｍｍｏｌ）を用いて表題化合物（白色粉末，５９ｍｇ，４５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，５Ｈ），３．３－３．４（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．６６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．８－３．９（ｍ，４Ｈ），４．６－４．７（ｍ，１Ｈ），５．５０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．７９（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），６．８－６．９（ｍ，２Ｈ），７．１－７．２（ｍ，２Ｈ），７．５１（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９７（ｄ，１Ｈ，Ｊ＝９Ｈｚ）．
ＭＳ：４３５．１５［Ｍ＋Ｈ］＋ Example 42
(R) -2- (4-morpholinophenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000208
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (70 mg, 0.30 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 The title compound (white powder, 59 mg, 45%) was obtained using 2- (4-morpholinophenyl) acetic acid (100 mg, 0.45 mmol) synthesized in Reference Example 23-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 5H) , 3.3-3.4 (m, 2H), 3.51 (s, 2H), 3.66 (dd, 1H, J = 6,10Hz), 3.8-3.9 (m, 4H) , 4.6-4.7 (m, 1H), 5.50 (d, 1H, J = 7Hz), 6.79 (dd, 1H, J = 3.9Hz), 6.8-6.9 ( m, 2H), 7.1-7.2 (m, 2H), 7.51 (d, 1H, J = 9Hz), 7.97 (d, 1H, J = 9Hz).
MS: 435.15 [M + H] +
実施例４３
２－（４－シクロプロピルフェニル）－Ｎ－（３－エチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000209
実施例３８と同様の手法に従い、参考例２４で合成した３－（２－（４－シクロプロピルフェニル）アセトアミド）－３－エチルピロリジン－１－カルボン酸ｔｅｒｔ－ブチル（７８２ｍｇ，２．１０ｍｍｏｌ）から２－（４－シクロプロピルフェニル）－Ｎ－（３－エチルピロリジン－３－イル）アセトアミド（黄色アモルファス，５７８ｍｇ）を合成し、３－ブロモ－５－（トリフルオロメチル）ピリジン（５７５ｍｇ，２．５４ｍｍｏｌ）を用いて表題化合物（橙色アモルファス，４００ｍｇ，４６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．８４（ｔ，３Ｈ，Ｊ＝８Ｈｚ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，２Ｈ），１．９－２．０（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），３．２－３．４（ｍ，３Ｈ），３．４９（ｓ，２Ｈ），３．６５（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），５．２１（ｓ，１Ｈ），６．８８（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），６．９－７．０（ｍ，２Ｈ），７．０－７．１（ｍ，２Ｈ），８．０５（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：４１８．１７［Ｍ＋Ｈ］＋ Example 43
2- (4-Cyclopropylphenyl) -N- (3-ethyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000209
From tert-butyl 3- (2- (4-cyclopropylphenyl) acetamide) -3-ethylpyrrolidin-1-carboxylate (782 mg, 2.10 mmol) synthesized in Reference Example 24 according to the same procedure as in Example 38. 2- (4-Cyclopropylphenyl) -N- (3-ethylpyrrolidin-3-yl) acetamide (yellow amorphous, 578 mg) was synthesized to synthesize 3-bromo-5- (trifluoromethyl) pyridine (575 mg, 2. 54 mmol) was used to give the title compound (orange amorphous, 400 mg, 46%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.84 (t, 3H, J = 8 Hz), 0.9-1.0 (m, 2H) , 1.8-1.9 (m, 2H), 1.9-2.0 (m, 1H), 2.0-2.1 (m, 1H), 2.2-2.3 (m, 1H), 3.2-3.4 (m, 3H), 3.49 (s, 2H), 3.65 (d, 1H, J = 10Hz), 5.21 (s, 1H), 6.88 (Dd, 1H, J = 2,2Hz), 6.9-7.0 (m, 2H), 7.0-7.1 (m, 2H), 8.05 (d, 1H, J = 3Hz) , 8.19 (s, 1H).
MS: 418.17 [M + H] +
実施例４４
（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000210
実施例２６と同様の手法に従い、参考例２２－４で合成した（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル（１０５ｍｇ，０．４５ｍｍｏｌ）から（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸（白色粉末）を合成し、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１０３ｍｇ，０．４５ｍｍｏｌ）を用いて表題化合物（白色粉末，８９ｍｇ，４６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．８（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝３，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．７－４．８（ｍ，１Ｈ），６．７１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８５（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．０－７．１（ｍ，１Ｈ），７．１６（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．５１（ｄｄ，１Ｈ，Ｊ＝５，８Ｈｚ），８．０４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１５（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ）．
ＭＳ：４３５．１０［Ｍ＋Ｈ］＋ Example 44
(1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000210
Methyl (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate (105 mg,) synthesized in Reference Example 22-4 according to the same procedure as in Example 26. (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylic acid (white powder) was synthesized from 0.45 mmol) and synthesized in Reference Example 1-2. The title compound (white powder, 89 mg, 46%) was obtained using (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (103 mg, 0.45 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H) , 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.27 (dd, 1H, J = 3,10Hz), 3.3-3.5 (m, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.7-4.8 (m, 1H), 6.71 ( d, 1H, J = 7Hz), 6.85 (dd, 1H, J = 2,2Hz), 7.0-7.1 (m, 1H), 7.16 (dd, 1H, J = 2.8Hz) ), 7.51 (dd, 1H, J = 5,8Hz), 8.04 (d, 1H, J = 3Hz), 8.15 (d, 1H, J = 0.8Hz).
MS: 435.10 [M + H] +
実施例４５
（１Ｓ，２Ｓ）－２－（５，６－ジフルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000211
実施例２６と同様の手法に従い、参考例２６－２で合成した（１Ｓ，２Ｓ）－２－（５，６－ジフルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル（６８ｍｇ，０．２７ｍｍｏｌ）から（１Ｓ，２Ｓ）－２－（５，６－ジフルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸（白色粉末）を合成し、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６２ｍｇ，０．２７ｍｍｏｌ）を用いて表題化合物（白色粉末，３５ｍｇ，２９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．８（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．２９（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．７－４．８（ｍ，１Ｈ），６．２５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９１（ｄｄ，１Ｈ，Ｊ＝２，２Ｈｚ），７．３０（ｄｄ，１Ｈ，Ｊ＝７，９Ｈｚ），７．３９（ｄｄ，１Ｈ，Ｊ＝８，１０Ｈｚ），８．１０（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ）．
ＭＳ：４５３．０９［Ｍ＋Ｈ］＋ Example 45
(1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine- 3-Il) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000211
Methyl (1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylate synthesized in Reference Example 26-2 according to the same procedure as in Example 26. (1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) cyclopropane-1-carboxylic acid (white powder) was synthesized from 68 mg, 0.27 mmol), and Reference Example 1- The title compound (white powder, 35 mg, 29%) using (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (62 mg, 0.27 mmol) synthesized in 2. Got
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H) , 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.29 (dd, 1H, J = 4,10Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.67 (dd, 1H, J = 6,10Hz), 4.7- 4.8 (m, 1H), 6.25 (d, 1H, J = 7Hz), 6.91 (dd, 1H, J = 2.2Hz), 7.30 (dd, 1H, J = 7.9Hz) ), 7.39 (dd, 1H, J = 8,10Hz), 8.10 (d, 1H, J = 3Hz), 8.19 (d, 1H, J = 0.8Hz).
MS: 453.09 [M + H] +
実施例４６
（Ｒ）－２－（４－（２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000212
実施例２６と同様の手法に従い、参考例２７で合成した２－（４－（２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル）フェニル）酢酸エチル（１．２６ｇ，４．８２ｍｍｏｌ）から２－（４－（２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル）フェニル）酢酸（白色粉末，１．０２ｇ）を合成し、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６０ｍｇ，０．２６ｍｍｏｌ）を用いて表題化合物（象牙色粉末，１０６ｍｇ，９１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．０９（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，２Ｈ），３．４７（ｓ，２Ｈ），３．６２（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．００（ｓ，４Ｈ），４．６－４．７（ｍ，１Ｈ），４．８３（ｓ，４Ｈ），５．７３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．４－６．５（ｍ，２Ｈ），６．８６（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．０－７．１（ｍ，２Ｈ），８．０４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１７（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ）．
ＭＳ：４４７．１９［Ｍ＋Ｈ］＋ Example 46
(R) -2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000212
2. Ethyl 2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) ethyl acetate synthesized in Reference Example 27 according to the same procedure as in Example 26 (1.26 g, 4. 2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) acetic acid (white powder, 1.02 g) was synthesized from 82 mmol) and synthesized in Reference Example 1-2. The title compound (dental powder, 106 mg, 91%) was obtained using (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol). ..
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.3-2.4 (m, 1H), 3.09 (dd, 1H, J = 5, 10Hz), 3.3-3.4 (m, 2H), 3.47 (s, 2H), 3.62 (dd, 1H, J = 6,10Hz), 4.00 (s, 4H), 4 .6-4.7 (m, 1H), 4.83 (s, 4H), 5.73 (d, 1H, J = 7Hz), 6.4-6.5 (m, 2H), 6.86 (Dd, 1H, J = 3.9Hz), 7.0-7.1 (m, 2H), 8.04 (d, 1H, J = 3Hz), 8.17 (d, 1H, J = 0. 8Hz).
MS: 447.19 [M + H] +
実施例４７
（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000213
実施例２６と同様の手法に従い、参考例２５－２で合成した（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル（１１０ｍｇ，０．５１ｍｍｏｌ）から（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸を合成し、参考例２５－２で合成した（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン（１２０ｍｇ，０．５１ｍｍｏｌ）を用いて表題化合物（白色粉末，９０ｍｇ，４２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．８（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．４４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．５－３．７（ｍ，２Ｈ），３．８０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．９５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９５（ｄ，１Ｈ，Ｊ＝０．８Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，１Ｈ），７．６－７．７（ｍ，１Ｈ）．
ＭＳ：４２３．０７［Ｍ＋Ｈ］＋ Example 47
(1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000213
Methyl (1S, 2S) -2- (benzo [d] oxazole-2-yl) cyclopropan-1-carboxylate (110 mg, 0.51 mmol) synthesized in Reference Example 25-2 according to the same procedure as in Example 26. ) To (1S, 2S) -2- (benzo [d] oxazole-2-yl) cyclopropan-1-carboxylic acid and synthesized in Reference Example 25-2 (R) -1-(4-( The title compound (white powder, 90 mg, 42%) was obtained using trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (120 mg, 0.51 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H) , 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.44 (dd, 1H, J = 4,10Hz), 3.5-3.7 (m, 2H), 3.80 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 5.95 ( d, 1H, J = 7Hz), 6.95 (d, 1H, J = 0.8Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H), 7.6-7.7 (m, 1H).
MS: 423.07 [M + H] +
実施例４８
（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000214
実施例２６と同様の手法に従い、参考例２２－４で合成した（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル（１２１ｍｇ，０．５１ｍｍｏｌ）から（１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸（象牙色粉末）を合成し、参考例２２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１１９ｍｇ，０．５１ｍｍｏｌ）を用いて表題化合物（白色粉末，１１８ｍｇ，５３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．８（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．２－２．３（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．２－３．３（ｍ，１Ｈ），３．３－３．４（ｍ，１Ｈ），３．４－３．５（ｍ，１Ｈ），３．６－３．７（ｍ，１Ｈ），４．７－４．８（ｍ，１Ｈ），６．７－６．８（ｍ，２Ｈ），７．０－７．１（ｍ，１Ｈ），７．１－７．２（ｍ，１Ｈ），７．３９（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．５０（ｄｄ，１Ｈ，Ｊ＝５，８Ｈｚ），７．９０（ｓ，１Ｈ）．
ＭＳ：４３５．１０［Ｍ＋Ｈ］＋ Example 48
(1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000214
Methyl (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylate synthesized in Reference Example 22-4 according to the same procedure as in Example 26 (121 mg, (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylic acid (dental powder) was synthesized from 0.51 mmol), and synthesized in Reference Example 22-2. The title compound (white powder, 118 mg, 53%) was obtained using (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (119 mg, 0.51 mmol). ..
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.1-2.2 (m, 1H) , 2.2-2.3 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.2-3.3 (m, 1H) 1H), 3.3-3.4 (m, 1H), 3.4-3.5 (m, 1H), 3.6-3.7 (m, 1H), 4.7-4.8 ( m, 1H), 6.7-6.8 (m, 2H), 7.0-7.1 (m, 1H), 7.1-7.2 (m, 1H), 7.39 (d, 1H, J = 8Hz), 7.50 (dd, 1H, J = 5,8Hz), 7.90 (s, 1H).
MS: 435.10 [M + H] +
実施例４９
（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000215
実施例２６と同様の手法に従い、参考例２８－２で合成した（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸メチル（４７ｍｇ，０．２０ｍｍｏｌ）から（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸（象牙色粉末）を合成し、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６６ｍｇ，０．２９ｍｍｏｌ）を用いて表題化合物（白色粉末，５１ｍｇ，５９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．８（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．２９（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），３．６９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．７－４．８（ｍ，１Ｈ），６．０７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，１Ｈ），７．０－７．１（ｍ，１Ｈ），７．２９（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．３７（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４３５．１０［Ｍ＋Ｈ］＋ Example 49
(1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000215
Methyl (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylate synthesized in Reference Example 28-2 according to the same procedure as in Example 26 (47 mg, (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylic acid (dental powder) was synthesized from 0.20 mmol), and synthesized in Reference Example 1-2. The title compound (white powder, 51 mg, 59%) was obtained using (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (66 mg, 0.29 mmol). ..
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H) , 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.29 (dd, 1H, J = 4,10Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.69 (dd, 1H, J = 6,10Hz), 4.7- 4.8 (m, 1H), 6.07 (d, 1H, J = 7Hz), 6.9-7.0 (m, 1H), 7.0-7.1 (m, 1H), 7. 29 (dd, 1H, J = 2.8Hz), 7.37 (dd, 1H, J = 4.9Hz), 8.12 (d, 1H, J = 3Hz), 8.22 (s, 1H).
MS: 435.10 [M + H] +
実施例５０
（１Ｒ，２Ｒ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000216
実施例２６と同様の手法に従い、参考例２９－３で合成したトランス－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸エチル（２００ｍｇ，０．８６ｍｍｏｌ）からトランス－２－（ベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸（象牙色粉末）を合成し、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２００ｍｇ，０．８６ｍｍｏｌ）を用いて表題化合物（白色アモルファス，７．３ｍｇ，２．０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．８（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．７－４．８（ｍ，１Ｈ），６．０７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．９－７．０（ｍ，１Ｈ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，１Ｈ），７．６－７．７（ｍ，１Ｈ），８．１０（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４１７．０９［Ｍ＋Ｈ］＋ Example 50
(1R, 2R) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000216
Trans-from ethyl trans-2- (benzo [d] oxazole-2-yl) cyclopropan-1-carboxylate (200 mg, 0.86 mmol) synthesized in Reference Example 29-3 according to the same procedure as in Example 26. 2- (Benzo [d] oxazole-2-yl) cyclopropan-1-carboxylic acid (ivory-colored powder) was synthesized, and (R) -1- (5- (trifluoromethyl-5)) synthesized in Reference Example 1-2 ) Pyridin-3-yl) pyrrolidine-3-amine (200 mg, 0.86 mmol) was used to give the title compound (white amorphous, 7.3 mg, 2.0%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H) , 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.27 (dd, 1H, J = 4,10Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.67 (dd, 1H, J = 6,10Hz), 4.7- 4.8 (m, 1H), 6.07 (d, 1H, J = 8Hz), 6.9-7.0 (m, 1H), 7.2-7.3 (m, 2H), 7. 4-7.5 (m, 1H), 7.6-7.7 (m, 1H), 8.10 (d, 1H, J = 2Hz), 8.20 (s, 1H).
MS: 417.09 [M + H] +
実施例５１
（１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000217
実施例２６と同様の手法に従い、参考例３０－３で合成した（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸エチル（１４１ｍｇ，０．５７ｍｍｏｌ）から（１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）シクロプロパン－１－カルボン酸（象牙色粉末）を合成し、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１３１ｍｇ，０．５７ｍｍｏｌ）を用いて表題化合物（白色アモルファス，６０ｍｇ，２４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．７（ｍ，１Ｈ），１．７－１．８（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．１－２．２（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．７－２．８（ｍ，１Ｈ），３．３０（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．５（ｍ，１Ｈ），３．５－３．６（ｍ，１Ｈ），３．６９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．７－４．８（ｍ，１Ｈ），６．２０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８０（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．０－７．１（ｍ，１Ｈ），７．２－７．３（ｍ，１Ｈ），７．３６（ｄｄ，１Ｈ，Ｊ＝４，８Ｈｚ），７．４６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９８（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：４３５．１０［Ｍ＋Ｈ］＋ Example 51
(1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000217
Ethyl (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylate synthesized in Reference Example 30-3 according to the same procedure as in Example 26 (141 mg, (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) cyclopropan-1-carboxylic acid (dental powder) was synthesized from 0.57 mmol), and synthesized in Reference Example 32-2. The title compound (white amorphous, 60 mg, 24%) was obtained using (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (131 mg, 0.57 mmol). ..
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.7 (m, 1H), 1.7-1.8 (m, 1H), 2.0-2.1 (m, 1H) , 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 1H), 3.30 (dd, 1H, J = 4,10Hz), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.69 (dd, 1H, J = 6,10Hz), 4.7- 4.8 (m, 1H), 6.20 (d, 1H, J = 7Hz), 6.80 (dd, 1H, J = 2.8Hz), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 1H), 7.36 (dd, 1H, J = 4.8Hz), 7.46 (d, 1H, J = 8Hz), 7.98 (d, 1H, J) = 2Hz).
MS: 435.10 [M + H] +
実施例５２
トランス－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000218
実施例３と同様の手法に従い、参考例３４で合成した（Ｒ）－（１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（２７３ｍｇ，０．８３ｍｍｏｌ）から（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－アミンの粗体（３１７ｍｇ）を合成し、トランス－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（４０ｍｇ，０．２０ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）においてＲｆ値＝０．４，淡黄色アモルファス，１６ｍｇ，１９％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．１５（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３－４．５（ｍ，１Ｈ），６．６３（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．０－７．２（ｍ，２Ｈ），７．３－７．５（ｍ，２Ｈ），７．４６（ｄ，２Ｈ，Ｊ＝９Ｈｚ），８．６４（ｄ，１Ｈ，Ｊ＝６Ｈｚ），１２．３８（ｓ，１Ｈ）．
ＭＳ：４１５．１６［Ｍ＋Ｈ］＋ Example 52
Trans-2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000218
Tert-Butyl (R)-(1- (4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate (273 mg, 0.83 mmol) synthesized in Reference Example 34 according to the same procedure as in Example 3. (R) -1- (4- (trifluoromethyl) phenyl) pyrrolidine-3-amine crude (317 mg) was synthesized from trans-2- (1H-benzo [d] imidazol-2-yl) cyclo. The title compound, diastereomer A (Rf value = 0.4, pale yellow amorphous, 16 mg, 19% in TLC (ethyl acetate)) was obtained using propane-1-carboxylic acid (40 mg, 0.20 mmol).
Diastereomer A
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.15 (dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.55 (dd, dd, 1H, J = 6,10Hz), 4.3-4.5 (m, 1H), 6.63 (d, 2H, J = 9Hz), 7.0-7.2 (m, 2H), 7. 3-7.5 (m, 2H), 7.46 (d, 2H, J = 9Hz), 8.64 (d, 1H, J = 6Hz), 12.38 (s, 1H).
MS: 415.16 [M + H] +
実施例５３
トランス－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｓ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000219
実施例３と同様の手法に従い、参考例３５で合成した（Ｓ）－（１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（２３６ｍｇ，０．７２ｍｍｏｌ）から（Ｓ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－アミンの粗体（１７０ｍｇ）を合成し、トランス－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（４０ｍｇ，０．２０ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）においてＲｆ値＝０．５，白色粉末，１４ｍｇ，１７％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．１５（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，３Ｈ），４．３－４．５（ｍ，１Ｈ），６．６３（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．０－７．２（ｍ，２Ｈ），７．３－７．５（ｍ，２Ｈ），７．４６（ｄ，２Ｈ，Ｊ＝９Ｈｚ），８．６４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１２．３９（ｓ，１Ｈ）．
ＭＳ：４１５．１８［Ｍ＋Ｈ］＋ Example 53
Trans-2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000219
(S)-(1- (4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) tert-butyl carbamate (236 mg, 0.72 mmol) synthesized in Reference Example 35 according to the same procedure as in Example 3. (S) -1- (4- (trifluoromethyl) phenyl) pyrrolidine-3-amine crude (170 mg) was synthesized from trans-2- (1H-benzo [d] imidazol-2-yl) cyclo. The title compound, diastereomer A (Rf value = 0.5, white powder, 14 mg, 17% in TLC (ethyl acetate)) was obtained using propane-1-carboxylic acid (40 mg, 0.20 mmol).
Diastereomer A
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.15 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 3H), 4.3-4. 5 (m, 1H), 6.63 (d, 2H, J = 9Hz), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 7.46 ( d, 2H, J = 9Hz), 8.64 (d, 1H, J = 7Hz), 12.39 (s, 1H).
MS: 415.18 [M + H] +
実施例５４
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000220
実施例３と同様の手法に従い、参考例３６で合成した（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（４２９ｍｇ，１．３０ｍｍｏｌ）から（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（３００ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（３２ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色粉末，３２ｍｇ，４８％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．９－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．２１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４－４．５（ｍ，１Ｈ），７．０１（ｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．０－７．２（ｍ，２Ｈ），７．３－７．５（ｍ，２Ｈ），７．５９（ｄ，１Ｈ，Ｊ＝９Ｈｚ），８．０４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．６５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１２．４１（ｓ，１Ｈ）．
ＭＳ：４１６．１８［Ｍ＋Ｈ］＋ Example 54
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000220
Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 36 according to the same procedure as in Example 3 (429 mg, A crude compound (300 mg) of (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from 1.30 mmol), and (1S, 2S) -2- (1H) was synthesized. The title compound (white powder, 32 mg, 48%) was obtained using -benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (32 mg, 0.16 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.21 (dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.60 (dd, dd, 1H, J = 6,10Hz), 4.4-4.5 (m, 1H), 7.01 (d, 1H, J = 3.9Hz), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 7.59 (d, 1H, J = 9Hz), 8.04 (d, 1H, J = 3Hz), 8.65 (d, 1H, J = 7Hz) ), 12.41 (s, 1H).
MS: 416.18 [M + H] +
実施例５５
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｓ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000221
実施例３と同様の手法に従い、参考例３７で合成した（Ｓ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（５９ｍｇ，０．１８ｍｍｏｌ）から（Ｓ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（３７ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（３２ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色粉末，４８ｍｇ，７３％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．９－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．１８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４－４．６（ｍ，１Ｈ），７．００（ｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．０－７．２（ｍ，２Ｈ），７．３－７．５（ｍ，２Ｈ），７．５８（ｄ，１Ｈ，Ｊ＝９Ｈｚ），８．０２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．６４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１２．３４（ｓ，１Ｈ）．
ＭＳ：４１６．１８［Ｍ＋Ｈ］＋ Example 55
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000221
Tert-butyl (S)-(1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 37 according to the same procedure as in Example 3 (59 mg, A crude compound (37 mg) of (S) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from 0.18 mmol), and (1S, 2S) -2- (1H) was synthesized. -Benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (32 mg, 0.16 mmol) was used to give the title compound (white powder, 48 mg, 73%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.18 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.60 (dd, dd, 1H, J = 6,10Hz), 4.4-4.6 (m, 1H), 7.00 (d, 1H, J = 3,9Hz), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 7.58 (d, 1H, J = 9Hz), 8.02 (d, 1H, J = 3Hz), 8.64 (d, 1H, J = 7Hz) ), 12.34 (s, 1H).
MS: 416.18 [M + H] +
実施例５６
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000222
実施例１と同様の手法に従い、参考例３８－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－アミン（４５ｍｇ，０．２０ｍｍｏｌ）及び（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（２０ｍｇ，０．１０ｍｍｏｌ）を用いて表題化合物（白色粉末，２８ｍｇ，６８％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．４９（ｄｄ，１Ｈ，Ｊ＝４，８Ｈｚ），３．６－３．７（ｍ，２Ｈ），３．７５（ｄｄ，１Ｈ，Ｊ＝６，１２Ｈｚ），４．３－４．５（ｍ，１Ｈ），７．０－７．２（ｍ，２Ｈ），７．３－７．５（ｍ，２Ｈ），８．６４（ｄ，１Ｈ，Ｊ＝６Ｈｚ），８．７１（ｓ，２Ｈ），１２．３９（ｓ，１Ｈ）．
ＭＳ：４１７．２０［Ｍ＋Ｈ］＋ Example 56
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyrimidine-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000222
(R) -1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-amine (45 mg, 0.20 mmol) synthesized in Reference Example 38-2 and the same procedure as in Example 1 and The title compound (white powder, 28 mg, 68%) was prepared with (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol). Obtained.
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.49 (dd, 1H, J = 4.8Hz), 3.6-3.7 (m, 2H), 3.75 (dd, dd, 1H, J = 6,12Hz), 4.3-4.5 (m, 1H), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 8. 64 (d, 1H, J = 6Hz), 8.71 (s, 2H), 12.39 (s, 1H).
MS: 417.20 [M + H] +
実施例５７
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000223
実施例３と同様の手法に従い、参考例３９で合成した（Ｒ）－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１１２ｍｇ，０．３２ｍｍｏｌ）から（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－アミンの粗体（８０ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（２１ｍｇ，０．１１ｍｍｏｌ）を用いて表題化合物（白色粉末，３５ｍｇ，７７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，２Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，２Ｈ），２．６－２．７（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３０（ｄｔ，１Ｈ，Ｊ＝５，９Ｈｚ），３．４－３．５（ｍ，１Ｈ），３．５９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），６．５１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．６－６．７（ｍ，２Ｈ），７．０５（ｔ，１Ｈ，Ｊ＝９Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，２Ｈ）．１Ｈ分観測できず
ＭＳ：４３３．１８［Ｍ＋Ｈ］＋ Example 57
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000223
Tert-Butyl (R)-(1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 39 according to the same procedure as in Example 3 (112 mg, A crude compound (80 mg) of (R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-amine was synthesized from 0.32 mmol), and (1S, 2S) -2- (1H) was synthesized. The title compound (white powder, 35 mg, 77%) was obtained using -benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (21 mg, 0.11 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.8 (m, 2H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 2H) , 2.6-2.7 (m, 1H), 3.23 (dd, 1H, J = 4,10Hz), 3.30 (dt, 1H, J = 5.9Hz), 3.4-3. 5 (m, 1H), 3.59 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 6.51 (d, 1H, J = 7Hz), 6. 6-6.7 (m, 2H), 7.05 (t, 1H, J = 9Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 2H). Cannot observe for 1H MS: 433.18 [M + H] +
実施例５８
（１Ｓ，２Ｓ）－Ｎ－（（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）－２－（キナゾリン－２－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000224
実施例３と同様の手法に従い、参考例３９で合成した（Ｒ）－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１１２ｍｇ，０．３２ｍｍｏｌ）から（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－アミンの粗体（８０ｍｇ）を合成し、参考例４０－３で合成した（１Ｓ，２Ｓ）－２－（キナゾリン－２－イル）シクロプロパン－１－カルボン酸（２０ｍｇ，０．０９ｍｍｏｌ）を用いて表題化合物（白色粉末，２３ｍｇ，５６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６９（ｄｄｄ，１Ｈ，Ｊ＝４，６，８Ｈｚ），１．７－１．８（ｍ，１Ｈ），１．９－２．１（ｍ，１Ｈ），２．１－２．４（ｍ，２Ｈ），２．９－３．０（ｍ，１Ｈ），３．２２（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３１（ｄｔ，１Ｈ，Ｊ＝５，９Ｈｚ），３．４－３．５（ｍ，１Ｈ），３．５９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．８８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．６－６．７（ｍ，２Ｈ），７．０６（ｔ，１Ｈ，Ｊ＝９Ｈｚ），７．５－７．６（ｍ，１Ｈ），７．８－８．０（ｍ，３Ｈ），９．２５（ｓ，１Ｈ）．
ＭＳ：４４５．１９［Ｍ＋Ｈ］＋ Example 58
(1S, 2S) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) -2- (quinazoline-2-yl) cyclopropane-1- Carboxamide
Figure JPOXMLDOC01-appb-C000224
Tert-Butyl (R)-(1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 39 according to the same procedure as in Example 3 (112 mg, A crude compound (80 mg) of (R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-amine was synthesized from 0.32 mmol) and synthesized in Reference Example 40-3 (1S). , 2S) -2- (quinazoline-2-yl) cyclopropan-1-carboxylic acid (20 mg, 0.09 mmol) was used to give the title compound (white powder, 23 mg, 56%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.69 (ddd, 1H, J = 4,6,8 Hz), 1.7-1.8 (m, 1H), 1.9-2.1 ( m, 1H), 2.1-2.4 (m, 2H), 2.9-3.0 (m, 1H), 3.22 (dd, 1H, J = 4,10Hz), 3.31 ( dt, 1H, J = 5,9Hz), 3.4-3.5 (m, 1H), 3.59 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H) ), 5.88 (d, 1H, J = 7Hz), 6.6-6.7 (m, 2H), 7.06 (t, 1H, J = 9Hz), 7.5-7.6 (m) , 1H), 7.8-8.0 (m, 3H), 9.25 (s, 1H).
MS: 445.19 [M + H] +
実施例５９
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－（メチルスルホニル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000225
実施例１と同様の手法に従い、参考例４１－２で合成した（Ｒ）－１－（３－（メチルスルホニル）フェニル）ピロリジン－３－アミン（６ｍｇ，０．０２ｍｍｏｌ）及び（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（５ｍｇ，０．０２ｍｍｏｌ）を用いて表題化合物（淡黄色粉末，７ｍｇ，６５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５－１．８（ｍ，２Ｈ），２．０－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，２Ｈ），２．６－２．７（ｍ，１Ｈ），３．０４（ｓ，３Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６２（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），６．５３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．７２（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．００（ｔ，１Ｈ，Ｊ＝２Ｈｚ），７．１－７．３（ｍ，３Ｈ），７．３６（ｔ，１Ｈ，Ｊ＝８Ｈｚ），７．４－７．６（ｍ，２Ｈ）．１Ｈ分観測できず
ＭＳ：４２５．１９［Ｍ＋Ｈ］＋ Example 59
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(3- (methylsulfonyl) phenyl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide
Figure JPOXMLDOC01-appb-C000225
(R) -1- (3- (methylsulfonyl) phenyl) pyrrolidine-3-amine (6 mg, 0.02 mmol) and (1S, 2S) synthesized in Reference Example 41-2 according to the same procedure as in Example 1. The title compound (pale yellow powder, 7 mg, 65%) was obtained using -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (5 mg, 0.02 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.5-1.8 (m, 2H), 2.0-2.1 (m, 1H), 2.2-2.4 (m, 2H) , 2.6-2.7 (m, 1H), 3.04 (s, 3H), 3.27 (dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H) , 3.62 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 6.53 (d, 1H, J = 7Hz), 6.72 (dd, 1H, J = 2.8Hz), 7.00 (t, 1H, J = 2Hz), 7.1-7.3 (m, 3H), 7.36 (t, 1H, J = 8Hz), 7.4- 7.6 (m, 2H). Cannot observe for 1H MS: 425.19 [M + H] +
実施例６０
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－シアノフェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000226
実施例１と同様の手法に従い、参考例４２－２で合成した（Ｒ）－３－（３－アミノピロリジン－１－イル）ベンゾニトリル（５ｍｇ，０．０２ｍｍｏｌ）及び（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（５ｍｇ，０．０２ｍｍｏｌ）を用いて表題化合物（淡黄色粉末，９ｍｇ，９６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，２Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，２Ｈ），２．６－２．８（ｍ，１Ｈ），３．２－３．５（ｍ，２Ｈ），３．２２（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．６０（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），６．６１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．７－６．８（ｍ，２Ｈ），６．９６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．１－７．３（ｍ，３Ｈ），７．４－７．６（ｍ，２Ｈ）．１Ｈ分観測できず
ＭＳ：３７２．２１［Ｍ＋Ｈ］＋ Example 60
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (3-cyanophenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000226
(R) -3- (3-aminopyrrolidine-1-yl) benzonitrile (5 mg, 0.02 mmol) and (1S, 2S) -2 synthesized in Reference Example 42-2 according to the same procedure as in Example 1. -(1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (5 mg, 0.02 mmol) was used to give the title compound (pale yellow powder, 9 mg, 96%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.8 (m, 2H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 2H) , 2.6-2.8 (m, 1H), 3.2-3.5 (m, 2H), 3.22 (dd, 1H, J = 4,10Hz), 3.60 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 6.61 (d, 1H, J = 7Hz), 6.7-6.8 (m, 2H), 6.96 ( d, 1H, J = 7Hz), 7.1-7.3 (m, 3H), 7.4-7.6 (m, 2H). Cannot observe for 1H MS: 372.21 [M + H] +
実施例６１
トランス－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000227
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３１ｍｇ，０．１４ｍｍｏｌ）及び参考例４３－３で合成したトランス－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（３１ｍｇ，０．１４ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（メタノール／酢酸エチル＝１／９）において上のスポット，白色粉末，２２ｍｇ，３７％）及び表題化合物のジアステレオマーＢ（ＴＬＣ（メタノール／酢酸エチル＝１／９）において下のスポット，白色粉末，１９ｍｇ，３２％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，２Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，２Ｈ），２．６－２．７（ｍ，１Ｈ），３．３１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７２（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），６．１６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８５（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４－７．６（ｍ，３Ｈ），７．８－７．９（ｍ，１Ｈ），８．０３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），９．７８（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４３９．２８［Ｍ－Ｈ］－
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．９（ｍ，２Ｈ），２．０－２．５（ｍ，３Ｈ），２．６－２．７（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．５８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），６．３５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．７７（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４－８．０（ｍ，４Ｈ），７．９４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），１０．０５（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４３９．２８［Ｍ－Ｈ］－ Example 61
Trans-2- (5-cyano-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000227
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (31 mg, 0.14 mmol) synthesized in Reference Example 1-2 and according to the same method as in Example 1. The title compound dia using trans-2- (5-cyano-1H-benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (31 mg, 0.14 mmol) synthesized in Reference Example 43-3. Stereomer A (upper spot in TLC (methanol / ethyl acetate = 1/9), white powder, 22 mg, 37%) and lower in the title compound Diasteromer B (TLC (methanol / ethyl acetate = 1/9)). Spot, white powder, 19 mg, 32%) was obtained.
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.8 (m, 2H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 2H) , 2.6-2.7 (m, 1H), 3.31 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.72 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 6.16 (d, 1H, J = 7Hz), 6.85 (dd, 1H, J = 3.9Hz), 7. 4-7.6 (m, 3H), 7.8-7.9 (m, 1H), 8.03 (d, 1H, J = 3Hz), 9.78 (br s, 1H).
MS: 439.28 [MH] -
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.9 (m, 2H), 2.0-2.5 (m, 3H), 2.6-2.7 (m, 1H) , 3.23 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.58 (dd, 1H, J = 6,10Hz), 4.6-4. 7 (m, 1H), 6.35 (d, 1H, J = 7Hz), 6.77 (dd, 1H, J = 3.9Hz), 7.4-8.0 (m, 4H), 7. 94 (d, 1H, J = 3Hz), 10.05 (br s, 1H).
MS: 439.28 [MH] -
実施例６２
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（２－（トリフルオロメチル）ピリジン－４－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000228
 実施例３と同様の手法に従い、参考例４４で合成した（Ｒ）－（１－（２－（トリフルオロメチル）ピリジン－４－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチルから（Ｒ）－１－（２－（トリフルオロメチル）ピリジン－４－イル）ピロリジン－３－アミンの粗体（３０ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（２０ｍｇ，０．１０ｍｍｏｌ）を用いて表題化合物（白色粉末，３１ｍｇ，７６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．２－２．５（ｍ，２Ｈ），２．５－２．７（ｍ，１Ｈ），３．３０（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７３（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．６－４．７（ｍ，１Ｈ），６．１９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．４９（ｄｄ，１Ｈ，Ｊ＝２，９Ｈｚ），６．７４（ｄ，１Ｈ，Ｊ＝２Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４－７．５（ｍ，２Ｈ），８．３１（ｄ，１Ｈ，Ｊ＝６Ｈｚ）．１Ｈ観測できず
ＭＳ：４１６．１７［Ｍ＋Ｈ］＋ Example 62
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyridin-4-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000228
 From tert-butyl (R)-(1- (2- (trifluoromethyl) pyridine-4-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 44 according to the same procedure as in Example 3 (R). ) -1- (2- (Trifluoromethyl) pyridine-4-yl) pyrrolidine-3-amine crude (30 mg) was synthesized to (1S, 2S) -2- (1H-benzo [d] imidazole-). The title compound (white powder, 31 mg, 76%) was obtained using 2-yl) cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.8 (m, 2H), 2.0-2.2 (m, 1H), 2.2-2.5 (m, 2H) , 2.5-2.7 (m, 1H), 3.30 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.73 (dd, 1H, J = 6,11Hz), 4.6-4.7 (m, 1H), 6.19 (d, 1H, J = 7Hz), 6.49 (dd, 1H, J = 2.9Hz), 6. 74 (d, 1H, J = 2Hz), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 2H), 8.31 (d, 1H, J = 6Hz). 1H could not be observed MS: 416.17 [M + H] +
実施例６３
トランス－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000229
実施例１と同様の手法に従い、参考例４５－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－アミン（５０ｍｇ，０．２０ｍｍｏｌ）及びトランス－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（４１ｍｇ，０．２０ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）において上のスポット，白色粉末，１４ｍｇ，１６％）及び表題化合物のジアステレオマーＢ（ＴＬＣ（酢酸エチル）において下のスポット，白色粉末，５ｍｇ，６％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－２．０（ｍ，６Ｈ），２．２－２．４（ｍ，１Ｈ），２．５－２．７（ｍ，１Ｈ），３．０８（ｄｄ，１Ｈ，Ｊ＝７，１２Ｈｚ），３．１－３．４（ｍ，２Ｈ），３．５５（ｄｄ，１Ｈ，Ｊ＝３，１２Ｈｚ），４．１－４．３（ｍ，１Ｈ），６．１４（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．３－７．４（ｍ，１Ｈ），７．４－７．６（ｍ，２Ｈ），８．３５（ｓ，１Ｈ），８．４９（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．１Ｈ分観測できず
ＭＳ：４３０．１７［Ｍ＋Ｈ］＋
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－２．０（ｍ，６Ｈ），２．２－２．３（ｍ，１Ｈ），２．６－２．７（ｍ，１Ｈ），３．１－３．３（ｍ，４Ｈ），４．１－４．３（ｍ，１Ｈ），６．４６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．１－７．３（ｍ，３Ｈ），７．４－７．６（ｍ，２Ｈ），８．２３（ｓ，１Ｈ），８．２８（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．１Ｈ分観測できず
ＭＳ：４３０．１８［Ｍ＋Ｈ］＋ Example 63
Trans-2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) cyclopropane- 1-carboxyamide
Figure JPOXMLDOC01-appb-C000229
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine (50 mg, 0.20 mmol) synthesized in Reference Example 45-2 and the same procedure as in Example 1 and Trans-2- (1H-benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (41 mg, 0.20 mmol) was used in the title compound diastereomer A (TLC (ethyl acetate) above). Spots, white powder, 14 mg, 16%) and diastereomeric B (lower spots, white powder, 5 mg, 6% in TLC (ethyl acetate)) of the title compound were obtained.
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-2.0 (m, 6H), 2.2-2.4 (m, 1H), 2.5-2.7 (m, 1H) , 3.08 (dd, 1H, J = 7,12Hz), 3.1-3.4 (m, 2H), 3.55 (dd, 1H, J = 3,12Hz), 4.1-4. 3 (m, 1H), 6.14 (d, 1H, J = 8Hz), 7.2-7.3 (m, 2H), 7.3-7.4 (m, 1H), 7.4- 7.6 (m, 2H), 8.35 (s, 1H), 8.49 (d, 1H, J = 3Hz). Cannot observe for 1H MS: 430.17 [M + H] +
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-2.0 (m, 6H), 2.2-2.3 (m, 1H), 2.6-2.7 (m, 1H) , 3.1-3.3 (m, 4H), 4.1-4.3 (m, 1H), 6.46 (d, 1H, J = 7Hz), 7.1-7.3 (m, 3H), 7.4-7.6 (m, 2H), 8.23 (s, 1H), 8.28 (d, 1H, J = 3Hz). Cannot observe for 1H MS: 430.18 [M + H] +
実施例６４
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000230
実施例１と同様の手法に従い、参考例４６－３で合成した（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン（２４ｍｇ，０．１０ｍｍｏｌ）及び（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（２０ｍｇ，０．１０ｍｍｏｌ）を用いて表題化合物（白色粉末，２０ｍｇ，４７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５－１．８（ｍ，２Ｈ），２．０－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，２Ｈ），２．５－２．７（ｍ，１Ｈ），３．４３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．５－３．７（ｍ，２Ｈ），３．８０（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．６－４．７（ｍ，１Ｈ），６．２９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９４（ｓ，１Ｈ），７．２－７．３（ｍ，２Ｈ），７．４－７．６（ｍ，２Ｈ）．１Ｈ分観測できず
ＭＳ：４２２．１３［Ｍ＋Ｈ］＋ Example 64
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000230
(R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (24 mg, 0.10 mmol) synthesized in Reference Example 46-3 and the same procedure as in Example 1. The title compound (white powder, 20 mg, 47%) was prepared with (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol). Obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.5-1.8 (m, 2H), 2.0-2.1 (m, 1H), 2.2-2.4 (m, 2H) , 2.5-2.7 (m, 1H), 3.43 (dd, 1H, J = 4,10Hz), 3.5-3.7 (m, 2H), 3.80 (dd, 1H, J = 6,11Hz), 4.6-4.7 (m, 1H), 6.29 (d, 1H, J = 7Hz), 6.94 (s, 1H), 7.2-7.3 ( m, 2H), 7.4-7.6 (m, 2H). Cannot observe for 1H MS: 422.13 [M + H] +
実施例６５
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000231
実施例１と同様の手法に従い、参考例４７－２で合成した（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピペリジン－３－アミン（２２ｍｇ，０．１０ｍｍｏｌ）及び（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（２０ｍｇ，０．１０ｍｍｏｌ）を用いて表題化合物（白色粉末，３０ｍｇ，７０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．９（ｍ，６Ｈ），２．２－２．４（ｍ，１Ｈ），２．６－２．７（ｍ，１Ｈ），３．１－３．４（ｍ，２Ｈ），３．１０（ｄｄ，１Ｈ，Ｊ＝７，１２Ｈｚ），３．５７（ｄｄ，１Ｈ，Ｊ＝３，１２Ｈｚ），４．１－４．３（ｍ，１Ｈ），６．１６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．９７（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．１－７．３（ｍ，２Ｈ），７．４－７．６（ｍ，２Ｈ），７．４９（ｄ，２Ｈ，Ｊ＝９Ｈｚ），９．６０（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４２９．１９［Ｍ＋Ｈ］＋ Example 65
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) piperidine-3-yl) cyclopropane- 1-carboxyamide
Figure JPOXMLDOC01-appb-C000231
(R) -1- (4- (trifluoromethyl) phenyl) piperidine-3-amine (22 mg, 0.10 mmol) and (1S, 2S) synthesized in Reference Example 47.2 according to the same procedure as in Example 1. ) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol) was used to give the title compound (white powder, 30 mg, 70%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.9 (m, 6H), 2.2-2.4 (m, 1H), 2.6-2.7 (m, 1H) , 3.1-3.4 (m, 2H), 3.10 (dd, 1H, J = 7,12Hz), 3.57 (dd, 1H, J = 3,12Hz), 4.1-4. 3 (m, 1H), 6.16 (d, 1H, J = 8Hz), 6.97 (d, 2H, J = 9Hz), 7.1-7.3 (m, 2H), 7.4- 7.6 (m, 2H), 7.49 (d, 2H, J = 9Hz), 9.60 (br s, 1H).
MS: 429.19 [M + H] +
実施例６６
トランス－２－（１Ｈ－インドール－３－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000232
実施例３と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１７ｍｇ，０．０７ｍｍｏｌ）及びトランス－２－（１Ｈ－インドール－３－イル）シクロプロパン－１－カルボン酸（１５ｍｇ，０．０７ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）においてＲｆ値＝０．９，淡黄色粉末，６ｍｇ，１９％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．３－１．４（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），２．６－２．７（ｍ，１Ｈ），３．２８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７２（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．７－４．８（ｍ，１Ｈ），５．８５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８４（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），６．９４（ｄｄ，１Ｈ，Ｊ＝１，２Ｈｚ），７．１４（ｄｔ，１Ｈ，Ｊ＝１，７Ｈｚ），７．２２（ｄｔ，１Ｈ，Ｊ＝１，７Ｈｚ），７．３６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．４９（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．６５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９７（ｂｒ　ｓ，１Ｈ），８．０２（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４１５．１８［Ｍ＋Ｈ］＋ Example 66
Trans-2- (1H-indole-3-yl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000232
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (17 mg, 0.07 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 3. Rf value = 0.9 in diastereomeric A (TLC (ethyl acetate)) of the title compound using trans-2- (1H-indole-3-yl) cyclopropan-1-carboxylic acid (15 mg, 0.07 mmol). , Pale yellow powder, 6 mg, 19%).
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.3-1.4 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.5 (m, 1H), 2.6-2.7 (m, 1H), 3.28 (dd, 1H, J = 4,10Hz), 3.4-3.6 ( m, 2H), 3.72 (dd, 1H, J = 6,10Hz), 4.7-4.8 (m, 1H), 5.85 (d, 1H, J = 7Hz), 6.84 ( dd, 1H, J = 3.9Hz), 6.94 (dd, 1H, J = 1,2Hz), 7.14 (dt, 1H, J = 1.7Hz), 7.22 (dt, 1H, J) = 1,7Hz), 7.36 (d, 1H, J = 8Hz), 7.49 (d, 1H, J = 9Hz), 7.65 (d, 1H, J = 8Hz), 7.97 (br) s, 1H), 8.02 (d, 1H, J = 3Hz).
MS: 415.18 [M + H] +
実施例６７
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000233
実施例１と同様の手法に従い、参考例４８－２で合成した（Ｒ）－１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１８ｍｇ，０．０７ｍｍｏｌ）及び（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（１４ｍｇ，０．０７ｍｍｏｌ）を用いて表題化合物（白色粉末，２１ｍｇ，６５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，２Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，２Ｈ），２．６－２．７（ｍ，１Ｈ），３．２－３．５（ｍ，３Ｈ），３．５７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．９６（ｓ，３Ｈ），４．６－４．８（ｍ，１Ｈ），６．１－６．３（ｍ，１Ｈ），７．１４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．３－７．７（ｍ，２Ｈ），７．６５（ｄ，１Ｈ，Ｊ＝３Ｈｚ），９．３９（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４４４．１７［Ｍ－Ｈ］－ Example 67
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-yl) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000233
(R) -1- (6-methoxy-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (18 mg, 0) synthesized in Reference Example 48-2 according to the same procedure as in Example 1. .07 mmol) and (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (14 mg, 0.07 mmol) with the title compound (white powder, 21 mg, 65%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.8 (m, 2H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 2H) , 2.6-2.7 (m, 1H), 3.2-3.5 (m, 3H), 3.57 (dd, 1H, J = 6,10Hz), 3.96 (s, 3H) , 4.6-4.8 (m, 1H), 6.1-6.3 (m, 1H), 7.14 (d, 1H, J = 3Hz), 7.2-7.3 (m, 2H), 7.3-7.7 (m, 2H), 7.65 (d, 1H, J = 3Hz), 9.39 (br s, 1H).
MS: 444.17 [MH] -
実施例６８
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（ｔｅｒｔ－ブチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000234
実施例１と同様の手法に従い、参考例４９－２で合成した（Ｒ）－１－（４－（ｔｅｒｔ－ブチル）チアゾール－２－イル）ピロリジン－３－アミン（２２ｍｇ，０．１０ｍｍｏｌ）及び（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（２０ｍｇ，０．１０ｍｍｏｌ）を用いて表題化合物（白色粉末，２３ｍｇ，５７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２７（ｓ，９Ｈ），１．６－１．８（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．２－２．５（ｍ，２Ｈ），２．５－２．７（ｍ，１Ｈ），３．４－３．６（ｍ，２Ｈ），３．４１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．７７（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．５－４．７（ｍ，１Ｈ），６．０９（ｓ，１Ｈ），６．１－６．３（ｍ，１Ｈ），７．１－７．３（ｍ，２Ｈ），７．３－７．７（ｍ，２Ｈ），９．６８（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４１０．２１［Ｍ＋Ｈ］＋ Example 68
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000234
(R) -1- (4- (tert-butyl) thiazole-2-yl) pyrrolidine-3-amine (22 mg, 0.10 mmol) synthesized in Reference Example 49-2 and the same procedure as in Example 1 and The title compound (white powder, 23 mg, 57%) was prepared with (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (20 mg, 0.10 mmol). Obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.27 (s, 9H), 1.6-1.8 (m, 2H), 2.0-2.2 (m, 1H), 2.2 -2.5 (m, 2H), 2.5-2.7 (m, 1H), 3.4-3.6 (m, 2H), 3.41 (dd, 1H, J = 4,10Hz) , 3.77 (dd, 1H, J = 6,11Hz), 4.5-4.7 (m, 1H), 6.09 (s, 1H), 6.1-6.3 (m, 1H) , 7.1-7.3 (m, 2H), 7.3-7.7 (m, 2H), 9.68 (br s, 1H).
MS: 410.21 [M + H] +
実施例６９
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリダジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000235
実施例３と同様の手法に従い、参考例５０で合成した（Ｒ）－（１－（６－（トリフルオロメチル）ピリダジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（９０ｍｇ，０．２７１ｍｍｏｌ）から（Ｒ）－１－（６－（トリフルオロメチル）ピリダジン－３－イル）ピロリジン－３－アミンの粗体（９１ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（１１０ｍｇ，０．５４２ｍｍｏｌ）を用いて表題化合物（白色粉末，６７ｍｇ，６０％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．９－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．３－３．４（ｍ，２Ｈ），３．５－３．８（ｍ，２Ｈ），４．４－４．５（ｍ，１Ｈ），７．０４（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），７．１０（ｄｄ，２Ｈ，Ｊ＝２，６Ｈｚ），７．４４（ｂｒ　ｓ，２Ｈ），７．７７（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），８．６６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１２．４（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４１７．２０［Ｍ＋Ｈ］＋ Example 69
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000235
Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 50 according to the same procedure as in Example 3 (90 mg, A crude compound (91 mg) of (R) -1- (6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-amine was synthesized from 0.271 mmol), and (1S, 2S) -2- (1H) was synthesized. -Benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (110 mg, 0.542 mmol) was used to give the title compound (white powder, 67 mg, 60%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.3-3.4 (m, 2H), 3.5-3.8 (m, 2H), 4.4-4.5 ( m, 1H), 7.04 (d, 1H, J = 10Hz), 7.10 (dd, 2H, J = 2.6Hz), 7.44 (br s, 2H), 7.77 (d, 1H) , J = 10Hz), 8.66 (d, 1H, J = 7Hz), 12.4 (br s, 1H).
MS: 417.20 [M + H] +
実施例７０
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000236
実施例３と同様の手法に従い、参考例５１で合成した（Ｒ）－（１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１２９ｍｇ，０．３８８ｍｍｏｌ）から（Ｒ）－１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－アミンの粗体（１０１ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（１５７ｍｇ，０．７７６ｍｍｏｌ）を用いて表題化合物（白色粉末，１４５ｍｇ，９０％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．９－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．２６（ｄｄ，１Ｈ，Ｊ＝４，１１Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．４－４．５（ｍ，１Ｈ），７．０－７．２（ｍ，２Ｈ），７．３－７．５（ｍ，２Ｈ），８．２５（ｓ，２Ｈ），８．６４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１２．４（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４１５．２７［Ｍ－Ｈ］－ Example 70
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000236
Tert-Butyl (R)-(1- (2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 51 according to the same procedure as in Example 3 (129 mg, A crude compound (101 mg) of (R) -1- (2- (trifluoromethyl) pyrimidin-5-yl) pyrrolidine-3-amine was synthesized from 0.388 mmol), and (1S, 2S) -2- (1H) was synthesized. The title compound (white powder, 145 mg, 90%) was obtained using -benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (157 mg, 0.776 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.26 (dd, 1H, J = 4,11Hz), 3.3-3.5 (m, 2H), 3.64 (dd, dd, 1H, J = 6,11Hz), 4.4-4.5 (m, 1H), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 2H), 8. 25 (s, 2H), 8.64 (d, 1H, J = 7Hz), 12.4 (br s, 1H).
MS: 415.27 [MH] -
実施例７１
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000237
実施例３と同様の手法に従い、参考例１－１で合成した（Ｒ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１０２ｍｇ，０．３０８ｍｍｏｌ）から（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（７９ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（１２５ｍｇ，０．６１６ｍｍｏｌ）を用いて表題化合物（白色粉末，７３ｍｇ，５７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５－１．８（ｍ，３Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，２Ｈ），２．６－２．７（ｍ，１Ｈ），３．２８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），６．６６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９２（ｓ，１Ｈ），７．１－７．３（ｍ，２Ｈ），７．４９（ｂｒ　ｓ，２Ｈ），８．０９（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４１６．１８［Ｍ＋Ｈ］＋ Example 71
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000237
Tert-Butyl (R)-(1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 1-1 according to the same procedure as in Example 3 ( A crude compound (79 mg) of (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from 102 mg, 0.308 mmol), and (1S, 2S) -2- The title compound (white powder, 73 mg, 57%) was obtained using (1H-benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (125 mg, 0.616 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.5-1.8 (m, 3H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 2H) , 2.6-2.7 (m, 1H), 3.28 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.67 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 6.66 (d, 1H, J = 7Hz), 6.92 (s, 1H), 7.1-7.3 ( m, 2H), 7.49 (br s, 2H), 8.09 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 416.18 [M + H] +
実施例７２
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000238
実施例３と同様の手法に従い、参考例５２で合成した（Ｒ）－（１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（８５ｍｇ，０．２５３ｍｍｏｌ）から（Ｒ）－１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－アミンの粗体（９３ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（９０ｍｇ，０．３８０ｍｍｏｌ）を用いて表題化合物（白色粉末，５０ｍｇ，４７％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．９－２．０（ｍ，１Ｈ），２．２－２．３（ｍ，２Ｈ），２．４－２．５（ｍ，１Ｈ），３．３－３．４（ｍ，１Ｈ），３．５－３．７（ｍ，２Ｈ），３．７３（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．４－４．５（ｍ，１Ｈ），７．０－７．２（ｍ，３Ｈ），７．３－７．５（ｍ，３Ｈ），７．７１（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），８．７０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），１２．４（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４２２．１４［Ｍ＋Ｈ］＋ Example 72
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000238
Tert-Butyl (R)-(1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) carbamate synthesized in Reference Example 52 according to the same procedure as in Example 3 (85 mg, A crude compound (93 mg) of (R) -1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-amine was synthesized from 0.253 mmol), and (1S, 2S) -2- (1H) was synthesized. The title compound (white powder, 50 mg, 47%) was obtained using -benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (90 mg, 0.380 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.9-2.0 (m, 1H), 2.2-2.3 (m, 2H), 2.4-2.5 (m, 1H), 3.3-3.4 (m, 1H), 3.5-3.7 (m, 2H), 3.73 (dd, 1H, J = 6,11Hz), 4.4-4.5 (m, 1H), 7.0-7.2 (m, 3H), 7.3-7.5 (m, 3H), 7.71 ( dd, 1H, J = 3.9Hz), 8.70 (d, 1H, J = 6Hz), 12.4 (br s, 1H).
MS: 422.14 [M + H] +
実施例７３
（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000239
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２１ｍｇ，０．０９０ｍｍｏｌ）及び参考例５４－２で合成した（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（３３ｍｇ，０．１３５ｍｍｏｌ）を用いて表題化合物（白色粉末，１５ｍｇ，３５％）を得た。
１Ｈ　ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）：δ＝１．０－１．２（ｍ，２Ｈ），１．２－１．４（ｍ，２Ｈ），１．６－１．７（ｍ，２Ｈ），２．０－２．３（ｍ，２Ｈ），２．３－２．５（ｍ，１Ｈ），２．８－３．０（ｍ，１Ｈ），３．３－３．６（ｍ，４Ｈ），３．７１（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．５－４．７（ｍ，１Ｈ），７．０７（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．１－７．３（ｍ，２Ｈ），７．５０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．５－７．６（ｍ，２Ｈ），７．９８（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．１Ｈ分観測できず
ＭＳ：４５６．２０［Ｍ＋Ｈ］＋ Example 73
(1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-yl)) Pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000239
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (21 mg, 0.090 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and Using (1S, 2S) -2- (1-cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropane-1-carboxylic acid (33 mg, 0.135 mmol) synthesized in Reference Example 54-2. The title compound (white powder, 15 mg, 35%) was obtained.
1 1 H NMR (CD 3 OD, 400 MHz): δ = 1.0-1.2 (m, 2H), 1.2-1.4 (m, 2H), 1.6-1.7 (m, 2H) ), 2.0-2.3 (m, 2H), 2.3-2.5 (m, 1H), 2.8-3.0 (m, 1H), 3.3-3.6 (m) , 4H), 3.71 (dd, 1H, J = 6,11Hz), 4.5-4.7 (m, 1H), 7.07 (dd, 1H, J = 3.9Hz), 7.1 -7.3 (m, 2H), 7.50 (d, 1H, J = 7Hz), 7.5-7.6 (m, 2H), 7.98 (d, 1H, J = 3Hz). Cannot observe for 1H MS: 456.20 [M + H] +
実施例７４
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－フルオロキノリン－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000240
実施例３と同様の手法に従い、参考例５３で合成した（Ｒ）－（１－（６－フルオロキノリン－２－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（３９ｍｇ，０．１１８ｍｍｏｌ）から（Ｒ）－１－（６－フルオロキノリン－２－イル）ピロリジン－３－アミンの粗体（８１ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（４２ｍｇ，０．１７７ｍｍｏｌ）を用いて表題化合物（淡黄色粉末，１０ｍｇ，２１％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），２．１－２．５（ｍ，３Ｈ），３．４－３．５（ｍ，１Ｈ），３．５－３．７（ｍ，２Ｈ），３．７６（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．３－４．５（ｍ，１Ｈ），６．９５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．０－７．２（ｍ，２Ｈ），７．３－７．６（ｍ，５Ｈ），８．０１（ｄ，１Ｈ，Ｊ＝９Ｈｚ），８．６４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１２．４（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４１６．１８［Ｍ＋Ｈ］＋ Example 74
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluoroquinoline-2-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide
Figure JPOXMLDOC01-appb-C000240
Tert-Butyl (R)-(1- (6-fluoroquinoline-2-yl) pyrrolidine-3-yl) carbamate (39 mg, 0.118 mmol) synthesized in Reference Example 53 according to the same procedure as in Example 3. (R) -1- (6-Fluoroquinoline-2-yl) pyrrolidine-3-amine crude (81 mg) was synthesized from (1S, 2S) -2- (1H-benzo [d] imidazole-2). -Il) Cyclopropan-1-carboxylic acid (42 mg, 0.177 mmol) was used to give the title compound (pale yellow powder, 10 mg, 21%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.5 (m, 3H), 3.4-3.5 (m, 1H), 3.5-3.7 (m, 2H), 3.76 (dd, 1H, J = 6,11Hz), 4.3-4. 5 (m, 1H), 6.95 (d, 1H, J = 9Hz), 7.0-7.2 (m, 2H), 7.3-7.6 (m, 5H), 8.01 ( d, 1H, J = 9Hz), 8.64 (d, 1H, J = 7Hz), 12.4 (br s, 1H).
MS: 416.18 [M + H] +
実施例７５
（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000241
実施例３と同様の手法に従い、参考例７７で合成した（Ｒ）－（１－（３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１０５ｍｇ，０．３１９ｍｍｏｌ）から（Ｒ）－１－（３－（トリフルオロメチル）フェニル）ピロリジン－３－アミンの粗体（９９ｍｇ）を合成し、参考例５４－２で合成した（１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（５２ｍｇ，０．２１３ｍｍｏｌ）を用いて表題化合物（白色粉末，２７ｍｇ，２８％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝０．９－１．３（ｍ，４Ｈ），１．４－１．６（ｍ，２Ｈ），１．９－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），２．６－２．８（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，３Ｈ），３．５６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．４－４．５（ｍ，１Ｈ），６．７２（ｓ，１Ｈ），６．８０（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），６．８９（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．１－７．３（ｍ，２Ｈ），７．３６（ｔ，１Ｈ，Ｊ＝８Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．５２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），８．６２（ｄ，１Ｈ，７Ｈｚ）．
ＭＳ：４５５．２０［Ｍ＋Ｈ］＋ Example 75
(1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(3- (trifluoromethyl) phenyl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000241
Tert-Butyl (R)-(1- (3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) carbamate (105 mg, 0.319 mmol) synthesized in Reference Example 77 according to the same procedure as in Example 3. (R) -1- (3- (trifluoromethyl) phenyl) pyrrolidine-3-amine crude (99 mg) was synthesized from (1S, 2S) -2- (1) synthesized in Reference Example 54-2. -Cyclopropyl-1H-benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (52 mg, 0.213 mmol) was used to give the title compound (white powder, 27 mg, 28%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 0.9-1.3 (m, 4H), 1.4-1.6 (m, 2H), 1.9-2.0 (m, 1H), 2.1-2.3 (m, 2H), 2.6-2.8 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 ( m, 3H), 3.56 (dd, 1H, J = 6,10Hz), 4.4-4.5 (m, 1H), 6.72 (s, 1H), 6.80 (dd, 1H, J = 2.8Hz), 6.89 (d, 1H, J = 8Hz), 7.1-7.3 (m, 2H), 7.36 (t, 1H, J = 8Hz), 7.47 ( d, 1H, J = 7Hz), 7.52 (d, 1H, J = 7Hz), 8.62 (d, 1H, 7Hz).
MS: 455.20 [M + H] +
実施例７６
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－ブロモピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000242
実施例３と同様の手法に従い、参考例５５で合成した（Ｒ）－（１－（５－ブロモピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（７１ｍｇ，０．２０９ｍｍｏｌ）から（Ｒ）－１－（５－ブロモピリジン－３－イル）ピロリジン－３－アミンの粗体（１３８ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（６３ｍｇ，０．３１４ｍｍｏｌ）を用いて表題化合物（白色粉末，５６ｍｇ，６２％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．５（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），２．１－２．５（ｍ，３Ｈ），３．１４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３－４．５（ｍ，１Ｈ），７．０－７．２（ｍ，３Ｈ），７．３－７．５（ｍ，２Ｈ），７．８９（ｄ，１Ｈ，Ｊ＝２Ｈｚ），７．９１（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．６０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１２．４（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４２６．０９［Ｍ＋Ｈ］＋ Example 76
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (5-bromopyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide
Figure JPOXMLDOC01-appb-C000242
(R)-(1- (5-bromopyridin-3-yl) pyrrolidine-3-yl) tert-butylcarbamate (71 mg, 0.209 mmol) synthesized in Reference Example 55 according to the same procedure as in Example 3. From (R) -1- (5-bromopyridin-3-yl) pyrrolidine-3-amine crude (138 mg) was synthesized, and (1S, 2S) -2- (1H-benzo [d] imidazole-2) was synthesized. -Il) Cyclopropan-1-carboxylic acid (63 mg, 0.314 mmol) was used to give the title compound (white powder, 56 mg, 62%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.5 (m, 2H), 1.8-2.0 (m, 1H), 2.1-2.5 (m, 3H), 3.14 (dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.53 (dd, 1H, J = 6,10Hz), 4.3- 4.5 (m, 1H), 7.0-7.2 (m, 3H), 7.3-7.5 (m, 2H), 7.89 (d, 1H, J = 2Hz), 7. 91 (d, 1H, J = 2Hz), 8.60 (d, 1H, J = 7Hz), 12.4 (br s, 1H).
MS: 426.09 [M + H] +
実施例７７
（Ｒ）－２－（キノリン－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000243
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２１６ｍｍｏｌ）及び６－キノリン酢酸（４９ｍｇ，０．２５９ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，８８ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．５７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７８（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），６．７３（ｓ，１Ｈ），６．８１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．３８（ｄｄ，１Ｈ，Ｊ＝４，８Ｈｚ），７．６０（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．６９（ｓ，１Ｈ），７．８５（ｂｒ　ｓ，１Ｈ），８．０－８．１（ｍ，３Ｈ），８．８６（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４０１．１９［Ｍ＋Ｈ］＋ Example 77
(R) -2- (quinoline-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000243
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 88 mg, 100%) was obtained using 6-quinoline acetic acid (49 mg, 0.259 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.14 (dd, 1H, J = 4, 10Hz), 3.2-3.4 (m, 2H), 3.57 (dd, 1H, J = 6,10Hz), 3.78 (s, 2H), 4.6-4.7 (m, 1H), 6.73 (s, 1H), 6.81 (d, 1H, J = 7Hz), 7.38 (dd, 1H, J = 4.8Hz), 7.60 (dd, 1H, J = 2.8Hz), 7.69 (s, 1H), 7.85 (br s, 1H), 8.0-8.1 (m, 3H), 8.86 (d, 1H, J = 3Hz).
MS: 401.19 [M + H] +
実施例７８
（Ｒ）－２－（１Ｈ－インドール－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000244
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２１６ｍｍｏｌ）及び３－インドール酢酸（４５ｍｇ，０．２５９ｍｍｏｌ）を用いて表題化合物（白色アモルファス，８７ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．１－３．４（ｍ，２Ｈ），３．５９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７６（ｓ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．７９（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８２（ｓ，１Ｈ），７．０－７．３（ｍ，３Ｈ），７．３９（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．４９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），８．００（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１８（ｓ，２Ｈ）．
ＭＳ：３８９．１９［Ｍ＋Ｈ］＋ Example 78
(R) -2- (1H-indole-3-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000244
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (50 mg, 0.216 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 87 mg, 100%) was obtained using 3-indoleacetic acid (45 mg, 0.259 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.07 (dd, 1H, J = 4, 10Hz), 3.1-3.4 (m, 2H), 3.59 (dd, 1H, J = 6,10Hz), 3.76 (s, 2H), 4.5-4.7 (m, 1H), 5.79 (d, 1H, J = 6Hz), 6.82 (s, 1H), 7.0-7.3 (m, 3H), 7.39 (d, 1H, J = 8Hz) , 7.49 (d, 1H, J = 7Hz), 8.00 (d, 1H, J = 3Hz), 8.18 (s, 2H).
MS: 389.19 [M + H] +
実施例７９
（Ｒ）－２－（キノリン－７－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド塩酸塩
Figure JPOXMLDOC01-appb-C000245
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（９９ｍｇ，０．４２７ｍｍｏｌ）及び７－キノリン酢酸（８０ｍｇ，０．４２７ｍｍｏｌ）を用いて（Ｒ）－２－（キノリン－７－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（無色油状物，５６ｍｇ）を得た。得られた（Ｒ）－２－（キノリン－７－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（５６ｍｇ）を酢酸エチル（２ｍＬ）に溶解し、２Ｍ塩化水素の酢酸エチル溶液（２ｍＬ）を加えてしばらく撹拌した後、減圧下溶媒を留去し表題化合物（黄色粉末，５２ｍｇ，２８％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．２－３．９（ｍ，６Ｈ），４．４－４．５（ｍ，１Ｈ），７．２－７．３（ｍ，１Ｈ），７．８４（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９－８．１（ｍ，１Ｈ），８．１－８．３（ｍ，４Ｈ），８．７－８．８（ｍ，１Ｈ），９．０－９．１（ｍ，１Ｈ），９．２４（ｄ，１Ｈ，Ｊ＝４Ｈｚ）．１Ｈ分観測できず
ＭＳ：４０１．１６［Ｍ＋Ｈ］＋ Example 79
(R) -2- (quinoline-7-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide hydrochloride
Figure JPOXMLDOC01-appb-C000245
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (99 mg, 0.427 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. (R) -2- (quinoline-7-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3 with 7-quinoline acetic acid (80 mg, 0.427 mmol) -Il) Acetamide (colorless oil, 56 mg) was obtained. The obtained (R) -2- (quinoline-7-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide (56 mg) was added to ethyl acetate (56 mg). It was dissolved in 2 mL), a 2M ethyl acetate solution of hydrogen chloride (2 mL) was added, and the mixture was stirred for a while, and then the solvent was distilled off under reduced pressure to obtain the title compound (yellow powder, 52 mg, 28%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.1-2.3 (m, 1H), 3.2-3.9 (m, 6H), 4.4-4.5 (m, 1H), 7.2-7.3 (m, 1H), 7.84 (d, 1H, J = 8Hz), 7.9-8.1 ( m, 1H), 8.1-8.3 (m, 4H), 8.7-8.8 (m, 1H), 9.0-9.1 (m, 1H), 9.24 (d, 1H, J = 4Hz). Cannot observe for 1H MS: 401.16 [M + H] +
実施例８０
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）オキサゾール－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000246
実施例２７と同様の手法に従い、参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（４３ｍｇ，０．１７６ｍｍｏｌ）及び２－ブロモ－４－（トリフルオロメチル）－１，３－オキサゾール（３８ｍｇ，０．１７６ｍｍｏｌ）を用いて表題化合物（白色粉末，６１ｍｇ，９２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．３（ｍ，１Ｈ），３．２８（ｄｄ，１Ｈ，Ｊ＝５，１１Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７７（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．５－４．６（ｍ，１Ｈ），５．４４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．０－７．２（ｍ，４Ｈ），７．４９（ｄｄ，１Ｈ，Ｊ＝１，３Ｈｚ）．
ＭＳ：４０２．１２［Ｍ＋Ｎａ］＋ Example 80
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) oxazole-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000246
2- (4-Cyclopropylphenyl) acetic acid (43 mg, 0.176 mmol) and 2-bromo-4- (trifluoromethyl) -1,3 synthesized in Reference Example 33-2 according to the same procedure as in Example 27. -Oxazole (38 mg, 0.176 mmol) was used to give the title compound (white powder, 61 mg, 92%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.3 (m, 1H), 3.28 (dd, 1H, J = 5,11Hz), 3.4-3.6 (m, 4H), 3.77 (dd, 1H, J = 6,11Hz), 4.5-4.6 (m, 1H), 5.44 (d, 1H, J = 7Hz), 7.0-7.2 (m, 4H), 7.49 ( dd, 1H, J = 1,3Hz).
MS: 402.12 [M + Na] +
実施例８１
（Ｒ）－２－（１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000247
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３５ｍｇ，０．１５１ｍｍｏｌ）及び２－（１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル）酢酸（３３ｍｇ，０．１５９ｍｍｏｌ）を用いて表題化合物（白色粉末，６２ｍｇ，９８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，４Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．９１（ｓ，３Ｈ），４．６－４．７（ｍ，１Ｈ），６．５４（ｓ，１Ｈ），６．６８（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．９４（ｔ，１Ｈ，Ｊ＝２Ｈｚ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｄ，１Ｈ，Ｊ＝１Ｈｚ）．
ＭＳ：４４４．０９［Ｍ＋Ｎａ］＋ Example 81
(R) -2- (1-Methyl-5- (trifluoromethyl) -1H-pyrazole-3-yl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 -Il) acetamide
Figure JPOXMLDOC01-appb-C000247
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (35 mg, 0.151 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 62 mg, 98%) was obtained using 2- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-3-yl) acetic acid (33 mg, 0.159 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.23 (dd, 1H, J = 4, 10Hz), 3.3-3.6 (m, 4H), 3.68 (dd, 1H, J = 6,10Hz), 3.91 (s, 3H), 4.6-4.7 (m, 1H), 6.54 (s, 1H), 6.68 (d, 1H, J = 6Hz), 6.94 (t, 1H, J = 2Hz), 8.12 (d, 1H, J = 3Hz) , 8.21 (d, 1H, J = 1Hz).
MS: 444.09 [M + Na] +
実施例８２
（Ｒ）－２－（６－（トリフルオロメチル）ピリジン－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000248
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２０ｍｇ，０．０８６５ｍｍｏｌ）及び２－（６－（トリフルオロメチル）ピリジン－３－イル）酢酸（２０ｍｇ，０．０９５２ｍｍｏｌ）を用いて表題化合物（白色粉末，２７ｍｇ，７４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．２４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６２（ｓ，２Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），６．０２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９２（ｓ，１Ｈ），７．６８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９０（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），８．０８（ｄ，１Ｈ，３Ｈｚ），８．２０（ｓ，１Ｈ），８．６２（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：４１９．０９［Ｍ＋Ｈ］＋ Example 82
(R) -2- (6- (Trifluoromethyl) Pyridine-3-yl) -N- (1- (5- (Trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide
Figure JPOXMLDOC01-appb-C000248
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (20 mg, 0.0865 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 27 mg, 74%) was obtained using 2- (6- (trifluoromethyl) pyridine-3-yl) acetic acid (20 mg, 0.0952 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.24 (dd, 1H, J = 4, 10Hz), 3.3-3.6 (m, 2H), 3.62 (s, 2H), 3.67 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 6.02 (d, 1H, J = 7Hz), 6.92 (s, 1H), 7.68 (d, 1H, J = 8Hz), 7.90 (dd, 1H, J = 1, 8Hz), 8.08 (d, 1H, 3Hz), 8.20 (s, 1H), 8.62 (d, 1H, J = 2Hz).
MS: 419.09 [M + H] +
実施例８３
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド－２，２－ｄ２
Figure JPOXMLDOC01-appb-C000249
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３４ｍｇ，０．１４５ｍｍｏｌ）及び参考例５６で合成した２－（４－（トリフルオロメチル）フェニル）酢酸－２，２－ｄ２（３０ｍｇ，０．１４５ｍｍｏｌ）を用いて表題化合物（白色結晶，３４ｍｇ，５７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．１９（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．６２（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．９－７．０（ｍ，１Ｈ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．１０（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４２０．１０［Ｍ＋Ｈ］＋ Example 83
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide-2,2-d 2
Figure JPOXMLDOC01-appb-C000249
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (34 mg, 0.145 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 34 mg, 57%) was obtained using 2- (4- (trifluoromethyl) phenyl) acetic acid-2,2-d 2 (30 mg, 0.145 mmol) synthesized in Reference Example 56. ..
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.19 (dd, 1H, J = 5, 10Hz), 3.3-3.5 (m, 2H), 3.67 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 5.62 (d, 1H, J = 6Hz), 6.9-7.0 (m, 1H), 7.40 (d, 2H, J = 8Hz), 7.61 (d, 2H, J = 8Hz), 8.10 ( d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 420.10 [M + H] +
実施例８４
（Ｒ）－２－（４－（３，３－ジフルオロピロリジン－１－イル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000250
実施例９と同様の手法に従い、参考例５７で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（８８ｍｇ，０．２０５ｍｍｏｌ）及び３，３－ジフルオロピロリジン塩酸塩（３５ｍｇ，０．２４７ｍｍｏｌ）を用いて表題化合物（淡黄色粉末，２２ｍｇ，２４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．６（ｍ，３Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３８（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．６－３．７（ｍ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．４９（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．４－６．６（ｍ，２Ｈ），６．７９（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．０－７．２（ｍ，２Ｈ），７．４７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９７（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４７７．１２［Ｍ＋Ｎａ］＋ Example 84
(R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000250
(R) -2- (4-bromophenyl) -N- (1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Reference Example 57 according to the same procedure as in Example 9 -Il) Acetamide (88 mg, 0.205 mmol) and 3,3-difluoropyrrolidine hydrochloride (35 mg, 0.247 mmol) were used to give the title compound (pale yellow powder, 22 mg, 24%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.6 (m, 3H), 3.11 (dd, 1H, J = 5, 10Hz), 3.38 (t, 2H, J = 7Hz), 3.4-3.6 (m, 4H), 3.6-3.7 (m, 3H), 4.5-4.7 ( m, 1H), 5.49 (d, 1H, J = 7Hz), 6.4-6.6 (m, 2H), 6.79 (dd, 1H, J = 3.8Hz), 7.0- 7.2 (m, 2H), 7.47 (d, 1H, J = 9Hz), 7.97 (d, 1H, J = 3Hz).
MS: 477.12 [M + Na] +
実施例８５
（Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000251
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２５ｍｇ，０．１０８ｍｍｏｌ）及び２－（１Ｈ－インドール－６－イル）酢酸（２３ｍｇ，０．１３０ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，３５ｍｇ，８４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１０（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７０（ｓ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．４５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．５－６．６（ｍ，１Ｈ），６．７５（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），６．９６（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．６２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１７（ｂｒ　ｓ，１Ｈ）．
ＭＳ：３８９．１２［Ｍ＋Ｈ］＋ Example 85
(R) -2- (1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000251
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (25 mg, 0.108 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (pale yellow amorphous, 35 mg, 84%) was obtained using 2- (1H-indole-6-yl) acetic acid (23 mg, 0.130 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.10 (dd, 1H, J = 5, 10Hz), 3.2-3.4 (m, 2H), 3.65 (dd, 1H, J = 6,10Hz), 3.70 (s, 2H), 4.5-4.7 (m, 1H), 5.45 (d, 1H, J = 7Hz), 6.5-6.6 (m, 1H), 6.75 (dd, 1H, J = 3.8Hz), 6.96 (dd, dd, 1H, J = 1.8Hz), 7.2-7.3 (m, 2H), 7.45 (d, 1H, J = 9Hz), 7.62 (d, 1H, J = 8Hz), 7. 94 (d, 1H, J = 3Hz), 8.17 (br s, 1H).
MS: 389.12 [M + H] +
実施例８６
２－（４－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリノ）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000252
実施例９と同様の手法に従い、実施例１７１で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（５０ｍｇ，０．１１７ｍｍｏｌ）及びシス－２，６－ジメチルモルホリン（１６ｍｇ，０．１４０ｍｍｏｌ）を用いて表題化合物（白色粉末，１２ｍｇ，２２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２６（ｄ，６Ｈ，Ｊ＝６Ｈｚ），１．８－２．０（ｍ，１Ｈ），２．２－２．５（ｍ，３Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３７（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４－３．５（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７－３．９（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．５２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．１２（ｄ，２Ｈ，Ｊ＝９Ｈｚ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４６３．１８［Ｍ＋Ｈ］＋ Example 86
2-(4-((2R, 6S) -2,6-dimethylmorpholino) phenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Acetamide
Figure JPOXMLDOC01-appb-C000252
(R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (50 mg, 0.117 mmol) and cis-2,6-dimethylmorpholine (16 mg, 0.140 mmol) were used to give the title compound (white powder, 12 mg, 22%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.26 (d, 6H, J = 6 Hz), 1.8-2.0 (m, 1H), 2.2-2.5 (m, 3H) , 3.11 (dd, 1H, J = 5,10Hz), 3.37 (t, 2H, J = 7Hz), 3.4-3.5 (m, 2H), 3.51 (s, 2H) , 3.65 (dd, 1H, J = 6,10Hz), 3.7-3.9 (m, 2H), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J = 7Hz), 6.8-7.0 (m, 3H), 7.12 (d, 2H, J = 9Hz), 8.07 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 463.18 [M + H] +
実施例８７
（Ｒ）－２－（４－（ピロリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000253
実施例９と同様の手法に従い、実施例１７１で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（５０ｍｇ，０．１１７ｍｍｏｌ）及びピロリジン（１２μＬ，０．１４０ｍｍｏｌ）を用いて表題化合物（白色結晶，８ｍｇ，１６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．１（ｍ，５Ｈ），２．２－２．４（ｍ，１Ｈ），３．０８（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．２－３．３（ｍ，４Ｈ），３．３５（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４９（ｓ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．５２（ｄ，２Ｈ，Ｊ＝９Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．０５（ｄ，２Ｈ，Ｊ＝９Ｈｚ），８．０６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：４１９．１７［Ｍ＋Ｈ］＋ Example 87
(R) -2- (4- (Pyrrolidine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000253
(R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (50 mg, 0.117 mmol) and pyrrolidine (12 μL, 0.140 mmol) were used to give the title compound (white crystals, 8 mg, 16%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.1 (m, 5H), 2.2-2.4 (m, 1H), 3.08 (dd, 1H, J = 5, 10Hz), 3.2-3.3 (m, 4H), 3.35 (t, 2H, J = 7Hz), 3.49 (s, 2H), 3.64 (dd, 1H, J = 6, 10Hz), 4.5-4.7 (m, 1H), 5.55 (d, 1H, J = 7Hz), 6.52 (d, 2H, J = 9Hz), 6.8-6.9 ( m, 1H), 7.05 (d, 2H, J = 9Hz), 8.06 (d, 1H, J = 3Hz), 8.19 (s, 1H).
MS: 419.17 [M + H] +
実施例８８
（Ｒ）－２－（４－（（２－メトキシエチル）（メチル）アミノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000254
実施例９と同様の手法に従い、実施例１７１で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（５０ｍｇ，０．１１７ｍｍｏｌ）及びＮ－（２－メトキシエチル）メチルアミン（１５μＬ，０．１４０ｍｍｏｌ）を用いて表題化合物（白色アモルファス，２．５ｍｇ，５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．９７（ｓ，３Ｈ），３．１０（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，５Ｈ），３．４－３．６（ｍ，６Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．６９（ｄ，２Ｈ，Ｊ＝９Ｈｚ），６．８－７．０（ｍ，１Ｈ），７．０６（ｄ，２Ｈ，Ｊ＝９Ｈｚ），８．０７（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４３７．１７［Ｍ＋Ｈ］＋ Example 88
(R) -2- (4-((2-Methoxyethyl) (methyl) amino) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000254
(R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (50 mg, 0.117 mmol) and N- (2-methoxyethyl) methylamine (15 μL, 0.140 mmol) were used to give the title compound (white amorphous, 2.5 mg, 5%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.97 (s, 3H), 3.10 (Dd, 1H, J = 5,10Hz), 3.3-3.4 (m, 5H), 3.4-3.6 (m, 6H), 3.65 (dd, 1H, J = 6, 10Hz), 4.5-4.7 (m, 1H), 5.54 (d, 1H, J = 7Hz), 6.69 (d, 2H, J = 9Hz), 6.8-7.0 ( m, 1H), 7.06 (d, 2H, J = 9Hz), 8.07 (d, 1H, J = 2Hz), 8.20 (s, 1H).
MS: 437.17 [M + H] +
実施例８９
２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000255
実施例１と同様の手法に従い、参考例５８－２で合成した１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－アミン（１５ｍｇ，０．０６６９１ｍｍｏｌ）及び４－（トリフルオロメチル）フェニル酢酸（１７ｍｇ，０．０８２９ｍｍｏｌ）を用いて表題化合物（白色結晶，２２ｍｇ，８０％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝３．５６（ｓ，２Ｈ），３．７７（ｄｄ，２Ｈ，Ｊ＝５，８Ｈｚ），４．２６（ｔ，２Ｈ，Ｊ＝８Ｈｚ），４．５－４．７（ｍ，１Ｈ），７．１－７．２（ｍ，１Ｈ），７．４９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．１１（ｔ，１Ｈ，Ｊ＝２Ｈｚ），８．２３（ｓ，１Ｈ），８．８９（ｄ，１Ｈ，Ｊ＝７Ｈｚ）．
ＭＳ：４０４．０６［Ｍ＋Ｈ］＋ Example 89
2- (4- (Trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000255
1- (5- (trifluoromethyl) pyridine-3-yl) azetidine-3-amine (15 mg, 0.06691 mmol) and 4- (tri) synthesized in Reference Example 58-2 according to the same procedure as in Example 1. The title compound (white crystals, 22 mg, 80%) was obtained using fluoromethyl) phenylacetic acid (17 mg, 0.0829 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 3.56 (s, 2H), 3.77 (dd, 2H, J = 5,8 Hz), 4.26 (t, 2H, J = 8 Hz) , 4.5-4.7 (m, 1H), 7.1-7.2 (m, 1H), 7.49 (d, 2H, J = 8Hz), 7.67 (d, 2H, J = 8Hz), 8.11 (t, 1H, J = 2Hz), 8.23 (s, 1H), 8.89 (d, 1H, J = 7Hz).
MS: 404.06 [M + H] +
実施例９０
２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000256
実施例１と同様の手法に従い、参考例５８－２で合成した１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－アミン（１５ｍｇ，０．０６９１ｍｍｏｌ）及び２－（１Ｈ－インドール－６－イル）酢酸（１５ｍｇ，０．０８２９ｍｍｏｌ）を用いて表題化合物（白色結晶，２０ｍｇ，７５％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝３．４８（ｓ，２Ｈ），３．７６（ｄｄ，２Ｈ，Ｊ＝６，８Ｈｚ），４．２５（ｔ，２Ｈ，Ｊ＝８Ｈｚ），４．５－４．７（ｍ，１Ｈ），６．３７（ｔ，１Ｈ，Ｊ＝２Ｈｚ），６．９０（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．１３（ｔ，１Ｈ，Ｊ＝２Ｈｚ），７．２－７．３（ｍ，２Ｈ），７．４４（ｔ，１Ｈ，Ｊ＝８Ｈｚ），８．１０（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２３（ｓ，１Ｈ），８．７２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），１１．０（ｓ，１Ｈ）．
ＭＳ：３７５．０９［Ｍ＋Ｈ］＋ Example 90
2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000256
1- (5- (trifluoromethyl) pyridine-3-yl) azetidine-3-amine (15 mg, 0.0691 mmol) and 2- (1H) synthesized in Reference Example 58-2 according to the same procedure as in Example 1. The title compound (white crystals, 20 mg, 75%) was obtained using -indole-6-yl) acetic acid (15 mg, 0.0829 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 3.48 (s, 2H), 3.76 (dd, 2H, J = 6.8 Hz), 4.25 (t, 2H, J = 8 Hz) , 4.5-4.7 (m, 1H), 6.37 (t, 1H, J = 2Hz), 6.90 (dd, 1H, J = 1.8Hz), 7.13 (t, 1H, J = 2Hz), 7.2-7.3 (m, 2H), 7.44 (t, 1H, J = 8Hz), 8.10 (d, 1H, J = 3Hz), 8.23 (s, 1H), 8.72 (d, 1H, J = 7Hz), 11.0 (s, 1H).
MS: 375.09 [M + H] +
実施例９１
（Ｒ）－２－（１－メチル－１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000257
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１２ｍｇ，０．０５２９ｍｍｏｌ）及び２－（１－メチル－１Ｈ－インドール－６－イル）酢酸（１０ｍｇ，０．０５２９ｍｍｏｌ）を用いて表題化合物（白色結晶，１４ｍｇ，６３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０８（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．６４（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７３（ｓ，２Ｈ），３．７７（ｓ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．５７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．４８（ｄ，１Ｈ，Ｊ＝２Ｈｚ），６．８－６．９（ｍ，１Ｈ），６．９５（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．１９（ｓ，１Ｈ），７．６０（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．０５（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：４０３．１１［Ｍ＋Ｈ］＋ Example 91
(R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000257
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (12 mg, 0.0529 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 14 mg, 63%) was obtained using 2- (1-methyl-1H-indole-6-yl) acetic acid (10 mg, 0.0529 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.08 (dd, 1H, J = 5, 10Hz), 3.2-3.4 (m, 2H), 3.64 (dd, 1H, J = 6,10Hz), 3.73 (s, 2H), 3.77 (s, 3H), 4 .5-4.7 (m, 1H), 5.57 (d, 1H, J = 7Hz), 6.48 (d, 1H, J = 2Hz), 6.8-6.9 (m, 1H) , 6.95 (dd, 1H, J = 1.8Hz), 7.07 (d, 1H, J = 3Hz), 7.19 (s, 1H), 7.60 (d, 1H, J = 8Hz) , 8.05 (d, 1H, J = 3Hz), 8.19 (s, 1H).
MS: 403.11 [M + H] +
実施例９２
（Ｒ）－２－（１－メチル－１Ｈ－インドール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000258
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１２ｍｇ，０．０５２９ｍｍｏｌ）及び２－（１－メチル－１Ｈ－インドール－６－イル）酢酸（１０ｍｇ，０．０５２９ｍｍｏｌ）を用いて表題化合物（白色結晶，９ｍｇ，４１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０９（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．７３（ｓ，２Ｈ），３．７６（ｓ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．５６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．４８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），６．７５（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），６．９４（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．１９（ｓ，１Ｈ），７．４５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．５９（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９３（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４０３．１１［Ｍ＋Ｈ］＋ Example 92
(R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000258
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (12 mg, 0.0529 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 9 mg, 41%) was obtained using 2- (1-methyl-1H-indole-6-yl) acetic acid (10 mg, 0.0529 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.09 (dd, 1H, J = 5, 10Hz), 3.2-3.4 (m, 2H), 3.65 (dd, 1H, J = 6,10Hz), 3.73 (s, 2H), 3.76 (s, 3H), 4 .5-4.7 (m, 1H), 5.56 (d, 1H, J = 7Hz), 6.48 (d, 1H, J = 3Hz), 6.75 (dd, 1H, J = 3, 9Hz), 6.94 (dd, 1H, J = 1.8Hz), 7.07 (d, 1H, J = 3Hz), 7.19 (s, 1H), 7.45 (d, 1H, J = 9Hz), 7.59 (d, 1H, J = 8Hz), 7.93 (d, 1H, J = 3Hz).
MS: 403.11 [M + H] +
実施例９３
（Ｒ）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000259
２－（４－（４－メチルピペラジン－１－イル）フェニル）酢酸エチル（９５ｍｇ，０．３６２ｍｍｏｌ）をメタノール（２ｍＬ）及び水（２ｍＬ）に溶解し、水酸化リチウム一水和物（４６ｍｇ，１．０９ｍｍｏｌ）を加えて室温で終夜撹拌した。反応液に水を加えて酢酸エチルで洗浄した後、水層に６Ｍ塩酸（１９０μＬ）を加え、再度酢酸エチルで洗浄した。水層を減圧下留去し２－（４－（４－メチルピペリジン－１－イル）フェニル）酢酸の粗体（無色油状物、１９２ｍｇ）を得た。得られた２－（４－（４－メチルピペリジン－１－イル）フェニル）酢酸の粗体（９６ｍｇ）及び参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３８ｍｇ，０．１６３ｍｍｏｌ）をメタノール（１．５ｍＬ）に溶解した後、ＤＭＴ－ＭＭ（９０ｍｇ，０．３２６ｍｍｏｌ）及びＤＩＰＥＡ（１６６μＬ，０．９７８ｍｍｏｌ）を加えて室温で終夜撹拌した。反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：５０－１００％）により精製し表題化合物（白色粉末，５１ｍｇ，６９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，４Ｈ），２．５８（ｔ，４Ｈ，Ｊ＝５Ｈｚ），３．１１（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．２１（ｔ，４Ｈ，Ｊ＝５Ｈｚ），３．３７（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５１（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．１－７．２（ｍ，２Ｈ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４４８．１７［Ｍ＋Ｈ］＋ Example 93
(R) -2- (4- (4-Methylpiperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000259
2- (4- (4-Methylpiperazin-1-yl) phenyl) ethyl acetate (95 mg, 0.362 mmol) was dissolved in methanol (2 mL) and water (2 mL) and lithium hydroxide monohydrate (46 mg, 1.09 mmol) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and washed with ethyl acetate, then 6M hydrochloric acid (190 μL) was added to the aqueous layer, and the mixture was washed again with ethyl acetate. The aqueous layer was distilled off under reduced pressure to obtain a crude product of 2- (4- (4-methylpiperidine-1-yl) phenyl) acetic acid (colorless oil, 192 mg). The obtained crude product of 2- (4- (4-methylpiperidin-1-yl) phenyl) acetic acid (96 mg) and (R) -1- (5- (trifluoromethyl) synthesized in Reference Example 1-2) After dissolving pyridine-3-yl) pyrrolidine-3-amine (38 mg, 0.163 mmol) in methanol (1.5 mL), DMT-MM (90 mg, 0.326 mmol) and DIPEA (166 μL, 0.978 mmol) were added. In addition, it was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 50-100%) to give the title compound (white powder, 51 mg, 69%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 4H), 2.58 (t, 4H, J = 5Hz) , 3.11 (dd, 1H, J = 5,10Hz), 3.21 (t, 4H, J = 5Hz), 3.37 (t, 2H, J = 7Hz), 3.51 (s, 2H) , 3.65 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J = 7Hz), 6.8-7.0 ( m, 3H), 7.1-7.2 (m, 2H), 8.07 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 448.17 [M + H] +
実施例９４
（Ｒ）－２－（４－（ピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000260
実施例３３と同様の手法に従い、参考例５９で合成した（Ｒ）－４－（４－（２－オキソ－２－（（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アミノ）エチル）フェニル）ピペラジン－１－カルボン酸ベンジル（１７６ｍｇ，０．３１０ｍｍｏｌ）を用いて表題化合物（白色粉末，１２２ｍｇ，９１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，９Ｈ），３．３７（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５１（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５１（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．１－７．２（ｍ，２Ｈ），８．０８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．１Ｈ分観測できず
ＭＳ：４３４．１５［Ｍ＋Ｎａ］＋ Example 94
(R) -2- (4- (Piperazine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000260
(R) -4- (4- (2-oxo-2-((1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine) synthesized in Reference Example 59 according to the same procedure as in Example 33) The title compound (white powder, 122 mg, 91%) was obtained using benzyl-3-yl) amino) ethyl) phenyl) piperazin-1-carboxylate (176 mg, 0.310 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 9H) , 3.37 (t, 2H, J = 7Hz), 3.51 (s, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H) , 5.51 (d, 1H, J = 7Hz), 6.8-7.0 (m, 3H), 7.1-7.2 (m, 2H), 8.08 (d, 1H, J = 3Hz), 8.20 (s, 1H). Cannot observe for 1H MS: 434.15 [M + Na] +
実施例９５
（Ｒ）－２－（４－（４－アセチルピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000261
実施例９４で合成した（Ｒ）－２－（４－（ピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（４５ｍｇ，０．１０４ｍｍｏｌ）及びトリエチルアミン（３６μＬ，０．１０４ｍｍｏｌ）をクロロホルム（２ｍＬ）に溶解した後、氷冷下で無水酢酸（１２μＬ，０．１２５ｍｍｏｌ）を加えて室温で撹拌した。１８時間後、減圧下溶媒を留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：９０－１００％）により精製し表題化合物（白色粉末，４３ｍｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．１５（ｓ，３Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，５Ｈ），３．３８（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５１（ｓ，２Ｈ），３．６－３．７（ｍ，３Ｈ），３．７７（ｔ，２Ｈ，Ｊ＝５Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．１－７．２（ｍ，２Ｈ），８．０８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４９８．１４［Ｍ＋Ｎａ］＋ Example 95
(R) -2- (4- (4-Acetylpiperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000261
(R) -2- (4- (piperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) synthesized in Example 94) After dissolving acetamide (45 mg, 0.104 mmol) and triethylamine (36 μL, 0.104 mmol) in chloroform (2 mL), acetic anhydride (12 μL, 0.125 mmol) was added under ice-cooling, and the mixture was stirred at room temperature. After 18 hours, the solvent was distilled off under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 90-100%) and the title compound (white powder, 43 mg, 86%). ) Was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.15 (s, 3H), 2.2-2.4 (m, 1H), 3.0 -3.2 (m, 5H), 3.38 (t, 2H, J = 7Hz), 3.51 (s, 2H), 3.6-3.7 (m, 3H), 3.77 (t) , 2H, J = 5Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J = 7Hz), 6.8-7.0 (m, 3H), 7.1 -7.2 (m, 2H), 8.08 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 498.14 [M + Na] +
実施例９６
（Ｒ）－２－（４－（２－オキソピペリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000262
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２１５ｍｍｏｌ）及び２－（４－（２－オキソピペリジン－１－イル）フェニル）酢酸（５５ｍｇ，０．２３６ｍｍｏｌ）を用いて表題化合物（白色粉末，４５ｍｇ，４７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．１（ｍ，５Ｈ），２．２－２．４（ｍ，１Ｈ），２．５３（ｔ，２Ｈ，Ｊ＝６Ｈｚ），３．１８（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．７（ｍ，７Ｈ），４．５－４．７（ｍ，１Ｈ），５．８８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．０（ｍ，１Ｈ），７．２－７．３（ｍ，４Ｈ），８．０８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４６９．１１［Ｍ＋Ｈ］＋ Example 96
(R) -2- (4- (2-oxopiperidine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000262
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (50 mg, 0.215 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white powder, 45 mg, 47%) was obtained using 2- (4- (2-oxopiperidine-1-yl) phenyl) acetic acid (55 mg, 0.236 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.1 (m, 5H), 2.2-2.4 (m, 1H), 2.53 (t, 2H, J = 6Hz) , 3.18 (dd, 1H, J = 5,10Hz), 3.3-3.7 (m, 7H), 4.5-4.7 (m, 1H), 5.88 (d, 1H, J = 7Hz), 6.8-7.0 (m, 1H), 7.2-7.3 (m, 4H), 8.08 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 469.11 [M + H] +
実施例９７
（Ｒ）－２－（６－クロロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000263
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４４ｍｇ，０．１８９ｍｍｏｌ）及び２－（６－クロロ－１，３－ベンゾオキサゾール－２－イル）酢酸（４０ｍｇ，０．１８９ｍｍｏｌ）を用いて表題化合物（黄色粉末，５７ｍｇ，７１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．１－２．２（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．３３（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．６９（ｓ，２Ｈ），４．６－４．８（ｍ，１Ｈ），６．９－７．０（ｍ，１Ｈ），７．３４（ｄｄ，１Ｈ，Ｊ＝２，９Ｈｚ），７．４５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．６５（ｄ，１Ｈ，Ｊ＝２Ｈｚ），７．９９（ｄ，１Ｈ，Ｊ＝６Ｈｚ），８．１３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４２５．０６［Ｍ＋Ｈ］＋ Example 97
(R) -2- (6-chlorobenzo [d] oxazole-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000263
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (44 mg, 0.189 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (yellow powder, 57 mg, 71%) was obtained using 2- (6-chloro-1,3-benzoxazole-2-yl) acetic acid (40 mg, 0.189 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.1-2.2 (m, 1H), 2.3-2.5 (m, 1H), 3.33 (dd, 1H, J = 4, 10Hz), 3.4-3.6 (m, 2H), 3.73 (dd, 1H, J = 6,10Hz), 3.69 (s, 2H), 4.6-4.8 (m, 1H), 6.9-7.0 (m, 1H), 7.34 (dd, 1H, J = 2.9Hz), 7.45 (d, 1H, J = 9Hz), 7.65 (d, 1H, J = 2Hz), 7.99 (d, 1H, J = 6Hz), 8.13 (d, 1H, J = 3Hz), 8.22 (s, 1H).
MS: 425.06 [M + H] +
実施例９８
（Ｒ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000264
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４０ｍｇ，０．１７３ｍｍｏｌ）及び２－（ベンゾ［ｄ］オキサゾール－２－イル）酢酸ナトリウム一水和物（４１ｍｇ，０．１９０ｍｍｏｌ）を用いて表題化合物（黄色粉末，５１ｍｇ，７６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．１－２．２（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．３４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．７３（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．９７（ｓ，２Ｈ），４．６－４．８（ｍ，１Ｈ），６．９－７．０（ｍ，１Ｈ），７．３－７．４（ｍ，２Ｈ），７．５－７．６（ｍ，１Ｈ），７．６－７．７（ｍ，１Ｈ），８．１３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，２Ｈ）．
ＭＳ：３９１．１０［Ｍ＋Ｈ］＋ Example 98
(R) -2- (benzo [d] oxazole-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000264
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (40 mg, 0.173 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (yellow powder, 51 mg, 76%) was obtained using 2- (benzo [d] oxazole-2-yl) sodium acetate monohydrate (41 mg, 0.190 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.1-2.2 (m, 1H), 2.3-2.5 (m, 1H), 3.34 (dd, 1H, J = 4, 10Hz), 3.4-3.6 (m, 2H), 3.73 (dd, 1H, J = 6,10Hz), 3.97 (s, 2H), 4.6-4.8 (m, 1H), 6.9-7.0 (m, 1H), 7.3-7.4 (m, 2H), 7.5-7.6 (m, 1H), 7.6-7.7 ( m, 1H), 8.13 (d, 1H, J = 3Hz), 8.21 (s, 2H).
MS: 391.10 [M + H] +
実施例９９
トランス－２－（３，５－ジクロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000265
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３０ｍｍｏｌ）及びトランス－２－（３，５－ジクロロフェニル）シクロプロパン－１－カルボン酸（３３ｍｇ，０．１４３ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）において上のスポット，白色粉末，２５ｍｇ，４２％）及びジアステレオマーＢ（ＴＬＣ（酢酸エチル）において下のスポット，白色粉末，１９ｍｇ，３２％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．６（ｍ，２Ｈ），３．２８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．８７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，３Ｈ），７．１９（ｔ，１Ｈ，Ｊ＝２Ｈｚ），８．１３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４４４．０２［Ｍ＋Ｈ］＋
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．５（ｍ，２Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．８８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，３Ｈ），７．１８（ｔ，１Ｈ，Ｊ＝２Ｈｚ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４４４．０１［Ｍ＋Ｈ］＋ Example 99
Trans-2- (3,5-dichlorophenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000265
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.130 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. Diastereomer A (TLC (ethyl acetate) above spot, white powder, 25 mg) with trans-2- (3,5-dichlorophenyl) cyclopropane-1-carboxylic acid (33 mg, 0.143 mmol). , 42%) and diastereomer B (lower spot on TLC (ethyl acetate), white powder, 19 mg, 32%).
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.6 (m, 2H), 3.28 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.69 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.87 (d, 1H, J = 7Hz), 6.9-7.0 (m, 3H), 7.19 ( t, 1H, J = 2Hz), 8.13 (d, 1H, J = 3Hz), 8.22 (s, 1H).
MS: 444.02 [M + H] +
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.5 (m, 2H), 3.27 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.88 (d, 1H, J = 7Hz), 6.9-7.0 (m, 3H), 7.18 ( t, 1H, J = 2Hz), 8.12 (d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 444.01 [M + H] +
実施例１００
トランス－２－（４－ブロモフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000266
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３０ｍｍｏｌ）及びトランス－２－（４－ブロモフェニル）シクロプロパン－１－カルボン酸（３４ｍｇ，０．１４３ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）において上のスポット，白色粉末，２６ｍｇ，４３％）及びジアステレオマーＢ（ＴＬＣ（酢酸エチル）において下のスポット，白色粉末，２３ｍｇ，３９％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．６（ｍ，２Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．８０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，３Ｈ），７．３－７．５（ｍ，２Ｈ），８．１３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４５４．００［Ｍ＋Ｈ］＋
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．６（ｍ，２Ｈ），３．２６（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．８４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，３Ｈ），７．３－７．４（ｍ，２Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４５４．０１［Ｍ＋Ｈ］＋ Example 100
Trans-2- (4-bromophenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000266
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.130 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The above spot in diastereomeric A (TLC (ethyl acetate), white powder, 26 mg, using trans-2- (4-bromophenyl) cyclopropane-1-carboxylic acid (34 mg, 0.143 mmol), 43%) and diastereomer B (lower spot on TLC (ethyl acetate), white powder, 23 mg, 39%) were obtained.
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J = 5,10Hz), 3.4-3.6 (m, 2H), 3.69 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.80 (d, 1H, J = 7Hz), 6.9-7.0 (m, 3H), 7.3 7.5 (m, 2H), 8.13 (d, 1H, J = 3Hz), 8.22 (s, 1H).
MS: 454.00 [M + H] +
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.6 (m, 2H), 3.26 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.84 (d, 1H, J = 7Hz), 6.9-7.0 (m, 3H), 7.3 7.4 (m, 2H), 8.12 (d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 454.01 [M + H] +
実施例１０１
（Ｒ）－２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000267
参考例６０で合成した２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）酢酸エチル（１６ｍｇ，０．０５２４ｍｍｏｌ）をメタノール（１ｍＬ）及び水（１ｍＬ）に溶解し、水酸化リチウム一水和物（７ｍｇ，０．１７６ｍｍｏｌ）を加えて室温で終夜撹拌した。反応液に水を加えて酢酸エチルで洗浄した後、水層に２Ｍ塩酸（８８μＬ）を加えて中和し、クロロホルム及びメタノールの混液で抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去し２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）酢酸の粗体（白色粉末、２８ｍｇ）を得た。実施例１と同様の手法に従い、得られた２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）酢酸の粗体（２８ｍｇ）及び参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２８ｍｇ，０．０５２４ｍｍｏｌ）を用いて表題化合物（白色粉末，１８ｍｇ，７０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，５Ｈ），２．２－２．４（ｍ，１Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．４（ｍ，６Ｈ），３．５０（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．００（ｓ，４Ｈ），４．５－４．７（ｍ，１Ｈ），５．５０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．０－７．２（ｍ，２Ｈ），８．０８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４９１．１８［Ｍ＋Ｈ］＋ Example 101
(R) -2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000267
Ethyl 2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) ethyl acetate (16 mg, 0.0524 mmol) synthesized in Reference Example 60 was added to methanol (1 mL) and water. It was dissolved in (1 mL), lithium hydroxide monohydrate (7 mg, 0.176 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate, neutralized by adding 2M hydrochloric acid (88 μL) to the aqueous layer, and extracted with a mixed solution of chloroform and methanol. The separated organic layer is dried over anhydrous sodium sulfate, the insoluble matter is filtered, and the solvent is distilled off under reduced pressure to remove 2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl). ) Phenyl) Acetic acid crude (white powder, 28 mg) was obtained. A crude compound (28 mg) of 2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) acetic acid obtained according to the same procedure as in Example 1 and Reference Example. The title compound (white powder, 18 mg, 70) was used with (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (28 mg, 0.0524 mmol) synthesized in 1-2. %) Was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 5H), 2.2-2.4 (m, 1H), 3.11 (dd, 1H, J = 5, 10Hz), 3.3-3.4 (m, 6H), 3.50 (s, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.00 (s, 4H), 4 .5-4.7 (m, 1H), 5.50 (d, 1H, J = 7Hz), 6.8-7.0 (m, 3H), 7.0-7.2 (m, 2H) , 8.08 (d, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 491.18 [M + H] +
実施例１０２
（Ｒ）－２－（４－（４－オキソピペリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000268
実施例１０１で合成した（Ｒ）－２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（１７ｍｇ，０．０３２ｍｍｏｌ）をエタノール（１．０ｍＬ）に溶解し、２Ｎ塩酸（１．０ｍＬ）を加えて窒素雰囲気下、終夜加熱還流した。室温まで放冷した反応液に飽和炭酸水素ナトリウム水溶液を加えて中和した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－５％）により精製し表題化合物（白色粉末，２ｍｇ，１４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．５６（ｔ，４Ｈ，６Ｈｚ），３．１４（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５２（ｓ，２Ｈ），３．６０（ｔ，４Ｈ，Ｊ＝６Ｈｚ），３．６６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５２（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．１６（ｄ，２Ｈ，Ｊ＝９Ｈｚ），８．０９（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４６９．１３［Ｍ＋Ｎａ］＋ Example 102
(R) -2- (4- (4-oxopiperidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000268
(R) -2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -N- (1- (5- (trifluoro)) synthesized in Example 101 Methyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide (17 mg, 0.032 mmol) is dissolved in ethanol (1.0 mL), 2N hydrochloric acid (1.0 mL) is added, and the mixture is heated under reflux overnight under a nitrogen atmosphere. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution allowed to cool to room temperature for neutralization, and the mixture was extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-5%) to give the title compound (white powder, 2 mg, 14%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.56 (t, 4H, 6Hz), 3 .14 (dd, 1H, J = 5,10Hz), 3.3-3.5 (m, 2H), 3.52 (s, 2H), 3.60 (t, 4H, J = 6Hz), 3 .66 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J = 6Hz), 6.8-7.0 (m, 3H), 7.16 (d, 2H, J = 9Hz), 8.09 (d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 469.13 [M + Na] +
実施例１０３
２－（４－シクロプロピルフェニル）－Ｎ－（３－（ヒドロキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000269
参考例６１－２で合成した（３－アミノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）メタノール（５１ｍｇ，０．１９５ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（３４ｍｇ，０．１９５ｍｍｏｌ）をエタノール（３ｍＬ）に溶解した後、ＤＭＴ－ＭＭ（８１ｍｇ，０．２９３ｍｍｏｌ）を加えて室温で終夜撹拌した。反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール）（濃度勾配：０－５％）により精製し表題化合物（白色粉末，５０ｍｇ，６１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．１－２．３（ｍ，２Ｈ），３．２－３．５（ｍ，３Ｈ），３．５４（ｓ，２Ｈ），３．５９（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），３・８２（ｄ，２Ｈ，Ｊ＝６Ｈｚ），４．０３（ｔ，１Ｈ，Ｊ＝６Ｈｚ），５．６２（ｓ，１Ｈ），６．８－７．１（ｍ，５Ｈ），８．０６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４２０．１４［Ｍ＋Ｈ］＋ Example 103
2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000269
(3-Amino-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) methanol (51 mg, 0.195 mmol) synthesized in Reference Example 61-2 and Reference Example 33-2. The synthesized 2- (4-cyclopropylphenyl) acetic acid (34 mg, 0.195 mmol) was dissolved in ethanol (3 mL), DMT-MM (81 mg, 0.293 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol) (concentration gradient: 0-5%) to give the title compound (white powder, 50 mg, 61%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.1-2.3 (m, 2H), 3.2-3.5 (m, 3H), 3.54 (s, 2H), 3.59 (d, 1H, J = 11Hz), 3 -82 (d, 2H, J = 6Hz), 4.03 (t, 1H, J = 6Hz), 5.62 (s, 1H), 6.8-7.1 (m, 5H), 8.06 (D, 1H, J = 3Hz), 8.22 (s, 1H).
MS: 420.14 [M + H] +
実施例１０４
酢酸（３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）メチル
Figure JPOXMLDOC01-appb-C000270
実施例９５と同様の手法に従い、実施例１０３で合成した２－（４－シクロプロピルフェニル）－Ｎ－（３－（ヒドロキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（１０ｍｇ，０．０２３８ｍｍｏｌ）を用いて表題化合物（無色油状物，１０ｍｇ，９１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．０２（ｓ，３Ｈ），２．１－２．４（ｍ，２Ｈ），３．３－３．５（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．５５（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），３．６３（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），４．３５（ｄｄ，２Ｈ，Ｊ＝１２，１６Ｈｚ），５．４９（ｓ，１Ｈ），６．８－７．２（ｍ，５Ｈ），８．０８（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４８４．１４［Ｍ＋Ｎａ］＋ Example 104
Acetic acid (3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methyl
Figure JPOXMLDOC01-appb-C000270
2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) synthesized in Example 103 according to the same procedure as in Example 95. ) Pyrrolidine-3-yl) acetamide (10 mg, 0.0238 mmol) was used to give the title compound (colorless oil, 10 mg, 91%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.02 (s, 3H), 2.1-2.4 (m, 2H), 3.3-3.5 (m, 2H), 3.51 (s, 2H), 3.55 (d) , 1H, J = 11Hz), 3.63 (d, 1H, J = 11Hz), 4.35 (dd, 2H, J = 12, 16Hz), 5.49 (s, 1H), 6.8-7 .2 (m, 5H), 8.08 (d, 1H, J = 2Hz), 8.22 (s, 1H).
MS: 484.14 [M + Na] +
実施例１０５
２－（４－シクロプロピルフェニル）－Ｎ－（３－（メトキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000271
実施例１０３で合成した２－（４－シクロプロピルフェニル）－Ｎ－（３－（ヒドロキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（３７ｍｇ，０．０８８２ｍｍｏｌ）をＴＨＦ（１ｍＬ）に溶解し、氷冷下で６０％水素化ナトリウム（４ｍｇ，０．０９２６ｍｍｏｌ）及びヨードメタン（６μＬ，０．０９２６ｍｍｏｌ）を加え、室温で終夜撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：６０－８０％）により精製し表題化合物（白色粉末，１６ｍｇ，４２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．１－２．５（ｍ，２Ｈ），３．３３（ｓ，３Ｈ），３．３９（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４－３．７（ｍ，６Ｈ），５．５８（ｓ，１Ｈ），６．８－７．０（ｍ，１Ｈ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４３４．１５［Ｍ＋Ｎａ］＋ Example 105
2- (4-Cyclopropylphenyl) -N- (3- (methoxymethyl) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000271
2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 103 ( 37 mg, 0.0882 mmol) was dissolved in THF (1 mL), 60% sodium hydride (4 mg, 0.0926 mmol) and iodomethane (6 μL, 0.0926 mmol) were added under ice-cooling, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 60-80%) to give the title compound (white powder, 16 mg, 42%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.1-2.5 (m, 2H), 3.33 (s, 3H), 3.39 (t, 2H, J = 7Hz), 3.4-3.7 (m, 6H), 5 .58 (s, 1H), 6.8-7.0 (m, 1H), 7.03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 8.08 (D, 1H, J = 3Hz), 8.20 (s, 1H).
MS: 434.15 [M + Na] +
実施例１０６
トランス－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000272
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６２ｍｇ，０．２１８ｍｍｏｌ）及びトランス－２－（４－シクロプロピルフェニル）シクロプロパン－１－カルボン酸（５９ｍｇ，０．２９４ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）において上のスポット，白色粉末，３７ｍｇ，３３％）及びジアステレオマーＢ（ＴＬＣ（酢酸エチル）において下のスポット，白色粉末，３５ｍｇ，３１％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，２Ｈ），３．２６（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．７８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，５Ｈ），８．１３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４１６．１４［Ｍ＋Ｈ］＋
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，２Ｈ），３．２４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．７８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．０（ｍ，５Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４１６．１４［Ｍ＋Ｈ］＋ Example 106
Trans-2- (4-cyclopropylphenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000272
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and the same procedure as in Example 1 and Top spot, white powder, 37 mg in the title compound diastereomeric A (TLC (ethyl acetate)) with trans-2- (4-cyclopropylphenyl) cyclopropane-1-carboxylic acid (59 mg, 0.294 mmol). , 33%) and diastereomer B (lower spot on TLC (ethyl acetate), white powder, 35 mg, 31%).
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.2-1.3 (m, 1H) , 1.5-1.7 (m, 2H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 2H), 3.26 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.6- 4.8 (m, 1H), 5.78 (d, 1H, J = 7Hz), 6.9-7.0 (m, 5H), 8.13 (d, 1H, J = 3Hz), 8. 21 (s, 1H).
MS: 416.14 [M + H] +
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.2-1.3 (m, 1H) , 1.5-1.7 (m, 2H), 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 2H), 3.24 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.6- 4.8 (m, 1H), 5.78 (d, 1H, J = 7Hz), 6.9-7.0 (m, 5H), 8.12 (d, 1H, J = 2Hz), 8. 21 (s, 1H).
MS: 416.14 [M + H] +
実施例１０７
トランス－２－（３，４－ジフルオロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000273
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６２ｍｇ，０．２１８ｍｍｏｌ）及びトランス－２－（３，４－ジフルオロフェニル）シクロプロパン－１－カルボン酸（５８ｍｇ，０．２９４ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）において上のスポット，白色粉末，４２ｍｇ，３８％）及びジアステレオマーＢ（ＴＬＣ（酢酸エチル）において下のスポット，白色粉末，３６ｍｇ，３３％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．１－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．６（ｍ，２Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６９（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．９０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－７．１（ｍ，４Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４１２．１０［Ｍ＋Ｈ］＋
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．１－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．６（ｍ，２Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．８７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．７－７．１（ｍ，４Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４１２．１０［Ｍ＋Ｈ］＋ Example 107
Trans-2- (3,4-difluorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000273
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The above spot in diastereomeric A (TLC (ethyl acetate), white powder, using trans-2- (3,4-difluorophenyl) cyclopropane-1-carboxylic acid (58 mg, 0.294 mmol). 42 mg, 38%) and diastereomeric B (lower spot on TLC (ethyl acetate), white powder, 36 mg, 33%) were obtained.
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.1-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.69 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.90 (d, 1H, J = 7Hz), 6.8-7.1 (m, 4H), 8.12 ( d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 421.10 [M + H] +
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.1-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J = 4,10Hz), 3.4-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.87 (d, 1H, J = 7Hz), 6.7-7.1 (m, 4H), 8.12 ( d, 1H, J = 2Hz), 8.21 (s, 1H).
MS: 421.10 [M + H] +
実施例１０８
トランス－２－（４－クロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000274
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６２ｍｇ，０．２１８ｍｍｏｌ）及びトランス－２－（４－クロロフェニル）シクロプロパン－１－カルボン酸（５８ｍｇ，０．２９４ｍｍｏｌ）を用いて表題化合物のジアステレオマーＡ（ＴＬＣ（酢酸エチル）において上のスポット，白色粉末，３９ｍｇ，３５％）及びジアステレオマーＢ（ＴＬＣ（酢酸エチル）において下のスポット，白色粉末，３３ｍｇ，３０％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．６（ｍ，２Ｈ），３．２７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．９０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．１（ｍ，３Ｈ），７．２－７．３（ｍ，２Ｈ），８．１２（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４１０．０７［Ｍ＋Ｈ］＋
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２－１．３（ｍ，１Ｈ），１．５－１．７（ｍ，２Ｈ），２．０－２．２（ｍ，１Ｈ），２．３－２．６（ｍ，２Ｈ），３．２６（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６８（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．８（ｍ，１Ｈ），５．８７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．１（ｍ，３Ｈ），７．２－７．３（ｍ，２Ｈ），８．１１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２１（ｓ，１Ｈ）．
ＭＳ：４１０．０７［Ｍ＋Ｈ］＋ Example 108
Trans-2- (4-chlorophenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000274
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (62 mg, 0.218 mmol) synthesized in Reference Example 1-2 and the same procedure as in Example 1 and The above spot, white powder, 39 mg, 35 in the title compound diastereomer A (TLC (ethyl acetate)) with trans-2- (4-chlorophenyl) cyclopropane-1-carboxylic acid (58 mg, 0.294 mmol). %) And diastereomer B (lower spot in TLC (ethyl acetate), white powder, 33 mg, 30%).
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.1 (m, 1H) , 2.3-2.6 (m, 2H), 3.27 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.90 (d, 1H, J = 7Hz), 6.9-7.1 (m, 3H), 7.2 7.3 (m, 2H), 8.12 (d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 410.07 [M + H] +
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.2-1.3 (m, 1H), 1.5-1.7 (m, 2H), 2.0-2.2 (m, 1H) , 2.3-2.6 (m, 2H), 3.26 (dd, 1H, J = 4,10Hz), 3.3-3.6 (m, 2H), 3.68 (dd, 1H, J = 6,10Hz), 4.6-4.8 (m, 1H), 5.87 (d, 1H, J = 7Hz), 6.9-7.1 (m, 3H), 7.2 7.3 (m, 2H), 8.11 (d, 1H, J = 3Hz), 8.21 (s, 1H).
MS: 410.07 [M + H] +
実施例１０９
２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－４－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000275
実施例９と同様の手法に従い、参考例６２で合成した２－（４－イソプロピルフェニル）－Ｎ－（ピペリジン－４－イル）アセトアミド（１００ｍｇ，０．３８４ｍｍｏｌ）及び３－ブロモ－５－（トリフルオロメチル）ピリジン（１０４ｍｇ，０．４６１ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，６２ｍｇ，３９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．１－１．５（ｍ，８Ｈ），２．０２（ｄ，２Ｈ，Ｊ＝１１Ｈｚ），２．８－３．１（ｍ，３Ｈ），３．５－３．７（ｍ，４Ｈ），３．９－４．１（ｍ，１Ｈ），５．３２（ｄ，１Ｈ，Ｊ＝６Ｈｚ），７．１－７．３（ｍ，５Ｈ），８．２９（ｓ，１Ｈ），８．４１（ｓ，１Ｈ）．
ＭＳ：４０４．２５［Ｍ－Ｈ］－ Example 109
2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-4-yl) acetamide
Figure JPOXMLDOC01-appb-C000275
2- (4-Isopropylphenyl) -N- (piperidine-4-yl) acetamide (100 mg, 0.384 mmol) and 3-bromo-5- (tri) synthesized in Reference Example 62 according to the same procedure as in Example 9. The title compound (pale yellow crystals, 62 mg, 39%) was obtained using fluoromethyl) pyridine (104 mg, 0.461 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.1-1.5 (m, 8H), 2.02 (d, 2H, J = 11 Hz), 2.8-3.1 (m, 3H) , 3.5-3.7 (m, 4H), 3.9-4.1 (m, 1H), 5.32 (d, 1H, J = 6Hz), 7.1-7.3 (m, 5H), 8.29 (s, 1H), 8.41 (s, 1H).
MS: 404.25 [MH] -
実施例１１０
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000276
実施例９と同様の手法に従い、参考例６３で合成した（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（２９６ｍｇ，１．２０ｍｍｏｌ）及び５－ブロモ－２－メトキシ－３－（トリフルオロメチル）ピリジン（３６９ｍｇ，１．４４ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，２９２ｍｇ，５７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２３（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．８－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．８－３．０（ｍ，１Ｈ），３．０６（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．５－３．６（ｍ，３Ｈ），３．９５（ｓ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．５３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．０９（ｄ，１Ｈ，Ｊ＝３Ｈｚ），７．１６（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．５９（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４２０．２６［Ｍ－Ｈ］－ Example 110
(R) -2- (4-Isopropylphenyl) -N- (1- (6-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000276
(R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (296 mg, 1.20 mmol) and 5-bromo-synthesized in Reference Example 63 according to the same procedure as in Example 9. The title compound (pale yellow crystals, 292 mg, 57%) was obtained using 2-methoxy-3- (trifluoromethyl) pyridine (369 mg, 1.44 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.23 (d, 6H, J = 7 Hz), 1.8-1.9 (m, 1H), 2.2-2.4 (m, 1H) , 2.8-3.0 (m, 1H), 3.06 (dd, 1H, J = 5,10Hz), 3.2-3.4 (m, 2H), 3.5-3.6 ( m, 3H), 3.95 (s, 3H), 4.5-4.7 (m, 1H), 5.53 (d, 1H, J = 7Hz), 7.09 (d, 1H, J = 3Hz), 7.16 (d, 2H, J = 8Hz), 7.20 (d, 2H, J = 8Hz), 7.59 (d, 1H, J = 3Hz).
MS: 420.26 [MH] -
実施例１１１
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000277
実施例２７と同様の手法に従い、参考例６３で合成した（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（９５ｍｇ，０．３８６ｍｍｏｌ）及び２－クロロ－５－（トリフルオロメチル）ピリミジン（７７ｍｇ，０．４２４ｍｍｏｌ）を用いて表題化合物（白色結晶，１２５ｍｇ，８２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２３（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．８－３．０（ｍ，１Ｈ），３．３６（ｄｄ，１Ｈ，Ｊ＝５，１２Ｈｚ），３．５５（ｓ，２Ｈ），３．６３（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．８８（ｄｄ，１Ｈ，Ｊ＝６，１２Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），７．１５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．４８（ｓ，２Ｈ）．
ＭＳ：３９１．２３［Ｍ－Ｈ］－ Example 111
(R) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000277
(R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (95 mg, 0.386 mmol) and 2-chloro- synthesized in Reference Example 63 according to the same procedure as in Example 27. The title compound (white crystals, 125 mg, 82%) was obtained using 5- (trifluoromethyl) pyrimidine (77 mg, 0.424 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.23 (d, 6H, J = 7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H) , 2.8-3.0 (m, 1H), 3.36 (dd, 1H, J = 5,12Hz), 3.55 (s, 2H), 3.63 (t, 2H, J = 7Hz) , 3.88 (dd, 1H, J = 6,12Hz), 4.5-4.7 (m, 1H), 5.50 (d, 1H, J = 6Hz), 7.15 (d, 2H, J = 8Hz), 7.19 (d, 2H, J = 8Hz), 8.48 (s, 2H).
MS: 391.23 [MH] -
実施例１１２
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000278
実施例９と同様の手法に従い、参考例６３で合成した（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（１００ｍｇ，０．４０６ｍｍｏｌ）及び２－ブロモ－４－（トリフルオロメチル）チアゾール（１１３ｍｇ，０．４８７ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，７７ｍｇ，４７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２４（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．８－３．０（ｍ，１Ｈ），３．２４（ｄｄ，１Ｈ，Ｊ＝５，１１Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７５（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５２（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．９２（ｓ，１Ｈ），７．１４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：３９６．１９［Ｍ－Ｈ］－ Example 112
(R) -2- (4-Isopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000278
(R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.406 mmol) and 2-bromo- synthesized in Reference Example 63 according to the same procedure as in Example 9. The title compound (pale yellow crystals, 77 mg, 47%) was obtained using 4- (trifluoromethyl) thiazole (113 mg, 0.487 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.24 (d, 6H, J = 7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H) , 2.8-3.0 (m, 1H), 3.24 (dd, 1H, J = 5,11Hz), 3.4-3.6 (m, 4H), 3.75 (dd, 1H, J = 6,11Hz), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J = 6Hz), 6.92 (s, 1H), 7.14 (d, 2H, J = 8Hz), 7.21 (d, 2H, J = 8Hz).
MS: 396.19 [MH] -
実施例１１３
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000279
実施例９と同様の手法に従い、参考例６３で合成した（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（１００ｍｇ，０．４０６ｍｍｏｌ）及び５－ブロモ－２－（トリフルオロメチル）ピリジン（１１０ｍｇ，０．４８７ｍｍｏｌ）を用いて表題化合物（白色結晶，９３ｍｇ，５８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２３（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．８－３．０（ｍ，１Ｈ），３．１３（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３８（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５５（ｓ，２Ｈ），３．６６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５７（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．７８（ｄｄ，１Ｈ，Ｊ＝２，９Ｈｚ），７．１６（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４６（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９５（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：３９０．２３［Ｍ－Ｈ］－ Example 113
(R) -2- (4-Isopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000279
(R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.406 mmol) and 5-bromo-synthesized in Reference Example 63 according to the same procedure as in Example 9. The title compound (white crystals, 93 mg, 58%) was obtained using 2- (trifluoromethyl) pyridine (110 mg, 0.487 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.23 (d, 6H, J = 7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H) , 2.8-3.0 (m, 1H), 3.13 (dd, 1H, J = 5,10Hz), 3.38 (t, 2H, J = 7Hz), 3.55 (s, 2H) , 3.66 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.57 (d, 1H, J = 6Hz), 6.78 (dd, 1H, J = 2.9Hz), 7.16 (d, 2H, J = 8Hz), 7.20 (d, 2H, J = 8Hz), 7.46 (d, 1H, J = 9Hz), 7.95 ( d, 1H, J = 2Hz).
MS: 390.23 [MH] -
実施例１１４
（Ｓ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000280
実施例１と同様の手法に従い、参考例６４－２で合成した（Ｓ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（９９ｍｇ，０．４２８ｍｍｏｌ）及び２－（４－イソプロピルフェニル）酢酸（９２ｍｇ，０．５１４ｍｍｏｌ）を用いて表題化合物（白色結晶，１４４ｍｇ，８６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２３（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．８－３．０（ｍ，１Ｈ），３．１２（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３６（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５５（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．６１（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８９（ｓ，１Ｈ），７．１６（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：３９０．１９［Ｍ－Ｈ］－ Example 114
(S) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000280
(S) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (99 mg, 0.428 mmol) synthesized in Reference Example 64-2 and the same procedure as in Example 1 and The title compound (white crystals, 144 mg, 86%) was obtained using 2- (4-isopropylphenyl) acetic acid (92 mg, 0.514 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.23 (d, 6H, J = 7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H) , 2.8-3.0 (m, 1H), 3.12 (dd, 1H, J = 5,10Hz), 3.36 (t, 2H, J = 7Hz), 3.55 (s, 2H) , 3.65 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.61 (d, 1H, J = 6Hz), 6.89 (s, 1H) , 7.16 (d, 2H, J = 8Hz), 7.20 (d, 2H, J = 8Hz), 8.06 (d, 1H, J = 3Hz), 8.19 (s, 1H).
MS: 390.19 [MH] -
実施例１１５
（Ｒ）－２－（４－（トリフルオロメトキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000281
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１０ｍｇ，０．０４３２ｍｍｏｌ）及び２－（４－（トリフルオロメトキシ）フェニル）酢酸（１１ｍｇ，０．０５１９ｍｍｏｌ）を用いて表題化合物（白色結晶，９ｍｇ，４６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１８（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５７（ｓ，２Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝７，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．６５（ｄ，１Ｈ，Ｊ＝５Ｈｚ），６．９１（ｓ，１Ｈ），７．１－７．４（ｍ，４Ｈ），８．０９（ｓ，１Ｈ），８．２１（ｓ，１Ｈ）．
ＭＳ：４３２．１４［Ｍ－Ｈ］－ Example 115
(R) -2- (4- (trifluoromethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000281
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (10 mg, 0.0432 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 9 mg, 46%) was obtained using 2- (4- (trifluoromethoxy) phenyl) acetic acid (11 mg, 0.0519 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.18 (dd, 1H, J = 4, 10Hz), 3.3-3.5 (m, 2H), 3.57 (s, 2H), 3.67 (dd, 1H, J = 7, 10Hz), 4.6-4.7 (m, 1H), 5.65 (d, 1H, J = 5Hz), 6.91 (s, 1H), 7.1-7.4 (m, 4H), 8.09 (s, 1H), 8.21 (S, 1H).
MS: 432.14 [MH] -
実施例１１６
（Ｒ）－２－（４－（２，２，２－トリフルオロエトキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000282
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１０ｍｇ，０．０４３２ｍｍｏｌ）及び２－（４－（２，２，２－トリフルオロエトキシ）フェニル）酢酸（１２ｍｇ，０．０５１９ｍｍｏｌ）を用いて表題化合物（白色結晶，２１ｍｇ，９９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１４（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５４（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．３４（ｑ，２Ｈ，Ｊ＝８Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５９（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８－７．０（ｍ，３Ｈ），７．２１（ｄ，２Ｈ，Ｊ＝９Ｈｚ），８．０７（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４４６．１４［Ｍ－Ｈ］－ Example 116
(R) -2- (4- (2,2,2-trifluoroethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000282
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (10 mg, 0.0432 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 21 mg, 99%) was obtained using 2- (4- (2,2,2-trifluoroethoxy) phenyl) acetic acid (12 mg, 0.0519 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.14 (dd, 1H, J = 5, 10Hz), 3.3-3.5 (m, 2H), 3.54 (s, 2H), 3.65 (dd, 1H, J = 6,10Hz), 4.34 (q, 2H, J = 8Hz), 4.5-4.7 (m, 1H), 5.59 (d, 1H, J = 6Hz), 6.8-7.0 (m, 3H), 7.21 (d, 2H, J = 9Hz), 8.07 (d, 1H, J = 2Hz), 8.20 (s, 1H).
MS: 446.14 [MH] -
実施例１１７
２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000283
実施例３６と同様の手法に従い、参考例６５で合成した３－（２－（４－イソプロピルフェニル）アセトアミド）アゼチジン－１－カルボン酸ｔｅｒｔ－ブチル（９６４ｍｇ，２．９０ｍｍｏｌ）からＮ－（アゼチジン－３－イル）－２－（４－イソプロピルフェニル）アセトアミドの粗体（６００ｍｇ）を合成し、得られた粗体の一部（１００ｍｇ）及び３－ブロモ－５－（トリフルオロメチル）ピリジン（１１８ｍｇ，０．５２ｍｍｏｌ）を用いて表題化合物（白色結晶，５７ｍｇ，４３％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．１８（ｄ，６Ｈ，Ｊ＝７Ｈｚ），２．７－２．９（ｍ，１Ｈ），３．３８（ｓ，２Ｈ），３．７－３．８（ｍ，２Ｈ），４．２－４．３（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），７．１－７．２（ｍ，５Ｈ），８．１０（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２３（ｓ，１Ｈ），８．７－８．８（ｍ，１Ｈ）．
ＭＳ：３７８．２１［Ｍ＋Ｈ］＋ Example 117
2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000283
N- (azetidine-) from tert-butyl 3- (2- (4-isopropylphenyl) acetamide) azetidine-1-carboxylate (964 mg, 2.90 mmol) synthesized in Reference Example 65 according to the same procedure as in Example 36. A crude (600 mg) of 3-yl) -2- (4-isopropylphenyl) acetamide was synthesized, and a part of the obtained crude (100 mg) and 3-bromo-5- (trifluoromethyl) pyridine (118 mg) were synthesized. , 0.52 mmol) was used to give the title compound (white crystals, 57 mg, 43%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.18 (d, 6H, J = 7 Hz), 2.7-2.9 (m, 1H), 3.38 (s, 2H), 3 .7-3.8 (m, 2H), 4.2-4.3 (m, 2H), 4.5-4.7 (m, 1H), 7.1-7.2 (m, 5H) , 8.10 (d, 1H, J = 2Hz), 8.23 (s, 1H), 8.7-8.8 (m, 1H).
MS: 378.21 [M + H] +
実施例１１８
２－（４－イソプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000284
実施例３６と同様の手法に従い、実施例１１７で３－（２－（４－イソプロピルフェニル）アセトアミド）アゼチジン－１－カルボン酸ｔｅｒｔ－ブチルから合成したＮ－（アゼチジン－３－イル）－２－（４－イソプロピルフェニル）アセトアミドの粗体（１００ｍｇ）及び５－ブロモ－２－（トリフルオロメチル）ピリジン（１１８ｍｇ，０．５２ｍｍｏｌ）を用いて表題化合物（白色結晶，５５ｍｇ，３４％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．１７（ｄ，６Ｈ，Ｊ＝７Ｈｚ），２．７－２．９（ｍ，１Ｈ），３．３８（ｓ，２Ｈ），３．７－３．９（ｍ，２Ｈ），４．２－４．３（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），６．９５（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．１７（ｓ，４Ｈ），７．６１（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．７－８．８（ｍ，１Ｈ）．
ＭＳ：３７８．２１［Ｍ＋Ｈ］＋ Example 118
2- (4-Isopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000284
According to the same procedure as in Example 36, N- (azetidine-3-yl) -2- synthesized from tert-butyl 3- (2- (4-isopropylphenyl) acetamide) azetidine-1-carboxylate in Example 117. The title compound (white crystals, 55 mg, 34%) was obtained using crude (100 mg) of (4-isopropylphenyl) acetamide and 5-bromo-2- (trifluoromethyl) pyridine (118 mg, 0.52 mmol). ..
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.17 (d, 6H, J = 7 Hz), 2.7-2.9 (m, 1H), 3.38 (s, 2H), 3 .7-3.9 (m, 2H), 4.2-4.3 (m, 2H), 4.5-4.7 (m, 1H), 6.95 (dd, 1H, J = 3, 8Hz), 7.17 (s, 4H), 7.61 (d, 1H, J = 8Hz), 7.93 (d, 1H, J = 3Hz), 8.7-8.8 (m, 1H) ..
MS: 378.21 [M + H] +
実施例１１９
（Ｒ）－２－（３，５－ジクロロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000285
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６０ｍｇ，０．２６ｍｍｏｌ）及び２－（３，５－ジクロロフェニル）酢酸（６４ｍｇ，０．３１ｍｍｏｌ）を用いて表題化合物（白色結晶，８３ｍｇ，７６％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．１－３．７（ｍ，４Ｈ），３．４６（ｓ，２Ｈ），４．３－４．５（ｍ，１Ｈ），７．１１（ｓ，１Ｈ），７．３０（ｄ，２Ｈ，Ｊ＝２Ｈｚ），７．４７（ｔ，１Ｈ，Ｊ＝２Ｈｚ），８．１４（ｓ，１Ｈ），８．２０（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．４－８．５（ｍ，１Ｈ）．
ＭＳ：４１６．１３［Ｍ－Ｈ］－ Example 119
(R) -2- (3,5-dichlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000285
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 83 mg, 76%) was obtained using 2- (3,5-dichlorophenyl) acetic acid (64 mg, 0.31 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.7 (m, 4H), 3.46 (s, 2H), 4.3-4.5 (m, 1H), 7.11 (s, 1H), 7.30 (d, 2H, J = 2Hz), 7.47 (T, 1H, J = 2Hz), 8.14 (s, 1H), 8.20 (d, 1H, J = 2Hz), 8.4-8.5 (m, 1H).
MS: 416.13 [MH] -
実施例１２０
（Ｒ）－２－（３－クロロ－５－フルオロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000286
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６０ｍｇ，０．２６ｍｍｏｌ）及び２－（３－クロロ－５－フルオロフェニル）酢酸（５８ｍｇ，０．３１ｍｍｏｌ）を用いて表題化合物（白色結晶，７０ｍｇ，６７％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．２－３．６（ｍ，３Ｈ），３．４５（ｓ，２Ｈ），４．３－４．５（ｍ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．１７（ｓ，１Ｈ），７．２８（ｄｔ，１Ｈ，Ｊ＝３，８Ｈｚ），８．１３（ｓ，１Ｈ），８．１９（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．４－８．５（ｍ，１Ｈ）．
ＭＳ：４００．１６［Ｍ－Ｈ］－ Example 120
(R) -2- (3-Chloro-5-fluorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000286
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 70 mg, 67%) was obtained using 2- (3-chloro-5-fluorophenyl) acetic acid (58 mg, 0.31 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.2 (m, 1H), 3.2-3.6 (m, 3H), 3.45 (s, 2H), 4.3-4.5 (m, 1H), 7.0-7.1 (m, 2H) , 7.17 (s, 1H), 7.28 (dt, 1H, J = 3.8Hz), 8.13 (s, 1H), 8.19 (d, 1H, J = 3Hz), 8.4 -8.5 (m, 1H).
MS: 400.16 [MH] -
実施例１２１
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000287
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６０ｍｇ，０．１８ｍｍｏｌ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（５１ｍｇ，０．２９ｍｍｏｌ）を用いて表題化合物（白色結晶，８９ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．３－３．４（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．５－４．７（ｍ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．７７（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９４（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：３８８．２２［Ｍ－Ｈ］－ Example 121
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000287
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.18 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 89 mg, 100%) was obtained using 2- (4-cyclopropylphenyl) acetic acid (51 mg, 0.29 mmol) synthesized in Reference Example 33-2.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.4 (m, 2H), 3.53 (s, 2H), 3 .6-3.7 (m, 1H), 4.5-4.7 (m, 1H), 5.5-5.7 (m, 1H), 6.77 (dd, 1H, J = 3, 8Hz), 7.03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 7.46 (d, 1H, J = 8Hz), 7.94 (d, 1H, J = 3Hz).
MS: 388.22 [MH] -
実施例１２２
（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）チオフェン－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000288
実施例９と同様の手法に従い、参考例６３で合成した（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（１００ｍｇ，０．４１ｍｍｏｌ）及び２－ブロモ－５－（トリフルオロメチル）チオフェン（１１４ｍｇ，０．４９ｍｍｏｌ）を用いて表題化合物（白色結晶，４９ｍｇ，３０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．２３（ｄ，６Ｈ，Ｊ＝７Ｈｚ），１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．８－３．０（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．２－３．４（ｍ，２Ｈ），３．５４（ｓ，２Ｈ），３．５－３．６（ｍ，１Ｈ），４．５－４．７（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），５．６３（ｄ，１Ｈ，Ｊ＝４Ｈｚ），７．０－７．２（ｍ，１Ｈ），７．１４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２０（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：３９５．２１［Ｍ－Ｈ］－ Example 122
(R) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) thiophen-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000288
(R) -2- (4-isopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.41 mmol) and 2-bromo- synthesized in Reference Example 63 according to the same procedure as in Example 9. The title compound (white crystals, 49 mg, 30%) was obtained using 5- (trifluoromethyl) thiophene (114 mg, 0.49 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.23 (d, 6H, J = 7 Hz), 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H) , 2.8-3.0 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.54 (s, 2H), 3 .5-3.6 (m, 1H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 5.63 (d, 1H, J = 4Hz) , 7.0-7.2 (m, 1H), 7.14 (d, 2H, J = 8Hz), 7.20 (d, 2H, J = 8Hz).
MS: 395.21 [MH] -
実施例１２３
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000289
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２２ｍｍｏｌ）及び２－（４－（トリフルオロメチル）フェニル）酢酸（５３ｍｇ，０．２６ｍｍｏｌ）を用いて表題化合物（白色結晶，８５ｍｇ，９２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．３－３．４（ｍ，２Ｈ），３．５－３．７（ｍ，１Ｈ），３．６３（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），６．４－６．６（ｍ，１Ｈ），６．８１（ｓ，１Ｈ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．５９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．９５（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．０９（ｓ，１Ｈ）．
ＭＳ：４１６．１９［Ｍ－Ｈ］－ Example 123
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000289
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 85 mg, 92%) was obtained using 2- (4- (trifluoromethyl) phenyl) acetic acid (53 mg, 0.26 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H) , 3.3-3.4 (m, 2H), 3.5-3.7 (m, 1H), 3.63 (s, 2H), 4.6-4.7 (m, 1H), 6 .4-6.6 (m, 1H), 6.81 (s, 1H), 7.40 (d, 2H, J = 8Hz), 7.59 (d, 2H, J = 8Hz), 7.95 (D, 1H, J = 2Hz), 8.09 (s, 1H).
MS: 416.19 [MH] -
実施例１２４
（Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000290
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５０ｍｇ，０．２２ｍｍｏｌ）及び２－（１Ｈ－インドール－６－イル）酢酸（５３ｍｇ，０．２６ｍｍｏｌ）を用いて表題化合物（白色結晶，８９ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．７－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），２．９－３．１（ｍ，１Ｈ），３．１－３．４（ｍ，２Ｈ），３．４－３．６（ｍ，１Ｈ），３．５２（ｓ，２Ｈ），４．５－４．７（ｍ，１Ｈ），４．６７（ｑ，２Ｈ，Ｊ＝９Ｈｚ），５．５－５．６（ｍ，１Ｈ），６．７５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），６．９２（ｄｄ．１Ｈ，Ｊ＝３，９Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．３９（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：３８７．２２［Ｍ－Ｈ］－ Example 124
(R) -2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000290
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (50 mg, 0.22 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 89 mg, 100%) was obtained using 2- (1H-indole-6-yl) acetic acid (53 mg, 0.26 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 2.9-3.1 (m, 1H), 3.1-3.4 (m, 2H), 3.4-3.6 (m, 1H), 3.52 (s, 2H), 4.5-4.7 (m, 1H), 4.67 (q, 2H, J = 9Hz), 5.5-5.6 (m, 1H) , 6.75 (d, 1H, J = 9Hz), 6.92 (dd.1H, J = 3,9Hz), 7.03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 7.39 (d, 1H, J = 3Hz).
MS: 387.22 [MH] -
実施例１２５
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（２，２，２－トリフルオロエトキシ）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000291
実施例９と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（５０ｍｇ，０．２０ｍｍｏｌ）及び５－ブロモ－２－（２，２，２－トリフルオロエトキシ）ピリジン（６１ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，４０ｍｇ，４５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．７－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），２．９－３．１（ｍ，１Ｈ），３．１－３．４（ｍ，２Ｈ），３．４－３．６（ｍ，１Ｈ），３．５２（ｓ，２Ｈ），４．５－４．７（ｍ，１Ｈ），４．６７（ｑ，２Ｈ，Ｊ＝９Ｈｚ），５．５－５．６（ｍ，１Ｈ），６．７５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），６．９２（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．３９（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４２０．１６［Ｍ＋Ｈ］＋ Example 125
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (2,2,2-trifluoroethoxy) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000291
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (50 mg, 0.20 mmol) and 5 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. -Bromo-2- (2,2,2-trifluoroethoxy) pyridine (61 mg, 0.24 mmol) was used to give the title compound (yellow amorphous, 40 mg, 45%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.9-3.1 (m, 1H), 3.1-3.4 (m, 2H), 3.4-3.6 ( m, 1H), 3.52 (s, 2H), 4.5-4.7 (m, 1H), 4.67 (q, 2H, J = 9Hz), 5.5-5.6 (m, 1H), 6.75 (d, 1H, J = 9Hz), 6.92 (dd, 1H, J = 3.9Hz), 7.03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 7.39 (d, 1H, J = 3Hz).
MS: 420.16 [M + H] +
実施例１２６
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（２，２，２－トリフルオロエトキシ）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000292
実施例９と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（５０ｍｇ，０．２０ｍｍｏｌ）及び３－ブロモ－５－（２，２，２－トリフルオロエトキシ）ピリジン（６１ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（黄色結晶，３６ｍｇ，４０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．３１（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５３（ｓ，２Ｈ），３．５－３．７（ｍ，１Ｈ），４．３７（ｑ，２Ｈ，Ｊ＝８Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．３３（ｔ，１Ｈ，Ｊ＝２Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６－７．７（ｍ，２Ｈ）．
ＭＳ：４２０．１６［Ｍ＋Ｈ］＋ Example 126
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (2,2,2-trifluoroethoxy) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000292
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (50 mg, 0.20 mmol) and 3 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. -Bromo-5- (2,2,2-trifluoroethoxy) pyridine (61 mg, 0.24 mmol) was used to give the title compound (yellow crystals, 36 mg, 40%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.31 (t, 2H, J = 7Hz), 3.53 (s, 2H), 3 .5-3.7 (m, 1H), 4.37 (q, 2H, J = 8Hz), 4.5-4.7 (m, 1H), 5.5-5.7 (m, 1H) , 6.33 (t, 1H, J = 2Hz), 7.03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 7.6-7.7 (m, 2H).
MS: 420.16 [M + H] +
実施例１２７
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（２，２，２－トリフルオロエトキシ）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000293
実施例２７と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（５０ｍｇ，０．２０ｍｍｏｌ）及び２－クロロ－４－（２，２，２－トリフルオロエトキシ）ピリジン（５１ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，７ｍｇ，６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，２Ｈ），２．２－２．３（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．４－３．５（ｍ，２Ｈ），３．５２（ｓ，２Ｈ），３．６－３．８（ｍ，１Ｈ），４．３５（ｑ，２Ｈ，Ｊ＝８Ｈｚ），４．５－４．６（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），５．７９（ｄ，１Ｈ，Ｊ＝２Ｈｚ），６．２０（ｄｄ，１Ｈ，Ｊ＝２，６Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０２（ｄ，１Ｈ，Ｊ＝６Ｈｚ）．
ＭＳ：４２０．１６［Ｍ＋Ｈ］＋ Example 127
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (2,2,2-trifluoroethoxy) pyridin-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000293
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (50 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 27. -Chloro-4- (2,2,2-trifluoroethoxy) pyridine (51 mg, 0.24 mmol) was used to give the title compound (yellow amorphous, 7 mg, 6%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 2H) , 2.2-2.3 (m, 1H), 3.1-3.3 (m, 1H), 3.4-3.5 (m, 2H), 3.52 (s, 2H), 3 .6-3.8 (m, 1H), 4.35 (q, 2H, J = 8Hz), 4.5-4.6 (m, 1H), 5.4-5.6 (m, 1H) , 5.79 (d, 1H, J = 2Hz), 6.20 (dd, 1H, J = 2.6Hz), 7.03 (d, 2H, J = 8Hz), 7.10 (d, 2H, J = 8Hz), 8.02 (d, 1H, J = 6Hz).
MS: 420.16 [M + H] +
実施例１２８
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（２－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000294
実施例９と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（１００ｍｇ，０．４０ｍｍｏｌ）及び３－ブロモ－２－メトキシ－５－（トリフルオロメチル）ピリジン（１２３ｍｇ，０．４８ｍｍｏｌ）を用いて表題化合物（白色結晶，４６ｍｇ，２７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．７－２．０（ｍ，２Ｈ），２．２－２．３（ｍ，１Ｈ），３．２－３．３（ｍ，２Ｈ），３．４－３．５（ｍ，１Ｈ），３．５２（ｓ，２Ｈ），３．５－３．６（ｍ，１Ｈ），３．９６（ｓ，３Ｈ），４．４－４．６（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．８１（ｄ，１Ｈ，Ｊ＝２Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．８６（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：４２０．１６［Ｍ＋Ｈ］＋ Example 128
(R) -2- (4-Cyclopropylphenyl) -N- (1- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000294
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (100 mg, 0.40 mmol) and 3 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. The title compound (white crystals, 46 mg, 27%) was obtained using -bromo-2-methoxy-5- (trifluoromethyl) pyridine (123 mg, 0.48 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-2.0 (m, 2H) , 2.2-2.3 (m, 1H), 3.2-3.3 (m, 2H), 3.4-3.5 (m, 1H), 3.52 (s, 2H), 3 .5-3.6 (m, 1H), 3.96 (s, 3H), 4.4-4.6 (m, 1H), 5.5-5.6 (m, 1H), 6.81 (D, 1H, J = 2Hz), 7.03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 7.86 (d, 1H, J = 2Hz).
MS: 420.16 [M + H] +
実施例１２９
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000295
実施例３と同様の手法に従い、参考例６６で合成した（Ｒ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１００ｍｇ，０．２９ｍｍｏｌ）から（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－アミンの粗体（７０ｍｇ）を合成し、得られた（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－アミンの粗体（７０ｍｇ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（７８ｍｇ，０．４４ｍｍｏｌ）を用いて表題化合物（白色結晶，８０ｍｇ，５８％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝０．５－０．７（ｍ，２Ｈ），０．８－１．０（ｍ，２Ｈ），１．４－１．６（ｍ，２Ｈ），１．７－２．０（ｍ，３Ｈ），２．７－２．９（ｍ，１Ｈ），２．９－３．１（ｍ，１Ｈ），３．２－３．５（ｍ，２Ｈ），３．６－３．８（ｍ，３Ｈ），６．９７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．５２（ｓ，１Ｈ），８．０－８．２（ｍ，１Ｈ），８．２４（ｓ，１Ｈ），８．５４（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４０４．１７［Ｍ＋Ｈ］＋ Example 129
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000295
Tert-Butyl (R)-(1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-yl) carbamate synthesized in Reference Example 66 according to the same procedure as in Example 3 (100 mg, A crude compound (70 mg) of (R) -1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine was synthesized from 0.29 mmol) to obtain (R) -1-(. A crude compound of 5- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine (70 mg) and 2- (4-cyclopropylphenyl) acetic acid (78 mg, 0.44 mmol) synthesized in Reference Example 33-2. Was used to give the title compound (white crystals, 80 mg, 58%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 0.5-0.7 (m, 2H), 0.8-1.0 (m, 2H), 1.4-1.6 (m, 2H), 1.7-2.0 (m, 3H), 2.7-2.9 (m, 1H), 2.9-3.1 (m, 1H), 3.2-3.5 ( m, 2H), 3.6-3.8 (m, 3H), 6.97 (d, 2H, J = 8Hz), 7.12 (d, 2H, J = 8Hz), 7.52 (s, 1H), 8.0-8.2 (m, 1H), 8.24 (s, 1H), 8.54 (d, 1H, J = 3Hz).
MS: 404.17 [M + H] +
実施例１３０
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000296
実施例３と同様の手法に従い、参考例７２で合成した（Ｒ）－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（４００ｍｇ，１．１６ｍｍｏｌ）から（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－アミンの粗体（２８０ｍｇ）を合成し、得られた（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－アミンの粗体の一部（７０ｍｇ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（７８ｍｇ，０．４４ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，６５ｍｇ，５４％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝０．５－０．７（ｍ，２Ｈ），０．８－１．０（ｍ，２Ｈ），１．４－１．６（ｍ，２Ｈ），１．７－１．９（ｍ，３Ｈ），２．８－３．０（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．２－３．５（ｍ，２Ｈ），３．６－３．８（ｍ，３Ｈ），６．９７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．３７（ｄｄ，１Ｈ，Ｊ＝３，７Ｈｚ），７．５８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．０－８．２（ｍ，１Ｈ），８．３７（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４０４．１７［Ｍ＋Ｈ］＋ Example 130
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000296
Tert-Butyl (R)-(1- (6- (trifluoromethyl) pyridine-3-yl) piperidine-3-yl) carbamate synthesized in Reference Example 72 according to the same procedure as in Example 3 (400 mg, A crude compound (280 mg) of (R) -1- (6- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine was synthesized from 1.16 mmol) to obtain (R) -1-(. A portion of a crude of 6- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine (70 mg) and 2- (4-cyclopropylphenyl) acetic acid (78 mg, 0) synthesized in Reference Example 33-2. .44 mmol) was used to give the title compound (pale yellow crystals, 65 mg, 54%).
1 H NMR (DMSO-d 6 , 400 MHz): δ = 0.5-0.7 (m, 2H), 0.8-1.0 (m, 2H), 1.4-1.6 (m, 2H), 1.7-1.9 (m, 3H), 2.8-3.0 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.5 ( m, 2H), 3.6-3.8 (m, 3H), 6.97 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 7.37 (dd, dd, 1H, J = 3,7Hz), 7.58 (d, 1H, J = 8Hz), 8.0-8.2 (m, 1H), 8.37 (d, 1H, J = 3Hz).
MS: 404.17 [M + H] +
実施例１３１
（Ｒ）－２－（４－（２－ヒドロキシプロパン－２－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000297
参考例７６－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３９ｍｇ，０．２０ｍｍｏｌ）、２－（４－（２－ヒドロキシプロパン－２－イル）フェニル）酢酸（２７ｍｇ，０．２４ｍｍｏｌ）及びＤＭＴ－ＭＭ（４６ｍｇ，０．１９ｍｍｏｌ）をイソプロパノール（０．８０ｍＬ）に溶解した後、室温で一晩撹拌した。反応液に水を加えてしばらく撹拌した後、酢酸エチルで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）（濃度勾配：０－４０％）により精製し表題化合物（白色アモルファス，５７ｍｇ，９９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５８（ｓ，３Ｈ），１．５９（ｓ，３Ｈ），１．７－１．９（ｂｒ　ｓ，１Ｈ），１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，２Ｈ），３．３－３．５（ｍ，２Ｈ），３．５８（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．６－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．９２（ｓ，１Ｈ），７．２６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．４７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０－８．１（ｍ，１Ｈ），８．２１（ｓ，１Ｈ）．
ＭＳ：４３０．１４［Ｍ＋Ｎａ］＋ Example 131
(R) -2- (4- (2-Hydroxypropane-2-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000297
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (39 mg, 0.20 mmol) synthesized in Reference Example 76-2, 2- (4- (2-hydroxy) Propane-2-yl) phenyl) acetic acid (27 mg, 0.24 mmol) and DMT-MM (46 mg, 0.19 mmol) were dissolved in isopropanol (0.80 mL) and then stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was stirred for a while, and then extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol) (concentration gradient: 0-40%) to give the title compound (white amorphous, 57 mg, 99%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.58 (s, 3H), 1.59 (s, 3H), 1.7-1.9 (br s, 1H), 1.9-2. 0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 2H), 3.3-3.5 (m, 2H), 3.58 ( s, 2H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.92 (s, 1H), 7.26 (d, 1H, J = 8Hz), 7.47 (d, 2H, J = 8Hz), 8.0-8.1 (m, 1H), 8.21 (s, 1H) ..
MS: 430.14 [M + Na] +
実施例１３２
（Ｒ）－２－（４－（３－メチルピラジン－２－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000298
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１０ｍｇ，０．０４８ｍｍｏｌ）及び２－（４－（３－メチルピラジン－２－イル）フェニル）酢酸（１０ｍｇ，０．０４４ｍｍｏｌ）を用いて表題化合物（白色結晶，１４ｍｇ，６２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．６３（ｓ，３Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．６６（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．７－５．９（ｍ、１Ｈ），６．９０（ｓ，１Ｈ），７．３９（ｄ，２Ｈ，Ｊ＝８Ｈ），７．５９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１９（ｓ，１Ｈ），８．４６（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．４８（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：４４２．１５［Ｍ＋Ｈ］＋ Example 132
(R) -2- (4- (3-methylpyrazine-2-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000298
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (10 mg, 0.048 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 14 mg, 62%) was obtained using 2- (4- (3-methylpyrazine-2-yl) phenyl) acetic acid (10 mg, 0.044 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.3-2.4 (m, 1H), 2.63 (s, 3H), 3.1 -3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.66 (s, 2H), 4.6-4 .7 (m, 1H), 5.7-5.9 (m, 1H), 6.90 (s, 1H), 7.39 (d, 2H, J = 8H), 7.59 (d, 2H) , J = 8Hz), 8.07 (d, 1H, J = 3Hz), 8.19 (s, 1H), 8.46 (d, 1H, J = 2Hz), 8.48 (d, 1H, J) = 2Hz).
MS: 442.15 [M + H] +
実施例１３３
（Ｒ）－２－（４－（４－メチルオキサゾール－５－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000299
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６ｍｇ，０．０２４ｍｍｏｌ）及び２－（４－（４－メチルオキサゾール－５－イル）フェニル）酢酸（４ｍｇ，０．０２０ｍｍｏｌ）を用いて表題化合物（白色結晶，８．６ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．４４（ｓ，３Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６１（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．６－４．７（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），６．９１（ｓ，１Ｈ），７．３４（ｄ，２Ｈ，Ｊ＝８Ｈｚ）７．５９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．８３（ｓ，１Ｈ），８．０８（ｓ，１Ｈ），８．２０（ｓ，１Ｈ）．
ＭＳ：４２９．１７［Ｍ－Ｈ］－ Example 133
(R) -2- (4- (4-Methyloxazole-5-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000299
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (6 mg, 0.024 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 8.6 mg, 100%) was obtained using 2- (4- (4-methyloxazole-5-yl) phenyl) acetic acid (4 mg, 0.020 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.44 (s, 3H), 3.1 -3.2 (m, 1H), 3.3-3.5 (m, 2H), 3.61 (s, 2H), 3.6-3.7 (m, 1H), 4.6-4 .7 (m, 1H), 5.4-5.6 (m, 1H), 6.91 (s, 1H), 7.34 (d, 2H, J = 8Hz) 7.59 (d, 2H, J = 8Hz), 7.83 (s, 1H), 8.08 (s, 1H), 8.20 (s, 1H).
MS: 429.17 [MH] -
実施例１３４
（Ｒ）－３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）－５－（トリフルオロメチル）ピリジン　１－オキシド
（３Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン　１－オキシド
Figure JPOXMLDOC01-appb-C000300
実施例１で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（８５ｍｇ，０．２２ｍｍｏｌ）をジクロロメタン（３．０ｍＬ）に溶解し、ｍ－ＣＰＢＡ（純度６５％，５８ｍｇ，０．２２ｍｍｏｌ）を加えた後、室温で一晩撹拌した。反応液を飽和炭酸水素ナトリウム水溶液で洗浄後、分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）（濃度勾配：０－２０％）により精製し、（Ｒ）－３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）－５－（トリフルオロメチル）ピリジン　１－オキシド（ＴＬＣ（ジクロロメタン：メタノール＝１０：１）においてＲｆ値＝０．４，淡黄色アモルファス，１２ｍｇ，１３％）及び（３Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン　１－オキシド（ＴＬＣ（ジクロロメタン：メタノール＝１０：１）においてＲｆ値＝０．２，白色アモルファス，４２ｍｇ，４７％）を得た。
（Ｒ）－３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）－５－（トリフルオロメチル）ピリジン　１－オキシド
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．３１（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５４（ｓ，２Ｈ），３．５－３．７（ｍ、１Ｈ），４．５－４．７（ｍ，１Ｈ），５．７－５．９（ｍ，１Ｈ），６．５４（ｓ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６３（ｓ，１Ｈ），７．８１（ｓ，１Ｈ）．
ＭＳ：４０６．１４［Ｍ＋Ｈ］＋
（３Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン　１－オキシド
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．４－２．６（ｍ，１Ｈ），２．７－２．９（ｍ，１Ｈ），３．５０（ｓ，２Ｈ），３．５－３．７（ｍ，１Ｈ），３．８－４．０（ｍ，２Ｈ），４．０－４．１（ｍ，１Ｈ），５．１－５．３（ｍ，１Ｈ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１８（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．７－７．８（ｍ，１Ｈ），８．８２（ｓ，１Ｈ），８．９５（ｓ，１Ｈ），９．１５（ｓ，１Ｈ）．
ＭＳ：４０６．１４［Ｍ＋Ｈ］＋ Example 134
(R) -3- (3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-yl) -5- (trifluoromethyl) pyridine 1-oxide (3R) -3- (2- (4) -Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine 1-oxide
Figure JPOXMLDOC01-appb-C000300
(R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 1 (85 mg, 0) .22 mmol) was dissolved in dichloromethane (3.0 mL), m-CPBA (purity 65%, 58 mg, 0.22 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, the separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol) (concentration gradient: 0-20%), and (R) -3- (3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine- 1-yl) -5- (trifluoromethyl) pyridine 1-oxide (Rf value = 0.4, pale yellow amorphous, 12 mg, 13% in TLC (dichloromethane: methanol = 10: 1)) and (3R) -3 -(2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine 1-oxide (TLC (dichloromethane: methanol = 10: 1) with Rf value = 0 2. White amorphous, 42 mg, 47%) was obtained.
(R) -3- (3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-yl) -5- (trifluoromethyl) pyridine 1-oxide
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.31 (t, 2H, J = 7Hz), 3.54 (s, 2H), 3 .5-3.7 (m, 1H), 4.5-4.7 (m, 1H), 5.7-5.9 (m, 1H), 6.54 (s, 1H), 7.04 (D, 2H, J = 8Hz), 7.12 (d, 2H, J = 8Hz), 7.63 (s, 1H), 7.81 (s, 1H).
MS: 406.14 [M + H] +
(3R) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine 1-oxide
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.4-2.6 (m, 1H), 2.7-2.9 (m, 1H), 3.50 (s, 2H), 3.5-3.7 (m, 1H), 3 .8-4.0 (m, 2H), 4.0-4.1 (m, 1H), 5.1-5.3 (m, 1H), 7.03 (d, 2H, J = 8Hz) , 7.18 (d, 2H, J = 8Hz), 7.7-7.8 (m, 1H), 8.82 (s, 1H), 8.95 (s, 1H), 9.15 (s) , 1H).
MS: 406.14 [M + H] +
実施例１３５
（Ｒ）－２－（４－シクロプロピルフェニル）－２－メチル－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド
Figure JPOXMLDOC01-appb-C000301
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（２５ｍｇ，０．１１ｍｍｏｌ）及び２－（４－シクロプロピルフェニル）－２－メチルプロパン酸（２３ｍｇ，０．１１ｍｍｏｌ）を用いて表題化合物（白色アモルファス，４５ｍｇ，９４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．５４（ｓ，３Ｈ），１．５５（ｓ，３Ｈ），１．７－１．９（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．２－３．４（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．５－４．６（ｍ，１Ｈ），５．２－５．３（ｍ，１Ｈ），６．８８（ｓ，１Ｈ），７．０２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０５（ｓ，１Ｈ），８．１９（ｓ，１Ｈ）．
ＭＳ：４１６．２１［Ｍ－Ｈ］－ Example 135
(R) -2- (4-Cyclopropylphenyl) -2-methyl-N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide
Figure JPOXMLDOC01-appb-C000301
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (25 mg, 0.11 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white amorphous, 45 mg, 94%) was obtained using 2- (4-cyclopropylphenyl) -2-methylpropanoic acid (23 mg, 0.11 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.54 (s, 3H), 1.55 (S, 3H), 1.7-1.9 (m, 2H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3 .4 (m, 2H), 3.6-3.7 (m, 1H), 4.5-4.6 (m, 1H), 5.2-5.3 (m, 1H), 6.88 (S, 1H), 7.02 (d, 2H, J = 8Hz), 7.21 (d, 2H, J = 8Hz), 8.05 (s, 1H), 8.19 (s, 1H).
MS: 416.21 [MH] -
実施例１３６
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－フルオロ－５－（トリフルオロメチル）フェニル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000302
実施例９と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（４２ｍｇ，０．１７ｍｍｏｌ）及び１－フルオロ－３－ヨード－５－（トリフルオロメチル）ベンゼン（５０ｍｇ，０．１７ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，３４ｍｇ，４９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．２－３．４（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），３．５－３．７（ｍ，１Ｈ），４．５－４．７（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），６．２－６．４（ｍ，１Ｈ），６．４７（ｓ，１Ｈ），６．５－６．７（ｍ，１Ｈ），７．０４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：４０７．１５［Ｍ＋Ｈ］＋ Example 136
(R) -2- (4-Cyclopropylphenyl) -N- (1- (3-fluoro-5- (trifluoromethyl) phenyl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000302
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (42 mg, 0.17 mmol) and 1 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. -Fluoro-3-iodo-5- (trifluoromethyl) benzene (50 mg, 0.17 mmol) was used to give the title compound (pale yellow amorphous, 34 mg, 49%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.53 (s, 2H), 3 .5-3.7 (m, 1H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.2-6.4 (m, 1H) , 6.47 (s, 1H), 6.5-6.7 (m, 1H), 7.04 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz).
MS: 407.15 [M + H] +
実施例１３７
２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000303
参考例６７で合成した（１－（４－シクロプロピルフェニル）－２－オキソ－２－（（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アミノ）エチル）カルバミン酸ｔｅｒｔ－ブチルのジアステレオマーＡ（１５ｍｇ，０．０３０ｍｍｏｌ）に氷冷下でトリフルオロ酢酸（０．５０ｍＬ）を加え、室温で１時間撹拌した。反応液の溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）（濃度勾配：０－２０％）により精製し、２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミドのジアステレオマーＡ（淡黄色アモルファス，３．８ｍｇ，９％）を得た。上記と同様の手法に従い、参考例６７で合成した（１－（４－シクロプロピルフェニル）－２－オキソ－２－（（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アミノ）エチル）カルバミン酸ｔｅｒｔ－ブチルのジアステレオマーＢ（１５ｍｇ，０．０３０ｍｍｏｌ）を用いて２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミドのジアステレオマーＢ（淡黄色アモルファス，３．４ｍｇ，８％）を得た。
ジアステレオマーＡ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．２－１．３（ｂｒ　ｓ，２Ｈ），１．８－２．０（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．３－３．６（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．４９（ｓ，１Ｈ），４．５－４．７（ｍ，１Ｈ），６．９４（ｓ，１Ｈ）７．０１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４－７．５（ｍ，１Ｈ），８．１１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４０５．１４［Ｍ＋Ｈ］＋
ジアステレオマーＢ
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．２－１．３（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．０－２．１（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．２－３．３（ｍ，１Ｈ），３．３－３．６（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．５０（ｓ，１Ｈ），４．６－４．７（ｍ，１Ｈ），６．９５（ｓ，１Ｈ），７．０５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．２５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４－７．５（ｍ，１Ｈ），８．１３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２２（ｓ，１Ｈ）．
ＭＳ：４０５．１４［Ｍ＋Ｈ］＋ Example 137
2-Amino-2- (4-cyclopropylphenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000303
(1- (4-Cyclopropylphenyl) -2-oxo-2-(((R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) synthesized in Reference Example 67 ) Trifluoroacetic acid (0.50 mL) was added to diastereomeric A (15 mg, 0.030 mmol) of tert-butyl carbamate (amino) ethyl) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol) (concentration gradient: 0-20%) and 2-amino-2- (4-cyclopropylphenyl). ) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide diastereomer A (pale yellow amorphous, 3.8 mg, 9%) Obtained. (1- (4-Cyclopropylphenyl) -2-oxo-2-(((R) -1-(5- (trifluoromethyl) pyridine-3-) synthesized in Reference Example 67 according to the same method as above. 2-Amino-2- (4-cyclopropylphenyl) -N-((Il) pyrrolidine-3-yl) amino) ethyl) tert-butyl carbamate diastereomer B (15 mg, 0.030 mmol). The diastereomer B (pale yellow amorphous, 3.4 mg, 8%) of R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide was obtained.
Diastereomer A
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.2-1.3 (br s, 2H) ), 1.8-2.0 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.1-3.3 (m) , 1H), 3.3-3.6 (m, 2H), 3.6-3.7 (m, 1H), 4.49 (s, 1H), 4.5-4.7 (m, 1H) ), 6.94 (s, 1H) 7.01 (d, 2H, J = 8Hz), 7.21 (d, 2H, J = 8Hz), 7.4-7.5 (m, 1H), 8 .11 (d, 1H, J = 3Hz), 8.22 (s, 1H).
MS: 405.14 [M + H] +
Diastereomer B
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.2-1.3 (m, 2H) , 1.8-1.9 (m, 1H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.2-3.3 (m, 1H), 3.3-3.6 (m, 2H), 3.6-3.7 (m, 1H), 4.50 (s, 1H), 4.6-4.7 (m, 1H) , 6.95 (s, 1H), 7.05 (d, 2H, J = 8Hz), 7.25 (d, 2H, J = 8Hz), 7.4-7.5 (m, 1H), 8 .13 (d, 1H, J = 3Hz), 8.22 (s, 1H).
MS: 405.14 [M + H] +
実施例１３８
２－（４－シクロプロピルフェニル）－２－（ジメチルアミノ）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド塩酸塩
Figure JPOXMLDOC01-appb-C000304
実施例１３７と同様の手法に従い、参考例６７で合成した（１－（４－シクロプロピルフェニル）－２－オキソ－２－（（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）アミノ）エチル）カルバミン酸ｔｅｒｔ－ブチル（２９０ｍｇ，０．５７ｍｍｏｌ）を用いて２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミドの粗体（２００ｍｇ）を得た。得られた２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミドの粗体の一部（５０ｍｇ）をジクロロメタン（１．０ｍＬ）に溶解し、パラホルムアルデヒド（１１ｍｇ，０．３６ｍｍｏｌ）、酢酸（１４μＬ，０．２４ｍｍｏｌ）及びトリアセトキシボロハイドライド（１２７ｍｇ，０．６ｍｍｏｌ）を加えた後、室温で一晩撹拌した。反応液を酢酸エチルで希釈し、有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄後、分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：１０－７０％）により精製し、２－（４－シクロプロピルフェニル）－２－（ジメチルアミノ）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミドを得た。得られた２－（４－シクロプロピルフェニル）－２－（ジメチルアミノ）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミドをメタノール（０．５ｍＬ）に溶解後、１Ｎ塩酸水溶液（０．５ｍＬ）を加え、減圧下溶媒を留去した。得られた残渣に蒸留水（０．１ｍＬ）を加え、凍結乾燥し、表題化合物（黄色結晶，１０ｍｇ，１９％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．１（ｍ，２Ｈ），１．７－２．３（ｍ，３Ｈ），２．５０（ｓ，３Ｈ），２．８７（ｓ，３Ｈ），３．０－３．８（ｍ，４Ｈ），４．３－４．５（ｍ，１Ｈ），４．８－５．０（ｍ，１Ｈ），７．１２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．１８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．２－７．４（ｍ，１Ｈ），７．４－７．５（ｍ，２Ｈ），８．１－８．３（ｍ，２Ｈ），９．３－９．６（ｍ，１Ｈ），１０．３－１０．５（ｍ，１Ｈ）．
ＭＳ：４３３．１８［Ｍ＋Ｈ］＋ Example 138
2- (4-Cyclopropylphenyl) -2- (dimethylamino) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide hydrochloride
Figure JPOXMLDOC01-appb-C000304
(1- (4-Cyclopropylphenyl) -2-oxo-2-(((R) -1- (5- (trifluoromethyl) pyridine-) synthesized in Reference Example 67 according to the same procedure as in Example 137. 2-Amino-2- (4-cyclopropylphenyl) -N-((R) -1- (5-() with tert-butyl 3-yl) amino) ethyl) carbamate (290 mg, 0.57 mmol) A crude (200 mg) of trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide was obtained. The obtained 2-amino-2- (4-cyclopropylphenyl) -N-((R)). A portion (50 mg) of a crude of -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide was dissolved in dichloromethane (1.0 mL) and paraformaldehyde (11 mg, 0). .36 mmol), acetic acid (14 μL, 0.24 mmol) and triacetoxyborohydride (127 mg, 0.6 mmol) were added and then stirred overnight at room temperature. The reaction was diluted with ethyl acetate and the organic layer was saturated with carbonic acid. After washing with an aqueous sodium hydrogen hydrogen solution, water and saturated saline, the separated organic layer was dried with anhydrous sodium sulfate, the insoluble material was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (heptan). : Purified with (ethyl acetate) (concentration gradient: 10-70%), 2- (4-cyclopropylphenyl) -2- (dimethylamino) -N- ((R) -1- (5- (trifluoromethyl) ) Pyridin-3-yl) pyrrolidine-3-yl) acetamide was obtained. The obtained 2- (4-cyclopropylphenyl) -2- (dimethylamino) -N-((R) -1- (5-) (Trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) Acetamide was dissolved in methanol (0.5 mL), a 1N aqueous hydrochloric acid solution (0.5 mL) was added, and the solvent was distilled off under reduced pressure. Distilled water (0.1 mL) was added to the residue, and the mixture was lyophilized to give the title compound (yellow crystals, 10 mg, 19%).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.7-2.3 (m, 3H), 2.50 (s, 3H), 2.87 (s, 3H), 3.0-3.8 (m, 4H), 4.3-4.5 (m, 1H), 4.8 -5.0 (m, 1H), 7.12 (d, 1H, J = 8Hz), 7.18 (d, 1H, J = 8Hz), 7.2-7.4 (m, 1H), 7 .4-7.5 (m, 2H), 8.1-8.3 (m, 2H), 9.3-9.6 (m, 1H), 10.3-10.5 (m, 1H) ..
MS: 433.18 [M + H] +
実施例１３９
（Ｒ）－２－（１－メチル－１Ｈ－インドール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000305
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（１３ｍｇ，０．０５８ｍｍｏｌ）及び２－（１－メチル－１Ｈ－インドール－５－イル）酢酸（１０ｍｇ，０．０５３ｍｍｏｌ）を用いて表題化合物（白色結晶，６ｍｇ，２６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．１（ｍ，１Ｈ），３．２－３．４（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３，７０（ｓ，２Ｈ），３．８０（ｓ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．４４（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．８６（ｓ，１Ｈ），７．０－７．１（ｍ，２Ｈ），７．２９（ｄ，１Ｈ，Ｊ－９Ｈｚ），７．４６（ｄ，１Ｈ，Ｊ＝１Ｈｚ），８．０３（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１７（ｓ，１Ｈ）．
ＭＳ：４０３．１３［Ｍ＋Ｈ］＋ Example 139
(R) -2- (1-methyl-1H-indole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000305
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (13 mg, 0.058 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 6 mg, 26%) was obtained using 2- (1-methyl-1H-indole-5-yl) acetic acid (10 mg, 0.053 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.1 (m, 1H) , 3.2-3.4 (m, 2H), 3.6-3.7 (m, 1H), 3,70 (s, 2H), 3.80 (s, 3H), 4.5-4 .7 (m, 1H), 5.5-5.6 (m, 1H), 6.44 (d, 1H, J = 6Hz), 6.86 (s, 1H), 7.0-7.1 (M, 2H), 7.29 (d, 1H, J-9Hz), 7.46 (d, 1H, J = 1Hz), 8.03 (d, 1H, J = 3Hz), 8.17 (s) , 1H).
MS: 403.13 [M + H] +
実施例１４０
（Ｒ）－２－（２，４－ビス（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000306
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（２，４－ビス（トリフルオロメチル）フェニル）酢酸（４４ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，５６ｍｇ，８９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．２（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７９（ｓ，２Ｈ），４．６－４．８（ｍ，１Ｈ），６．５－６．６（ｍ，１Ｈ），６．８３（ｓ，１Ｈ），７．６８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．８２（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９１（ｓ，１Ｈ），８．００（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１２（ｓ，１Ｈ）．
ＭＳ：４８４．１１［Ｍ－Ｈ］－ Example 140
(R) -2- (2,4-bis (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000306
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 56 mg, 89%) was obtained using 2- (2,4-bis (trifluoromethyl) phenyl) acetic acid (44 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.2 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H) , 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.79 (s, 2H), 4.6-4.8 (m, 1H), 6 .5-6.6 (m, 1H), 6.83 (s, 1H), 7.68 (d, 1H, J = 8Hz), 7.82 (d, 1H, J = 8Hz), 7.91 (S, 1H), 8.00 (d, 1H, J = 2Hz), 8.12 (s, 1H).
MS: 484.11 [MH] -
実施例１４１
（Ｒ）－２－（２－フルオロ－４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000307
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（２－フルオロ－４－（トリフルオロメチル）フェニル）酢酸（３６ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，５９ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．６４（ｓ，２Ｈ），４．６－４．８（ｍ，１Ｈ），６．６－６．８（ｍ，１Ｈ），６．８２（ｓ，１Ｈ），７．３３（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），７．４１（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．４９（ｔ，１Ｈ，Ｊ＝８Ｈｚ），７．９９（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．１２（ｓ，１Ｈ）．
ＭＳ：４３４．１２［Ｍ－Ｈ］－ Example 141
(R) -2- (2-Fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000307
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 59 mg, 100%) was obtained using 2- (2-fluoro-4- (trifluoromethyl) phenyl) acetic acid (36 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.0-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H) , 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.64 (s, 2H), 4.6-4.8 (m, 1H), 6 .6-6.8 (m, 1H), 6.82 (s, 1H), 7.33 (d, 1H, J = 10Hz), 7.41 (d, 1H, J = 8Hz), 7.49 (T, 1H, J = 8Hz), 7.99 (d, 1H, J = 8Hz), 8.12 (s, 1H).
MS: 434.12 [MH] -
実施例１４２
（Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000308
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（１－メチル－１Ｈ－インダゾール－５－イル）酢酸（３２ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，３６ｍｇ，５６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．３５（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．６－３．７（ｍ、１Ｈ），３．６９（ｓ，２Ｈ），４．０８（ｓ，３Ｈ），４．６－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．８７（ｓ，１Ｈ），７．２－７．３（ｍ，１Ｈ），７．３８（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．５９（ｓ，１Ｈ），７．９４（ｓ，１Ｈ），８．０４（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１８（ｓ，１Ｈ）．
ＭＳ：４０４．１０［Ｍ＋Ｈ］＋ Example 142
(R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000308
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 36 mg, 56%) was obtained using 2- (1-methyl-1H-indazole-5-yl) acetic acid (32 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H) , 3.35 (t, 2H, J = 7Hz), 3.6-3.7 (m, 1H), 3.69 (s, 2H), 4.08 (s, 3H), 4.6-4 .7 (m, 1H), 5.5-5.6 (m, 1H), 6.87 (s, 1H), 7.2-7.3 (m, 1H), 7.38 (d, 1H) , J = 9Hz), 7.59 (s, 1H), 7.94 (s, 1H), 8.04 (d, 1H, J = 2Hz), 8.18 (s, 1H).
MS: 404.10 [M + H] +
実施例１４３
（Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000309
実施例１と同様の手法に従い、参考例１２－２で合成した（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン（３１ｍｇ，０．１３ｍｍｏｌ）及び２－（１－メチル－１Ｈ－インダゾール－５－イル）酢酸（３２ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，３５ｍｇ，６６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．４－３．６（ｍ，２Ｈ），３．６８（ｓ，２Ｈ），３．７－３．８（ｍ，１Ｈ），４．０９（ｓ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），６．９１（ｓ，１Ｈ），７．２－７．３（ｍ，１Ｈ），７．３８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．５８（ｓ，１Ｈ），７．９５（ｓ，１Ｈ）．
ＭＳ：４１０．０６［Ｍ＋Ｈ］＋ Example 143
(R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000309
According to the same procedure as in Example 1, (R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (31 mg, 0.13 mmol) synthesized in Reference Example 12-2 and The title compound (white crystals, 35 mg, 66%) was obtained using 2- (1-methyl-1H-indazole-5-yl) acetic acid (32 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H) , 3.4-3.6 (m, 2H), 3.68 (s, 2H), 3.7-3.8 (m, 1H), 4.09 (s, 3H), 4.5-4 .7 (m, 1H), 5.4-5.6 (m, 1H), 6.91 (s, 1H), 7.2-7.3 (m, 1H), 7.38 (d, 1H) , J = 8Hz), 7.58 (s, 1H), 7.95 (s, 1H).
MS: 410.06 [M + H] +
実施例１４４
（Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000310
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（１－メチル－１Ｈ－インダゾール－５－イル）酢酸（３２ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，３５ｍｇ，６７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．３６（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．６－３．７（ｍ，１Ｈ），３．６９（ｓ，２Ｈ），４．０８（ｓ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），６．７６（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．２－７．３（ｍ，１Ｈ），７．３７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．４５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．５９（ｓ，１Ｈ），７．９－８．０（ｍ，２Ｈ）．
ＭＳ：４０４．１０［Ｍ＋Ｈ］＋ Example 144
(R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000310
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 35 mg, 67%) was obtained using 2- (1-methyl-1H-indazole-5-yl) acetic acid (32 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H) , 3.36 (t, 2H, J = 7Hz), 3.6-3.7 (m, 1H), 3.69 (s, 2H), 4.08 (s, 3H), 4.5-4 .7 (m, 1H), 5.4-5.6 (m, 1H), 6.76 (dd, 1H, J = 3.9Hz), 7.2-7.3 (m, 1H), 7 .37 (d, 1H, J = 9Hz), 7.45 (d, 1H, J = 8Hz), 7.59 (s, 1H), 7.9-8.0 (m, 2H).
MS: 404.10 [M + H] +
実施例１４５
（Ｒ）－２－（４－（２，２－ジメチルモルホリノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000311
実施例９と同様の手法に従い、実施例１７１で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（４０ｍｇ，０．０９３ｍｍｏｌ）及び２，２－ジメチルモルホリン（２１ｍｇ，０．１９ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，２．１ｍｇ，５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．３２（ｓ，６Ｈ），１．８－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），２．９４（ｓ，２Ｈ），３．０－３．２（ｍ，３Ｈ），３．３－３．４（ｍ，２Ｈ），３．５１（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ）３．８－３．９（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），６．８５（ｄ，２Ｈ，Ｊ＝８Ｈｚ），６．９４（ｓ，１Ｈ），７．１２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０－８．４（ｍ，２Ｈ）．
ＭＳ：４６３．１５［Ｍ＋Ｈ］＋ Example 145
(R) -2- (4- (2,2-dimethylmorpholino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000311
(R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (40 mg, 0.093 mmol) and 2,2-dimethylmorpholine (21 mg, 0.19 mmol) were used to give the title compound (yellow amorphous, 2.1 mg, 5%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.32 (s, 6H), 1.8-2.0 (m, 1H), 2.3-2.4 (m, 1H), 2.94 (S, 2H), 3.0-3.2 (m, 3H), 3.3-3.4 (m, 2H), 3.51 (s, 2H), 3.6-3.7 (m) , 1H) 3.8-3.9 (m, 2H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.85 (d, 2H, J = 8Hz), 6.94 (s, 1H), 7.12 (d, 2H, J = 8Hz), 8.0-8.4 (m, 2H).
MS: 463.15 [M + H] +
実施例１４６
（Ｒ）－２－（４－（１Ｈ－ピラゾール－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000312
実施例１７１で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（４０ｍｇ，０．０９３ｍｍｏｌ）、ピラゾール（１３ｍｇ，０．１９ｍｍｏｌ）、ヨウ化銅（Ｉ）（２ｍｇ，９．３μｍｍｏｌ），Ｎ，Ｎ’－ジメチルエチレンジアミン（２μＬ，１８．６μｍｍｏｌ）及び炭酸セシウム（９１ｍｇ，０．３０ｍｍｏｌ）をＤＭＦ（１．０ｍＬ）に懸濁し、２００℃（マイクロウエーブ）で２時間撹拌した。室温まで放冷した反応液に酢酸エチルを加えて、有機層を水及び飽和食塩水で洗浄した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル）（濃度勾配：０－１００％）により精製し表題化合物（白色結晶，２２ｍｇ，５７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６２（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），４．６－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．４－６．５（ｍ，１Ｈ），６．９－７．０（ｍ，１Ｈ），７．３５（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．６９（ｄ，２Ｈ，Ｊ＝９Ｈｚ），７．７３（ｄ，１Ｈ，Ｊ＝１Ｈｚ），７．９２（ｄ，１Ｈ，Ｊ＝１Ｈｚ），８．０－８．１（ｍ，１Ｈ），８．２０（ｓ，１Ｈ）．
ＭＳ：４１６．１１［Ｍ＋Ｈ］＋ Example 146
(R) -2- (4- (1H-pyrazole-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000312
(R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide synthesized in Example 171 (40 mg, 0. 093 mmol), pyrazole (13 mg, 0.19 mmol), copper (I) iodide (2 mg, 9.3 μ mmol), N, N'-dimethylethylenediamine (2 μL, 18.6 μ mmol) and cesium carbonate (91 mg, 0.30 mmol). Was suspended in DMF (1.0 mL) and stirred at 200 ° C. (microwave) for 2 hours. Ethyl acetate was added to the reaction solution allowed to cool to room temperature, and the organic layer was washed with water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) (concentration gradient: 0-100%) to give the title compound (white crystals, 22 mg, 57%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H) , 3.3-3.5 (m, 2H), 3.62 (s, 2H), 3.6-3.7 (m, 1H), 4.6-4.7 (m, 1H), 5 .5-5.6 (m, 1H), 6.4-6.5 (m, 1H), 6.9-7.0 (m, 1H), 7.35 (d, 2H, J = 9Hz) , 7.69 (d, 2H, J = 9Hz), 7.73 (d, 1H, J = 1Hz), 7.92 (d, 1H, J = 1Hz), 8.0-8.1 (m, 1H), 8.20 (s, 1H).
MS: 416.11 [M + H] +
実施例１４７
（Ｒ）－Ｎ－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－モルホリノフェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000313
実施例３と同様の手法に従い、参考例６８で合成した（Ｒ）－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（４７ｍｇ，０．２３ｍｍｏｌ）から（Ｒ）－３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（５０ｍｇ）を合成し、得られた（Ｒ）－３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体の一部（２０ｍｇ）及び参考例２３－２で合成した２－（４－モルホリノフェニル）酢酸（３０ｍｇ，０．１２ｍｍｏｌ）を用いて表題化合物（白色結晶，２２ｍｇ，６１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５３（ｓ，３Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１３（ｔ，４Ｈ，Ｊ＝４Ｈｚ），３．２－３．４（ｍ，３Ｈ），３．４６（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．８６（ｔ，４Ｈ，Ｊ＝４Ｈｚ），５．３７（ｂｒ　ｓ，１Ｈ），６．８４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），６．８９（ｓ，１Ｈ），７．０９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０６（ｓ，１Ｈ），８．１９（ｓ，１Ｈ）．
ＭＳ：４４９．１５［Ｍ＋Ｈ］＋ Example 147
(R) -N- (3-Methyl-1- (5- (trifluoromethyl) Pyridine-3-yl) Pyrrolidine-3-yl) -2- (4-morpholinophenyl) acetamide
Figure JPOXMLDOC01-appb-C000313
(R)-(3-Methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 68 according to the same procedure as in Example 3. Obtained by synthesizing a crude compound (50 mg) of (R) -3-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine from butyl (47 mg, 0.23 mmol). A part (20 mg) of a crude compound of (R) -3-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine and 2- synthesized in Reference Example 23-2. The title compound (white crystals, 22 mg, 61%) was obtained using (4-morpholinophenyl) acetic acid (30 mg, 0.12 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.53 (s, 3H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.13 (T, 4H, J = 4Hz), 3.2-3.4 (m, 3H), 3.46 (s, 2H), 3.6-3.7 (m, 1H), 3.86 (t) , 4H, J = 4Hz), 5.37 (br s, 1H), 6.84 (d, 2H, J = 8Hz), 6.89 (s, 1H), 7.09 (d, 2H, J = 8Hz), 8.06 (s, 1H), 8.19 (s, 1H).
MS: 449.15 [M + H] +
実施例１４８
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000314
実施例３と同様の手法に従い、参考例６８で合成した（Ｒ）－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（４７ｍｇ，０．２３ｍｍｏｌ）から（Ｒ）－３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（２０ｍｇ）を合成し、得られた（Ｒ）－３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体の一部（７ｍｇ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（８ｍｇ，０．０４４ｍｍｏｌ）を用いて表題化合物（白色アモルファス，１２ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．５３（ｓ，３Ｈ），１．８－１．９（ｍ，１Ｈ），１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２－３．４（ｍ，３Ｈ），３．４８（ｓ，２Ｈ），３．６２（ｄ，１Ｈ，Ｊ＝１０Ｈｚ），５．３６（ｂｒ　ｓ，１Ｈ），６．８８（ｓ，１Ｈ），７．００（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．０７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０５（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：４０４．１２［Ｍ＋Ｈ］＋ Example 148
(R) -2- (4-Cyclopropylphenyl) -N- (3-methyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000314
(R)-(3-Methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 68 according to the same procedure as in Example 3. Obtained by synthesizing a crude compound (20 mg) of (R) -3-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine from butyl (47 mg, 0.23 mmol). A part (7 mg) of a crude compound of (R) -3-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine and 2- synthesized in Reference Example 33-2. The title compound (white amorphous, 12 mg, 100%) was obtained using (4-cyclopropylphenyl) acetic acid (8 mg, 0.044 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.53 (s, 3H), 1.8 -1.9 (m, 1H), 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.4 (m, 3H), 3 .48 (s, 2H), 3.62 (d, 1H, J = 10Hz), 5.36 (br s, 1H), 6.88 (s, 1H), 7.00 (d, 2H, J = 8Hz), 7.07 (d, 2H, J = 8Hz), 8.05 (d, 1H, J = 2Hz), 8.19 (s, 1H).
MS: 404.12 [M + H] +
実施例１４９
２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000315
参考例６９で合成した２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）酢酸エチル（８７ｍｇ，０．３２ｍｍｏｌ）をエタノール（１．６ｍＬ）に溶解し、８Ｎ水酸化ナトリウム水溶液（０．２０ｍＬ，１．６ｍｍｏｌ）を加えて室温で２時間撹拌した。氷浴下で反応液に１Ｎ塩酸水溶液（１．６ｍＬ，１．６ｍｍｏｌ）を加えた後、減圧留去した。得られた残渣にクロロホルム：メタノール＝１０：１の混液（５ｍＬ）を加え、不溶物をろ過後、減圧下溶媒を留去して２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）酢酸の粗体（白色結晶）を得た。続いて、実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３５ｍｇ，０．１５ｍｍｏｌ）及び上記で合成した２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）酢酸の粗体の半分を用いて表題化合物（淡黄色結晶，５０ｍｇ，７１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．２（ｍ，５Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．３７（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４－３．６（ｍ，２Ｈ），３．４９（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．８－３．９（ｍ，２Ｈ），４．０－４．１（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．７６（ｄ，２Ｈ，Ｊ＝９Ｈｚ），６．９０（ｓ，１Ｈ），７．１０（ｄ，２Ｈ，Ｊ＝９Ｈｚ）８．０８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４６１．１７［Ｍ＋Ｈ］＋ Example 149
2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-3) Il) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000315
Ethyl 2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) ethyl acetate (87 mg, 0.32 mmol) synthesized in Reference Example 69 was added to ethanol (1.6 mL). 8N aqueous sodium hydroxide solution (0.20 mL, 1.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A 1N aqueous hydrochloric acid solution (1.6 mL, 1.6 mmol) was added to the reaction solution under an ice bath, and then distilled off under reduced pressure. A mixed solution (5 mL) of chloroform: methanol = 10: 1 was added to the obtained residue, the insoluble material was filtered, and the solvent was distilled off under reduced pressure to 2- (4- (3-oxa-8-azabicyclo] [3. 2.1] Octane-8-yl) Phenyl) Acetic acid crude (white crystals) was obtained. Subsequently, according to the same method as in Example 1, (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (35 mg, 0.) synthesized in Reference Example 1-2. The title compound (pale yellow crystals) using half of the crude of 2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) acetic acid synthesized above (15 mmol). , 50 mg, 71%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.2 (m, 5H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H) , 3.37 (t, 2H, J = 7Hz), 3.4-3.6 (m, 2H), 3.49 (s, 2H), 3.6-3.7 (m, 1H), 3 .8-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H) , 6.76 (d, 2H, J = 9Hz), 6.90 (s, 1H), 7.10 (d, 2H, J = 9Hz) 8.08 (d, 1H, J = 3Hz), 8. 20 (s, 1H).
MS: 461.17 [M + H] +
実施例１５０
２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000316
実施例１４９と同様の手法に従い、参考例６９で合成した２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）酢酸エチル（８７ｍｇ，０．３２ｍｍｏｌ）から２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）酢酸の粗体（白色結晶）を得た。参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３５ｍｇ，０．１５ｍｍｏｌ）及び上記で合成した２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）酢酸の粗体の半分を用いて表題化合物（淡黄色結晶，５１ｍｇ，７３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．２（ｍ，５Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．３－３．４（ｍ，２Ｈ），３．４－３．６（ｍ，２Ｈ），３．４９（ｓ，２Ｈ），３．６－３．８（ｍ，１Ｈ），３．８－３．９（ｍ，２Ｈ），４．０－４．１（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．７－６．８（ｍ，３Ｈ），７．０８（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９６（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４６１．１７［Ｍ＋Ｈ］＋ Example 150
2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000316
Ethyl 2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) ethyl acetate (87 mg, 0.) synthesized in Reference Example 69 according to the same procedure as in Example 149. A crude (white crystals) of 2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) acetic acid was obtained from 32 mmol). (R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 32-2 and 2- (4- (4-4-yl) synthesized above. The title compound (pale yellow crystals, 51 mg, 73%) was obtained using half of the crude (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenylacetic acid.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.2 (m, 5H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H) , 3.3-3.4 (m, 2H), 3.4-3.6 (m, 2H), 3.49 (s, 2H), 3.6-3.8 (m, 1H), 3 .8-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H) , 6.7-6.8 (m, 3H), 7.08 (d, 2H, J = 8Hz), 7.46 (d, 1H, J = 8Hz), 7.96 (d, 1H, J = 3Hz).
MS: 461.17 [M + H] +
実施例１５１
（Ｒ）－２－（ベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000317
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（ベンゾ［ｄ］オキサゾール－５－イル）酢酸（３５ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，２６ｍｇ，５２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７０（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．７６（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ）７．３０（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．４５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．５６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．６７（ｄ，１Ｈ，Ｊ＝１Ｈｚ），７．９４（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１１（ｓ，１Ｈ）．
ＭＳ：３９１．１０［Ｍ＋Ｈ］＋ Example 151
(R) -2- (benzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000317
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 26 mg, 52%) was obtained using 2- (benzo [d] oxazole-5-yl) acetic acid (35 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.3 (m, 1H) , 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.70 (s, 2H), 3.6-3.7 (m, 1H), 5 .5-5.7 (m, 1H), 6.76 (dd, 1H, J = 3.9Hz) 7.30 (dd, 1H, J = 1.8Hz), 7.45 (d, 1H, J) = 9Hz), 7.56 (d, 1H, J = 8Hz), 7.67 (d, 1H, J = 1Hz), 7.94 (d, 1H, J = 3Hz), 8.11 (s, 1H) ).
MS: 391.10 [M + H] +
実施例１５２
（Ｒ）－２－（ベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000318
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（ベンゾ［ｄ］オキサゾール－５－イル）酢酸（３５ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，３３ｍｇ，６５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７１（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），５．６－５．８（ｍ，１Ｈ）６．８８（ｓ，１Ｈ），７．３１（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．５７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．６８（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．０－８．３（ｍ，２Ｈ），８．１２（ｓ，１Ｈ）．
ＭＳ：３９１．１０［Ｍ＋Ｈ］＋ Example 152
(R) -2- (benzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000318
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow crystals, 33 mg, 65%) was obtained using 2- (benzo [d] oxazole-5-yl) acetic acid (35 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 1H) , 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.71 (s, 2H), 3.6-3.7 (m, 1H), 5 6.-5.8 (m, 1H) 6.88 (s, 1H), 7.31 (dd, 1H, J = 2.8Hz), 7.57 (d, 1H, J = 8Hz), 7. 68 (d, 1H, J = 2Hz), 8.0-8.3 (m, 2H), 8.12 (s, 1H).
MS: 391.10 [M + H] +
実施例１５３
（Ｒ）－２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000319
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び上記で合成した２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）酢酸（３５ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（淡黄色結晶，４８ｍｇ，８９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．６５（ｓ，３Ｈ），３．０－３．２（ｍ，１Ｈ），３．３６（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．６－３．７（ｍ，１Ｈ），３．８９（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．８８（ｓ，１Ｈ），７．１９（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．４４（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．５２（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．０５（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．１９（ｓ，１Ｈ）．
ＭＳ：４０５．１２［Ｍ＋Ｈ］＋ Example 153
(R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000319
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow crystals, 48 mg, 89%) was obtained using 2- (2-methylbenzo [d] oxazole-5-yl) acetic acid (35 mg, 0.16 mmol) synthesized above.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.65 (s, 3H), 3.0 -3.2 (m, 1H), 3.36 (t, 2H, J = 7Hz), 3.6-3.7 (m, 1H), 3.89 (s, 2H), 4.6-4 .7 (m, 1H), 5.5-5.7 (m, 1H), 6.88 (s, 1H), 7.19 (dd, 1H, J = 2.8Hz), 7.44 (d) , 1H, J = 8Hz), 7.52 (d, 1H, J = 2Hz), 8.05 (d, 1H, J = 2Hz), 8.19 (s, 1H).
MS: 405.12 [M + H] +
実施例１５４
（Ｒ）－２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000320
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）酢酸（３１ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，５３ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．６４（ｓ，３Ｈ），３．０－３．２（ｍ，１Ｈ），３．３７（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．６－３．７（ｍ，１Ｈ），３．６８（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．６－５．８（ｍ，１Ｈ），６．７５（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．１９（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．４３（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．４５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．５１（ｄ，１Ｈ，Ｊ＝２Ｈｚ），７．９１（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４０５．１１［Ｍ＋Ｈ］＋ Example 154
(R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000320
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 53 mg, 100%) was obtained using 2- (2-methylbenzo [d] oxazole-5-yl) acetic acid (31 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.64 (s, 3H), 3.0 -3.2 (m, 1H), 3.37 (t, 2H, J = 7Hz), 3.6-3.7 (m, 1H), 3.68 (s, 2H), 4.6-4 .7 (m, 1H), 5.6-5.8 (m, 1H), 6.75 (dd, 1H, J = 3.9Hz), 7.19 (dd, 1H, J = 2.8Hz) , 7.43 (d, 1H, J = 8Hz), 7.45 (d, 1H, J = 9Hz), 7.51 (d, 1H, J = 2Hz), 7.91 (d, 1H, J = 3Hz).
MS: 405.11 [M + H] +
実施例１５５
２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000321
参考例７０で合成した２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）酢酸エチル（１１２ｍｇ，０．４１ｍｍｏｌ）をエタノール（２．０ｍＬ）に溶解し、８Ｎ水酸化ナトリウム水溶液（０．３０ｍＬ，２．４ｍｍｏｌ）を加えて室温で２時間撹拌した。氷浴下で反応液に１Ｎ塩酸水溶液（２．４ｍＬ，２．４ｍｍｏｌ）を加えた後、減圧留去した。得られた残渣にクロロホルム：メタノール＝１０：１の混液（５ｍＬ）を加え、不溶物をろ過後、減圧下溶媒を留去して２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）酢酸の粗体（白色結晶，８４ｍｇ）を得た。続いて、実施例１３１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４２ｍｇ，０．１８ｍｍｏｌ）及び上記で合成した２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）酢酸の粗体の一部（４１ｍｇ）を用いて表題化合物（淡黄色結晶，４０ｍｇ，４７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，１Ｈ），１．８－２．０（ｍ，２Ｈ），２．０－２．３（ｍ，２Ｈ），２．３－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．２－３．４（ｍ，３Ｈ），３．４９（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７－３．９（ｍ，２Ｈ），４．０－４．１（ｍ，２Ｈ），４．１－４．２（ｍ，１Ｈ），４．５－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．６０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），６．９１（ｓ，１Ｈ），７．０９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０８（ｓ，１Ｈ），８．２０（ｓ，１Ｈ）．
ＭＳ：４６１．１７［Ｍ＋Ｈ］＋ Example 155
2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) -N-((R) -1-(5- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide
Figure JPOXMLDOC01-appb-C000321
2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) ethyl acetate (112 mg, 0.41 mmol) synthesized in Reference Example 70 It was dissolved in ethanol (2.0 mL), 8N aqueous sodium hydroxide solution (0.30 mL, 2.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A 1N aqueous hydrochloric acid solution (2.4 mL, 2.4 mmol) was added to the reaction solution under an ice bath, and the mixture was distilled off under reduced pressure. A mixed solution (5 mL) of chloroform: methanol = 10: 1 was added to the obtained residue, the insoluble material was filtered, and the solvent was distilled off under reduced pressure to 2-(4-((1S, 4S) -2-oxa-. A crude (white crystals, 84 mg) of 5-azabicyclo [2.2.2] octane-5-yl) phenyl) acetic acid was obtained. Subsequently, according to the same method as in Example 131, (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (42 mg, 0.) synthesized in Reference Example 1-2. 18 mmol) and part of the crude of 2- (4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) acetic acid synthesized above (41 mg) ) Was used to obtain the title compound (pale yellow crystals, 40 mg, 47%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.8 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.3 (m, 2H) , 2.3-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.2-3.4 (m, 3H), 3.49 (s, 2H), 3 .6-3.7 (m, 1H), 3.7-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.1-4.2 (m, 1H) , 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.60 (d, 2H, J = 8Hz), 6.91 (s, 1H), 7 .09 (d, 2H, J = 8Hz), 8.08 (s, 1H), 8.20 (s, 1H).
MS: 461.17 [M + H] +
実施例１５６
２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000322
実施例１５５と同様の手法に従い、参考例７０で合成した２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）酢酸エチルの粗体（１１２ｍｇ，０．４１ｍｍｏｌ）から２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）酢酸の粗体（白色結晶，８４ｍｇ）を得た。続いて、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４２ｍｇ，０．１８ｍｍｏｌ）及び上記で合成した２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）酢酸の粗体の一部（４１ｍｇ）を用いて表題化合物（白色結晶，１６ｍｇ，１８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．６－１．８（ｍ，１Ｈ），１．８－２．０（ｍ，２Ｈ），２．０－２．３（ｍ，２Ｈ），２．３－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，３Ｈ），３．４９（ｓ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７－３．９（ｍ，２Ｈ），４．０－４．１（ｍ，２Ｈ），４．１－４．２（ｍ，１Ｈ），４．５－４．７（ｍ，１Ｈ），５．５－５．６（ｍ，１Ｈ），６．５９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），６．７８（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．０８（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．９９（ｓ，１Ｈ）．
ＭＳ：４６１．１７［Ｍ＋Ｈ］＋ Example 156
2-(4-(((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) -N-((R) -1- (6- (trifluoro)) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide
Figure JPOXMLDOC01-appb-C000322
2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) acetic acid synthesized in Reference Example 70 according to the same procedure as in Example 155. Crude of ethyl (112 mg, 0.41 mmol) to crude of 2- (4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) acetic acid (White crystals, 84 mg) were obtained. Subsequently, (R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (42 mg, 0.18 mmol) synthesized in Reference Example 32-2 and 2- synthesized above. (4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) The title compound (white crystals) using a portion (41 mg) of a crude acetic acid. , 16 mg, 18%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.6-1.8 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.3 (m, 2H) , 2.3-2.4 (m, 1H), 3.0-3.2 (m, 1H), 3.3-3.5 (m, 3H), 3.49 (s, 2H), 3 .6-3.7 (m, 1H), 3.7-3.9 (m, 2H), 4.0-4.1 (m, 2H), 4.1-4.2 (m, 1H) , 4.5-4.7 (m, 1H), 5.5-5.6 (m, 1H), 6.59 (d, 2H, J = 8Hz), 6.78 (dd, 1H, J = 3.9Hz), 7.08 (d, 2H, J = 8Hz), 7.47 (d, 1H, J = 9Hz), 7.99 (s, 1H).
MS: 461.17 [M + H] +
実施例１５７
（Ｒ）－２－（ベンゾ［ｄ］チアゾール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000323
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（ベンゾ［ｄ］チアゾール－６－イル）酢酸（３１ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（淡黄色アモルファス，３３ｍｇ，６１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７４（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．６－５．８（ｍ，１Ｈ），６．９０（ｓ，１Ｈ），７．４１（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．８９（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．０－８．１（ｍ，１Ｈ），８．１１（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．１９（ｓ，１Ｈ），９．００（ｓ，１Ｈ）．
ＭＳ：４０７．０８［Ｍ＋Ｈ］＋ Example 157
(R) -2- (benzo [d] thiazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000323
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (pale yellow amorphous, 33 mg, 61%) was obtained using 2- (benzo [d] thiazole-6-yl) acetic acid (31 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H) , 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.74 (s, 2H), 4.6-4.7 (m, 1H), 5 .6-5.8 (m, 1H), 6.90 (s, 1H), 7.41 (dd, 1H, J = 2.8Hz), 7.89 (d, 1H, J = 2Hz), 8 .0-8.1 (m, 1H), 8.11 (d, 1H, J = 8Hz), 8.19 (s, 1H), 9.00 (s, 1H).
MS: 407.08 [M + H] +
実施例１５８
（Ｒ）－２－（ベンゾ［ｄ］チアゾール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000324
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（ベンゾ［ｄ］チアゾール－６－イル）酢酸（３１ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，２０ｍｇ，３６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．０（ｍ，１Ｈ），２．３－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７３（ｓ，２Ｈ），４．６－４．７（ｍ，１Ｈ），５．７－５．８（ｍ，１Ｈ），６．７６（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．４０（ｄ，１Ｈ，Ｊ＝２Ｈｚ），７．４５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．８８（ｓ，１Ｈ），７．９１（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１０（ｄ，１Ｈ，Ｊ＝８Ｈｚ），９．００（ｓ，１Ｈ）．
ＭＳ：４２９．０５［Ｍ＋Ｎａ］＋ Example 158
(R) -2- (benzo [d] thiazole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000324
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 and The title compound (white crystals, 20 mg, 36%) was obtained using 2- (benzo [d] thiazole-6-yl) acetic acid (31 mg, 0.16 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.0 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.2 (m, 1H) , 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.73 (s, 2H), 4.6-4.7 (m, 1H), 5 .7-5.8 (m, 1H), 6.76 (dd, 1H, J = 2.8Hz), 7.40 (d, 1H, J = 2Hz), 7.45 (d, 1H, J = 8Hz), 7.88 (s, 1H), 7.91 (d, 1H, J = 3Hz), 8.10 (d, 1H, J = 8Hz), 9.00 (s, 1H).
MS: 429.05 [M + Na] +
実施例１５９
（Ｒ）－２－（１Ｈ－インダゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000325
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６０ｍｇ，０．２６ｍｍｏｌ）及び２－（１Ｈ－インダゾール－５－イル）酢酸（５６ｍｇ，０．３２ｍｍｏｌ）を用いて表題化合物（白色結晶，５９ｍｇ，５７％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．１－３．３（ｍ，１Ｈ），３．３－３．７（ｍ，４Ｈ），３．４９（ｓ，２Ｈ），４．３９（ｂｒ　ｓ，１Ｈ），７．１１（ｓ，１Ｈ），７．２５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．４５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．５９（ｓ，１Ｈ），８．００（ｓ，１Ｈ），８．１５（ｓ，１Ｈ），８．２１（ｓ，１Ｈ），８．３－８．５（ｍ，１Ｈ）．
ＭＳ：３９０．１２［Ｍ＋Ｈ］＋ Example 159
(R) -2- (1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000325
(R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 59 mg, 57%) was obtained using 2- (1H-indazole-5-yl) acetic acid (56 mg, 0.32 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.3 (m, 1H), 3.3-3.7 (m, 4H), 3.49 (s, 2H), 4.39 (br s, 1H), 7.11 (s, 1H), 7.25 (d, 1H, J = 8Hz), 7.45 (d, 1H, J = 8Hz), 7.59 (s, 1H), 8.00 (s, 1H), 8.15 (s, 1H), 8.21 (S, 1H), 8.3-8.5 (m, 1H).
MS: 390.12 [M + H] +
実施例１６０
（Ｒ）－２－（１Ｈ－インダゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000326
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（６０ｍｇ，０．２６ｍｍｏｌ）及び２－（１Ｈ－インダゾール－５－イル）酢酸（５６ｍｇ，０．３２ｍｍｏｌ）を用いて表題化合物（白色結晶，５５ｍｇ，５３％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．１－２．３（ｍ，１Ｈ），３．１－３．５（ｍ，３Ｈ），３．４９（ｓ，２Ｈ），３．５－３．７（ｍ，１Ｈ），４．３－４．５（ｍ，１Ｈ），７．０１（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．２４（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．４５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．５－７．７（ｍ，２Ｈ），７．９９（ｓ，１Ｈ），８．０４（ｄ，２Ｈ，Ｊ＝３Ｈｚ），８．３－８．５（ｍ，１Ｈ）．
ＭＳ：３９０．１２［Ｍ＋Ｈ］＋ Example 160
(R) -2- (1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000326
(R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-amine (60 mg, 0.26 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 The title compound (white crystals, 55 mg, 53%) was obtained using 2- (1H-indazole-5-yl) acetic acid (56 mg, 0.32 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.1-2.3 (m, 1H), 3.1-3.5 (m, 3H), 3.49 (s, 2H), 3.5-3.7 (m, 1H), 4.3-4.5 (m, 1H), 7.01 (dd, 1H, J = 3, 8Hz), 7.24 (d, 1H, J = 8Hz), 7.45 (d, 1H, J = 8Hz), 7.5-7.7 (m, 2H), 7.99 (s, 1H) , 8.04 (d, 2H, J = 3Hz), 8.3-8.5 (m, 1H).
MS: 390.12 [M + H] +
実施例１６１
２－（４－シクロプロピルフェニル）－Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000327
実施例３と同様の手法に従い、参考例７１で合成した（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１４５ｍｇ，０．３６ｍｍｏｌ）から３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（５８ｍｇ）を合成し、得られた３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体の一部（２９ｍｇ）及び参考例３３－２で合成した２－（４－シクロプロピルフェニル）酢酸（２６ｍｇ，０．１５ｍｍｏｌ）を用いて表題化合物（白色アモルファス，１１ｍｇ，２５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－１．９（ｍ，１Ｈ），２．５－２．６（ｍ，２Ｈ），３．４－３．６（ｍ，２Ｈ），３．５６（ｓ，２Ｈ），３．８６（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），３．９６（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），５．４５（ｂｒ　ｓ，１Ｈ），６．９４（ｓ，１Ｈ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．９０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０－８．２（ｍ，１Ｈ），８．２－８．３（ｍ，１Ｈ）．
ＭＳ：４５８．１３［Ｍ＋Ｈ］＋ Example 161
2- (4-Cyclopropylphenyl) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000327
(3- (Trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 71 according to the same method as in Example 3. Obtained by synthesizing a crude compound (58 mg) of 3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine from butyl (145 mg, 0.36 mmol). Part of a crude product of 3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (29 mg) and 2- synthesized in Reference Example 33-2. The title compound (white amorphous, 11 mg, 25%) was obtained using (4-cyclopropylphenyl) acetic acid (26 mg, 0.15 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-1.9 (m, 1H) , 2.5-2.6 (m, 2H), 3.4-3.6 (m, 2H), 3.56 (s, 2H), 3.86 (d, 1H, J = 11Hz), 3 .96 (d, 1H, J = 11Hz), 5.45 (br s, 1H), 6.94 (s, 1H), 7.40 (d, 2H, J = 8Hz), 7.90 (d, 2H, J = 8Hz), 8.0-8.2 (m, 1H), 8.2-8.3 (m, 1H).
MS: 458.13 [M + H] +
実施例１６２
Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000328
実施例３と同様の手法に従い、参考例７１で合成した（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（１４５ｍｇ，０．３６ｍｍｏｌ）から３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体（５８ｍｇ）を合成し、得られた３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミンの粗体の一部（２９ｍｇ）及び２－（４－（トリフルオロメチル）フェニル）酢酸（３０ｍｇ，０．１５ｍｍｏｌ）を用いて表題化合物（白色アモルファス，２５ｍｇ，５１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝２．５－２．７（ｍ，２Ｈ），３．４－３．６（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．６６（ｓ，２Ｈ），３．９１（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），３．９５（ｄ，１Ｈ，Ｊ＝１１Ｈｚ），５．５２（ｂｒ　ｓ，１Ｈ），６．９６（ｓ，１Ｈ），７．３７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．１－８．２（ｍ，１Ｈ），８．２－８．３（ｍ，１Ｈ）．
ＭＳ：４８６．０９［Ｍ＋Ｈ］＋ Example 162
N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide
Figure JPOXMLDOC01-appb-C000328
(3- (Trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) carbamate tert- synthesized in Reference Example 71 according to the same method as in Example 3. A crude compound (58 mg) of 3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine was synthesized from butyl (145 mg, 0.36 mmol). Part of a crude compound of 3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (29 mg) and 2- (4- (trifluoromethyl)) The title compound (white amorphous, 25 mg, 51%) was obtained using phenyl) acetic acid (30 mg, 0.15 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 2.5-2.7 (m, 2H), 3.4-3.6 (t, 2H, J = 7 Hz), 3.66 (s, 2H) , 3.91 (d, 1H, J = 11Hz), 3.95 (d, 1H, J = 11Hz), 5.52 (br s, 1H), 6.96 (s, 1H), 7.37 ( d, 2H, J = 8Hz), 7.62 (d, 2H, J = 8Hz), 8.1-8.2 (m, 1H), 8.2-8.3 (m, 1H).
MS: 486.09 [M + H] +
実施例１６３
（Ｒ）－２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000329
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）酢酸（２８ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，３０ｍｇ，５７％）を得た。
１Ｈ　ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２－３．３（ｍ，１Ｈ），３．３－３．５（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．６６（ｓ，２Ｈ），４．４－４．６（ｍ，１Ｈ），７．１１（ｓ，１Ｈ），７．３８（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．７－７．８（ｍ，２Ｈ），８．０４（ｓ，１Ｈ），８．０７（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．２Ｈ分観測できず
ＭＳ：３９１．１１［Ｍ＋Ｈ］＋ Example 163
(R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide
Figure JPOXMLDOC01-appb-C000329
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (white crystals, 30 mg, 57%) was obtained using 2- (1H-benzo [d] [1,2,3] triazole-5-yl) acetic acid (28 mg, 0.16 mmol).
1 1 H NMR (CD 3 OD, 400 MHz): δ = 2.0-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.3 (m, 1H) ), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.66 (s, 2H), 4.4-4.6 (m, 1H), 7.11 (s, 1H), 7.38 (d, 1H, J = 9Hz), 7.7-7.8 (m, 2H), 8.04 (s, 1H), 8.07 (d, 1H, J = 3Hz). Unable to observe for 2 hours MS: 391.11 [M + H] +
実施例１６４
（Ｒ）－２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000330
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３０ｍｇ，０．１３ｍｍｏｌ）及び２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）酢酸（２８ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，２０ｍｇ，３７％）を得た。
１Ｈ　ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）：δ＝２．０－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２－３．３（ｍ，１Ｈ），３．４－３．６（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．６６（ｓ，２Ｈ），４．４－４．６（ｍ，１Ｈ），７．０１（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．３８（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．５２（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．７－７．８（ｍ，２Ｈ），７．９３（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．２Ｈ分観測できず
ＭＳ：３９１．１１［Ｍ＋Ｈ］＋ Example 164
(R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide
Figure JPOXMLDOC01-appb-C000330
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (30 mg, 0.13 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 The title compound (white crystals, 20 mg, 37%) was obtained using 2- (1H-benzo [d] [1,2,3] triazole-5-yl) acetic acid (28 mg, 0.16 mmol).
1 1 H NMR (CD 3 OD, 400 MHz): δ = 2.0-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.3 (m, 1H) ), 3.4-3.6 (m, 2H), 3.6-3.7 (m, 1H), 3.66 (s, 2H), 4.4-4.6 (m, 1H), 7.01 (dd, 1H, J = 3,9Hz), 7.38 (d, 1H, J = 8Hz), 7.52 (d, 1H, J = 9Hz), 7.7-7.8 (m) , 2H), 7.93 (d, 1H, J = 3Hz). Unable to observe for 2 hours MS: 391.11 [M + H] +
実施例１６５
２－（４－（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000331
実施例３８と同様の手法に従い、４－ブロモフェニル酢酸エチル（１０９ｍｇ，０．４５ｍｍｏｌ）及び２－オキサ－５－アザビシクロ［２．２．１］ヘプタン塩酸塩（９１ｍｇ，０．６７ｍｍｏｌ）を用いて、２－（４－（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）酢酸エチルの粗体（１０６ｍｇ）を合成し、続いて、実施例１５５と同様の手法に従い、上記で得た２－（４－（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）酢酸エチルの粗体（１０６ｍｇ）から２－（４－（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）酢酸の粗体（白色結晶，８８ｍｇ）を得た。続いて、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４４ｍｇ，０．１９ｍｍｏｌ）及び上記で合成した２－（４－（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）酢酸の粗体の一部（４４ｍｇ）を用いて表題化合物のジアステレオマーＡ（淡黄色アモルファス，４１ｍｇ，４７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．１（ｍ，３Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，２Ｈ），３．３６（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４９（ｓ，２Ｈ），３．５４（ｄ，１Ｈ，Ｊ＝９Ｈｚ），３．６－３．７（ｍ，１Ｈ），３．８－３．９（ｍ，２Ｈ），４．３８（ｓ，１Ｈ），４．５－４．７（ｍ，１Ｈ），４．６５（ｓ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．５４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），６．９０（ｓ，１Ｈ），７．０７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０７（ｓ，１Ｈ），８．１９（ｓ，１Ｈ）．
ＭＳ：４４７．１７［Ｍ＋Ｈ］＋ Example 165
2- (4- (2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-3) Il) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000331
Following the same procedure as in Example 38, using ethyl 4-bromophenylacetate (109 mg, 0.45 mmol) and 2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride (91 mg, 0.67 mmol). , 2- (4- (2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) ethyl acetate crude (106 mg) was synthesized, followed by the same as in Example 155. According to the procedure, the crude (106 mg) to 2- (4- (4- (4- (2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) ethyl acetate obtained above A crude (white crystals, 88 mg) of 2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) acetic acid was obtained. Subsequently, (R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (44 mg, 0.19 mmol) synthesized in Reference Example 1-2 and 2- synthesized above. Diastereomer A (pale yellow amorphous) of the title compound using a portion (44 mg) of a crude of (4- (2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) acetic acid. , 41 mg, 47%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.1 (m, 3H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 2H) , 3.36 (t, 2H, J = 7Hz), 3.49 (s, 2H), 3.54 (d, 1H, J = 9Hz), 3.6-3.7 (m, 1H), 3 .8-3.9 (m, 2H), 4.38 (s, 1H), 4.5-4.7 (m, 1H), 4.65 (s, 1H), 5.5-5.7 (M, 1H), 6.54 (d, 2H, J = 8Hz), 6.90 (s, 1H), 7.07 (d, 2H, J = 8Hz), 8.07 (s, 1H), 8.19 (s, 1H).
MS: 447.17 [M + H] +
実施例１６６
２－（４－（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000332
実施例１６５と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（４４ｍｇ，０．１９ｍｍｏｌ）及び実施例１６５で合成した２－（４－（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）酢酸の粗体の一部（４４ｍｇ）を用いて表題化合物のジアステレオマーＡ（淡黄色結晶，４１ｍｇ，４７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．１（ｍ，３Ｈ），２．２－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，２Ｈ），３．３８（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４９（ｓ，２Ｈ），３．５５（ｄ，１Ｈ，Ｊ＝９Ｈｚ），３．６－３．７（ｍ，１Ｈ），３．８－３．９（ｍ，２Ｈ），４．３８（ｓ，１Ｈ），４．５－４．７（ｍ，１Ｈ），４．６５（ｓ，１Ｈ），５．５－５．７（ｍ，１Ｈ），６．５４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），６．７－６．９（ｍ，１Ｈ），７．０７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．９－８．０（ｍ，１Ｈ）．
ＭＳ：４４７．１５［Ｍ＋Ｈ］＋ Example 166
2- (4- (2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000332
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (44 mg, 0.19 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 165. Part of the crude of 2- (4- (2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) acetic acid synthesized in Example 165 (44 mg) of the title compound. Diastereomer A (pale yellow crystals, 41 mg, 47%) was obtained.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.1 (m, 3H), 2.2-2.4 (m, 1H), 3.1-3.2 (m, 2H) , 3.38 (t, 2H, J = 7Hz), 3.49 (s, 2H), 3.55 (d, 1H, J = 9Hz), 3.6-3.7 (m, 1H), 3 .8-3.9 (m, 2H), 4.38 (s, 1H), 4.5-4.7 (m, 1H), 4.65 (s, 1H), 5.5-5.7 (M, 1H), 6.54 (d, 2H, J = 8Hz), 6.7-6.9 (m, 1H), 7.07 (d, 2H, J = 8Hz), 7.47 (d) , 1H, J = 8Hz), 7.9-8.0 (m, 1H).
MS: 447.15 [M + H] +
実施例１６７
（Ｒ）－２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000333
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３５ｍｇ，０．１５ｍｍｏｌ）及び２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）酢酸（３０ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（黄色アモルファス，３９ｍｇ，６４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１－３．２（ｍ，１Ｈ），３．２－３．４（ｍ，２Ｈ），３．５－３．７（ｍ，１Ｈ），３．３７（ｓ，２Ｈ），４．２７（ｓ，３Ｈ），４．６－４．７（ｍ，１Ｈ），６．４８（ｂｒ　ｓ，１Ｈ），６．７８（ｓ，１Ｈ），７．４７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．５０（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．８８（ｓ，１Ｈ），７．９６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１０（ｓ，１Ｈ）．
ＭＳ：４０５．１２［Ｍ＋Ｈ］＋ Example 167
(R) -2- (1-Methyl-1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) Pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000333
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 1-2 and according to the same procedure as in Example 1. The title compound (yellow amorphous, 39 mg, 64%) was obtained using 2- (1-methyl-1H-benzo [d] [1,2,3] triazole-5-yl) acetic acid (30 mg, 0.16 mmol). It was.
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.1-3.2 (m, 1H) , 3.2-3.4 (m, 2H), 3.5-3.7 (m, 1H), 3.37 (s, 2H), 4.27 (s, 3H), 4.6-4 .7 (m, 1H), 6.48 (br s, 1H), 6.78 (s, 1H), 7.47 (d, 1H, J = 9Hz), 7.50 (d, 1H, J = 9Hz), 7.88 (s, 1H), 7.96 (d, 1H, J = 3Hz), 8.10 (s, 1H).
MS: 405.12 [M + H] +
実施例１６８
（Ｒ）－２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000334
実施例１と同様の手法に従い、参考例３２－２で合成した（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（３５ｍｇ，０．１５ｍｍｏｌ）及び２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）酢酸（３０ｍｇ，０．１６ｍｍｏｌ）を用いて表題化合物（白色結晶，８ｍｇ，１３％）を得た。
１Ｈ　ＮＭＲ（ＣＤ３ＯＤ，４００ＭＨｚ）：δ＝２．０－２．２（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．２－３．４（ｍ，１Ｈ），３．４－３．６（ｍ，２Ｈ），３．６－３．７（ｍ，１Ｈ），３．７０（ｓ，２Ｈ），４．３２（ｓ，３Ｈ），４．４－４．６（ｍ，１Ｈ），７．０４（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．５２（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），７．５６（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．６９（ｄ，１Ｈ，Ｊ＝８Ｈｚ），７．８８（ｓ，１Ｈ），７．９６（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．１Ｈ分観測できず
ＭＳ：４０５．１２［Ｍ＋Ｈ］＋ Example 168
(R) -2- (1-Methyl-1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000334
(R) -1- (6- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (35 mg, 0.15 mmol) synthesized in Reference Example 32-2 and the same procedure as in Example 1 The title compound (white crystals, 8 mg, 13%) was obtained using 2- (1-methyl-1H-benzo [d] [1,2,3] triazole-5-yl) acetic acid (30 mg, 0.16 mmol). It was.
1 1 H NMR (CD 3 OD, 400 MHz): δ = 2.0-2.2 (m, 1H), 2.2-2.4 (m, 1H), 3.2-3.4 (m, 1H) ), 3.4-3.6 (m, 2H), 3.6-3.7 (m, 1H), 3.70 (s, 2H), 4.32 (s, 3H), 4.4- 4.6 (m, 1H), 7.04 (dd, 1H, J = 3.9Hz), 7.52 (dd, 1H, J = 1.8Hz), 7.56 (d, 1H, J = 8Hz) ), 7.69 (d, 1H, J = 8Hz), 7.88 (s, 1H), 7.96 (d, 1H, J = 3Hz). Cannot observe for 1H MS: 405.12 [M + H] +
実施例１６９
２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）フェニル）アゼチジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000335
実施例９と同様の手法に従い、参考例７５－２で合成したＮ－（アゼチジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド（４０ｍｇ，０．１７ｍｍｏｌ）及び１－ブロモ－４－（トリフルオロメチル）ベンゼン（２９μＬ，０．２１ｍｍｏｌ）を用いて表題化合物（淡黄色固体，３３ｍｇ，５０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．１（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），３．５－３．７（ｍ，４Ｈ），４．２３（ｔ，２Ｈ，Ｊ＝８Ｈｚ），４．７－４．９（ｍ，１Ｈ），５．７８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．３９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．０６（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４２（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．　
ＭＳ：３９７．１２［Ｍ＋Ｎａ］＋ Example 169
2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) phenyl) azetidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000335
N- (azetidine-3-yl) -2- (4-cyclopropylphenyl) acetamide (40 mg, 0.17 mmol) and 1-bromo-4 synthesized in Reference Example 75-2 according to the same procedure as in Example 9. -(Trifluoromethyl) benzene (29 μL, 0.21 mmol) was used to give the title compound (pale yellow solid, 33 mg, 50%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 1H) , 3.5-3.7 (m, 4H), 4.23 (t, 2H, J = 8Hz), 4.7-4.9 (m, 1H), 5.78 (d, 1H, J = 7Hz), 6.39 (d, 2H, J = 8Hz), 7.06 (d, 2H, J = 8Hz), 7.13 (d, 2H, J = 8Hz), 7.42 (d, 2H, J = 8Hz).
MS: 397.12 [M + Na] +
実施例１７０
２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）アゼチジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000336
実施例９と同様の手法に従い、参考例７５－２で合成したＮ－（アゼチジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド（４０ｍｇ，０．１７ｍｍｏｌ）及び４－ブロモ－１－フルオロ－２－（トリフルオロメチル）ベンゼン（２９μＬ，０．２１ｍｍｏｌ）を用いて表題化合物（淡黄色固体，２７ｍｇ，３８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．１（ｍ，２Ｈ），１．８－２．０（ｍ，１Ｈ），３．４－３．７（ｍ，４Ｈ），４．１６（ｔ，２Ｈ，Ｊ＝８Ｈｚ），４．７－４．９（ｍ，１Ｈ），５．７８（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．３－６．６（ｍ，２Ｈ），６．９－７．２（ｍ，５Ｈ）．
ＭＳ：４１５．１１［Ｍ＋Ｎａ］＋ Example 170
2- (4-Cyclopropylphenyl) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) azetidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000336
N- (azetidine-3-yl) -2- (4-cyclopropylphenyl) acetamide (40 mg, 0.17 mmol) and 4-bromo-1 synthesized in Reference Example 75-2 according to the same procedure as in Example 9. -Fluoro-2- (trifluoromethyl) benzene (29 μL, 0.21 mmol) was used to give the title compound (pale yellow solid, 27 mg, 38%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 1H) , 3.4-3.7 (m, 4H), 4.16 (t, 2H, J = 8Hz), 4.7-4.9 (m, 1H), 5.78 (d, 1H, J = 6Hz), 6.3-6.6 (m, 2H), 6.9-7.2 (m, 5H).
MS: 415.11 [M + Na] +
実施例１７１
（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000337
実施例１と同様の手法に従い、参考例１－２で合成した（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－アミン（５２ｍｇ，０．２２ｍｍｏｌ）及び２－（４－ブロモフェニル）酢酸（６０ｍｇ，０．２８ｍｍｏｌ）を用いて表題化合物（白色固体，１００ｍｇ，１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３６（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．５２（ｓ，２Ｈ），３．６２（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．６－４．７（ｍ，１Ｈ），６．２２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．８－６．９（ｍ，１Ｈ），７．１４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４６（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．９８（ｄ，１Ｈ，Ｊ＝３Ｈｚ），８．１３（ｓ，１Ｈ）．
ＭＳ：４２８．０２［Ｍ＋Ｈ］＋ Example 171
(R) -2- (4-Bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000337
(R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-amine (52 mg, 0.22 mmol) synthesized in Reference Example 1-2 and the same procedure as in Example 1 and The title compound (white solid, 100 mg, 100%) was obtained using 2- (4-bromophenyl) acetic acid (60 mg, 0.28 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.2-2.4 (m, 1H), 3.14 (dd, 1H, J = 4, 10Hz), 3.36 (t, 2H, J = 7Hz), 3.52 (s, 2H), 3.62 (dd, 1H, J = 6,10Hz), 4.6-4.7 (m, 1H), 6.22 (d, 1H, J = 7Hz), 6.8-6.9 (m, 1H), 7.14 (d, 2H, J = 8Hz), 7.46 (d, 2H, J = 8Hz), 7.98 (d, 1H, J = 3Hz), 8.13 (s, 1H).
MS: 428.02 [M + H] +
実施例１７２
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000338
参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（４９ｍｇ，０．２０ｍｍｏｌ）をＤＭＦ（１．０ｍＬ）に溶解した後、２－クロロ－６－フルオロベンゾ［ｄ］チアゾール（４５ｍｇ，０．２４ｍｍｏｌ）及び炭酸セシウム（７８ｍｇ，０．２４ｍｍｏｌ）を加えて１００℃で２時間撹拌した。室温まで放冷した反応液に飽和炭酸水素ナトリウムを加えた後、クロロホルムで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：５０－１００％）により精製し表題化合物（白色固体，６０ｍｇ，７１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．３１（ｄｄ，１Ｈ，Ｊ＝５，１１Ｈｚ），３．５－３．７（ｍ，２Ｈ），３．５３（ｓ，２Ｈ），３．８２（ｄｄ，１Ｈ，Ｊ＝７，１１Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．４８（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．９－７．１（ｍ，３Ｈ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．３１（ｄｄ，１Ｈ，Ｊ＝３，８Ｈｚ），７．４８（ｄｄ，１Ｈ，Ｊ＝５，９Ｈｚ）．
ＭＳ：３９６．１３［Ｍ＋Ｈ］＋ Example 172
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000338
After dissolving (R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) synthesized in Reference Example 74-2 in DMF (1.0 mL). , 2-Chloro-6-fluorobenzo [d] thiazole (45 mg, 0.24 mmol) and cesium carbonate (78 mg, 0.24 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction solution allowed to cool to room temperature, and the mixture was extracted with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 50-100%) to give the title compound (white solid, 60 mg, 71%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.31 (dd, 1H, J = 5,11Hz), 3.5-3.7 (m, 2H), 3.53 (s, 2H) , 3.82 (dd, 1H, J = 7,11Hz), 4.5-4.7 (m, 1H), 5.48 (d, 1H, J = 7Hz), 6.9-7.1 ( m, 3H), 7.11 (d, 2H, J = 8Hz), 7.31 (dd, 1H, J = 3.8Hz), 7.48 (dd, 1H, J = 5,9Hz).
MS: 396.13 [M + H] +
実施例１７３
（Ｒ）－Ｎ－（１－（５－ブロモチアゾール－２－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000339
実施例１７２と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（４９ｍｇ，０．２０ｍｍｏｌ）及び２，５－ジブロモチアゾール（５８ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（淡黄色固体，２６ｍｇ，３２％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．１６（ｄｄ，１Ｈ，Ｊ＝５，１１Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５２（ｓ，２Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．４６（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．０－７．１（ｍ，３Ｈ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：４２８．０２［Ｍ＋Ｎａ］＋ Example 173
(R) -N- (1- (5-bromothiazole-2-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000339
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 172. , 5-Dibromothiazole (58 mg, 0.24 mmol) was used to give the title compound (pale yellow solid, 26 mg, 32%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.16 (dd, 1H, J = 5,11Hz), 3.3-3.5 (m, 2H), 3.52 (s, 2H) , 3.67 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.46 (d, 1H, J = 7Hz), 7.0-7.1 ( m, 3H), 7.11 (d, 2H, J = 8Hz).
MS: 428.02 [M + Na] +
実施例１７４
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000340
実施例９と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（７３ｍｇ，０．３０ｍｍｏｌ）及び４－ブロモ－１－フルオロ－２－（トリフルオロメチル）ベンゼン（５１μＬ，０．３６ｍｍｏｌ）を用いて表題化合物（白色固体，１０２ｍｇ，８４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．１（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．０４（ｄｄ，１Ｈ，Ｊ＝４，９Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．４－３．６（ｍ，１Ｈ），３．５２（ｓ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．５０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．５－６．７（ｍ，２Ｈ），６．９－７．２（ｍ，５Ｈ）．
ＭＳ：４０７．１６［Ｍ＋Ｈ］＋ Example 174
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000340
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (73 mg, 0.30 mmol) and 4 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. -Bromo-1-fluoro-2- (trifluoromethyl) benzene (51 μL, 0.36 mmol) was used to give the title compound (white solid, 102 mg, 84%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.04 (dd, 1H, J = 4.9Hz), 3.2-3.4 (m, 2H), 3.4-3.6 ( m, 1H), 3.52 (s, 2H), 4.5-4.7 (m, 1H), 5.50 (d, 1H, J = 7Hz), 6.5-6.7 (m, 2H), 6.9-7.2 (m, 5H).
MS: 407.16 [M + H] +
実施例１７５
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－メトキシフェニル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000341
実施例９と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（２４４ｍｇ，１．０ｍｍｏｌ）及び１－ブロモ－３－メトキシベンゼン（１５２μＬ，１．２ｍｍｏｌ）を用いて表題化合物（白色固体，２０３ｍｇ，５８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．７－１．９（ｍ，２Ｈ），２．１－２．３（ｍ，１Ｈ），３．０５（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．２－３．４（ｍ，２Ｈ），３．５－３．６（ｍ，３Ｈ），３．５１（ｓ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．５３（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．０７（ｔ，１Ｈ，Ｊ＝２Ｈｚ），６．１５（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ），６．２８（ｄｄ，１Ｈ，Ｊ＝２，８Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．０－７．２（ｍ，３Ｈ）．
ＭＳ：３５１．１９［Ｍ＋Ｈ］＋ Example 175
(R) -2- (4-Cyclopropylphenyl) -N- (1- (3-methoxyphenyl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000341
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (244 mg, 1.0 mmol) and 1 synthesized in Reference Example 74-2 according to the same procedure as in Example 9. -Bromo-3-methoxybenzene (152 μL, 1.2 mmol) was used to give the title compound (white solid, 203 mg, 58%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.7-1.9 (m, 2H) , 2.1-2.3 (m, 1H), 3.05 (dd, 1H, J = 4,10Hz), 3.2-3.4 (m, 2H), 3.5-3.6 ( m, 3H), 3.51 (s, 3H), 4.5-4.7 (m, 1H), 5.53 (d, 1H, J = 7Hz), 6.07 (t, 1H, J = 2Hz), 6.15 (dd, 1H, J = 1.8Hz), 6.28 (dd, 1H, J = 2.8Hz), 7.03 (d, 2H, J = 8Hz), 7.0- 7.2 (m, 3H).
MS: 351.19 [M + H] +
実施例１７６
（Ｒ）－２－（４－（３，３－ジフルオロピロリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000342
実施例９と同様の手法に従い、実施例１７１で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（４３ｍｇ，０．１０ｍｍｏｌ）及び３，３－ジフルオロピロリジン塩酸塩（１７ｍｇ，０．１２ｍｍｏｌ）を用いて表題化合物（白色固体，１１ｍｇ，２４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），２．４－２．６（ｍ，２Ｈ），３．１０（ｄｄ，１Ｈ，Ｊ＝５，１０Ｈｚ），３．３６（ｔ，２Ｈ，Ｊ＝７Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．６－３．８（ｍ，３Ｈ），４．５－４．７（ｍ，１Ｈ），５．５２（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．５２（ｄ，２Ｈ，Ｊ＝９Ｈｚ），６．９０（ｓ，１Ｈ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０７（ｓ，１Ｈ），８．２０（ｓ，１Ｈ）．
ＭＳ：４５５．１５［Ｍ＋Ｈ］＋ Example 176
(R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000342
(R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (43 mg, 0.10 mmol) and 3,3-difluoropyrrolidine hydrochloride (17 mg, 0.12 mmol) were used to give the title compound (white solid, 11 mg, 24%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.4-2.6 (m, 2H) , 3.10 (dd, 1H, J = 5,10Hz), 3.36 (t, 2H, J = 7Hz), 3.4-3.6 (m, 4H), 3.6-3.8 ( m, 3H), 4.5-4.7 (m, 1H), 5.52 (d, 1H, J = 7Hz), 6.52 (d, 2H, J = 9Hz), 6.90 (s, 1H), 7.11 (d, 2H, J = 8Hz), 8.07 (s, 1H), 8.20 (s, 1H).
MS: 455.15 [M + H] +
実施例１７７
（Ｒ）－２－（３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）フェノキシ）－２－メチルプロパン酸エチル
Figure JPOXMLDOC01-appb-C000343
実施例９と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（９８ｍｇ，０．４０ｍｍｏｌ）及び参考例７６で合成した２－（３－ブロモフェノキシ）－２－メチルプロパン酸エチル（１３８ｍｇ，０．４８ｍｍｏｌ）を用いて表題化合物（白色固体，４３ｍｇ，２４％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．２５（ｔ，３Ｈ，Ｊ＝７Ｈｚ），１．５９（ｓ，６Ｈ），１．７－２．０（ｍ，２Ｈ），２．１－２．３（ｍ，１Ｈ），３．０１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．１－３．４（ｍ，２Ｈ），３．４－３．６（ｍ，３Ｈ），４．２２（ｄｄ，２Ｈ，Ｊ＝７，１５Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５５（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．０－６．１（ｍ，１Ｈ），６．１－６．２（ｍ，２Ｈ），７．０－７．１（ｍ，３Ｈ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：４５１．２２［Ｍ＋Ｈ］＋ Example 177
Ethyl (R) -2- (3- (3- (2- (4-cyclopropylphenyl) acetamide) pyrrolidine-1-yl) phenoxy) -2-methylpropanoate
Figure JPOXMLDOC01-appb-C000343
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide synthesized in Reference Example 74-2 and reference (98 mg, 0.40 mmol) according to the same procedure as in Example 9. Ethyl 2- (3-bromophenoxy) -2-methylpropanoate (138 mg, 0.48 mmol) synthesized in Example 76 was used to give the title compound (white solid, 43 mg, 24%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.0 (m, 2H), 1.25 (t, 3H, J = 7 Hz) , 1.59 (s, 6H), 1.7-2.0 (m, 2H), 2.1-2.3 (m, 1H), 3.01 (dd, 1H, J = 4,10Hz) , 3.1-3.4 (m, 2H), 3.4-3.6 (m, 3H), 4.22 (dd, 2H, J = 7,15Hz), 4.5-4.7 ( m, 1H), 5.55 (d, 1H, J = 7Hz), 6.0-6.1 (m, 1H), 6.1-6.2 (m, 2H), 7.0-7. 1 (m, 3H), 7.11 (d, 2H, J = 8Hz).
MS: 451.22 [M + H] +
実施例１７８
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－ヒドロキシフェニル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000344
実施例１７５で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－メトキシフェニル）ピロリジン－３－イル）アセトアミド（３５ｍｇ，０．１０ｍｍｏｌ）にピリジン塩酸塩（５００ｍｇ）を加えて１５０℃で３時間加熱した。室温まで放冷した反応液に飽和炭酸水素ナトリウムを加えた後、酢酸エチルで抽出した。分離した有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘプタン：酢酸エチル）（濃度勾配：５０－１００％）により精製し表題化合物（白色固体，２６ｍｇ，７７％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５－２．０（ｍ，５Ｈ），２．１－２．３（ｍ，１Ｈ），３．０４（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．１－３．４（ｍ，２Ｈ），３．４－３．６（ｍ，３Ｈ），４．５－４．７（ｍ，１Ｈ），４．８－５．０（ｍ，１Ｈ），５．５４（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．０－６．４（ｍ，４Ｈ），７．０－７．２（ｍ，３Ｈ），７．２９（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：３３７．１７［Ｍ＋Ｈ］＋ Example 178
(R) -2- (4-Cyclopropylphenyl) -N- (1- (3-hydroxyphenyl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000344
Pyridine hydrochloride (35 mg, 0.10 mmol) to (R) -2- (4-cyclopropylphenyl) -N- (1- (3-methoxyphenyl) pyrrolidine-3-yl) acetamide synthesized in Example 175 ( 500 mg) was added and heated at 150 ° C. for 3 hours. Saturated sodium hydrogen carbonate was added to the reaction solution allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the insoluble matter was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (heptane: ethyl acetate) (concentration gradient: 50-100%) to give the title compound (white solid, 26 mg, 77%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.5-2.0 (m, 5H), 2.1-2.3 (m, 1H), 3.04 (dd, 1H, J = 4, 10Hz), 3.1-3.4 (m, 2H), 3.4-3.6 (m, 3H), 4.5-4.7 (m, 1H), 4.8-5.0 ( m, 1H), 5.54 (d, 1H, J = 7Hz), 6.0-6.4 (m, 4H), 7.0-7.2 (m, 3H), 7.29 (d, 2H, J = 8Hz).
MS: 337.17 [M + H] +
実施例１７９
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000345
実施例１７２と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（４９ｍｇ，０．２０ｍｍｏｌ）及び２－クロロ－６－（トリフルオロメチル）ピリジン（４４ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（淡黄色固体，２１ｍｇ，２６％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．２４（ｄｄ，１Ｈ，Ｊ＝５，１１Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７６（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．６０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），６．４５（ｄ，１Ｈ，Ｊ＝８Ｈｚ），６．９０（ｄ，１Ｈ，Ｊ＝７Ｈｚ），７．０２（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．５３（ｔ，１Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：４１２．１３［Ｍ＋Ｎａ］＋ Example 179
(R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000345
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 172. -Chloro-6- (trifluoromethyl) pyridine (44 mg, 0.24 mmol) was used to give the title compound (pale yellow solid, 21 mg, 26%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.24 (dd, 1H, J = 5,11Hz), 3.4-3.6 (m, 4H), 3.76 (dd, 1H, J = 6,11Hz), 4.5-4.7 (m, 1H), 5.60 (d, 1H, J = 7Hz), 6.45 (d, 1H, J = 8Hz), 6.90 ( d, 1H, J = 7Hz), 7.02 (d, 2H, J = 8Hz), 7.10 (d, 2H, J = 8Hz), 7.53 (t, 1H, J = 8Hz).
MS: 421.13 [M + Na] +
実施例１８０
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４，６－ジメトキシピリミジン－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000346
実施例１７２と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（４９ｍｇ，０．２０ｍｍｏｌ）及び２－クロロ－４，６－ジメトキシピリジン（４４ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（白色固体，５６ｍｇ，７３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．８（ｍ，２Ｈ），０．９－１．１（ｍ，２Ｈ），１．７－２．０（ｍ，２Ｈ），２．１－２．３（ｍ，１Ｈ），３．２－３．４（ｍ，１Ｈ），３．５－３．７（ｍ，４Ｈ），３．７－３．９（ｍ，１Ｈ），３．８４（ｓ，６Ｈ），４．４－４．６（ｍ，１Ｈ），５．３７（ｓ，１Ｈ），５．５１（ｄ，１Ｈ，Ｊ＝５Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝７Ｈｚ）．
ＭＳ：４０５．１６［Ｍ＋Ｎａ］＋ Example 180
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4,6-dimethoxypyrimidine-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000346
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 172. -Chloro-4,6-dimethoxypyridine (44 mg, 0.24 mmol) was used to give the title compound (white solid, 56 mg, 73%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.8 (m, 2H), 0.9-1.1 (m, 2H), 1.7-2.0 (m, 2H) , 2.1-2.3 (m, 1H), 3.2-3.4 (m, 1H), 3.5-3.7 (m, 4H), 3.7-3.9 (m, 1H), 3.84 (s, 6H), 4.4-4.6 (m, 1H), 5.37 (s, 1H), 5.51 (d, 1H, J = 5Hz), 7.03 (D, 2H, J = 8Hz), 7.11 (d, 2H, J = 7Hz).
MS: 405.16 [M + Na] +
実施例１８１
（Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000347
実施例９と同様の手法に従い、実施例１７１で合成した（Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド（８６ｍｇ，０．２０ｍｍｏｌ）及びモルホリン（３５μＬ，０．４０ｍｍｏｌ）を用いて表題化合物（白色固体，１２ｍｇ，１３％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．０－３．２（ｍ，５Ｈ），３．３７（ｔ，２Ｈ，Ｊ＝７Ｈｚ）．３．５１（ｓ，２Ｈ），３．６５（ｄｄ，１Ｈ，Ｊ＝７，１０Ｈｚ），３．８－３．９（ｍ，４Ｈ），４．５－４．７（ｍ，１Ｈ），５．４－５．６（ｍ，１Ｈ），６．８－７．０（ｍ，３Ｈ），７．１４（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．０７（ｄ，１Ｈ，Ｊ＝２Ｈｚ），８．２０（ｓ，１Ｈ）．
ＭＳ：４３５．１７［Ｍ＋Ｈ］＋ Example 181
(R) -2- (4-morpholinophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000347
(R) -2- (4-bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3 synthesized in Example 171 according to the same procedure as in Example 9 -Il) Acetamide (86 mg, 0.20 mmol) and morpholine (35 μL, 0.40 mmol) were used to give the title compound (white solid, 12 mg, 13%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.0-3.2 (m, 5H) , 3.37 (t, 2H, J = 7Hz). 3.51 (s, 2H), 3.65 (dd, 1H, J = 7,10Hz), 3.8-3.9 (m, 4H), 4.5-4.7 (m, 1H), 5.4-5.6 (m, 1H), 6.8-7.0 (m, 3H), 7.14 (d, 2H, J = 8Hz), 8.07 (d, 1H, J = 2Hz) ), 8.20 (s, 1H).
MS: 435.17 [M + H] +
実施例１８２
（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000348
実施例１７２と同様の手法に従い、参考例７４－２で合成した（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（ピロリジン－３－イル）アセトアミド（４９ｍｇ，０．２０ｍｍｏｌ）及び２－クロロ－４－（トリフルオロメチル）ピリジン（４４ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（白色固体，４０ｍｇ，５１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝０．６－０．７（ｍ，２Ｈ），０．９－１．０（ｍ，２Ｈ），１．８－２．０（ｍ，２Ｈ），２．２－２．４（ｍ，１Ｈ），３．２３（ｄｄ，１Ｈ，Ｊ＝５，１１Ｈｚ），３．４－３．６（ｍ，４Ｈ），３．７６（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．４９（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．４８（ｓ，１Ｈ），６．７３（ｄ，１Ｈ，Ｊ＝５Ｈｚ），７．０３（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．１１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），８．２５（ｄ，１Ｈ，Ｊ＝５Ｈｚ）．
ＭＳ：３９０．１４［Ｍ＋Ｈ］＋ Example 182
(R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) pyridin-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000348
(R) -2- (4-cyclopropylphenyl) -N- (pyrrolidin-3-yl) acetamide (49 mg, 0.20 mmol) and 2 synthesized in Reference Example 74-2 according to the same procedure as in Example 172. -Chloro-4- (trifluoromethyl) pyridine (44 mg, 0.24 mmol) was used to give the title compound (white solid, 40 mg, 51%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 0.6-0.7 (m, 2H), 0.9-1.0 (m, 2H), 1.8-2.0 (m, 2H) , 2.2-2.4 (m, 1H), 3.23 (dd, 1H, J = 5,11Hz), 3.4-3.6 (m, 4H), 3.76 (dd, 1H, J = 6,10Hz), 4.5-4.7 (m, 1H), 5.49 (d, 1H, J = 6Hz), 6.48 (s, 1H), 6.73 (d, 1H, J = 5Hz), 7.03 (d, 2H, J = 8Hz), 7.11 (d, 2H, J = 8Hz), 8.25 (d, 1H, J = 5Hz).
MS: 390.14 [M + H] +
実施例１８３
（Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000349
実施例９と同様の手法に従い、参考例７３－２で合成した（Ｒ）－Ｎ－（ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド（５５ｍｇ，０．２０ｍｍｏｌ）及び５－ブロモ－２－（トリフルオロメチル）ピリジン（５４ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（淡黄色固体，２４ｍｇ，２９％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．９－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．１９（ｄｄ，１Ｈ，Ｊ＝４，１１Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．６２（ｓ，２Ｈ），３．６７（ｄｄ，１Ｈ，Ｊ＝６，８Ｈｚ），４．６－４．７（ｍ，１Ｈ），５．７０（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．７９（ｄｄ，１Ｈ，Ｊ＝３，９Ｈｚ），７．４０（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．４７（ｄ，１Ｈ，Ｊ＝９Ｈｚ），７．６１（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．９５（ｄ，１Ｈ，Ｊ＝２Ｈｚ）．
ＭＳ：４１８．１１［Ｍ＋Ｈ］＋ Example 183
(R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000349
(R) -N- (pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide (55 mg, 0.20 mmol) synthesized in Reference Example 73-2 according to the same procedure as in Example 9. ) And 5-bromo-2- (trifluoromethyl) pyridine (54 mg, 0.24 mmol) were used to give the title compound (pale yellow solid, 24 mg, 29%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.9-2.1 (m, 1H), 2.3-2.5 (m, 1H), 3.19 (dd, 1H, J = 4, 11Hz), 3.3-3.5 (m, 2H), 3.62 (s, 2H), 3.67 (dd, 1H, J = 6.8Hz), 4.6-4.7 (m, 1H), 5.70 (d, 1H, J = 6Hz), 6.79 (dd, 1H, J = 3.9Hz), 7.40 (d, 2H, J = 8Hz), 7.47 (d, 1H, J = 9Hz), 7.61 (d, 2H, J = 8Hz), 7.95 (d, 1H, J = 2Hz).
MS: 418.11 [M + H] +
実施例１８４
（Ｒ）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド
Figure JPOXMLDOC01-appb-C000350
実施例９と同様の手法に従い、参考例７３－２で合成した（Ｒ）－Ｎ－（ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド（５５ｍｇ，０．２０ｍｍｏｌ）及び４－ブロモ－１－フルオロ－２－（トリフルオロメチル）ベンゼン（５８ｍｇ，０．２４ｍｍｏｌ）を用いて表題化合物（淡黄色固体，２２ｍｇ，２５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．８－２．０（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１１（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．２－３．５（ｍ，２Ｈ），３．５７（ｄｄ，１Ｈ，Ｊ＝６，１０Ｈｚ），３．６１（ｓ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．５６（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．５－６．７（ｍ，２Ｈ），７．０５（ｔ，１Ｈ，Ｊ＝９Ｈｚ），７．３９（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．６１（ｄ，２Ｈ，Ｊ＝８Ｈｚ）．
ＭＳ：４３５．１１［Ｍ＋Ｈ］＋ Example 184
(R) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide
Figure JPOXMLDOC01-appb-C000350
(R) -N- (pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide (55 mg, 0.20 mmol) synthesized in Reference Example 73-2 according to the same procedure as in Example 9. ) And 4-bromo-1-fluoro-2- (trifluoromethyl) benzene (58 mg, 0.24 mmol) were used to give the title compound (pale yellow solid, 22 mg, 25%).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.8-2.0 (m, 1H), 2.2-2.4 (m, 1H), 3.11 (dd, 1H, J = 4, 10Hz), 3.2-3.5 (m, 2H), 3.57 (dd, 1H, J = 6,10Hz), 3.61 (s, 2H), 4.5-4.7 (m, 1H), 5.56 (d, 1H, J = 6Hz), 6.5-6.7 (m, 2H), 7.05 (t, 1H, J = 9Hz), 7.39 (d, 2H, J = 8Hz), 7.61 (d, 2H, J = 8Hz).
MS: 435.11 [M + H] +
実施例１８５
２－（４－（トリフルオロメチル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド
Figure JPOXMLDOC01-appb-C000351
参考例７３－１で合成した（Ｒ）－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）ピロリジン－１－カルバミン酸ｔｅｒｔ－ブチル（１４９ｍｇ，０．４０ｍｍｏｌ）をＤＭＦ（２ｍＬ）に溶解し、水素化ナトリウム（６０％オイル，２４ｍｇ，０．６０ｍｍｏｌ）及びヨウ化メチル（３７μＬ，０．６０ｍｍｏｌ）を加え、室温で１時間撹拌した。得られた残渣に氷冷化で飽和炭酸水素ナトリウムを加えた後にクロロホルムで抽出した。分離した有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ過後、減圧下溶媒を留去して（３Ｒ）－３－（２－（４－トリフルオロメチル）フェニル）プロパンアミド）ピロリジン－１－カルバミン酸ｔｅｒｔ－ブチルの粗体を得た。その後、実施例３６と同様の手法に従い、得られた（３Ｒ）３－（２－（４－トリフルオロメチル）フェニル）プロパンアミド）ピロリジン－１－カルバミン酸ｔｅｒｔ－ブチルの粗体及び５－ブロモ－２－（トリフルオロメチル）ピリジン（９２ｍｇ，０．４１ｍｍｏｌ）を用いて表題化合物（白色固体，２５ｍｇ，３段階１５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．５３（ｄ，３Ｈ，Ｊ＝７Ｈｚ），１．９－２．１（ｍ，１Ｈ），２．３－２．５（ｍ，１Ｈ），３．０７（ｄｄ，１Ｈ，Ｊ＝４，１０Ｈｚ），３．３－３．５（ｍ，２Ｈ），３．５－３．７（ｍ，２Ｈ），４．５－４．７（ｍ，１Ｈ），５．６９（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．７５（ｄｄ，１Ｈ，Ｊ＝３，７Ｈｚ），７．３－７．５（ｍ，３Ｈ），７．５７（ｄ，２Ｈ，Ｊ＝８Ｈｚ），７．８９（ｄ，１Ｈ，Ｊ＝３Ｈｚ）．
ＭＳ：４５４．０９［Ｍ＋Ｎａ］＋ Example 185
2- (4- (Trifluoromethyl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide
Figure JPOXMLDOC01-appb-C000351
Tert-Butyl (149 mg, 0.40 mmol) of (R) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) pyrrolidine-1-carbamic acid synthesized in Reference Example 73-1 was added to DMF (2 mL). Sodium hydride (60% oil, 24 mg, 0.60 mmol) and methyl iodide (37 μL, 0.60 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate was added to the obtained residue by ice cooling, and then the mixture was extracted with chloroform. The separated organic layer is dried over anhydrous sodium sulfate, the insoluble matter is filtered, and the solvent is distilled off under reduced pressure to (3R) -3- (2- (4-trifluoromethyl) phenyl) propanamide) pyrrolidine-1. A crude product of tert-butyl carbamate was obtained. Then, according to the same procedure as in Example 36, the obtained crude product of tert-butyl (3R) 3- (2- (4-trifluoromethyl) phenyl) propanamide) pyrrolidine-1-carbamate and 5-bromo The title compound (white solid, 25 mg, 3 steps 15%) was obtained using -2- (trifluoromethyl) pyridine (92 mg, 0.41 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.53 (d, 3H, J = 7 Hz), 1.9-2.1 (m, 1H), 2.3-2.5 (m, 1H) , 3.07 (dd, 1H, J = 4,10Hz), 3.3-3.5 (m, 2H), 3.5-3.7 (m, 2H), 4.5-4.7 ( m, 1H), 5.69 (d, 1H, J = 6Hz), 6.75 (dd, 1H, J = 3,7Hz), 7.3-7.5 (m, 3H), 7.57 ( d, 2H, J = 8Hz), 7.89 (d, 1H, J = 3Hz).
MS: 454.09 [M + Na] +
実施例１８６
（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000352
実施例３と同様の手法に従い、参考例６６で合成した（Ｒ）－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）カルバミン酸ｔｅｒｔ－ブチル（７６ｍｇ，０．２１９ｍｍｏｌ）から（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－アミンの粗体（１６６ｍｇ）を合成し、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）シクロプロパン－１－カルボン酸（６６ｍｇ，０．３２９ｍｍｏｌ）を用いて表題化合物（白色粉末，７０ｍｇ，７４％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ＝１．４－１．６（ｍ，４Ｈ），１．７－１．９（ｍ，２Ｈ），２．２－２．５（ｍ，２Ｈ），２．８８（ｄｄ，１Ｈ，Ｊ＝９，１２Ｈｚ），２．９－３．１（ｍ，１Ｈ），３．６－３．９（ｍ，３Ｈ），７．０－７．２（ｍ，２Ｈ），７．３－７．６（ｍ，３Ｈ），８．２４（ｓ，１Ｈ），８．３７（ｄ，１Ｈ，Ｊ＝７Ｈｚ），８．５６（ｄ，１Ｈ，Ｊ＝３Ｈｚ），１２．４（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４３０．１８［Ｍ＋Ｈ］＋ Example 186
(1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide
Figure JPOXMLDOC01-appb-C000352
Tert-Butyl (R)-(1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-yl) carbamate synthesized in Reference Example 66 according to the same procedure as in Example 3 (76 mg, A crude compound (166 mg) of (R) -1- (5- (trifluoromethyl) pyridine-3-yl) piperidine-3-amine was synthesized from 0.219 mmol) to synthesize (1S, 2S) -2- (1H). The title compound (white powder, 70 mg, 74%) was obtained using -benzo [d] imidazol-2-yl) cyclopropan-1-carboxylic acid (66 mg, 0.329 mmol).
1 1 H NMR (DMSO-d 6 , 400 MHz): δ = 1.4-1.6 (m, 4H), 1.7-1.9 (m, 2H), 2.2-2.5 (m, 2H), 2.88 (dd, 1H, J = 9,12Hz), 2.9-3.1 (m, 1H), 3.6-3.9 (m, 3H), 7.0-7. 2 (m, 2H), 7.3-7.6 (m, 3H), 8.24 (s, 1H), 8.37 (d, 1H, J = 7Hz), 8.56 (d, 1H, J = 3 Hz), 12.4 (br s, 1H).
MS: 430.18 [M + H] +
実施例１８７
（Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド
Figure JPOXMLDOC01-appb-C000353
実施例１と同様の手法に従い、参考例１２－２で合成した（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－アミン（３８ｍｇ，０．１６０ｍｍｏｌ）及び２－（１Ｈ－インドール－６－イル）酢酸（３４ｍｇ，０．１９２ｍｍｏｌ）を用いて表題化合物（淡黄色粉末，３６ｍｇ，５８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）：δ＝１．７－１．９（ｍ，１Ｈ），２．２－２．４（ｍ，１Ｈ），３．１９（ｄｄ，１Ｈ，Ｊ＝５，１１Ｈｚ），３．３－３．６（ｍ，２Ｈ），３．６９（ｓ，２Ｈ），３．７２（ｄｄ，１Ｈ，Ｊ＝６，１１Ｈｚ），４．５－４．７（ｍ，１Ｈ），５．５９（ｄ，１Ｈ，Ｊ＝６Ｈｚ），６．５－６．６（ｍ，１Ｈ），６．８９（ｄ，１Ｈ，Ｊ＝１Ｈｚ），６．９５（ｄｄ，１Ｈ，Ｊ＝１，８Ｈｚ）７．２－７．３（ｍ，２Ｈ），７．６１（ｄ，１Ｈ，Ｊ＝８Ｈｚ），８．２５（ｂｒ　ｓ，１Ｈ）．
ＭＳ：４１７．０７［Ｍ＋Ｎａ］＋ Example 187
(R) -2- (1H-indole-6-yl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000353
(R) -1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-amine (38 mg, 0.160 mmol) synthesized in Reference Example 12-2 and the same procedure as in Example 1. The title compound (pale yellow powder, 36 mg, 58%) was obtained using 2- (1H-indole-6-yl) acetic acid (34 mg, 0.192 mmol).
1 1 H NMR (CDCl 3 , 400 MHz): δ = 1.7-1.9 (m, 1H), 2.2-2.4 (m, 1H), 3.19 (dd, 1H, J = 5, 11Hz), 3.3-3.6 (m, 2H), 3.69 (s, 2H), 3.72 (dd, 1H, J = 6,11Hz), 4.5-4.7 (m, 1H), 5.59 (d, 1H, J = 6Hz), 6.5-6.6 (m, 1H), 6.89 (d, 1H, J = 1Hz), 6.95 (dd, 1H, J = 1.8Hz) 7.2-7.3 (m, 2H), 7.61 (d, 1H, J = 8Hz), 8.25 (br s, 1H).
MS: 417.07 [M + Na] +
実施例１８８
薬理試験１
Ｔ型カルシウム阻害作用
（試験方法）
（１）ヒトＣａｖ３．２チャネル定常発現細胞の構築
　ヒトＣａｖ３．２チャネルＯＲＦ（Ｏｐｅｎ　Ｒｅａｄｉｎｇ　Ｆｒａｍｅ）遺伝子の５’側にＨｉｎｄＩＩＩサイト及びｋｏｚａｋ配列（ＧＣＣＡＣＣ）、３’側にＫｐｎＩサイトを付与した配列をｐｃＤＮＡ３．１（+）（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ　Ｓｃｉｅｎｔｉｆｉｃ＃Ｖ７９０－２０）に組み込み、ＦｕＧＥＮＥ（登録商標）ＨＤ　Ｔｒａｎｓｆｅｃｔｉｏｎ　Ｒｅａｇｅｎｔ（Ｐｒｏｍｅｇａ＃Ｅ２３１１）のプロトコールに従いＨＥＫ２９３細胞（ＡＴＣＣ　Ｎｏ．ＣＲＬ－１５７３）に導入した。 Example 188
Pharmacological test 1
T-type calcium inhibitory effect (test method)
(1) Construction of human Cav3.2 channel constant expression cells A sequence in which the HindIII site and the kozak sequence (GCCACC) are added to the 5'side of the human Cav3.2 channel ORF (Open Reading Frame) gene and the KpnI site is added to the 3'side. It was incorporated into pcDNA3.1 (+) (Thermo Fisher Scientific # V790-20) and introduced into HEK293 cells (ATCC No. CRL-1573) according to the FuGENE® HD Transfection Reagent (Promega # E2311) protocol.
（２）細胞内カルシウム濃度測定方法
　試験方法（１）により作製したヒトＣａｖ３．２チャネル定常発現細胞を９６穴プレートに播種した（培地は、１０％牛胎児血清（ＦＢＳ）を含む、ダルベッコ変法イーグル培地（ＤＭＥＭ）培地を用いた）。細胞を播種し３７℃，５％ＣＯ２条件下で４８時間培養した。その後、培地を除くため細胞をＡバッファーで洗浄した。各ウェルを、２２μｇのカルシウム蛍光指示薬Ｆｌｕｏ－４　ＡＭ（同仁化学研究所＃Ｆ３１１），２０μＬのＤＭＳＯ，１μＬの１０％Ｐｌｕｒｏｎｉｃ　Ｆ－１２７（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ　Ｓｃｉｅｎｔｉｆｉｃ＃Ｐ６８６６）及び４ｍＬのＡバッファーを混合して作製した蛍光色素溶液８０μＬで処理した。室温、遮光下で４５分間静置した後、溶液を完全に置換するため細胞をＢバッファーで洗浄した。ネガティブコントロールとして被検化合物の場合と同濃度のＤＭＳＯ、ポジティブコントロールとして既知の遮断薬ＲＱ－００３１１６５１を１μＭ及び被検化合物を、各々Ｂバッファーに含む形で、各ウェルに７０μＬ添加した。被検化合物は１００％ＤＭＳＯに溶解し、終濃度０．１％で添加した。そして細胞を室温、遮光下でさらに１５分間静置し、マイクロプレートリーダーＥｎＶｉｓｉｏｎ（パーキンエルマー社）に置いた。各ウェルでバックグラウンドの蛍光を測定した後、Ｂバッファー中に５μｇ／ｍLのグラミシジン溶液を１０μＬ／ウェルで添加した。９０秒後にベースラインの蛍光を測定した後、Ｂバッファー中に８３．８ｍＭ のＫＣｌを２０μＬ／ウェルで添加し、その刺激により生じたカルシウム流入による蛍光上昇を１０秒間測定した。ベースラインからの最大蛍光上昇値から阻害百分率を算出し、さらに化合物濃度の対数値と阻害活性をプロットすることでＩＣ５０値を算出した。測定は４８５ｎｍの励起光を細胞に照射した際に発する５１０ｎｍの蛍光を観測した。
（バッファー組成）
Ａバッファー：１４０ｍＭ　ＮａＣｌ，５ｍＭ　ＫＣｌ，１ｍＭ　ＭｇＣｌ２，０．５ｍＭ　ＣａＣｌ２，１０ｍＭ　Ｇｌｕｃｏｓｅ，１０ｍＭ　ＨＥＰＥＳ，ｐＨ７．３
Ｂバッファー：１３７．９ｍＭ　Ｃｈｏｌｉｎｅ－Ｃｌ，４．１ｍＭ　ＫＣｌ，１ｍＭ　ＭｇＣｌ２，０．５ｍＭ　ＣａＣｌ２，１０ｍＭ　Ｇｌｕｃｏｓｅ，１０ｍＭ　ＨＥＰＥＳ，ｐＨ７．３ (2) Intracellular calcium concentration measurement method Human Cav3.2 channel constantly expressed cells prepared by the test method (1) were seeded on a 96-well plate (medium is a modified Dalveco method containing 10% fetal bovine serum (FBS)). Eagle's medium (DMEM) medium was used). The cells were seeded and cultured at 37 ° C. under 5% CO 2 conditions for 48 hours. The cells were then washed with A buffer to remove the medium. Each well is mixed with 22 μg of calcium fluorescence indicator Fluo-4 AM (Dojin Kagaku Kenkyusho # F311), 20 μL of DMSO, 1 μL of 10% Pluronic F-127 (Thermo Fisher Scientific # P6866) and 4 mL of A buffer. It was treated with 80 μL of the prepared fluorescent dye solution. After allowing to stand at room temperature in the dark for 45 minutes, the cells were washed with B buffer to completely replace the solution. As a negative control, DMSO having the same concentration as that of the test compound, 1 μM of the blocker RQ-00311651 known as a positive control, and 70 μL of the test compound were added to each well in the form of containing each in the B buffer. The test compound was dissolved in 100% DMSO and added at a final concentration of 0.1%. The cells were then allowed to stand at room temperature under shading for an additional 15 minutes and placed on a microplate reader EnVision (PerkinElmer). After measuring background fluorescence in each well, 5 μg / mL grammicidin solution was added at 10 μL / well in B buffer. After 90 seconds, the baseline fluorescence was measured, then 83.8 mM KCl was added to B buffer at 20 μL / well, and the increase in fluorescence due to calcium influx caused by the stimulation was measured for 10 seconds. Calculating the percent inhibition from the maximum fluorescence increase from baseline, IC 50 values were calculated by plotting logarithmic values and inhibitory activity of further compounds concentration. In the measurement, the fluorescence of 510 nm emitted when the cells were irradiated with the excitation light of 485 nm was observed.
(Buffer composition)
A buffer: 140 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 0.5 mM CaCl 2 , 10 mM Glucose, 10 mM HEPES, pH 7.3
B buffer: 137.9 mM Choline-Cl, 4.1 mM KCl, 1 mM MgCl 2 , 0.5 mM CaCl 2 , 10 mM Glucose, 10 mM HEPES, pH 7.3
（試験結果）
試験結果を表１～３に示す。その結果、今回試験を行った実施例全ての化合物が、Ｃａｖ３．２チャネルの阻害作用を持つことが分かった。 (Test results)
The test results are shown in Tables 1 to 3. As a result, it was found that all the compounds of the examples tested this time had an inhibitory effect on the Cav3.2 channel.
Figure JPOXMLDOC01-appb-T000354
Figure JPOXMLDOC01-appb-T000354
Figure JPOXMLDOC01-appb-T000355
Figure JPOXMLDOC01-appb-T000355
Figure JPOXMLDOC01-appb-T000356
Figure JPOXMLDOC01-appb-T000356
実施例１８９
薬理試験２
ＣＦＡ誘発関節リウマチモデル
（試験方法）
　７週齢の雄性Ｃ５７ＢＬ／６Ｊマウス（ジャクソン研究所）を用いて、逃避反応の潜時（Ｐａｗ　Ｗｉｔｈｄｒａｗａｌ　Ｌａｔｅｎｃｙ：ＰＷＬ）を指標として、関節リウマチに対する作用を検討した。ＣＦＡを用いたモデルマウスは炎症と痛みを伴う点で、ヒトの関節リウマチでの臨床症状に類似していると云われている。
　実験は１群５～７匹で行った。ＣＦＡとしてはＳｉｇｍａ－Ａｌｄｒｉｃｈから購入したものを、コントロール（対照）としてはＰｏｓｐｈａｔｅ　Ｂｕｆｆｅｒｄ　Ｓａｌｉｎｅ（ＰＢＳ）を使用した。また、実施例１４４の化合物（以下、「化合物Ａ」という。）は、１％メチルセルロース（ＭＣ）水溶液に懸濁したものを投与液とした。
　マウスの後肢足底に２０μＬのＣＦＡ溶液を皮下注入して熱痛覚過敏を惹起した。ＣＦＡ注入の約３日後、マウスは９０分以上絶食させ、さらに１時間馴化させてから、薬物（３０ｍｇ／ｋｇの化合物Ａ）を経口投与した。投与後０．５，１，２，３，４時間後の熱痛覚過敏をハーグリーブス装置（Ｕｇｏ　ｂａｓｉｌｅ　ＳＲＬ）でマウスが逃避反応の潜時を測定し評価した。対照群として、ビヒクルを経口投与した。
　ＰＷＬのデータは、ｔｗｏ－ｗａｙ　ＡＮＯＶＡで解析後、Ｄｕｎｎｅｔｔ’ｓ　ｔｅｓｔにより有意差検定を行った。有意水準は５％（対照群との比較）とした。統計計算はＧｒａｐｈＰａｄ　Ｐｒｉｓｍ７．０４（ＧｒａｐｈＰａｄ　Ｓｏｆｔｗａｒｅ，　Ｉｎｃ．）を用い、データは平均値と標準誤差で示した。
（試験結果）
　図１に結果を示す。ＰＷＬは、Ｓｈａｍ群（ＣＦＡ注入時にＰＢＳ溶液を、薬物投与時に１％ＭＣ溶液をそれぞれ投与した。）と比較して、ＣＦＡの投与により短縮したことから、ＣＦＡにより熱痛覚過敏が惹起されたことが理解できる。ＣＦＡと同時に化合物Ａを投与することにより、ＣＦＡ単独と比較してＰＷＬが延長する傾向がみられ、投与後２時間では有意差が確認された。このことから、化合物ＡはＣＦＡ誘発の熱痛覚過敏を抑制することが示された。
　以上の結果から、化合物Ａは関節リウマチを改善できることが示された。 Example 189
Pharmacological test 2
CFA-induced rheumatoid arthritis model (test method)
Using a 7-week-old male C57BL / 6J mouse (Jackson Laboratory), the effect on rheumatoid arthritis was examined using the latency of the escape reaction (Paw Withdrawal Latency: PWL) as an index. Model mice using CFA are said to resemble clinical symptoms in human rheumatoid arthritis in that they are inflamed and painful.
The experiment was carried out with 5 to 7 animals per group. The CFA was purchased from Sigma-Aldrich, and the control (control) was Phosphate Buffered Saline (PBS). The compound of Example 144 (hereinafter referred to as "Compound A") was suspended in a 1% aqueous solution of methyl cellulose (MC) as an administration solution.
A 20 μL CFA solution was subcutaneously injected into the sole of the hind limb of the mouse to induce thermal hyperalgesia. Approximately 3 days after CFA infusion, the mice were fasted for 90 minutes or longer, acclimatized for an additional hour, and then the drug (30 mg / kg compound A) was orally administered. Heat hyperalgesia 0.5, 1, 2, 3, and 4 hours after administration was evaluated by measuring the latency of the escape response in mice with a Hargreaves device (Ugo basele SRL). As a control group, the vehicle was orally administered.
The PWL data was analyzed by two-way ANOVA, and then a significant difference test was performed by Dunnett's test. The significance level was 5% (comparison with the control group). Statistical calculations were performed using GraphPad Prism 7.04 (GraphPad Software, Inc.), and the data were shown with mean values and standard errors.
(Test results)
The results are shown in FIG. The PWL was shortened by the administration of CFA as compared with the Sham group (PBS solution was administered at the time of CFA injection and 1% MC solution was administered at the time of drug administration), and thus CFA induced hyperalgesia. Can be understood. By administering Compound A at the same time as CFA, PWL tended to be prolonged as compared with CFA alone, and a significant difference was confirmed 2 hours after administration. From this, it was shown that Compound A suppresses CFA-induced hyperalgesia.
From the above results, it was shown that Compound A can improve rheumatoid arthritis.
　本発明化合物は、Ｃａｖ３．２チャネルの阻害作用を有し、関節リウマチの治療又は予防のための医薬として利用できる。 The compound of the present invention has an inhibitory effect on Cav3.2 channel and can be used as a drug for the treatment or prevention of rheumatoid arthritis.

Claims (76)

  1. 　次の一般式（Ｉ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000001
    （式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接する環状アミンの窒素原子と結合し、
    　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＸと結合し、
    　Ｒ１及びＲ２は、同一又は異なっていても良く、水素原子、ハロゲン原子、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基を表すか、
    　又は、Ｒ１、Ｒ２及びＲ１とＲ２が結合する炭素原子が一緒になって、３～５員のシクロアルキル基を形成しても良く、
    　Ｒ３は、水素原子、ハロゲン原子、カルボキシル基、シアノ基、カルバモイル基、Ｃ１－８アルキル基、Ｃ１－８アルコキシカルボニル基、Ｃ１－８アルコキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アシルオキシ基で置換されたＣ１－８アルキル基を表すか、
    　又は、Ｒ２及びＲ３が一緒になって、メチレン又はエチレンを形成しても良く、
    Ｘは、
    Figure JPOXMLDOC01-appb-C000002
    又は
    Figure JPOXMLDOC01-appb-C000003
    を表し、
    ここで、波線は結合位置を表し、
    　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
    又はＲ４、Ｒ５及びＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良く、
    　ｎ及びｍは、同一又は異なっていても良く、０または１で、
    　ｐは１、２を表す。
    　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
    　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシ基で置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
    　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ[３．３]ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。）     A rheumatoid arthritis containing a compound represented by the following general formula (I), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000001
    (In the formula, A 1 is composed of phenyl, which may have a substituent, and 1 to 3 heteroatoms and carbon atoms, which are the same or different, selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms. It represents a 4- to 6-membered heteroaryl ring, or a heterocondensed ring consisting of the heteroaryl ring and a benzene ring or a 6-membered heteroaryl ring consisting of 1 to 2 nitrogen atoms and a carbon atom, wherein the heteroaryl The ring, the heterofused ring, may have substituents and is bonded to the nitrogen atom of the adjacent cyclic amine via the carbon atoms constituting these rings.
    B 1 is a 5- or 6-membered phenyl atom which may have a substituent and 1 to 3 heteroatoms and carbon atoms which are the same or different and are selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms. The heteroaryl ring, or the heteroaryl ring and the benzene ring, or the heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the hetero The fused ring may have substituents and is bonded to the adjacent X via the carbon atoms that make up these rings.
    R 1 and R 2 may be the same or different, and represent a hydrogen atom, a halogen atom, a hydroxy group, a C 1-8 alkyl group, and a C 1-8 alkyl group substituted with 1 to 3 halogen atoms. Suka
    Alternatively, the carbon atoms to which R 1 , R 2 and R 1 and R 2 are bonded may be combined to form a 3- to 5-membered cycloalkyl group.
    R 3 represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, a carbamoyl group, C 1-8 alkyl group, C 1-8 alkoxycarbonyl group, C 1-8 alkyl group substituted by a C 1-8 alkoxy group Represents a C 1-8 alkyl group substituted with a hydroxy group, a C 1-8 alkyl group substituted with 1 to 3 halogen atoms, a C 1-8 alkyl group substituted with an acyloxy group, or
    Alternatively, R 2 and R 3 may be combined to form methylene or ethylene.
    X is
    Figure JPOXMLDOC01-appb-C000002
    Or
    Figure JPOXMLDOC01-appb-C000003
    Represents
    Here, the wavy line represents the coupling position and
    R 4 and R 5 may be the same or different, a hydrogen atom, a deuterium, hydroxy group, C 1-8 alkyl groups, one to three C 1-8 alkyl group substituted with a halogen atom, an amino Represents a group, C 1-8 alkylamino group, C 2-12 dialkylamino group,
    Alternatively, R 4 , R 5 and the carbon atom to which R 4 and R 5 are bonded may be combined to form a 3- to 5-membered cycloalkyl group.
    n and m may be the same or different, 0 or 1,
    p represents 1 and 2.
    The phenyl of the A 1, as the heteroaryl and heteroaryl fused ring substituent that may have the A 1 of the A 1, C 1-8 alkyl, C 1-8 alkoxy group, 1 to C 1-8 alkyl group substituted with 3 halogen atoms, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, hydroxy group It is selected from substituted C 1-8 alkoxy groups, hydroxy groups, halogen atoms, cyano groups, C 1-8 alkylsulfonyl groups, and C 1-8 alkoxy groups substituted with C 1-8 alkoxycarbonyl groups. Yes,
    Phenyl above B 1, as the heteroaryl and heteroaryl fused ring substituent that may have the B 1 of the B 1, C 1-8 alkyl, C 1-8 alkoxy groups, one to three C 1-8 alkyl group substituted with halogen atom, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, substituted with hydroxy group and C 1-8 alkoxy group, hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, C 1-8 alkylamino group, C 2-12 dialkylamino group, (C 1-8 alkyl) (C 1- C 1-8 alkyl) amino group substituted with 8 alkoxy group, tri (C 1-8 alkyl) silyl group, acyl amino group, (N-acyl) ( NC 1-8 alkyl) amino group, 3-6 cyclic ether-membered, cyclic amino group, or a halogen atom as a substituent, a C 1-8 alkyl group, C 1-8 alkoxy groups, one to three C 1-8 alkyl group substituted with a halogen atom, 1 to The same or different 1 to selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the C 1-8 alkoxy groups substituted with 3 halogen atoms. It is selected from a 4- to 6-membered heteroaryl ring consisting of 3 hetero-atoms and carbon atoms.
    Wherein phenyl of the B 1, cyclic amino group heteroaryl ring and substituent that may have hetero condensed ring of said B 1 is the B 1 represents a pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1,4-dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] ] Heptan-6-yl, 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa Selected from -5-azabicyclo [2.2.1] heptane-5-yl, such cyclic amino groups may be further substituted with C 1-8 alkyl groups, halogen atoms and acyl groups. )
  2. 　Ｘが、
    Figure JPOXMLDOC01-appb-C000004
    である請求項１に記載の医薬。     X is
    Figure JPOXMLDOC01-appb-C000004
    The medicament according to claim 1.
  3. 　Ａ１が置換基を有しても良いフェニルである請求項１又は２に記載の医薬。 The medicament according to claim 1 or 2, wherein A 1 is a phenyl which may have a substituent.
  4. 　Ａ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である請求項１又は２に記載の医薬。 Phenyl in which A 1 may have a substituent, or 1 to 3 heteroatoms of the same or different selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms which may have a substituent. The medicament according to claim 1 or 2, which is a 4- to 6-membered heteroaryl ring composed of a carbon atom and a carbon atom.
  5. 　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン又はピリダジンである請求項４に記載の医薬。 The medicament according to claim 4, wherein the heteroaryl ring of A 1 is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine or pyridazine.
  6. 　Ａ１のヘテロアリール環がピリジンである請求項４に記載の医薬。 The medicament according to claim 4, wherein the heteroaryl ring of A 1 is pyridine.
  7. 　Ａ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である請求項１又は２に記載の医薬。 A 4- to 6-membered heteroaryl composed of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which A 1 may have a substituent. The medicament according to claim 1 or 2, which is a heterofused ring of a ring and a benzene ring.
  8. 　Ａ１のヘテロ縮合環がキノリン、ベンゾ［ｄ］チアゾールである請求項７に記載の医薬。 Heteroaryl fused quinolines of A 1, A medicament according to claim 7, which is a benzo [d] thiazole.
  9. 　Ｂ１が置換基を有しても良いフェニルである請求項１～８のいずれかに記載の医薬。 The medicament according to any one of claims 1 to 8, wherein B 1 is a phenyl which may have a substituent.
  10. 　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である請求項１～８のいずれかに記載の医薬。 Phenyl, where B 1 may have a substituent, or 1 to 3 heteroatoms, the same or different, selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms that may have substituents. The medicament according to any one of claims 1 to 8, which is a 5- or 6-membered heteroaryl ring composed of a carbon atom and a carbon atom.
  11. 　Ｂ１のヘテロアリール環が、ピリジンである請求項１０に記載の医薬。 The medicament according to claim 10, wherein the heteroaryl ring of B 1 is pyridine.
  12. 　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い６員のヘテロアリール環であるとき、該置換基は４位（パラ位）で置換している請求項９～１１のいずれかに記載の医薬。 Claim that when B 1 is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position). Item 8. The medicament according to any one of Items 9 to 11.
  13. 　Ｂ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である請求項１～８のいずれかに記載の医薬。 A 5- or 6-membered heteroaryl composed of 1 to 3 identical or different heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which B 1 may have a substituent. The medicament according to any one of claims 1 to 8, which is a heterofused ring of a ring and a benzene ring.
  14. 　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである請求項１３に記載の医薬。 The medicament according to claim 13, wherein the heterocondensation ring of B 1 is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
  15. 　Ｂ１のヘテロ縮合環が、インダゾールである請求項１３に記載の医薬。 The medicament according to claim 13, wherein the heterocondensed ring of B 1 is indazole.
  16. 　ｎが１で、ｍが０である請求項１～１５のいずれかに記載の医薬。 The medicament according to any one of claims 1 to 15, wherein n is 1 and m is 0.
  17. 　ｐが１である請求項１～１６のいずれかに記載の医薬。 The medicament according to any one of claims 1 to 16, wherein p is 1.
  18. 　Ｒ１及びＲ２が水素原子である請求項１～１７のいずれかに記載の医薬。 The medicament according to any one of claims 1 to 17, wherein R 1 and R 2 are hydrogen atoms.
  19. 　Ｒ３が水素原子である請求項１～１８のいずれかに記載の医薬。 The medicament according to any one of claims 1 to 18, wherein R 3 is a hydrogen atom.
  20. 　次の一般式（ＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000005
    （式中、Ｄ，Ｅ，Ｆ，Ｇ及びＪは、何れか２つがＮで他が同一又は異なっても良いＣＲか、或いは何れか１つがＮで他が同一又は異なっても良いＣＲか、全てが同一又は異なっても良いＣＲである。
    　ここで、Ｒは、水素原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基を表す。
    　Ｒａ１、Ｒａ２、Ｒｂ１及びＲｂ２は、同一又は異なっても良い水素原子、ハロゲン原子、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基を表すか、
    　又は、Ｒａ１、Ｒａ２及びＲａ１とＲａ２が結合する炭素原子が一緒になって、或いはＲｂ１、Ｒｂ２及びＲｂ１とＲｂ２が結合する炭素原子が一緒になって、３～５員のシクロアルキル基を形成しても良く、
    　ｓは０、１、２を表し、
    　ｔは１、２を表す。
    　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＸと結合し、
    　Ｘは、
    Figure JPOXMLDOC01-appb-C000006
    又は
    Figure JPOXMLDOC01-appb-C000007
    を表し、
    ここで、波線は結合位置を表し、
    　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
    又はＲ４、Ｒ５とＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良い。
    　そして、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
    　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ[３．３]ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。     A rheumatoid arthritis containing a compound represented by the following general formula (II), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000005
    (In the formula, D, E, F, G and J are CRs in which any two are N and the other may be the same or different, or any one is N and the other may be the same or different. All are CRs that may be the same or different.
    Here, R is substituted with a hydrogen atom, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. has been a C 1-8 alkoxy group, C 1-8 alkyl group substituted by a hydroxy group, a C 1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, C 1-8 alkylsulfonyl group, a C 1-8 alkoxy group substituted with a C 1-8 alkoxycarbonyl group.
    R a1, R a2, R b1 and R b2 are the same or different and which may represent a hydrogen atom, a halogen atom, hydroxy group, C 1-8 alkyl, C 1-8 substituted with 1 to 3 halogen atoms Represents an alkyl group
    Alternatively, the carbon atoms to which R a1 , R a2 and R a1 and R a2 are bonded together, or the carbon atoms to which R b1 , R b2 and R b1 and R b2 are bonded together, 3 to 5 A member cycloalkyl group may be formed.
    s represents 0, 1, 2 and
    t represents 1 and 2.
    B 1 is a 5- or 6-membered phenyl atom which may have a substituent and 1 to 3 heteroatoms and carbon atoms which are the same or different and are selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms. The heteroaryl ring, or the heteroaryl ring and the benzene ring, or the heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the hetero The fused ring may have substituents and is bonded to the adjacent X via the carbon atoms that make up these rings.
    X is
    Figure JPOXMLDOC01-appb-C000006
    Or
    Figure JPOXMLDOC01-appb-C000007
    Represents
    Here, the wavy line represents the coupling position and
    R 4 and R 5 may be the same or different, a hydrogen atom, a deuterium, hydroxy group, C 1-8 alkyl groups, one to three C 1-8 alkyl group substituted with a halogen atom, an amino Represents a group, C 1-8 alkylamino group, C 2-12 dialkylamino group,
    Alternatively, it may form a 3- to 5-membered cycloalkyl group together with the carbon atom to which R 4 , R 5 and R 4 and R 5 are bonded.
    The phenyl of the B 1, as the heteroaryl and heteroaryl fused ring substituent that may have the B 1 of the B 1, C 1-8 alkyl, C 1-8 alkoxy group, 1 to C 1-8 alkyl group substituted with 3 halogen atoms, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, hydroxy group Substituted C 1-8 alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 alkylamino group, C 2-12 dialkylamino group, (C 1-8 alkyl) (C C 1-8 alkyl) amino group substituted with 1-8 alkoxy, tri (C 1-8 alkyl) silyl group, acyl amino group, (N-acyl) ( NC 1-8 alkyl) amino group, 3 to 6-membered cyclic ether, cyclic amino group, or halogen atom as substituent, C 1-8 alkyl group, C 1-8 alkoxy group, C 1-8 alkyl group substituted with 1 to 3 halogen atoms, 1 The same or different 1 selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from C 1-8 alkoxy groups substituted with up to 3 halogen atoms. It is selected from a 4- to 6-membered heteroaryl ring consisting of up to 3 heteroatoms and carbon atoms.
    Wherein phenyl of the B 1, cyclic amino group heteroaryl ring and substituent that may have hetero condensed ring of said B 1 is the B 1 represents a pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1,4-dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] ] Heptan-6-yl, 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa Selected from -5-azabicyclo [2.2.1] heptane-5-yl, such cyclic amino groups may be further substituted with C 1-8 alkyl groups, halogen atoms and acyl groups.
  21. 　次の一般式（ＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000008
    （式中、Ｄ，Ｅ，Ｆ，Ｇ及びＪは、何れか２つがＮで他が同一又は異なっても良いＣＲか、或いは何れか１つがＮで他が同一又は異なっても良いＣＲか、全てが同一又は異なっても良いＣＲである。
    　ここで、Ｒは、水素原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基を表す。
    　Ｒａ１、Ｒａ２、Ｒｂ１及びＲｂ２は、同一又は異なっても良い水素原子、ハロゲン原子、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基を表すか、
    　又は、Ｒａ１、Ｒａ２及びＲａ１とＲａ２が結合する炭素原子が一緒になって、或いはＲｂ１、Ｒｂ２及びＲｂ１とＲｂ２が結合する炭素原子が一緒になって、３～５員のシクロアルキル基を形成しても良く、
    　ｓは０、１、２を表し、
    　ｔは１、２を表す。
    　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＸと結合し、
    　Ｘは、
    Figure JPOXMLDOC01-appb-C000009
    又は
    Figure JPOXMLDOC01-appb-C000010
    を表し、
    ここで、波線は結合位置を表し、
    　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
    又はＲ４、Ｒ５とＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良い。
    　そして、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
    　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ[３．３]ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。
    　但し、Ｄ～Ｊからなる６員環が、置換基を有していても良いフェニル又は置換基を有していても良いピリダジンで、Ｘが、
    Figure JPOXMLDOC01-appb-C000011
    の時、Ｂ１は、前記の置換基を有していてもよいヘテロ縮合環である。）     A rheumatoid arthritis containing a compound represented by the following general formula (II), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000008
    (In the formula, D, E, F, G and J are CRs in which any two are N and the other may be the same or different, or any one is N and the other may be the same or different. All are CRs that may be the same or different.
    Here, R is substituted with a hydrogen atom, a C 1-8 alkyl group, a C 1-8 alkoxy group, a C 1-8 alkyl group substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. has been a C 1-8 alkoxy group, C 1-8 alkyl group substituted by a hydroxy group, a C 1-8 alkoxy group substituted with a hydroxy group, a hydroxy group, a halogen atom, a cyano group, C 1-8 alkylsulfonyl group, a C 1-8 alkoxy group substituted with a C 1-8 alkoxycarbonyl group.
    R a1, R a2, R b1 and R b2 are the same or different and which may represent a hydrogen atom, a halogen atom, hydroxy group, C 1-8 alkyl, C 1-8 substituted with 1 to 3 halogen atoms Represents an alkyl group
    Alternatively, the carbon atoms to which R a1 , R a2 and R a1 and R a2 are bonded together, or the carbon atoms to which R b1 , R b2 and R b1 and R b2 are bonded together, 3 to 5 A member cycloalkyl group may be formed.
    s represents 0, 1, 2 and
    t represents 1 and 2.
    B 1 is a 5- or 6-membered phenyl atom which may have a substituent and 1 to 3 heteroatoms and carbon atoms which are the same or different and are selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms. The heteroaryl ring, or the heteroaryl ring and the benzene ring, or the heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the hetero The fused ring may have substituents and is bonded to the adjacent X via the carbon atoms that make up these rings.
    X is
    Figure JPOXMLDOC01-appb-C000009
    Or
    Figure JPOXMLDOC01-appb-C000010
    Represents
    Here, the wavy line represents the coupling position and
    R 4 and R 5 may be the same or different, a hydrogen atom, a deuterium, hydroxy group, C 1-8 alkyl groups, one to three C 1-8 alkyl group substituted with a halogen atom, an amino Represents a group, C 1-8 alkylamino group, C 2-12 dialkylamino group,
    Alternatively, it may form a 3- to 5-membered cycloalkyl group together with the carbon atom to which R 4 , R 5 and R 4 and R 5 are bonded.
    The phenyl of the B 1, as the heteroaryl and heteroaryl fused ring substituent that may have the B 1 of the B 1, C 1-8 alkyl, C 1-8 alkoxy group, 1 to C 1-8 alkyl group substituted with 3 halogen atoms, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, hydroxy group Substituted C 1-8 alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, amino group, C 1-8 alkylamino group, C 2-12 dialkylamino group, (C 1-8 alkyl) (C C 1-8 alkyl) amino group substituted with 1-8 alkoxy, tri (C 1-8 alkyl) silyl group, acyl amino group, (N-acyl) ( NC 1-8 alkyl) amino group, 3 to 6-membered cyclic ether, cyclic amino group, or halogen atom as substituent, C 1-8 alkyl group, C 1-8 alkoxy group, C 1-8 alkyl group substituted with 1 to 3 halogen atoms, 1 The same or different 1 selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from C 1-8 alkoxy groups substituted with up to 3 halogen atoms. It is selected from a 4- to 6-membered heteroaryl ring consisting of up to 3 heteroatoms and carbon atoms.
    Wherein phenyl of the B 1, cyclic amino group heteroaryl ring and substituent that may have hetero condensed ring of said B 1 is the B 1 represents a pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1,4-dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] ] Heptan-6-yl, 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa Selected from -5-azabicyclo [2.2.1] heptane-5-yl, such cyclic amino groups may be further substituted with C 1-8 alkyl groups, halogen atoms and acyl groups.
    However, the 6-membered ring composed of D to J is phenyl which may have a substituent or pyridazine which may have a substituent, and X is
    Figure JPOXMLDOC01-appb-C000011
    At the time, B 1 is a hetero-fused ring which may have the above-mentioned substituent. )
  22. 　Ｘが、
    Figure JPOXMLDOC01-appb-C000012
    である請求項２０又は２１に記載の医薬。     X is
    Figure JPOXMLDOC01-appb-C000012
    The medicament according to claim 20 or 21.
  23. 　ＤとＪが共にＣＨである請求項２０～２２のいずれかに記載の医薬。 The medicament according to any one of claims 20 to 22, wherein both D and J are CH.
  24. 　Ｄ、Ｅ、Ｆ、Ｇ及びＪの何れか１つがＮで、他がＣＲである請求項２０～２２のいずれかに記載の医薬。 The medicament according to any one of claims 20 to 22, wherein any one of D, E, F, G and J is N and the other is CR.
  25. 　Ｄ、Ｅ、Ｆ及びＪが同一又は異なっても良いＣＲで、ＧがＮである請求項２０～２２のいずれかに記載の医薬。 The medicament according to any one of claims 20 to 22, wherein D, E, F and J are CRs which may be the same or different and G is N.
  26. 　Ｂ１が置換基を有しても良いフェニルである請求項２０～２５のいずれかに記載の医薬。 The medicament according to any one of claims 20 to 25, wherein B 1 is a phenyl which may have a substituent.
  27. 　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である請求項２０～２５のいずれかに記載の医薬。 Phenyl, where B 1 may have a substituent, or 1 to 3 heteroatoms, the same or different, selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms that may have substituents. The medicament according to any one of claims 20 to 25, which is a 5- or 6-membered heteroaryl ring consisting of a carbon atom and a carbon atom.
  28. 　Ｂ１のヘテロアリール環が、ピリジンである請求項２７に記載の医薬。 The medicament according to claim 27, wherein the heteroaryl ring of B 1 is pyridine.
  29. 　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い６員のヘテロアリール環であるとき、該置換基は４位（パラ位）で置換している請求項２６～２８のいずれかに記載の医薬。 Claim that when B 1 is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position). Item 8. The medicament according to any one of Items 26 to 28.
  30. 　Ｂ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である請求項２０～２５のいずれかに記載の医薬。 A 5- or 6-membered heteroaryl consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which B 1 may have a substituent. The medicament according to any one of claims 20 to 25, which is a heterofused ring of a ring and a benzene ring.
  31. 　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである請求項３０に記載の医薬。 The medicament according to claim 30, wherein the heterocondensation ring of B 1 is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
  32. 　Ｂａのヘテロ縮合環が、インダゾールである請求項３０に記載の医薬。 Hetero condensed B a is A medicament according to claim 30 which is a indazole.
  33. 　ｓが１である請求項２０～３２のいずれかに記載の医薬。 The medicament according to any one of claims 20 to 32, wherein s is 1.
  34. 　ｔが１である請求項２０～３３のいずれかに記載の医薬。 The medicament according to any one of claims 20 to 33, wherein t is 1.
  35. 　Ｒａ１、Ｒａ２、Ｒｂ１及びＲｂ２が水素原子である請求項２０～３４のいずれかに記載の医薬。 The medicament according to any one of claims 20 to 34, wherein R a1 , R a2 , R b1 and R b2 are hydrogen atoms.
  36. 　次の一般式（ＩＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000013
    （式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するピロリジンの窒素原子と結合し、
    　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＣ（Ｒ４）（Ｒ５）と結合する。
    　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
    又はＲ４、Ｒ５と及びＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良く、
    　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
    　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
    　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。     A rheumatoid arthritis containing a compound represented by the following general formula (III), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000013
    (In the formula, A 1 is composed of phenyl, which may have a substituent, and 1 to 3 heteroatoms and carbon atoms, which are the same or different, selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms. It represents a 4- to 6-membered heteroaryl ring, or a heterocondensed ring consisting of the heteroaryl ring and a benzene ring or a 6-membered heteroaryl ring consisting of 1 to 2 nitrogen atoms and carbon atoms, wherein the heteroaryl is represented. The ring, the heterofused ring, may have substituents and may be bonded to the nitrogen atom of the adjacent pyrrolidine via the carbon atoms constituting these rings.
    B 1 is a 5- or 6-membered phenyl atom which may have a substituent and 1 to 3 heteroatoms and carbon atoms which are the same or different and are selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms. The heteroaryl ring, or the heteroaryl ring and the benzene ring, or the heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the hetero The fused ring may have substituents and is bonded to adjacent C (R 4 ) (R 5 ) via the carbon atoms constituting these rings.
    R 4 and R 5 may be the same or different, a hydrogen atom, a deuterium, hydroxy group, C 1-8 alkyl groups, one to three C 1-8 alkyl group substituted with a halogen atom, an amino Represents a group, C 1-8 alkylamino group, C 2-12 dialkylamino group,
    Alternatively, it may form a 3- to 5-membered cycloalkyl group together with the carbon atom to which R 4 , R 5 and R 4 and R 5 are bonded.
    The phenyl of the A 1, as the heteroaryl and heteroaryl fused ring substituent that may have the A 1 of the A 1, C 1-8 alkyl, C 1-8 alkoxy group, 1 to C 1-8 alkyl group substituted with 3 halogen atoms, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, hydroxy group It is selected from substituted C 1-8 alkoxy groups, hydroxy groups, halogen atoms, cyano groups, C 1-8 alkylsulfonyl groups, and C 1-8 alkoxy groups substituted with C 1-8 alkoxycarbonyl groups. Yes,
    Phenyl above B 1, as the heteroaryl and heteroaryl fused ring substituent that may have the B 1 of the B 1, C 1-8 alkyl, C 1-8 alkoxy groups, one to three C 1-8 alkyl group substituted with halogen atom, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, substituted with hydroxy group and C 1-8 alkoxy group, hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, C 1-8 alkylamino group, C 2-12 dialkylamino group, (C 1-8 alkyl) (C 1- 8- alkoxy substituted C 1-8 alkyl) amino group, tri (C 1-8 alkyl) silyl group, acyl amino group, (N-acyl) ( NC 1-8 alkyl) amino group, 3-6 members cyclic ethers, cyclic amino group, or a halogen atom as a substituent, a C 1-8 alkyl group, C 1-8 alkoxy groups, one to three C 1-8 alkyl group substituted with a halogen atom, 1-3 The same or different 1-3 selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from C 1-8 alkoxy groups substituted with 15 halogen atoms. It is selected from a 4- to 6-membered heteroaryl ring consisting of a hetero atom and a carbon atom.
    Wherein phenyl of the B 1, cyclic amino group heteroaryl ring and substituent that may have hetero condensed ring of said B 1 is the B 1 represents a pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1,4-dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] ] Heptan-6-yl, 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa Selected from -5-azabicyclo [2.2.1] heptane-5-yl, such cyclic amino groups may be further substituted with C 1-8 alkyl groups, halogen atoms and acyl groups.
  37. 　次の一般式（ＩＩＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000014
    （式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するピロリジンの窒素原子と結合し、
    　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するＣ（Ｒ４）（Ｒ５）と結合する。
    　Ｒ４及びＲ５は、同一又は異なっていても良く、水素原子、重水素、ヒドロキシ基、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基を表すか、
    又はＲ４、Ｒ５及びＲ４とＲ５が結合する炭素原子と一緒になって、３～５員のシクロアルキル基を形成しても良く、
    　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
    　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ基、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
    　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピロリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル、２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。
    　但し、Ａ１が、置換基を有していても良いフェニル、置換基を有していても良いピリダジン及び置換基を有していても良いキナゾリンの時、Ｂ１は、前記の置換基を有していても良いヘテロ縮合環である。）     A rheumatoid arthritis containing a compound represented by the following general formula (III), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000014
    (In the formula, A 1 is composed of phenyl, which may have a substituent, and 1 to 3 heteroatoms and carbon atoms, which are the same or different, selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms. It represents a 4- to 6-membered heteroaryl ring, or a heterocondensed ring consisting of the heteroaryl ring and a benzene ring or a 6-membered heteroaryl ring consisting of 1 to 2 nitrogen atoms and carbon atoms, wherein the heteroaryl is represented. The ring, the heterofused ring, may have substituents and is bonded to the nitrogen atom of the adjacent pyrrolidine via the carbon atoms that make up these rings.
    B 1 is a 5- or 6-membered phenyl atom which may have a substituent and 1 to 3 heteroatoms and carbon atoms which are the same or different and are selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms. The heteroaryl ring, or the heteroaryl ring and the benzene ring, or the heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of one or two nitrogen atoms and a carbon atom, wherein the heteroaryl ring and the hetero The fused ring may have substituents and is bonded to adjacent C (R 4 ) (R 5 ) via the carbon atoms constituting these rings.
    R 4 and R 5 may be the same or different, a hydrogen atom, a deuterium, hydroxy group, C 1-8 alkyl groups, one to three C 1-8 alkyl group substituted with a halogen atom, an amino Represents a group, C 1-8 alkylamino group, C 2-12 dialkylamino group,
    Alternatively, R 4 , R 5 and the carbon atom to which R 4 and R 5 are bonded may be combined to form a 3- to 5-membered cycloalkyl group.
    The phenyl of the A 1, as the heteroaryl and heteroaryl fused ring substituent that may have the A 1 of the A 1, C 1-8 alkyl, C 1-8 alkoxy group, 1 to C 1-8 alkyl group substituted with 3 halogen atoms, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, hydroxy group It is selected from substituted C 1-8 alkoxy groups, hydroxy groups, halogen atoms, cyano groups, C 1-8 alkylsulfonyl groups, and C 1-8 alkoxy groups substituted with C 1-8 alkoxycarbonyl groups. Yes,
    Phenyl above B 1, as the heteroaryl and heteroaryl fused ring substituent that may have the B 1 of the B 1, C 1-8 alkyl, C 1-8 alkoxy groups, one to three C 1-8 alkyl group substituted with halogen atom, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, substituted with hydroxy group and C 1-8 alkoxy group, hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, C 1-8 alkylamino group, C 2-12 dialkylamino group, (C 1-8 alkyl) (C 1- 8- alkoxy substituted C 1-8 alkyl) amino group, tri (C 1-8 alkyl) silyl group, acyl amino group, (N-acyl) ( NC 1-8 alkyl) amino group, 3-6 members cyclic ethers, cyclic amino group, or a halogen atom as a substituent, a C 1-8 alkyl group, C 1-8 alkoxy groups, one to three C 1-8 alkyl group substituted with a halogen atom, 1-3 The same or different 1-3 selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms, which may be substituted with a substituent selected from C 1-8 alkoxy groups substituted with 15 halogen atoms. It is selected from a 4- to 6-membered heteroaryl ring consisting of a hetero atom and a carbon atom.
    Wherein phenyl of the B 1, cyclic amino group heteroaryl ring and substituent that may have hetero condensed ring of said B 1 is the B 1 represents a pyrrolidino, piperidino, piperazino, 2 or 3-oxopyrrolidino, 2,3 or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1,4-dioxa-8-azaspiro [4.5] decane-8-yl, 2-oxa-6-azaspiro [3.3] ] Heptan-6-yl, 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 2-oxa-5-azabicyclo [2.2.2] octane-5-yl, 2-oxa Selected from -5-azabicyclo [2.2.1] heptane-5-yl, such cyclic amino groups may be further substituted with C 1-8 alkyl groups, halogen atoms and acyl groups.
    However, when A 1 is phenyl which may have a substituent, pyridazine which may have a substituent and quinazoline which may have a substituent, B 1 uses the above-mentioned substituent. It is a heterofused ring which may be possessed. )
  38. 　Ａ１が置換基を有しても良いフェニルである請求項３６又は３７に記載の医薬。 The medicament according to claim 36 or 37, wherein A 1 is a phenyl which may have a substituent.
  39. 　Ａ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である請求項３６又は３７に記載の医薬。 Phenyl in which A 1 may have a substituent, or 1 to 3 heteroatoms of the same or different selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms which may have a substituent. The medicament according to claim 36 or 37, which is a 4- to 6-membered heteroaryl ring consisting of a carbon atom and a carbon atom.
  40. 　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン、ピリダジンである請求項３９に記載の医薬。 39. The medicament according to claim 39, wherein the heteroaryl ring of A 1 is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
  41. 　Ａ１のヘテロアリール環がピリジンである請求項３９に記載の医薬。 The medicament according to claim 39, wherein the heteroaryl ring of A 1 is pyridine.
  42. 　Ａ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である請求項３６又は３７に記載の医薬。 A 4- to 6-membered heteroaryl composed of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which A 1 may have a substituent. The medicament according to claim 36 or 37, which is a heterofused ring of a ring and a benzene ring.
  43. 　Ａ１のヘテロ縮合環がキノリン、ベンゾ［ｄ］チアゾールである請求項４２に記載の医薬。 Heteroaryl fused quinolines of A 1, A medicament according to claim 42 which is a benzo [d] thiazole.
  44. 　Ｂ１が置換基を有しても良いフェニルである請求項３６～４３のいずれかに記載の医薬。 The medicament according to any one of claims 36 to 43, wherein B 1 is a phenyl which may have a substituent.
  45. 　Ｂ１が置換基を有していても良いフェニル、又は置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である請求項３６～４３のいずれかに記載の医薬。 B 1 may have a substituent or a phenyl, or may have a substituent as a ring-constituting atom selected from an oxygen atom, a sulfur atom and a nitrogen atom with the same or different 1 to 3 heteroatoms. The medicament according to any one of claims 36 to 43, which is a 5- or 6-membered heteroaryl ring composed of carbon atoms.
  46. 　Ｂ１のヘテロアリール環が、ピリジンである請求項４５に記載の医薬。 The medicament according to claim 45, wherein the heteroaryl ring of B 1 is pyridine.
  47. 　Ｂ１が置換基を有していても良いフェニル、又は置換基を有していても良い６員のヘテロアリール環であるとき、該置換基は４位（パラ位）で置換している請求項４４～４６のいずれかに記載の医薬。 Claim that when B 1 is a phenyl that may have a substituent or a 6-membered heteroaryl ring that may have a substituent, the substituent is substituted at the 4-position (para-position). Item 8. The medicament according to any one of Items 44 to 46.
  48. 　Ｂ１が置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である請求項３６～４３のいずれかに記載の医薬。 A 5- or 6-membered heteroaryl composed of 1 to 3 identical or different heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which B 1 may have a substituent. The medicament according to any one of claims 36 to 43, which is a heterofused ring of a ring and a benzene ring.
  49. 　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである請求項４８に記載の医薬。 The medicament according to claim 48, wherein the heterocondensation ring of B 1 is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
  50. 　Ｂ１のヘテロ縮合環が、インダゾールである請求項４８に記載の医薬。 The medicament according to claim 48, wherein the heterocondensation ring of B 1 is indazole.
  51. 　Ｒ４及びＲ５が共に水素原子である請求項３６～５０のいずれかに記載の医薬。 The medicament according to any one of claims 36 to 50, wherein both R 4 and R 5 are hydrogen atoms.
  52. 　次の一般式（ＩＶ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000015
    （式中、Ｒ６，Ｒ７及びＲ８は、同一又は異なって、水素原子、ハロゲン原子、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基を表し、
    　Ｒ９は、１～３個のハロゲン原子で置換されたＣ１－８アルキル、ｔ－ブチル又はシクロプロピルを表し、
    そして、ｒは０、１、２を表す。）     A rheumatoid arthritis containing a compound represented by the following general formula (IV), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000015
    (Wherein, R 6, R 7 and R 8 are the same or different, a hydrogen atom, a halogen atom, C 1-8 alkyl groups, one to three C 1-8 alkyl group substituted with a halogen atom, Represents a C 1-8 alkoxy group, a C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, a hydroxy group, and a C 1-8 alkoxy group substituted with a C 1-8 alkoxycarbonyl group.
    R 9 represents C 1-8 alkyl, t-butyl or cyclopropyl substituted with 1 to 3 halogen atoms.
    And r represents 0, 1, 2. )
  53. 　Ｒ６，Ｒ７及びＲ８が、異なって、水素原子、ハロゲン原子、Ｃ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、Ｃ１－８アルコキシ基である請求項５２に記載の医薬。 R 6, R 7 and R 8 are different, a hydrogen atom, a halogen atom, C 1-8 alkyl groups, one to three C 1-8 alkyl group substituted with a halogen atom, C 1-8 alkoxy group 52. The medicament according to claim 52.
  54. 　Ｒ９がトリフルオロメチル又はシクロプロピルである請求項５２～５３のいずれかに記載の医薬。 The medicament according to any one of claims 52 to 53, wherein R 9 is trifluoromethyl or cyclopropyl.
  55. 　ｒが１である請求項５２～５４のいずれかに記載の医薬。 The medicament according to any one of claims 52 to 54, wherein r is 1.
  56. 　次の一般式（Ｖ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000016
    （式中、Ａ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するピロリジンの窒素原子と結合し
    　Ｂ１は、置換基を有していても良いフェニル、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環、又は該ヘテロアリール環とベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロアリール環、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するシクロプロピルと結合する。
    　そして、上記Ａ１のフェニル、上記Ａ１のヘテロアリール環及び上記Ａ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
    　上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、３～５員のシクロアルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
    　ここで、上記Ｂ１のフェニル、上記Ｂ１のヘテロアリール環及び上記Ｂ１のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピペリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキソ－８－アザスピロ［４．５］デカンー８－イル、２－オキソ－６－アザスピロ［３．３］ヘプタンー６－イル、３－オキソー８－アザビシクロ［３．２．１］オクタンー８－イル、２－オキソー５－アザビシクロ［２．２．２］オクタンー５－イル、２－オキソ－５－アザビシクロ［２．２．１］ヘプタンー５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良い。）     A rheumatoid arthritis containing a compound represented by the following general formula (V), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000016
    (In the formula, A 1 is composed of phenyl, which may have a substituent, and 1 to 3 heteroatoms and carbon atoms, which are the same or different, selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms. It represents a 4- to 6-membered heteroaryl ring, or a hetero-condensed ring consisting of the heteroaryl ring and a benzene ring or a 6-membered heteroaryl ring consisting of 1 to 2 nitrogen atoms and carbon atoms, wherein the heteroaryl is represented. ring, the heterocyclic fused ring may have a substituent, and B 1 attached to the nitrogen atom of the pyrrolidine to be adjacent to each other via a carbon atom constituting the ring may have a substituent Also good phenyl, a 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, or the heteroaryl ring. It represents a benzene ring or a heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of 1 to 2 nitrogen atoms and a carbon atom, where the heteroaryl ring and the heterocondensed ring may have a substituent. Well, it binds to adjacent cyclopropyls via the carbon atoms that make up these rings.
    The phenyl of the A 1, as the heteroaryl and heteroaryl fused ring substituent that may have the A 1 of the A 1, C 1-8 alkyl, C 1-8 alkoxy group, 1 to C 1-8 alkyl group substituted with 3 halogen atoms, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, hydroxy group It is selected from substituted C 1-8 alkoxy groups, hydroxy groups, halogen atoms, cyano groups, C 1-8 alkylsulfonyl groups, and C 1-8 alkoxy groups substituted with C 1-8 alkoxycarbonyl groups. Yes,
    Phenyl above B 1, as the heteroaryl and heteroaryl fused ring substituent that may have the B 1 of the B 1, C 1-8 alkyl, C 1-8 alkoxy groups, one to three C 1-8 alkyl group substituted with halogen atom, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, substituted with hydroxy group C 1-8 alkoxy group, hydroxy group, halogen atom, cyano group, nitro group, 3-5 member cycloalkyl group, amino group, C 1-8 alkylamino group, C 2-12 dialkylamino group, (C 1-8 alkyl) (C 1-8 C 1-8 alkyl substituted by alkoxy) amino, tri (C 1-8 alkyl) silyl group, an acylamino group, (N-acyl) (N-C 1-8 alkyl ) amino group, 3- to 6-membered cyclic ether, cyclic amino group, or a halogen atom as a substituent, C 1-8 alkyl, C 1-8 alkoxy groups, C 1 substituted with 1 to 3 halogen atoms, Select from oxygen atom, sulfur atom and nitrogen atom as the ring-constituting atom, which may be substituted with a substituent selected from the -8 alkyl group and the C 1-8 alkoxy group substituted with 1 to 3 halogen atoms. It is selected from a 4- to 6-membered heteroaryl ring consisting of the same or different 1 to 3 hetero atoms and carbon atoms.
    Wherein phenyl of the B 1, cyclic amino group heteroaryl ring and substituent that may be hetero condensed ring has the B1 of the B 1 represents a pyrrolidino, piperidino, piperazino, 2 or 3 Okisopiperijino, 2 3, or 4-oxopiperidino, morphorlino, 1,1-dioxidethiomorpholino, 1,4-dioxo-8-azaspiro [4.5] decane-8-yl, 2-oxo-6-azaspiro [3.3] heptane 6-yl, 3-oxo-8-azabicyclo [3.2.1] octane-8-yl, 2-oxo-5-azabicyclo [2.2.2] octane-5-yl, 2-oxo-5-azabicyclo [2. 2.1] Selected from heptane-5-yl, such cyclic amino groups may be further substituted with C 1-8 alkyl groups, halogen atoms and acyl groups. )
  57. 　Ａ１が置換基を有しても良いフェニルである請求項５６に記載の医薬。 The medicament according to claim 56, wherein A 1 is a phenyl which may have a substituent.
  58. 　Ａ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である請求項５６に記載の医薬。 A 4- to 6-membered heteroaryl ring consisting of 1 to 3 identical or different heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which A 1 may have a substituent The medicament according to claim 56.
  59. 　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン、ピリダジンである請求項５８に記載の医薬。 The medicament according to claim 58, wherein the heteroaryl ring of A 1 is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
  60. 　Ａ１のヘテロアリール環がピリジンである請求項５８に記載の医薬。 The medicament according to claim 58, wherein the heteroaryl ring of A 1 is pyridine.
  61. 　Ａ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である請求項５６に記載の医薬。 A 4- to 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which A 1 may have a substituent. The medicament according to claim 56, which is a heterofused ring of a benzene ring.
  62. 　Ａ１のヘテロ縮合環がキノリン、ベンゾ［ｄ］チアゾールである請求項６１に記載の医薬。 Heteroaryl fused quinolines of A 1, A medicament according to claim 61 which is benzo [d] thiazole.
  63. 　Ｂ１が置換基を有しても良いフェニルである請求項５６～６２のいずれかに記載の医薬。 The medicament according to any one of claims 56 to 62, wherein B 1 is a phenyl which may have a substituent.
  64. 　Ｂ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環である請求項５６～６２のいずれかに記載の医薬。 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which B 1 may have a substituent. The medicament according to any one of claims 56 to 62.
  65. 　Ｂ１のヘテロアリール環が、ピリジンである請求項６３に記載の医薬。 The medicament according to claim 63, wherein the heteroaryl ring of B 1 is pyridine.
  66. 　Ｂ１が置換基を有しても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環とベンゼン環とのヘテロ縮合環である請求項５６～６２のいずれかに記載の医薬。 A 5- or 6-membered heteroaryl ring consisting of the same or different 1 to 3 heteroatoms and carbon atoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms in which B 1 may have a substituent. The medicament according to any one of claims 56 to 62, which is a heterofused ring of a benzene ring.
  67. 　Ｂ１のヘテロ縮合環が、インドール、ベンゾイミダゾール、インダゾール、ベンゾオキサゾール、ベンゾチアゾール、ベンゾ［ｄ］［１，２，３］トリアゾール、キノリンである請求項６６に記載の医薬。 The medicament according to claim 66, wherein the heterocondensation ring of B 1 is indole, benzimidazole, indazole, benzoxazole, benzothiazole, benzo [d] [1,2,3] triazole, quinoline.
  68. 　Ｂ１のヘテロ縮合環が、ベンゾ［ｄ］オキサゾールである請求項６６に記載の医薬。 The medicament according to claim 66, wherein the heterocondensation ring of B 1 is benzo [d] oxazole.
  69. 　次の一般式（ＶＩ）で表される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。
    Figure JPOXMLDOC01-appb-C000017
    （式中、Ａ１は、置換基を有していても良いフェニル、又は環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環、ここで、該ヘテロアリール環、該ヘテロ縮合環、置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接する環状アミンの窒素原子と結合し
    　Ｂ２は、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる５若しくは６員のヘテロアリール環と、ベンゼン環若しくは１～２個の窒素原子と炭素原子からなる６員のヘテロアリール環からなるヘテロ縮合環を表し、ここで、該ヘテロ縮合環は置換基を有していても良く、そしてこれらの環を構成する炭素原子を介して隣接するメチレン基と結合する。
    　そして、上記Ａ１のフェニル及び上記Ａ１のヘテロアリール環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、Ｃ１－８アルキルスルホニル基、Ｃ１－８アルコキシカルボニル基で置換されたＣ１－８アルコキシ基から選択されるものであり、
    　上記Ｂ２のヘテロ縮合環が有しても良い置換基としては、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基、ヒドロキシ基で置換されたＣ１－８アルキル基、ヒドロキシ基で置換されたＣ１－８アルコキシ基、ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、３～５員のシクロアルキル基、アミノ基、Ｃ１－８アルキルアミノ基、Ｃ２－１２ジアルキルアミノ基、（Ｃ１－８アルキル）（Ｃ１－８アルコキシで置換されたＣ１－８アルキル）アミノ、トリ（Ｃ１－８アルキル）シリル基、アシルアミノ基、（Ｎ－アシル）（Ｎ－Ｃ１－８アルキル）アミノ基、３～６員の環状エーテル、環状アミノ基、又は置換基としてハロゲン原子、Ｃ１－８アルキル基、Ｃ１－８アルコキシ基、１～３個のハロゲン原子で置換されたＣ１－８アルキル基、１～３個のハロゲン原子で置換されたＣ１－８アルコキシ基から選択される置換基で置換されていても良い、環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環から選択されるものであり、
    　ここで、上記Ｂ２のヘテロ縮合環が有しても良い置換基の環状アミノ基は、ピロリジノ、ピペリジノ、ピペラジノ、２又は３－オキソピペリジノ、２、３又は４－オキソピペリジノ、モルホルリノ、１，１－ジオキサイドチオモルホリノ、１，４－ジオキソ－８－アザスピロ［４．５］デカン－８－イル、２－オキソ－６－アザスピロ［３．３］ヘプタン－６－イル、３－オキソ－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキソー５－アザビシクロ［２．２．２］オクタン－５－イル、２－オキソ－５－アザビシクロ［２．２．１］ヘプタンー５－イルから選択され、かかる環状アミノ基は、更にＣ１－８アルキル基、ハロゲン原子、アシル基で置換されていても良く、
    　ｕは０、１、２を表す。）     A rheumatoid arthritis containing a compound represented by the following general formula (VI), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Medicine for treatment or prevention.
    Figure JPOXMLDOC01-appb-C000017
    (In the formula, A 1 is derived from phenyl, which may have a substituent, or 1 to 3 heteroatoms and carbon atoms, which are the same or different, selected from oxygen atom, sulfur atom and nitrogen atom as ring-constituting atoms. A 4- to 6-membered heteroaryl ring, which may have the heteroaryl ring, the heterocondensation ring, a substituent, and an adjacent cyclic amine via a carbon atom constituting these rings. B 2 bonded to the nitrogen atom, an oxygen atom, the heteroaryl ring of the same or different 1 to 5 or 6 membered of 3 heteroatoms and carbon atoms selected from sulfur atom and a nitrogen atom as a ring-constituting atom, Represents a benzene ring or a heterocondensed ring consisting of a 6-membered heteroaryl ring consisting of 1 to 2 nitrogen atoms and carbon atoms, where the heterocondensed ring may have substituents, and these It bonds to an adjacent methylene group via a carbon atom that constitutes a ring.
    Then, as the phenyl and heteroaryl ring substituent that may have the A 1 of the A 1, it is substituted with C 1-8 alkyl, C 1-8 alkoxy groups, 1-3 halogen atoms C 1-8 alkyl group, C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, C 1-8 alkoxy substituted with hydroxy group It is selected from a group, a hydroxy group, a halogen atom, a cyano group, a C 1-8 alkyl sulfonyl group, and a C 1-8 alkoxy group substituted with a C 1-8 alkoxycarbonyl group.
    Examples of the substituent that the heterofused ring of B 2 may have include a C 1-8 alkyl group, a C 1-8 alkoxy group, and a C 1-8 alkyl group substituted with 1 to 3 halogen atoms. C 1-8 alkoxy group substituted with 1 to 3 halogen atoms, C 1-8 alkyl group substituted with hydroxy group, C 1-8 alkoxy group substituted with hydroxy group, hydroxy group, halogen atom, Substituted with cyano group, nitro group, 3-5 membered cycloalkyl group, amino group, C 1-8 alkyl amino group, C 2-12 dialkyl amino group, (C 1-8 alkyl) (C 1-8 alkoxy) C 1-8 alkyl) amino, tri (C 1-8 alkyl) silyl group, acyl amino group, (N-acyl) ( NC 1-8 alkyl) amino group, 3 to 6-membered cyclic ether, cyclic amino Group or substituent, halogen atom, C 1-8 alkyl group, C 1-8 alkoxy group, C 1-8 alkyl group substituted with 1 to 3 halogen atoms, substituted with 1 to 3 halogen atoms The same or different 1 to 3 heteroatoms and carbon selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms, which may be substituted with a substituent selected from the C 1-8 alkoxy groups. It is selected from a 4- to 6-membered heteroaryl ring consisting of atoms.
    Here, cyclic amino group substituent that may have hetero condensed ring of the B 2 is the pyrrolidino, piperidino, piperazino, 2 or 3 Okisopiperijino, 2, 3 or 4 Okisopiperijino, Moruhorurino, 1,1 Dioxide thiomorpholino, 1,4-dioxo-8-azaspiro [4.5] decane-8-yl, 2-oxo-6-azaspiro [3.3] heptane-6-yl, 3-oxo-8-azabicyclo [3.2.1] Octane-8-yl, 2-oxo-5-azabicyclo [2.2.2] Octane-5-yl, 2-oxo-5-azabicyclo [2.2.1] Heptane-5-yl The cyclic amino group may be further substituted with a C 1-8 alkyl group, a halogen atom, an acyl group, and the like.
    u represents 0, 1, and 2. )
  70. 　Ａ１が置換基を有していても良いフェニル、又は置換基を有していても良い環構成原子として酸素原子、硫黄原子及び窒素原子から選択される同一若しくは異なる１～３個のヘテロ原子と炭素原子からなる４～６員のヘテロアリール環である請求項６９に記載の医薬。 Phenyl in which A 1 may have a substituent, or 1 to 3 heteroatoms of the same or different selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms which may have a substituent. The medicament according to claim 69, which is a 4- to 6-membered heteroaryl ring consisting of a carbon atom and a carbon atom.
  71. 　Ａ１のヘテロアリール環がチオフェン、オキサゾール、チアゾール、ピリジン、ピラジン、ピリミジン、ピリダジンである請求項７０に記載の医薬。 The medicament according to claim 70, wherein the heteroaryl ring of A 1 is thiophene, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine.
  72. 　Ａ１のヘテロアリール環がピリジンである請求項７０に記載の医薬。 The medicament according to claim 70, wherein the heteroaryl ring of A 1 is pyridine.
  73. 　（Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（５－（トリフルオロメチル）ピリジン－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－ヒドロキシ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（５－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（６－（トリフルオロメチル）ピリジン－３－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（５－（４－（トリフルオロメチル）チアゾール－２－イル）－５－アザスピロ［２．４］ヘプタン－７－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｒ，５Ｓ）－５－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（（１Ｓ，５Ｒ）－３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（（１Ｒ，５Ｓ）－３－（５－（トリフルオロメチル）ピリジン－３－イル）－３－アザビシクロ［３．１．０］ヘキサン－１－イル）アセトアミド、
    （Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピラジン－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－Ｎ－（１－（６－シアノ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
    （Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
    （Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
    （Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸、
    （Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸、
    （Ｒ）－２－（１Ｈ－インダゾール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、（Ｒ）－２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
    （Ｓ）－２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－メチル－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（２－ヒドロキシプロパン－２－イル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（８－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－６－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボキシアミド、
    （Ｓ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボキシアミド、
    （Ｒ）－２－（４－ヒドロキシフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（１，１－ジオキサイドチオモルホリノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－１－（４－クロロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （Ｒ）－２－（４－ブロモフェニル）－２－ヒドロキシ－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－（４－ブロモフェニル）－２－ヒドロキシ－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリメチルシリル）フェニル）アセトアミド、
    （Ｒ）－２－（４－（２－ヒドロキシ－２－メチルプロポキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（（３Ｓ，４Ｓ）－４－フルオロ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（ジメチルアミノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－ニトロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－（４－イソブチルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
    （Ｒ）－２－（３－フルオロ－４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－アミノフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－１－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （Ｒ）－２－（４－アセトアミドフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－Ｎ－（３－シアノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
    （Ｓ）－Ｎ－（３－シアノ－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
    （Ｒ）－３－（２－（１Ｈ－インドール－６－イル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
    （Ｓ）－３－（２－（１Ｈ－インドール－６－イル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
    （Ｒ）－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
    （Ｓ）－３－（２－（４－（トリフルオロメチル）フェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
    （１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
    ３－（２－（４－モルホリノフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－カルボン酸メチル、
    （Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－エチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－エチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（５，６－ジフルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （Ｒ）－２－（４－（２－オキサ－６－アザスピロ［３．３］ヘプタン－６－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（６－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（５－フルオロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｓ）－１－（４－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｓ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－Ｎ－（（Ｒ）－１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）－２－（キナゾリン－２－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－（メチルスルホニル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－シアノフェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（５－シアノ－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（２－（トリフルオロメチル）ピリジン－４－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（トリフルオロメチル）フェニル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－インドール－３－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（１Ｈ－インドール－３－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、（１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（４－（ｔｅｒｔ－ブチル）チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリダジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（２－（トリフルオロメチル）ピリミジン－５－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（６－フルオロキノリン－２－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１－シクロプロピル－１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－ブロモピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （Ｒ）－２－（キノリン－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１Ｈ－インドール－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（キノリン－７－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）オキサゾール－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－５－（トリフルオロメチル）－１Ｈ－ピラゾール－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（６－（トリフルオロメチル）ピリジン－３－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド－２，２－ｄ２、
    （Ｒ）－２－（４－（３，３－ジフルオロピロリジン－１－イル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（（２Ｒ，６Ｓ）－２，６－ジメチルモルホリノ）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（ピロリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（（２－メトキシエチル）（メチル）アミノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
    ２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－インドール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（４－メチルピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（ピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（４－アセチルピペラジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（２－オキソピペリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（６－クロロベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（ベンゾ［ｄ］オキサゾール－２－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （１Ｓ，２Ｓ）－２－（３，５－ジクロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（３，５－ジクロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（４－ブロモフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（４－ブロモフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （Ｒ）－２－（４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（４－オキソピペリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（ヒドロキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（ヒドロキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－酢酸（３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）メチル、
    （Ｓ）－酢酸（３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）メチル、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（メトキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－（メトキシメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （１Ｓ，２Ｓ）－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（３，４－ジフルオロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（３，４－ジフルオロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｓ，２Ｓ）－２－（４－クロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （１Ｒ，２Ｒ）－２－（４－クロロフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    ２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－４－イル）アセトアミド、
    （Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（６－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、（Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリミジン－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（トリフルオロメトキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（２，２，２－トリフルオロエトキシ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
    ２－（４－イソプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）アゼチジン－３－イル）アセトアミド、
    （Ｒ）－２－（３，５－ジクロロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（３－クロロ－５－フルオロフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－イソプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）チオフェン－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（２，２，２－トリフルオロエトキシ）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（２，２，２－トリフルオロエトキシ）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（２，２，２－トリフルオロエトキシ）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（２－メトキシ－５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（２－ヒドロキシプロパン－２－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（３－メチルピラジン－２－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（４－メチルオキサゾール－５－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）－５－（トリフルオロメチル）ピリジン　１－オキシド、
    （３Ｒ）－３－（２－（４－シクロプロピルフェニル）アセトアミド）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン　１－オキシド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－２－メチル－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－フルオロ－５－（トリフルオロメチル）フェニル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－アミノ－２－（４－シクロプロピルフェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－２－（ジメチルアミノ）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｓ）－２－（４－シクロプロピルフェニル）－２－（ジメチルアミノ）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－インドール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（２，４－ビス（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（２－フルオロ－４－（トリフルオロメチル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－インダゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（２，２－ジメチルモルホリノ）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（１Ｈ－ピラゾール－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－Ｎ－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－モルホリノフェニル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（３－メチル－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（ベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（ベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（２－メチルベンゾ［ｄ］オキサゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．２］オクタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（ベンゾ［ｄ］チアゾール－６－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（ベンゾ［ｄ］チアゾール－６－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１Ｈ－インダゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１Ｈ－インダゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド、
    （Ｓ）－Ｎ－（３－（トリフルオロメチル）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド、
    （Ｒ）－２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（（１Ｒ，４Ｒ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（（１Ｒ，４Ｒ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－（（１Ｓ，４Ｓ）－２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（１－メチル－１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）フェニル）アゼチジン－３－イル）アセトアミド、
    ２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）アゼチジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－ブロモフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－フルオロベンゾ［ｄ］チアゾール－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－Ｎ－（１－（５－ブロモチアゾール－２－イル）ピロリジン－３－イル）－２－（４－シクロプロピルフェニル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－メトキシフェニル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（３，３－ジフルオロピロリジン－１－イル）フェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（３－（３－（２－（４－シクロプロピルフェニル）アセトアミド）ピロリジン－１－イル）フェノキシ）－２－メチルプロパン酸エチル、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（３－ヒドロキシフェニル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４，６－ジメトキシピリミジン－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－モルホリノフェニル）－Ｎ－（１－（５－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－シクロプロピルフェニル）－Ｎ－（１－（４－（トリフルオロメチル）ピリジン－２－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド、
    （Ｒ）－Ｎ－（１－（４－フルオロ－３－（トリフルオロメチル）フェニル）ピロリジン－３－イル）－２－（４－（トリフルオロメチル）フェニル）アセトアミド、
    （Ｒ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
    （Ｓ）－２－（４－（トリフルオロメチル）フェニル）－Ｎ－（（Ｒ）－１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）プロパンアミド、
    （１Ｓ，２Ｓ）－２－（１Ｈ－ベンゾ［ｄ］イミダゾール－２－イル）－Ｎ－（（Ｒ）－１－（５－（トリフルオロメチル）ピリジン－３－イル）ピペリジン－３－イル）シクロプロパン－１－カルボキシアミド、
    （Ｒ）－２－（１Ｈ－インドール－６－イル）－Ｎ－（１－（４－（トリフルオロメチル）チアゾール－２－イル）ピロリジン－３－イル）アセトアミド及び
    （Ｒ）－２－（１－メチル－１Ｈ－インドール－５－イル）－Ｎ－（１－（６－（トリフルオロメチル）ピリジン－３－イル）ピロリジン－３－イル）アセトアミド
    から選択される化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する、関節リウマチの治療又は予防のための医薬。     (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (5- (trifluoromethyl) pyridin-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-isopropylphenyl) -N- (1- (2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-hydroxy-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (5- (5- (trifluoromethyl) pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (5- (6- (trifluoromethyl) Pyridine-3-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (5- (4- (trifluoromethyl) thiazole-2-yl) -5-azaspiro [2.4] heptane-7-yl) acetamide,
    2- (4-Cyclopropylphenyl) -N-((3R, 5S) -5-methyl-1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
    2- (4-Cyclopropylphenyl) -N-((1S, 5R) -3- (5- (trifluoromethyl) pyridin-3-yl) -3-azabicyclo [3.1.0] hexane-1- Il) acetamide,
    2- (4-Cyclopropylphenyl) -N-((1R, 5S) -3- (5- (trifluoromethyl) pyridine-3-yl) -3-azabicyclo [3.1.0] hexane-1- Il) acetamide,
    (R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (6- (trifluoromethyl) pyrazine-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -N- (1- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
    Methyl (R) -3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate,
    (S) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate methyl,
    (R) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylic acid,
    (S) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylic acid,
    (R) -2- (1H-indazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide, (R) -2- (4-) Isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) propanamide,
    (S) -2- (4-isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (6-methyl-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (2-hydroxypropan-2-yl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (8- (trifluoromethyl) imidazole [1,2-a] pyridin-6-yl) pyrrolidine-3-yl) acetamide,
    (R) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxyamide,
    (S) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxyamide,
    (R) -2- (4-Hydroxyphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (1,1-dioxidethiomorpholino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -1- (4-chlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide,
    (R) -2- (4-Bromophenyl) -2-hydroxy-N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (S) -2- (4-Bromophenyl) -2-hydroxy-N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -N- (1- (5- (trifluoromethyl) Pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trimethylsilyl) phenyl) acetamide,
    (R) -2- (4- (2-Hydroxy-2-methylpropoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    2- (4-Cyclopropylphenyl) -N-((3S, 4S) -4-fluoro-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (dimethylamino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-nitrophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (S) -2- (4-isobutylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
    (R) -2- (3-Fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-aminophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -1- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide,
    (R) -2- (4-acetamide phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -N- (3-cyano-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
    (S) -N- (3-cyano-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
    (R) -3- (2- (1H-indole-6-yl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylate methyl,
    (S) -3- (2- (1H-indole-6-yl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-carboxylate methyl,
    Methyl (R) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate,
    (S) -3- (2- (4- (trifluoromethyl) phenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate methyl,
    (1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
    (R) -2- (4-morpholinophenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide,
    Methyl 3- (2- (4-morpholinophenyl) acetamide) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-carboxylate,
    (R) -2- (4-morpholinophenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (3-ethyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (S) -2- (4-Cyclopropylphenyl) -N- (3-ethyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (5,6-difluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine- 3-Il) Cyclopropane-1-carboxyamide,
    (R) -2- (4- (2-oxa-6-azaspiro [3.3] heptane-6-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide,
    (1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
    (1S, 2S) -2- (6-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (5-fluorobenzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
    (1R, 2R) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
    (1S, 2S) -2- (benzo [d] oxazole-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclo Propane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
    (1R, 2R) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(4- (trifluoromethyl) phenyl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
    (1R, 2R) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((S) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyrimidine-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -N-((R) -1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) -2- (quinazoline-2-yl) cyclopropane-1- Carboxamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(3- (methylsulfonyl) phenyl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (3-cyanophenyl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide ,
    (1S, 2S) -2- (5-cyano-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-yl) Cyclopropane-1-carboxyamide,
    (1R, 2R) -2- (5-cyano-1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-yl) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyridin-4-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1R, 2R) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (trifluoromethyl) phenyl) piperidine-3-yl) cyclopropane- 1-carboxyamide,
    (1S, 2S) -2- (1H-indole-3-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
    (1R, 2R) -2- (1H-indole-3-yl) -N-((R) -1-(6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine -3-Il) Cyclopropan-1-carboxyamide, (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(4- (tert-) Butyl) thiazole-2-yl) pyrrolidine-3-yl) cyclopropan-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(6- (trifluoromethyl) pyridazine-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(2- (trifluoromethyl) pyrimidine-5-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (6-fluoroquinoline-2-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
    (1S, 2S) -2- (1-Cyclopropyl-1H-benzo [d] imidazol-2-yl) -N-((R) -1- (3- (trifluoromethyl) phenyl) pyrrolidine-3- Il) Cyclopropane-1-carboxyamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1- (5-bromopyridin-3-yl) pyrrolidine-3-yl) cyclopropane- 1-carboxyamide,
    (R) -2- (quinoline-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1H-indole-3-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (quinoline-7-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) oxazole-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1-Methyl-5- (trifluoromethyl) -1H-pyrazole-3-yl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3 -Il) acetamide,
    (R) -2- (6- (trifluoromethyl) pyridin-3-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide-2,2-d2,
    (R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide ,
    (R) -2- (1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    2-(4-((2R, 6S) -2,6-dimethylmorpholino) phenyl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) ) Acetamide,
    (R) -2- (4- (Pyrrolidine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-((2-Methoxyethyl) (methyl) amino) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide ,
    2- (4- (Trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
    2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
    (R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1-methyl-1H-indole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (4-Methylpiperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (piperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (4-Acetylpiperazin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (2-oxopiperidine-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (6-chlorobenzo [d] oxazole-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (benzo [d] oxazole-2-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (1S, 2S) -2- (3,5-dichlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
    (1R, 2R) -2- (3,5-dichlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
    (1S, 2S) -2- (4-bromophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxy Amide,
    (1R, 2R) -2- (4-bromophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxy Amide,
    (R) -2- (4- (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (4-oxopiperidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
    (S) -2- (4-Cyclopropylphenyl) -N- (3- (hydroxymethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -Acetic acid (3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methyl,
    (S) -Acetic acid (3- (2- (4-cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) methyl,
    (R) -2- (4-Cyclopropylphenyl) -N- (3- (methoxymethyl) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (S) -2- (4-Cyclopropylphenyl) -N- (3- (methoxymethyl) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (1S, 2S) -2- (4-Cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
    (1R, 2R) -2- (4-Cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1- Carboxamide,
    (1S, 2S) -2- (3,4-difluorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide,
    (1R, 2R) -2- (3,4-difluorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1 -Carboxamide,
    (1S, 2S) -2- (4-chlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide ,
    (1R, 2R) -2- (4-chlorophenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) cyclopropane-1-carboxyamide ,
    2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-4-yl) acetamide,
    (R) -2- (4-isopropylphenyl) -N- (1- (6-methoxy-5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide, (R) -2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyrimidin-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-isopropylphenyl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-isopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (S) -2- (4-isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (trifluoromethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (2,2,2-trifluoroethoxy) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    2- (4-Isopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
    2- (4-Isopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) azetidine-3-yl) acetamide,
    (R) -2- (3,5-dichlorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (3-Chloro-5-fluorophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-isopropylphenyl) -N- (1- (5- (trifluoromethyl) thiophen-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1H-indole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (2,2,2-trifluoroethoxy) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (2,2,2-trifluoroethoxy) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (2,2,2-trifluoroethoxy) pyridin-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (2-methoxy-5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) acetamide,
    (R) -2- (4- (2-Hydroxypropane-2-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (3-methylpyrazine-2-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (4-Methyloxazole-5-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -3- (3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-yl) -5- (trifluoromethyl) pyridine 1-oxide,
    (3R) -3- (2- (4-Cyclopropylphenyl) acetamide) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine 1-oxide,
    (R) -2- (4-Cyclopropylphenyl) -2-methyl-N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (3-fluoro-5- (trifluoromethyl) phenyl) pyrrolidine-3-yl) acetamide,
    (R) -2-amino-2- (4-cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (S) -2-amino-2- (4-cyclopropylphenyl) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -2- (dimethylamino) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) Acetamide,
    (S) -2- (4-Cyclopropylphenyl) -2- (dimethylamino) -N-((R) -1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) Acetamide,
    (R) -2- (1-methyl-1H-indole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (2,4-bis (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (2-fluoro-4- (trifluoromethyl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1-methyl-1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1-Methyl-1H-indazole-5-yl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1-methyl-1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (2,2-dimethylmorpholino) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (1H-pyrazole-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -N- (3-Methyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) -2- (4-morpholinophenyl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (3-methyl-1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) -N-((R) -1- (5- (trifluoromethyl) pyridine-3-3) Il) pyrrolidine-3-yl) acetamide,
    2- (4- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridine-3-) Il) pyrrolidine-3-yl) acetamide,
    (R) -2- (benzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (benzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (2-methylbenzo [d] oxazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) -N-((R) -1-(5- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
    2-(4-(((1S, 4S) -2-oxa-5-azabicyclo [2.2.2] octane-5-yl) phenyl) -N-((R) -1- (6- (trifluoro)) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
    (R) -2- (benzo [d] thiazole-6-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (benzo [d] thiazole-6-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1H-indazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (1H-indazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    2- (4-Cyclopropylphenyl) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) Acetamide,
    (S) -N- (3- (trifluoromethyl) -1- (5- (trifluoromethyl) pyridine-3-yl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) Acetamide,
    (R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide,
    (R) -2- (1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3- Il) acetamide,
    2-(4-((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(5- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
    2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(5- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
    2-(4-((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(6- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
    2-(4-((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane-5-yl) phenyl) -N-((R) -1-(6- (trifluoro) Methyl) Pyridine-3-yl) Pyrrolidine-3-yl) Acetamide,
    (R) -2- (1-Methyl-1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (5- (trifluoromethyl) pyridine-3-yl) Pyrrolidine-3-yl) acetamide,
    (R) -2- (1-Methyl-1H-benzo [d] [1,2,3] triazole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) Pyrrolidine-3-yl) acetamide,
    2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) phenyl) azetidine-3-yl) acetamide,
    2- (4-Cyclopropylphenyl) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) azetidine-3-yl) acetamide,
    (R) -2- (4-Bromophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (6-fluorobenzo [d] thiazole-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -N- (1- (5-bromothiazole-2-yl) pyrrolidine-3-yl) -2- (4-cyclopropylphenyl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (3-methoxyphenyl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (3,3-difluoropyrrolidin-1-yl) phenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide ,
    (R) -2- (3- (3- (2- (4-Cyclopropylphenyl) acetamide) pyrrolidine-1-yl) phenoxy) -2-methylpropanoate ethyl,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (3-hydroxyphenyl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (6- (trifluoromethyl) pyridin-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (4,6-dimethoxypyrimidine-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-morpholinophenyl) -N- (1- (5- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4-Cyclopropylphenyl) -N- (1- (4- (trifluoromethyl) pyridin-2-yl) pyrrolidine-3-yl) acetamide,
    (R) -2- (4- (trifluoromethyl) phenyl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide,
    (R) -N- (1- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-3-yl) -2- (4- (trifluoromethyl) phenyl) acetamide,
    (R) -2- (4- (trifluoromethyl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
    (S) -2- (4- (trifluoromethyl) phenyl) -N-((R) -1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) propanamide,
    (1S, 2S) -2- (1H-benzo [d] imidazol-2-yl) -N-((R) -1-(5- (trifluoromethyl) pyridin-3-yl) piperidine-3-yl) ) Cyclopropane-1-carboxyamide,
    (R) -2- (1H-indole-6-yl) -N- (1- (4- (trifluoromethyl) thiazole-2-yl) pyrrolidine-3-yl) acetamide and (R) -2-( Compounds selected from 1-methyl-1H-indole-5-yl) -N- (1- (6- (trifluoromethyl) pyridin-3-yl) pyrrolidine-3-yl) acetamide, mutual mutation of the compounds A drug for the treatment or prevention of rheumatoid arthritis, which contains a sex compound, a steric isomer, a pharmaceutically acceptable salt thereof, or a mixture thereof as an active ingredient.
  74. 　関節リウマチの予防又は治療のための医薬を製造するための、請求項１～７３のいずれかに記載の化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物の使用。 The compound according to any one of claims 1 to 73, a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof for producing a drug for preventing or treating rheumatoid arthritis. Or use of their solvates.
  75. 　関節リウマチの予防又は治療のために使用される請求項１～７３のいずれかに記載の化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物。 The compound according to any one of claims 1 to 73 used for the prevention or treatment of rheumatoid arthritis, a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent thereof. Japanese product.
  76. 　ヒトにおける関節リウマチを処置する方法であって、前記方法が有効量の請求項１～７３のいずれかに記載の化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を、それを必要とする対象に投与する工程を含む方法。 A method for treating rheumatoid arthritis in humans, wherein the method is an effective amount of the compound according to any one of claims 1 to 73, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable thereof. A method comprising the step of administering a salt or a solvate thereof to a subject in need thereof.
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