BR122021009601B1 - PYRROLIDINE COMPOUND - Google Patents

Abstract

The present invention should provide a method for efficiently producing and providing a compound having a spirooxindole backbone, for example, a compound having a spirooxindole backbone and having antitumor activity that inhibits the interaction between Mdm2 protein and p53 protein, or an intermediate thereof, using an asymmetric catalyst. A compound having an optically active tricyclic dispiroindole backbone is efficiently obtained through a catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate and using a chiral ligand and a Lewis acid.

Description

TECHNICAL FIELD

[001] The present invention relates to a method for producing a pyrrolidine compound having a spirooxindole structure.

PRIOR TECHNIQUE

[002] A method that involves using, as a reaction substrate, aldimine synthesized from an aldehyde and an amine as starting materials to synthesize a racemic compound by means of a 1,3-dipolar cycloaddition reaction in the presence of or in the presence of absence of a catalyst promoting the reaction is known as a method for synthesizing a pyrrolidine compound having a bicyclic spirooxindole structure (Non-Patent References 1 to 4). The obtained racemic compound can be resolved using a chiral column based technique such as HPLC or supercritical fluid chromatography (SFC) to separate out a desired optically active form.

[003] An asymmetric synthesis method by a 1,3-dipolar cycloaddition ratio using a chiral element has been reported as a method to stereoselectively synthesize the above-mentioned compound (Non-Patent References 5 and 6). Furthermore, a method for producing a pyrrolidine compound having a tricyclic dispirooxindole structure by a 1,3-dipolar addition reaction using, as a reaction substrate, ketimine synthesized with an amine and a ketone as starting materials has also been discovered. reported (Patent Reference 1).

[004] However, as for the methods of asymmetric catalytic synthesis of the aforementioned compound, a large number of studies have been carried out on asymmetric 1,3-dipolar cycloaddition reactions using aldimine as a reaction substrate (Non-Patent References 7 to 18). However, no reports have been made on the synthesis of a tricyclic dispiroindole using ketimine with a ketone and an amine as reaction substrates.

LIST OF QUOTES patent references

[005] Patent Reference 1: WO2012/121361.

Non-patent references

[006] Non-patent Reference 1: Jorgensen, K. A. et al., Org. Lett. 2005, 21, 4569.

[007] Non-patent Reference 2: Jorgensen, K. A. et al., Chem. Rev. 1998, 98, 863.

[008] Non-Patent Reference 3: Grigg, R. et al., Tetrahedron, 1992, 48, 10431.

[009] Non-patent Reference 4: Schreiber, S.L. et al., J. Am. chem. Soc. 2003, 125, 10174.

[0010] Non-patent Reference 5: Carretero, J.C. et al., Tetrahedron, 2007, 63, 6587.

[0011] Non-patent Reference 6: Wang, S. et al., J. Am. chem. Soc., 2005, 127, 10130.

[0012] Non-patent Reference 7: Wang, S. et al., J. Med. chem. 2006, 49, 3432.

[0013] Non-patent Reference 8: Williams, R.M. et al., J. Am. chem. Soc. 2000, 122, 5666.

[0014] Non-patent Reference 9: Gong, L.-Z. et al., J. Am. chem. Soc., 2009, 131, 13819.

[0015] Non-patent Reference 10: Gong, L.-Z. et al., Org. Lett., 2011, 13, 2418.

[0016] Non-patent Reference 11: Gong, L.-Z. et al., Chem. eur. J., 2012, 18, 6885.

[0017] Non-patent Reference 12: Waldmann, H. et al., Nat. Chem., 2010, 2, 735.

[0018] Non-patent Reference 13: Waldmann, H. et al., Tetrahedron, 2011, 67, 10195.

[0019] Non-patent Reference 14: Wang, C.-J. et al., Org. Biomol. Chem., 2011, 9, 1980.

[0020] Non-patent Reference 15: Arai, T. et al., Chem. eur. J., 2012, 18, 8287.

[0021] Non-patent Reference 16: Amedohkouh, M. et al., Tetrahedron Asymmetry, 2005, 8, 1411.

[0022] Non-patent Reference 17: Cordova, A. et al., Chem. Comm. 2006, 460.

[0023] Non-patent Reference 18: Ma, J.A. et al., Org. Lett. 2007, 9, 923.

SUMMARY OF THE INVENTION Technical problem

[0024] The present invention is intended to provide a method for efficiently producing and supplying a compound having a spirooxindole backbone, for example, a compound having a spirooxindole backbone and having antitumor activity that inhibits the interaction between the Mdm2 protein and the protein p53, or an intermediate thereof using an asymmetric catalyst.

Solution of the problem

[0025] The present inventors have conducted diligent studies and consequently established a method for efficiently synthesizing a compound having an optically active tricyclic dispiroindole backbone by selecting a chiral linker which promotes a catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate, and a Lewis acid serving as a core metal thereof, and the optimal reaction conditions.

[0026] Specifically, the present invention relates to the following (1) to (20): (1) A method for reacting a compound represented by formula (I): [Formula 1] a compound represented by formula (II): [Formula 2] and a compound represented by formula (III): [Formula 3] in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof: [Formula 4] wherein: R1 represents a hydrogen atom, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from the group A below, or a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from the group A below, R2 represents a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenyl group, a C3-C6 cycloalkyl group, or a C3-C6 cycloalkenyl group, wherein: the 5- or 6-membered heteroaryl group, the phenyl group, the C3-C6 cycloalkyl group, and the C3-C6 cycloalkenyl group optionally each have 1 to 3 independently selected substituents from the group consisting of a halogen atom, a vinyl group, an ethynyl group, a cyano group, a hydroxyl group, an amino group, a carboxyl group, an aminocarbonyl group, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from the group A below, a C3-C4 cycloalkyl group optionally having 1 to 3 substituents independently selected from the group A below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from the group A below, a cycloalkoxy group C3-C4 optionally having 1 to 3 substituents independently selected from the group A below, a C1-C6 alkylamino group optionally having 1 to 3 substituents independently selected from the group A below, a diC1-C6amino group optionally having 1 to 3 substituents independently selected from the group A below, a 4- to 7-membered saturated heterocyclic group containing a nitrogen atom in the ring and optionally having 1 to 3 substituents independently selected from group B below, a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from the group A below, a C3-C4 cycloalkoxycarbonyl group optionally having 1 to 3 substituents independently selected from the group A below, a C1-C6 alkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from the group A below, and a C3-C4 cycloalkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from the group A below, R3 and R4 each independently represent a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from the group C below, or R3 and R4 optionally together form a C4C6 cycloalkyl ring, a tetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring, wherein: the C4-C6 cycloalkyl ring, a tetrahydrofuran ring, the tetrahydropyran ring, and the piperidine ring optionally have, each, 1 to 8 substituents independently selected from the group D below, R5 represents a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from the group E below, a C3-C8 cycloalkoxy group optionally having 1 to 3 substituents independently selected from the group E below, a C2-C6 alkenyloxy group, or -NR51R52, R51 and R52 each independently represent a hydrogen atom, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from the group E to below, a C3-C8 cycloalkyl group optionally having 1 to 3 substituents independently selected from the group E below, or a 3- to 6-membered saturated heterocyclic group having, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from the group E below, and ring Z represents a benzene ring optionally having 1 to 4 substituents independently selected from the group E below, a pyridine ring optionally having 1 to 3 substituents independently selected from the group E below, or a pyrimidine ring optionally having 1 or 2 substituents independently selected from the group E below: group A: a halogen atom, a hydroxyl group, a C1-C6 alkyl group, a amino group, and a phenyl group, group B: a C1-C6 alkyl group, and a hydroxyl group group C: a halogen atom, a hydroxyl group, a phenyl group, a pyridyl group, and an amino group group D: a atom of halogen and a C1-C6 alkyl group optionally having 1 to 3 halogen atoms, and E group: a halogen atom, a hydroxyl group, a vinyl group, an ethynyl group, a cyano group, a C1-C6 alkoxy group, an aminocarbonyl group, and a C1-C6 alkyl group optionally having 1 to 3 halogen atoms. (2) A method for reacting a compound represented by formula (I): [Formula 5] and a compound represented by formula (V): [Formula 6] in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof: [Formula 7] wherein R1, R2, R3, R4, R5, and Z are as defined in (1). (3) A method according to (1) or (2), wherein the asymmetric catalyst is a catalyst prepared from a Lewis acid and a chiral ligand, wherein: the Lewis acid is a selected Lewis acid from the group consisting of a Lewis acid of Zn(II), a Lewis acid of Ag(I), a Lewis acid of Ni(II), a Lewis acid of Co(II), a Lewis acid of Ru (I), a Lewis acid of Cu(I), and a Lewis acid of Cu(II), and the chiral ligand is a chiral ligand selected from the group consisting of a compound represented by the following formula (VI): [Formula 8] a compound represented by the following formula (VII): [Formula 9] a compound represented by the following formula (VIII): [Formula 10] a compound represented by the following formula (IX): [Formula 11] a compound represented by the following formula (X): [Formula 12] a compound represented by the following formula (XI): [Formula 13] and a compound represented by the following formula (XII): [Formula 14] wherein: R6 represents a phenyl group optionally having 1 to 3 substituents independently selected from the group F below, ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring optionally having 1 to 4 halogen atoms, R7 represents a phenyl group optionally having 1 to 3 substituents independently selected from the group G below, or a furanyl group optionally having 1 to 3 substituents independently selected from the group G below, R8 represents a hydrogen atom or a C1-C6 alkoxy group, R9 represents a C1-C6 alkoxy group, or two R9 moieties optionally together form a 7- to 12-membered heterocyclic ring containing two oxygen atoms in the ring, X represents CH, CR10, or a nitrogen atom, wherein: R10 represents a group C1-C6 alkoxy, V represents a phenyl group having a P(R11)2 or PH(O)R12, wherein: R11 represents a C1-C6 alkyl group, a cyclohexyl group, or a phenyl group optionally having two groups trifluoromethyl, and R12 represents a C1-C6 alkyl group or a phenyl group, W represents a C1-C6 alkylthio group, a dihydrooxazolyl group optionally having a C1-C6 alkyl group, CH(CH3)P(R13)2, or CHR14R15 , wherein: R13 represents a cyclohexyl group, a C1-C6 alkyl group, or a phenyl group optionally having 1 or 2 substituents independently selected from the group H below, R14 represents a phenyl group optionally substituted with a P(R16) 2, R15 represents a C1-C6 alkyl group or a diC1-C6 alkylamino group, and R16 represents a phenyl group or a cyclohexyl group, U represents any one of the following Ua to Ud: [Formula 15] R17 represents a phenyl group optionally having 1 to 3 substituents independently selected from the group F below, R18 represents a C1-C6 alkyl group or a phenyl group, R19 represents a hydrogen atom or a C1-C6 alkyl group, and R20 and R21 each independently represent a C1-C6 alkyl group: F group: a C1-C6 alkyl group and a C1-C6 alkoxy group, G group: a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkoxy group C1-C6 dialkylamino, and H group: a C1-C6 alkyl group and a C1-C6 alkyl group optionally having three halogen atoms. (4) A method according to any one of (1) to (3), wherein the Lewis acid used in preparing the asymmetric catalyst is a Cu(I) Lewis acid or a Cu(II) Lewis acid ). (5) A method according to any one of (1) to (4), wherein the Lewis acid used in preparing the asymmetric catalyst is a Lewis acid selected from the group consisting of CuOAc, CuCl, CuBr, CuI, CuOTf , CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2, and CuSO4. (6) A method according to any one of (1) to (5), wherein the chiral ligand used in preparing the asymmetric catalyst is a chiral ligand selected from the group consisting of a compound represented by formula (V), a compound represented by the formula (VI), a compound represented by the formula (VII), a compound represented by the formula (VIII), a compound represented by the formula (IX), a compound represented by the formula (X), and a compound represented by the formula ( XI), wherein: R6 represents a phenyl group optionally having 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group, and a methoxy group, ring Y represents a benzene ring, a cyclohexane ring , or a dioxolane ring, R7 represents a phenyl group or a furanyl group, wherein: the phenyl group and the furanyl group each optionally have 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-group butyl, and a methoxy group, R8 represents a hydrogen atom or a methoxy group, R9 represents a methoxy group, or, two R9 moieties optionally together form a 9-membered heterocyclic ring containing two oxygen atoms in the ring, X represents CH, CR10, or a nitrogen atom, R10 represents a methoxy group, V represents P(R11)2, wherein: R11 represents a phenyl group optionally having two trifluoromethyl groups, W represents a t-butylthio group, a dihydrooxazolyl group optionally substituted with an isopropyl group, or CH(CH3)P(R13)2, wherein: R13 represents a phenyl group optionally having 1 or 2 methyl groups, U represents Ua or Ud mentioned above, R17 represents a phenyl group, R18 represents a isopropyl group, a t-butyl group, or a phenyl group, R19 represents a hydrogen atom, and R20 and R21 each independently represent a methyl group or a t-butyl group. (7) A method according to any one of (1) to (6), wherein the chiral ligand used in preparing the asymmetric catalyst is a chiral ligand selected from the following group: [Formula 16] [Formula 17] (8) A method according to any one of (1) to (7), wherein the solvent used in the reaction is one or more solvents selected from the group consisting of N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2- propanol, toluene, and ethyl acetate. (9) A method according to any one of (1) to (8), wherein the compound produced or the salt thereof has the following configuration: [Formula 18] wherein R1, R2, R3, R4, R5, and Z are as defined in (1). (10) A method according to any one of (1) to (9), wherein R1 is a hydrogen atom. (11) A method according to any one of (1) to (10), wherein in formula (I), ring Z is a benzene ring optionally having 1 to 4 halogen atoms. (12) A method according to any one of (1) to (11), wherein in formula (I) or formula (IV), R2 is a pyridyl group optionally having 1 to 3 halogen atoms, or a phenyl group optionally having 1 to 3 halogen atoms. (13) A method according to any one of (1) to (12), wherein in formula (II) or formula (V), R3 and R4 each represent a methyl group, or R3 and R4 together form a cyclopentane ring, a cyclohexane ring, or a tetrahydropyran ring, wherein: the cyclopentane ring, the cyclohexane ring, and the tetrahydropyran ring optionally each have 1 to 4 C1-C6 alkyl groups in the ring. (14) A method according to any one of (1) to (13), wherein in formula (III) or formula (V), R5 is a substituent represented by the following: [Formula 19] (15) A method according to any one of (1) to (13), wherein in formula (III) or formula (V), R5 is a C1-C6 alkoxy group. (16) A method for hydrolyzing a compound or a salt thereof produced using a method according to (15) to produce a compound represented by the following formula (XIV) or a salt thereof: [Formula 20] and condensing the compound or salt with a compound represented by NHR22R23 to produce a compound represented by the following formula (XV) or a salt thereof: [Formula 21] wherein: R1, R2, R3, R4, and Z are as defined in any one of (1) to (13), and R22 and R23 each independently represent a hydrogen atom, optionally a C1-C6 alkyl group having 1 to 3 substituents independently selected from the group I below, a C1-C6 alkylsulfonyl group optionally having 1 to 3 substituents independently selected from the group I below, a C3-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from the group I to next, a 3- to 6-membered saturated heterocyclic group having, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from the group I below, a phenyl group optionally having 1 to 3 substituents independently selected from the group I below, or a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, a oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group I below, or R22 and R23 optionally together form a piperazine ring optionally having 1 to 3 substituents independently selected from group I below: group I: a halogen atom, a hydroxyl group, an oxo group, a carboxyl group, a formyl group, an amino group, an aminocarbonyl group, a cyano group, a C1-C6 alkylamino group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylsulfonylamide group , a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from the group J below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from the group J below, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from the group J below, a C3-C6 cycloalkylcarbonyl group optionally having 1 to 3 substituents independently selected from the group J below, a C4-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from the group J below, one C1-C6alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from the group J below, a piperidinyl group optionally having 1 to 3 substituents independently selected from the group J below, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from the group Ja below, a piperazinyl group optionally having 1 to 3 substituents independently selected from the group J below, a phenyl group optionally having 1 to 3 substituents independently selected from the group J below, a tetrazolyl group, an azetidinyl group optionally having 1 to 3 substituents independently group selected from the group J below, a morpholino group optionally having 1 to 3 substituents independently selected from the group J below, a dihydropyrazolyl group optionally having 1 to 3 substituents independently selected from the group J below, and an oxadiazolyl group, and group J: a halogen atom, a hydroxyl group, an amino group, a carboxyl group, an aminocarbonyl group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkylamino group, a diC1-C6 alkylamino group, a C1-C1 alkyl group C6carbonyl, a C3-C6 cycloalkyl group, a C1-C6 alkylsulfonyl group, and a C1-C6 alkylsulfonylamide group. (17) A method according to (16), wherein: R22 represents a hydrogen atom, and R23 is a substituent represented by the following formula: [Formula 22] (18) A method for reacting: a compound represented by formula (XVI): [Formula 23] a compound represented by the formula (XVII): [Formula 24] and a compound represented by formula (XVIII): [Formula 25] in a solvent using an asymmetric catalyst prepared from a Lewis acid selected from the group consisting of a Lewis acid of Cu(I) and a Lewis acid of Cu(II) and a chiral ligand selected from the following group: [Formula 26] [Formula 27] to stereoselectively produce a compound represented by formula (XIX) or a salt thereof: [Formula 28] where: M represents a nitrogen atom or CH, L represents a single bond, an oxygen atom, CH2, or C(CH3)2, and R53 represents a C1-C6 alkyl group. (19) A method for reacting a compound represented by formula (XVI): [Formula 29] and a compound represented by the formula (XX): [Formula 30] in a solvent using an asymmetric catalyst prepared from a Lewis acid selected from the group consisting of a Lewis acid of Cu(I) and a Lewis acid of Cu(II) and a chiral ligand selected from the following group: [Formula 31] [Formula 32] to stereoselectively produce a compound represented by formula (XIX) or a salt thereof: [Formula 33] where: M, L, and R53 are as defined in (18). (20) A method for hydrolyzing a compound or a salt thereof produced using a method according to (18) or (19) to produce a compound represented by the following formula (XXI) or a salt thereof: [Formula 34] and condensing the compound or salt with a compound represented by the following formula: [Formula 35] to produce a compound represented by the following formula (XXII) or a salt thereof: where: M and L are as defined in (18) or (19).

ADVANTAGEOUS EFFECTS OF THE INVENTION

[0027] According to the present invention, a compound having a spirooxindole backbone, for example, a compound having a spirooxindole backbone and having antitumor activity that inhibits the interaction between Mdm2 protein and p53 protein can be stereoselectively synthesized in a efficient and inexpensive way.

DESCRIPTION OF MODALITIES

[0028] In the present invention, a "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0029] In the present invention, a "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, a isohexyl, or a 4-methylpentyl group.

[0030] In the present invention, a "C3-C6 cycloalkyl" group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0031] In the present invention, a "C3-C4 cycloalkyl" group is a cyclopropyl group or a cyclobutyl group.

[0032] In the present invention, a "C1-C6 alkoxy" group refers to a group in which a C1-C6 alkyl group mentioned above is substituted with an oxo group, and is a methoxy group, an ethoxy group, a propoxyl, an isopropoxyl group, a butoxyl group, an isobutoxyl group, a s-butoxyl group, a t-butoxyl group, a pentoxyl group, an isopentoxyl group, a 2-methylbutoxyl group, a hexyloxyl group, or an isohexyloxyl group .

[0033] In the present invention, a "C3-C6 cycloalkoxy" group refers to a group in which a C3-C6 cycloalkyl group mentioned above is substituted with an oxy group, and is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy, or a cyclohexyloxy group.

[0034] In the present invention, a "C3-C4 cycloalkoxy" group is a cyclopropoxy group or a cyclobutoxy group.

[0035] In the present invention, a "C3-C8 cycloalkoxy" group is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, or a cyclooctyloxy group.

[0036] In the present invention, a "C1-C6 alkylthio" group refers to a group in which a C1-C6 alkyl group mentioned above is replaced with a thio group. Examples thereof include a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.

[0037] In the present invention, a "C1-C6 alkylsulfonyl" group refers to a group in which a C1-C6 alkyl group mentioned above is replaced with a sulfonyl group. Examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group.

[0038] In the present invention, a "C1-C6 alkylsulfonylamide" group refers to a group in which a C1-C6 alkylsulfonyl group mentioned above is replaced with an amino group. Examples thereof include a methylsulfonylamide group, an ethylsulfonylamide group, a propylsulfonylamide group, and an isopropylsulfonylamide group.

[0039] In the present invention, a "C1-C6 alkylcarbonyl" group refers to a group in which a C1-C6 alkyl group mentioned above is replaced with a carbonyl group. Examples thereof include an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, and an isopropylcarbonyl group.

[0040] In the present invention, a "C1-C6 alkoxycarbonyl" group refers to a group in which a C1-C6 alkoxy group mentioned above is replaced with a carbonyl group. Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and an isopropoxycarbonyl group.

[0041] In the present invention, a "C3-C6 cycloalkylcarbonyl" group refers to a group in which a C3-C6 cycloalkyl group mentioned above is substituted with a carbonyl group, and is a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group , or a cyclohexylcarbonyl group.

[0042] In the present invention, a "C3-C6 cycloalkoxycarbonyl" group refers to a group in which a C3-C6 cycloalkoxy group mentioned above is substituted with a carbonyl group, and is a cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group , or a cyclohexyloxycarbonyl group.

[0043] In the present invention, a "C1-C6 alkylamino" group refers to a group in which a C1-C6 alkyl group mentioned above is replaced with an amino group. Examples thereof include a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group.

[0044] In the present invention, a "dialkyl-C1-C6amino" group refers to a group in which two identical or different C1-C6 alkyl groups mentioned above are replaced with an amino group. Examples thereof include a dimethylamino group, a diethylamino group, a dipropylamino group, and a diisopropylamino group.

[0045] In the present invention, a "C1-C6 alkylaminocarbonyl" group refers to a group in which a C1-C6 alkylamino group mentioned above is substituted with a carbonyl group. Examples thereof include a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, and an isopropylaminocarbonyl group.

[0046] In the present invention, a "C3-C6 cycloalkylaminocarbonyl" group refers to a group in which a C3-C6 cycloalkyl group mentioned above is attached to the amino group side of a group (-NH-C(=O)- ), and is a cyclopropylaminocarbonyl group, a cyclobutylaminocarbonyl group, a cyclopentylaminocarbonyl group, or a cyclohexylaminocarbonyl group.

[0047] In the present invention, a "C3-C8 cycloalkylamino" group refers to a group in which a C3-C8 cycloalkyl group mentioned above is attached to an amino group, and is a cyclopropylamino group, a cyclobutylamino group, or a group cyclopentylamino.

[0048] In the present invention, a "C2-C6 alkenyloxy" group refers to a group in which a straight or branched C2-C6 alkenyl group having 2 to 6 carbon atoms is attached to an oxy group. Examples thereof include a vinyloxy group, an allyloxy group, and an isopropenyloxy group.

[0049] In the present invention, a "C3-C6 cycloalkenyl" group is a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group.

[0050] In the present invention, a "5- or 6-membered heteroaryl group" refers to a group derived from a 5- or 6-membered aromatic compound containing 1 to 3 atoms, each independently selected from the group consisting of one atom of nitrogen, an oxygen atom and a sulfur atom in addition to the carbon atom as atoms constituting the ring. Examples thereof include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl, and a pyridazinyl group.

[0051] In the present invention, a "3- to 6-membered saturated heterocyclic group" refers to a group derived from a 3- to 6-membered monocyclic saturated heterocyclic compound containing an atom selected from the group consisting of a nitrogen atom, a oxygen atom and a sulfur atom in addition to carbon as atoms constituting the ring. Examples thereof include an aziridinyl group, an oxiranyl group, a thiiranyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a piperidinyl group, a tetrahydropyranyl group, and a tetrahydrothiopyranyl group.

[0052] In the present invention, an "asymmetric catalyst" refers to a catalyst for use in asymmetric synthesis. Examples thereof include catalysts having a metal atom therein.

[0053] In the present invention, a "Lewis acid" refers to a substance capable of accepting an electron pair. Examples thereof include Zn(OTf)2, AgOAc, Cu(OTf)2, CuOAc, Ni(OAc)2, Co(OAc)2, CuCl, CuBr, CuI, CuPF6, CuBF4, Cu(OAc)2, Cu( OTf)2, and CuSO4.

[0054] In the present invention, a "chiral ligand" refers to a substance having asymmetry and capable of forming a coordinate bond with a metal, and includes not only unidentate ligands but multidentate ligands. Examples thereof include BINAP derivatives, MeBIPHEP derivatives, TunePHOS derivatives, P-Phos derivatives, JOSIPHOS derivatives, Walphos derivatives, FESULPHOS derivatives, Taniaphos derivatives, Jospophos derivatives, FOXAP derivatives, Mandyphos derivatives, Ferrocelane derivatives, PHOX derivatives, and QuinoxP derivatives.

[0055] In the present invention, the phrase "having asymmetry" means having an asymmetric center, an axial quilarity, a planar chilarity.

[0056] In the present invention, the symbol "*" means an asymmetric center or an axial chilarity.

[0057] In the present invention, the symbol "Cy" is an abbreviation of a cyclopentyl group.

[0058] In the present invention, a "ketimine" refers to an imine formed from a ketone and an amine and is a compound having a structure in which the carbonyl group of the ketone is replaced with the nitrogen atom of the amine.

[0059] A compound represented by formula (I), a compound represented by formula (II), a compound represented by formula (III), a compound represented by formula (IV) or a salt thereof, a compound represented by formula ( V), a compound represented by the formula (VI), a compound represented by the formula (VII), a compound represented by the formula (VIII), a compound represented by the formula (IX), a compound represented by the formula (X), a compound represented by the formula (XI), a compound represented by the formula (XII), a compound represented by the formula (XIII) or a salt thereof, a compound represented by the formula (XIV) or a salt thereof, a compound represented by the formula ( XV) or a salt thereof, a compound represented by the formula (XVI), a compound represented by the formula (XVII), a compound represented by the formula (XVIII), a compound represented by the formula (XIX) or a salt thereof, a compound represented by the formula (XX), a compound represented by the formula (XXI) or a salt thereof, and a compound represented by the formula (XXII) or a salt thereof according to the present invention include all isomers (diastereomers, isomers optical, geometric isomers, rotational isomers, etc.)

[0060] In the compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or a salt thereof, the compound represented by formula ( V), the compound represented by the formula (VI), the compound represented by the formula (VII), the compound represented by the formula (VIII), the compound represented by the formula (IX), the compound represented by the formula (X), the compound represented by the formula (XI), the compound represented by the formula (XII), the compound represented by the formula (XIII) or a salt thereof, the compound represented by the formula (XIV) or a salt thereof, the compound represented by the formula ( XV) or a salt thereof, the compound represented by the formula (XVI), the compound represented by the formula (XVII), the compound represented by the formula (XVIII), the compound represented by the formula (XIX) or a salt thereof, the compound represented by formula (XX), the compound represented by general formula (XXI) or a salt thereof, and the compound represented by formula (XXII) or a salt thereof, isomers thereof and mixtures of these isomers are all represented by individual formulas . Thus, the present invention includes all these isomers and all mixtures of these isomers in arbitrary ratios.

[0061] A compound represented by the formula (IV), a compound represented by the formula (XIII), a compound represented by the formula (XIV), a compound represented by the formula (XV), a compound represented by the formula (XIX), a compound represented by the formula (XXI), and a compound represented by the formula (XXII) according to the present invention can each be converted into a salt by its reaction with an acid when having a basic group or by its reaction with a base when having an acidic group.

[0062] Examples of a salt based on a basic group may include: hydrochloride such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; C1-C6 alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; and carboxylates such as acetate, oxalate, tartrate, and maleate.

[0063] On the other hand, examples of a salt based on an acidic group may include: alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; metal salts such as aluminum salt and iron salt; inorganic salts such as ammonium salt; amine salts of organic salts, etc., such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglycamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0064] A compound represented by the formula (IV) or a salt thereof, a compound represented by the formula (XIII) or a salt thereof, a compound represented by the formula (XIV) or a salt thereof, a compound represented by the formula (XV) or a salt thereof, a compound represented by the formula (XIX) or a salt thereof, a compound represented by the formula (XXI) or a salt thereof, and a compound represented by the formula (XXII) or a salt thereof even according to the present invention, when left in contact with air or when recrystallized, they can each incorporate a water molecule to form a hydrate. Such a hydrate is also included in a salt of the present invention.

[0065] A compound represented by the formula (IV) or a salt thereof, a compound represented by the formula (XIII) or a salt thereof, a compound represented by the formula (XIV) or a salt thereof, a compound represented by the formula (XV) or a salt thereof, a compound represented by the formula (XIX) or a salt thereof, a compound represented by the formula (XXI) or a salt thereof, and a compound represented by the formula (XXII) or a salt thereof even according to the present invention, when left in a solvent or when recrystallized, they can each absorb a certain type of solvent to form a solvate. Such a solvate is also included in a salt of the present invention.

[0066] Examples of a solvent include: ether-based solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol-based solvents such as methanol, ethanol, and 2-propanol; hydrocarbon based solvents such as toluene; nitrile based solvent such as acetonitrile; aliphatic ester based solvents such as ethyl acetate; and amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide.

[0067] In the following, preferred embodiments of the present invention will be described.

[0068] The preferred forms of each substituent in a compound represented by formula (I), a compound represented by formula (II), a compound represented by formula (III), a compound represented by formula (IV), a compound represented by the formula (V), a compound represented by the formula (XIII), a compound represented by the formula (XIV), and a compound represented by the formula (XV).

[0069] R1 represents a hydrogen atom, a C1-C6 alkylcarbonyl group, or a C1-C6 alkoxycarbonyl group optionally having a phenyl group. R1 is more preferably a hydrogen atom, an acetyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, further preferably a hydrogen atom.

[0070] R2 represents a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a phenyl group, in which the 5- or 6-membered heteroaryl group and the phenyl group optionally each have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an aminocarbonyl group, and a C1 alkyl group -C6.

[0071] R2 is more preferably a phenyl group optionally having 1 to 3 halogen atoms, or a pyridyl group optionally having 1 to 3 halogen atoms, even more preferably a phenyl group having a fluorine atom and a chlorine atom, or a pyridyl group having a fluorine atom and a chlorine atom.

[0072] Ring Z is a benzene ring optionally having 1 to 4 halogen atoms and is more preferably a benzene ring having a chlorine atom.

[0073] R3 and R4 each independently represent a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxyl group, and an amino group. Both R3 and R4 are more preferably the same C1-C6 alkyl groups, even more preferably methyl groups.

[0074] In another form of R3 and R4, preferably, R3 and R4 together form a C4-C6 cycloalkyl ring optionally having 1 to 3 C1-C6 alkyl groups in the ring, a piperidine ring optionally having 1 to 3 C1 alkyl groups -C6 in the ring, or a tetrahydropyran ring optionally having 1 to 3 C1-C6 alkyl groups in the ring. The ring formed is most preferably a cyclopentane ring optionally having 1 to 3 C1-C6 alkyl groups in the ring, a cyclohexane ring optionally having 1 to 3 C1-C6 alkyl groups in the ring, or a tetrahydropyran ring optionally having 1 to 3 C1-C6 alkyl groups on the ring, even more preferably a 4,4-dimethylcyclohexane ring.

[0075] R5 represents a C1-C6 alkoxy group, a C3-C8 cycloalkoxy group, a C2-C6 alkenyloxy group, a C1-C6 alkylamino group, a C3-C8 cycloalkylamino group, or a tetrahydropyranylamino group. R5 is more preferably a C1-C6 alkoxy group or a tetrahydropyranylamino group, even more preferably a C1-C6 alkoxy group.

[0076] R22 and R23 each independently represent a hydrogen atom, a C1-C6 alkyl group optionally having 1 to 3 substituents independently selected from group I below, a C1-C6 alkylsulfonyl group optionally having 1 to 3 substituents independently selected from group I below, a C3-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from group I below, an azetidinyl group optionally having 1 to 3 substituents independently selected from group I below, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from the group I below, a piperidinyl group optionally having 1 to 3 substituents independently selected from the group I below, a piperazinyl group optionally having 1 to 3 substituents independently selected from the group I below, a morpholino group optionally having 1 to 3 substituents independently selected from group I below, a phenyl group optionally having 1 to 3 substituents independently selected from group I below, a pyridyl group optionally having 1 to 3 substituents independently selected from group I below, a pyrimidinyl group optionally having 1 to 3 substituents independently selected from the group I below, the pyridazinyl group optionally having 1 to 3 substituents independently selected from the group I below, the pyrrolyl group optionally having 1 to 3 substituents independently selected from the group I below, the pyrazolyl group optionally having 1 to 3 substituents independently selected from the group I below, an imidazolyl group optionally having 1 to 3 substituents independently selected from the group I below, an oxazolyl group optionally having 1 to 3 substituents independently selected from the group I below, an oxadiazolyl group optionally having 1 to 3 substituents independently selected from the group I below, or a triazolyl group optionally having 1 to 3 substituents independently selected from the group I below: group I: a halogen atom, a hydroxyl group, an oxo group, a group carboxyl, a formyl group, an amino group, an aminocarbonyl group, a cyano group, a C1-C6 alkylamino group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylsulfonylamide group, a C1-C6 alkyl group optionally having 1 to 3 independently selected substituents from the group J below, a C1-C6 alkoxy group optionally having 1 to 3 substituents independently selected from the group J below, a C1-C6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from the group J below, a cycloalkylC3-C6carbonyl group optionally having 1 to 3 substituents independently selected from the group J below, a C4-C6 cycloalkyl group optionally having 1 to 3 substituents independently selected from the group J below, a C1-C6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from the group J below, a piperidinyl group optionally having 1 to 3 substituents independently selected from the group J below, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from the group J below, a piperazinyl group optionally having 1 to 3 substituents independently selected from the group J below, a phenyl group optionally having 1 to 3 substituents independently selected from the group J below, a tetrazolyl group, an azetidinyl group optionally having 1 to 3 substituents independently selected from the group J below, a morpholinyl group optionally having 1 to 3 substituents independently selected from the group J below, a dihydropyrazolyl group optionally having 1 to 3 substituents independently selected from the group J below, and an oxadiazolyl group: group J: a halogen atom, a hydroxyl group, an amino group, a carboxyl group, an aminocarbonyl group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkylamino group, a diC1-C6 alkylamino group, a C1-C6 alkylcarbonyl group, a C3-C6 cycloalkyl group, a C1-C6 alkylsulfonyl group, and a C1-C6 alkylsulfonylamide group.

[0077] R22 and R23 are, more preferably, each independently a hydrogen atom, a methyl group, a methylsulfonyl group, or any one of the following T1 to T35: [Formula 37-1] [Formula 37-2]

[0078] M is a nitrogen atom or CH and is most preferably a nitrogen atom.

[0079] L is CH2 or C(CH3)2 and is more preferably C(CH3)2.

[0080] R53 is a C1-C6 alkyl group.

[0081] In a preferred combination of substituents in the compound represented by formula (I), R1 is a hydrogen atom, R2 is a phenyl group having a fluorine atom and a chlorine atom, and ring Z is a benzene ring having a chlorine atom.

[0082] In a preferred combination of substituents in the compound represented by formula (V), R3 and R4 together form a 4,4-dimethylcyclohexane ring, and R5 is a C1-C6 alkoxy group.

[0083] In a preferred combination of the substituents in the compound represented by the formula (IV) or the compound represented by the formula (XIII) in the present invention, R1 is a hydrogen atom, R2 is a phenyl group having a fluorine atom and a fluorine atom. of chlorine, ring Z is a benzene ring having a chlorine atom, R3 and R4 together form a 4,4-dimethylcyclohexane ring, and R5 is a C1-C6 alkoxy group.

[0084] In a preferred combination of the substituents in the compound represented by formula (XIV), R1 is a hydrogen atom, R2 is a phenyl group having a fluorine atom and a chlorine atom, ring Z is a benzene ring having a chlorine atom, and R3 and R4 together form a 4,4-dimethylcyclohexane ring.

[0085] In a preferred combination of the substituents in the compound represented by formula (XV), R1 is a hydrogen atom, R2 is a phenyl group having a fluorine atom and a chlorine atom, ring Z is a benzene ring having a chlorine atom, R3 and R4 together form a 4,4-dimethylcyclohexane ring, and each of R22 and R23 is T24 mentioned above.

[0086] In a preferred combination of the substituents in the compound represented by the formula (XIX), M is a nitrogen atom, L is C(CH3)2, and R53 is a C1-C6 alkyl group.

[0087] In a preferred combination of substituents in the compound represented by formula (XX), L is C(CH3)2, and R53 is a C1-C6 alkyl group.

[0088] In a preferred combination of substituents in the compound represented by formula (XXI) or the compound represented by formula (XXII), M is a nitrogen atom, and L is C(CH3)2.

[0089] In the following, the preferred compounds of the compound represented by the formula (VI), the compound represented by the formula (VII), the compound represented by the formula (VIII), the compound represented by the formula (IX), the compound represented by the formula (IX) will be described. by formula (X), the compound represented by formula (XI), and the compound represented by formula (XII).

[0090] The compound represented by formula (VI) is a derivative of BINAP and is preferably a compound represented by any one of the following formulas: [Formula 38] more preferably a compound represented by any one of the following formulas: [Formula 39]

[0091] The compound represented by formula (VII) is a MeBIOPHEP derivative, a P-Phos derivative, or a TunePHOS derivative and is preferably a compound represented by any one of the following formulas: [Formula 40] [Formula 41] more preferably a compound represented by any one of the following formulas: [Formula 41]

[0092] The compound represented by formula (VIII) is a JOSIPHOS derivative, a Walphos derivative, a FESULPHOS derivative, a Taniaphos derivative, a Jospophos derivative, or a FOXAP derivative, and is preferably a compound represented by any one of the following formulas: [Formula 43] [Formula 44-1] [Formula 44-2] [Formula 45-1] [Formula 45-2] [Formula 46] more preferably a compound represented by any one of the following formulas: [Formula 47]

[0093] The compound represented by formula (IX) is a derivative of Mandyphos and is preferably a compound represented by any one of the following formulas: [Formula 48]

[0094] The compound represented by formula (X) is a derivative of Ferrocellane and is preferably a compound represented by any of the following formula: [Formula 49-1] [Formula 49-2]

[0095] The compound represented by formula (XI) is a derivative of PHOX and is preferably a compound represented by any of the following formulas: [Formula 50]

[0096] The compound represented by the formula (XII) is a derivative of QuinoxP and is preferably a compound represented by the following formula: [Formula 51]

[0097] In the present invention, the Lewis acid is CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF6, CuBF4, Cu(OAc)2, Cu(OTf)2, or CuSO4 and is more preferably CuOAc or Cu(OAc) two.

[0098] In the present invention, a preferred combination of the Lewis acid and the chiral ligand is CuOAc or Cu(OAc)2 as the Lewis acid and a compound represented by any one of the following formulas as the chiral ligand: [Formula 52] [Formula 53]

[0099] In the present invention, the solvent is preferably one or two selected from the group consisting of N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2-propanol, toluene, and ethyl acetate, more preferably one or two selected from the group consisting of N,N-dimethylacetamide and ethyl acetate. Alternatively, a mixture of the solvents in an arbitrary ratio can be used.

[00100] Next, the present invention will be described. It should be understood that the reaction conditions of the present invention are not limited to those described herein. In the present invention, a functional group in a compound can be protected with an appropriate protecting group. Examples of such a functional group might include a hydroxyl group, a carboxyl group, and an amino group. For the type of protecting group and conditions for the introduction and removal of the protecting group, refer to the one(s) described in, for example, “Protective Groups in Organic Synthesis” (TW Greene and PGM Wuts, John Wiley & Sons , Inc., New York, 2006). [PRODUCTION METHODS] 1) Method for producing a compound represented by formula (IV) [Formula 54]

[00101] A compound represented by formula (IV) is obtained by reacting a compound represented by formula (I), a compound represented by formula (II), and a compound represented by formula (III) in the presence of an asymmetric catalyst prepared from a Lewis acid and a chiral ligand, and a solvent. Also, the compound represented by the formula (IV) can be obtained by forming in advance a compound represented by the formula (V) (ketimine) from a compound represented by the formula (II) and a compound represented by the formula (III) and then by the reaction of ketimine with a compound represented by formula (I).

[00102] The reaction is preferably carried out in the presence of a base.

[00103] A compound represented by formula (I) can be produced according to various references (for example, WO2006/091646 and WO2012/121361).

[00104] The amount of the compound represented by formula (II) used is in the range of 0.5 equivalent to 10 equivalents with respect to the compound represented by formula (I) and is preferably in the range of 1.0 equivalent to 3.0 equivalent with respect to the compound represented by formula (I).

[00105] The amount of the compound represented by formula (III) used is in the range of 0.5 equivalent to 10 equivalents with respect to the compound represented by formula (I) and is preferably in the range of 1.0 equivalent to 3.0 equivalent with respect to the compound represented by formula (I).

[00106] Examples of the Lewis acid that can be used include a Lewis acid of Zn(II), a Lewis acid of Ag(I), a Lewis acid of Ni(II), a Lewis acid of Co( II), a Lewis acid of Ru(I), a Lewis acid of Cu(I), and a Lewis acid of Cu(II). The Lewis acid is preferably CuOAc, CuCl, CuBr, CuI, CuOTf, Cu4PF6, Cu4BF4 Cu(OAc)2, Cu(OTf)2, or CuSO4.

[00107] As for the amount of Lewis acid and chiral ligand used, the ligand is preferably added in the range of 0.8 equivalent to 3.0 equivalent with respect to Lewis acid and in the range of 0.01% to 100% in mol of the Lewis acid with respect to the compound represented by formula (I). More preferably, the binder is added in the range of 1.01 equivalents to 2.4 equivalents with respect to the Lewis acid and in the range of 0.5% to 20% in mol of the Lewis acid with respect to compound (I).

[00108] Examples of the chiral linker that can be used include BINAP derivatives, MeBIPHEP derivatives, TunePHOS derivatives, P-Phos derivatives, JOSIPHOS derivatives, Walphos derivatives, FESULPHOS derivatives, Taniaphos derivatives, Jospophos derivatives, FOXAP derivatives, Mandyphos derivatives, Ferrocellane derivatives, PHOX derivatives, and QuinoxP derivatives. The chiral linker is preferably a BINAP derivative, a Tunephos derivative, a MeBIPHEP derivative, a P-Phos derivative, a JOSIPHOS derivative, a FOXAP derivative, a FESULPHOS derivative, or the like.

[00109] [0001] The chiral linker can be purchased from, for example, Sigma-Aldrich Inc., Tokyo Chemical Industry Co., Ltd., Wako Pure Chemical Industries, Ltd., or Strem Chemicals Inc.

[00110] Examples of the base that can be used include: tertiary amines such as triethylamine and N,N-diisopropylethylamine; organic bases such as sodium ethoxide, potassium t-butoxide; and inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, potassium carbonate, potassium bicarbonate, and potassium acetate. The base is preferably a tertiary amine such as triethylamine or N,N-diisopropylethylamine, more preferably triethylamine.

[00111] The amount of the base used is in the range of 0.01 equivalent to 10 equivalents with respect to the compound represented by formula (I) and is preferably in the range of 0.01 equivalent to 0.2 equivalents with respect to the compound represented by formula (I).

[00112] Examples of the solvent include: ether-based solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol-based solvents such as methanol, ethanol, and 2-propanol; hydrocarbon based solvents such as toluene; nitrile based solvents such as acetonitrile; aliphatic ester based solvents such as ethyl acetate; and amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide. These solvents can be used alone or as a mixture in an arbitrary ratio. Preferably, ether based solvents like tetrahydrofuran, amide based solvents like N,N-dimethylacetamide, and aliphatic ester based solvents like ethyl acetate are preferably used alone or as a mixture in an arbitrary ratio.

[00113] The amount of solvent used is in the range of 1 to 100 times the amount of compound (I) and is preferably in the range of 5 to 50 times the amount of the compound represented by formula (I), more preferably in the range of 8 to 25 times the amount of the compound represented by formula (I).

[00114] The reaction temperature is in the range of -88°C to the boiling point of the solvent used and is preferably in the range of -20°C to 60°C.

[00115] The reaction time is in the range of 30 minutes to 96 hours and is preferably in the range of 30 minutes to 64 hours, more preferably in the range of 30 minutes to 48 hours. 2) Method for producing a compound represented by formula (XIV) [Formula 55]

[00116] A compound represented by formula (XIV) is obtained by hydrolysis of a compound represented by formula (IV) (provided that R5 is not -NR51R52).

[00117] The hydrolysis can be performed by adding a base or an acid to a solvent.

[00118] Examples of the base that can be used include: organic bases such as sodium ethoxide and potassium t-butoxide; and inorganic bases such as sodium hydroxide, lithium hydroxide, sodium carbonate, potassium hydroxide, and potassium carbonate. The base is preferably an inorganic base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, most preferably sodium hydroxide.

[00119] The amount of the base used is in the range of 1 equivalent to 10 equivalents with respect to the compound represented by formula (IV) and is preferably in the range of 1 equivalent to 5 equivalents with respect to the compound represented by formula (IV), more preferably in the range of 1 equivalent to 3 equivalents with respect to the compound represented by formula (IV).

[00120] Examples of the acid include: hydrochloric acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; inorganic acids such as nitric acid, perchloric acid, sulfuric acid, and phosphoric acid; C1-C6 alkylsulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and ethanesulfonic acid; arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; and carboxylic acids such as acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, and malic acid. The acid is preferably trifluoroacetic acid or hydrochloric acid.

[00121] The amount of acid used is in the range of 1 equivalent to 100 equivalents with respect to the compound represented by formula (IV) and is preferably in the range of 1 equivalent to 10 equivalents with respect to the compound represented by formula (IV).

[00122] Examples of the solvent include: ether-based solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol-based solvents such as methanol, ethanol, and 2-propanol; hydrocarbon based solvents such as toluene; nitrile based solvents such as acetonitrile; aliphatic ester based solvents such as ethyl acetate; amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide; and halogen-based solvents such as dichloromethane and chloroform. These solvents can be used alone or as a mixture in an arbitrary ratio. The solvent is preferably a halogen-based solvent such as dichloromethane, an alcohol-based solvent such as methanol, or a mixed solvent of an ether-based solvent such as tetrahydrofuran and an alcohol-based solvent such as methanol.

[00123] The amount of solvent used is in the range of 1 to 100 times the amount of the compound represented by the formula (IV) and is preferably in the range of 5 to 50 times the amount of the compound represented by the formula (IV), more preferably in the range from 8 to 25 times the amount of the compound represented by formula (IV).

[00124] The reaction temperature is in the range of -88°C to the boiling point of the solvent used and is preferably in the range of -20°C to 60°C.

[00125] The reaction time is in the range of 30 minutes to 96 hours and is preferably in the range of 30 minutes to 64 hours, more preferably in the range of 30 minutes to 48 hours. 3) Method for producing a compound represented by formula (XV) [Formula 56]

[00126] A compound represented by the formula (XV) is obtained by condensing a compound represented by the formula (XIV) with an amine NHR22R23 using a condensing agent in a solvent. The amine can be produced according to various references (eg WO2006/091646 and WO2012/121361).

[00127] The amount of the amine used is in the range of 0.5 equivalent to 10 equivalents with respect to the compound represented by formula (XIV) and is preferably in the range of 1.0 equivalent to 2.0 equivalents with respect to the compound represented by formula (XIV).

[00128] Examples of the condensing agent include: azodicarboxylic acid triphenylphosphine di-lower alkyl ester such as triphenylphosphine azodicarboxylic acid diethyl ester; carbodiimide derivatives such as N,N'-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); halo-1-lower-alkyl-pyridinium 2-halides such as 2-chloro-1-methylpyridinium iodide; diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA); phosphoryl chlorides such as diethylphosphoryl chloride; imidazole derivatives such as N,N'-carbodiimidazole (CDI); benzotriazole derivatives such as benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HATU), and (1H-benzotriazol-1-yloxy)tripyrolidinophosphonium hexafluorophosphate (PyBOP); and triazine derivatives such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DM-TMM). The condensing agent is preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (HATU), (1H-benzotriazol-1-yloxy)tripyrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DM-TMM).

[00129] The amount of the condensing agent used is in the range of 1 equivalent to 10 equivalents with respect to the compound represented by the formula (XIV) and is preferably in the range of 1 equivalent to 5 equivalents with respect to the compound represented by the formula (XIV) , more preferably in the range of 1 equivalent to 2 equivalents with respect to the compound represented by formula (XIV).

[00130] Examples of the solvent that can be used include: ether-based solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol-based solvents such as methanol, ethanol, and 2-propanol; hydrocarbon based solvents such as toluene; nitrile based solvents such as acetonitrile; aliphatic ester based solvents such as ethyl acetate; and amide solvents such as N,N-dimethylacetamide and N,N-dimethylformamide. The solvent is preferably an amide solvent such as N,N-dimethylacetamide.

[00131] The amount of solvent used is in the range of 1 to 100 times the amount of the compound represented by the formula (XIV) and is preferably in the range of 3 to 50 times the amount of the compound represented by the formula (XIV), more preferably in the range from 5 to 25 times the amount of the compound represented by formula (XIV).

[00132] The reaction temperature is in the range of -88°C to the boiling point of the solvent used and is preferably in the range of -20°C to 60°C.

[00133] The reaction time is in the range of 30 minutes to 96 hours and is preferably in the range of 30 minutes to 64 hours, more preferably in the range of 30 minutes to 48 hours.

EXAMPLES

[00134] Hereinafter, the present invention will be described in more detail with reference to Examples. However, it is not intended that the scope of the present invention be limited thereby.

[00135] Abbreviations used in the Examples are as defined below. mg: milligram, g: gram, mL: milliliter, L: liter, MHz: megahertz.

[00136] In the Examples below, 1H nuclear magnetic resonance (hereinafter referred to as 1H NMR; 500 MHz) spectra were indicated by the δ (ppm) chemical shift value with tetramethylsilane as a standard. As for splitting patterns, s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, and br: broad. In the present Examples, "UHPLC" or "ultrahigh-performance liquid chromatography" was performed using Prominence UFLC (Shimadzu Corp.). [Example 1] (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxo-1'',2''-di - ethyl hydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [Formula 57]

[00137] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) ( 99.9 mg, 0.32 mmol), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of cyclohexanone (50.4 µL, 0.49 mmol), glycine ethyl ester (39.6 µL, 0.39 mmol) and triethylamine (6.8 µL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under an atmosphere of nitrogen, and the resulting mixture was stirred at room temperature for 40 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was stirred vigorously to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and all organic layers were combined and then washed with water three times (5 mL each). The obtained organic layer was concentrated under reduced pressure. To the residue, ethyl acetate (6 mL) and silica gel (500 mg) were added, and the silica gel was filtered. The filtrate was concentrated under reduced pressure. To the residue, ethanol (1.25 ml) was added, then water (1 ml) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (102.9 mg, yield: 65%, 91% ee) as a solid. 1H NMR (500 MHz, CDCl3): δ = 0.91-1.60 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 1.38-1.74 (m, 6H), 1.87-2.0 (m, 1H), 2.12-2.20 (m, 1H), 3.19 (s, 1H), 4.074.20 (m, 2H), 4.54 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.83-6 .89 (m, 1H), 7.05 (dd, J = 8.3, 1.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.36 (dd, J = 8 .0, 2.0 Hz, 1H), 7.49-7.55 (m, 1H), 7.65 (s, 1H). (High Performance Liquid Chromatography (HPLC) conditions for measuring optical purity) Column: CHIRALPAK IC 4.6 mm x 250 mm, 5 μm Mobile phase: 10 mM AcOH buffer solution : MeCN = 40:60 Flow rate: 1 ,0 min/min Column temperature: 40°C Detection wavelength: 254 nm Injection amount: 5 μL Retention time: title compound = 14.1 min, enantiomer = 11.4 min [Example 2] ( 3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2''-oxo-1'',2''- Ethyl dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [Formula 58]

[00138] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) ( 98.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of 4,4-dimethylcyclohexanone (61.4 mg, 0 .48 mmol), glycine ethyl ester (39.5 µL, 0.39 mmol) and triethylamine (6.8 µL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under a nitrogen atmosphere , and the resulting mixture was stirred at room temperature for 22 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was stirred vigorously to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and all organic layers were combined and washed with water three times (5 mL each). The obtained organic layer was concentrated under reduced pressure. To the residue, ethyl acetate (6 mL) and silica gel (500 mg) were added, and the silica gel layer was filtered. The filtrate was concentrated under reduced pressure. To the residue, ethanol (1.0 ml) was added, then water (1 ml) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (137 mg, yield: 82%, 94% ee) as a solid. 1H NMR (500 MHz, CDCl3): δ = 0.67 (s, 3H), 0.91 (s, 3H), 1.10-1.19 (m, 2H), 1.17 (t, J= 7.3 Hz, 3H), 1.25-1.33 (m, 1H), 1.44-1.72 (m, 3H), 1.87-2.01 (m, 1H), 3.16 (s, 1H), 4.07-4.21 (m, 2H), 4.52 (d, J = 8.5 Hz, 1H), 4.83 (d, J = 8.5 Hz, 1H) , 6.74 (d, J = 1.5Hz, 1H), 6.81-6.86 (m, 1H), 7.06 (dd, J = 8.3, 2.8Hz, 1H), 7 .10-7.16 (m, 1H), 7.37 (dd, J=8.3, 1.8 Hz, 1H), 7.48-7.54 (m, 1H), 7.81 (s , 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK OD-3R 4.6 mm x 150 mm, 3 μm Mobile phase: 10 mM phosphate buffer solution : MeCN = 40:60 Flow rate: 1.0 min/min Column temperature: 40°C Detection wavelength: 254 nm Injection amount: 5 μL Retention time: title compound = 13.8 min, enantiomer = 12.9 min [Example 3] (3'R,4'S ,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2''-oxo-1'',2''-dihydrospiro[cyclohexane Ethyl-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [Formula 59]

[00139] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361) (99.2 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of cyclohexanone (50.4 μL, 0.49 mmol), glycine ethyl ester (39.6 μL, 0.39 mmol), and triethylamine (6.8 μL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) was added under an atmosphere of nitrogen, and the resulting mixture was stirred at 0°C for 18 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was stirred vigorously to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and all organic layers were combined and washed with water three times (5 mL each). The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate = 1:1 (v/v)]. To the obtained residue, ethanol (1.0 mL) was added, then water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (101.2 mg, yield: 64%, 99% ee) as a solid. 1H NMR (500 MHz, CDCl3): δ = 0.9-1.1 (m, 2H), 1.19 (t, J=7.3 Hz, 3H), 1.44 (td, J = 12, 9, 3.2 Hz, 1H)m, 1.48-1.70 (m, 1H), 3.2 (s, 1H), 4.12-4.20 (m, 2H), 4.53 ( d, J = 9.0 Hz, 1H), 4.82 (d, J = 10.0 Hz, 1H), 6.77 (d, J = 2.0Hz, 1H), 7.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.34 (dd, J = 8.3, 1.8 Hz, 1H), 7.5-7.56 (m, 1H), 7.59 ( s, 1H), 8.06 (d, J = 5.0 Hz, 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK OD-3R 4.6 mm x 150 mm, 3 μm Mobile phase: 10 mM phosphate buffer solution : MeCN = 40:60 Flow rate: 1.0 min/min Column temperature: 40°C Detection wavelength: 254 nm Injection amount: 5 μL Retention time: title compound = 7.7 min, enantiomer = 8.7 min [Example 4] (3'R,4'S ,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-di Ethyl-hydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [Formula 60]

[00140] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361) (100.7 mg), (R)-BINAP (12.1 mg, 0.019 mmol), and CuOAc (2.0 mg, 0.016 mmol), a solution of 4,4-dimethylcyclohexanone (61.4 mg, 0.48 mmol), glycine ethyl ester (39.5 µL, 0.39 mmol), and triethylamine (6.8 µL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL ) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 14 hours. To the reaction mixture, ethyl acetate (2 mL), water (1 mL), and a 20% aqueous ammonium chloride solution (1 mL) were added, and the mixture was stirred vigorously to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2 mL each), and all organic layers were combined and washed with water three times (5 mL each). The obtained organic layer was concentrated under reduced pressure. To the residue, ethyl acetate (6 mL) and silica gel (500 mg) were added, and the silica gel layer was filtered. The filtrate was concentrated under reduced pressure. To the residue, ethanol (1.0 ml) was added, then water (1 ml) was added dropwise, and the mixture was stirred overnight at room temperature. The deposited solid was filtered and dried under reduced pressure at 40°C to obtain the title compound (134.9 mg, yield: 80%, 99% ee) as a solid. 1H NMR (500 MHz, CDCl3): δ = 0.67 (s, 3H), 0.91 (s, 3H), 1.11-1.21 (m, 2H), 1.19 (t, J= 7.0 Hz, 3H), 1.24-1.34 (m, 1H), 1.43-1.58 (m, 2H), 1.60-1.72 (m, 1H), 1.85 -1.95 (m, 1H), 3.19 (s, 1H), 4.10-4.21 (m, 2H), 4.51 (d, J = 9.0 Hz, 1H), 4, 82 (d, J = 9.5 Hz, 1H), 6.77 (d, J = 2.0Hz, 1H), 7.07 (dd, J = 8.5, 1.5 Hz, 1H), 7 .36 (dd, J = 8.3, 1.8 Hz, 1H), 7.5-7.55 (m, 1H), 7.68 (bs, 1H), 8.05 (d, J = 5 .5Hz, 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK OD-3R 4.6 mm x 150 mm, 3 μm Mobile phase: 10 mM phosphate buffer solution : MeCN = 40:60 Flow rate: 1.0 min/min Column temperature: 40°C Detection wavelength: 254 nm Injection amount: 5 μL Retention time: title compound = 9.4 min, enantiomer = 10.5 min [Example 5] (3'R,4'S ,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-3',3'-dimethyl-2-oxo-1,2-dihydrospiro[indole-3,3'- ethyl pyrrolidine]-5'-carboxylate [Formula 61]

[00141] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) ( 50.8 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), an acetone solution (23.8 µL, 0.32 mmol), glycine ethyl ester (26.4 µL, 0.26 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under an atmosphere of nitrogen, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was stirred vigorously to separate a layer organic. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and all organic layers were combined and washed with water three times (2.5 mL each). The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (66.8 mg, yield: 90%, ratio of diastereomers: 84 (title compound):13:3, optical purity of the title compound: 92% ee) as a oily compound. 1H NMR (500 MHz, CDCl3): δ = 1.07 (s, 3H), 1.17 (t, J =7.0 Hz, 3H), 1.48 (s, 3H), 3.40-3 .62 (m, 1H), 4.07-4.23 (m, 2H), 4.55 (d, J = 9.0 Hz, 1H), 4.91 (d, J = 9.5 Hz, 1H), 6.75-6.80 (m, 1H), 6.80 (d, J = 1.5Hz, 1H), 7.06 (dd, J = 8.0, 2.0Hz, 1H) , 7.09-7.15 (m, 1H), 7.38 (dd, J=8.3, 2.3 Hz, 1H), 7.45-7.50 (m, 1H), 8.62 (s, 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK IC 4.6 mm x 250 mm, 5 μm Mobile phase: HCOOH aq. 0.1% : MeCN = 70:30 Flow rate: 1.0 min/min Column temperature: 27°C Detection wavelength: 254 nm Injection amount: 5 μL Retention time: title compound = 10.3 min, enantiomer = 11.1 min [Example 6] (3'R,4'S,5'R)-6-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2-oxo-1 Ethyl ,2-dihydrospiro[indole-3,3'-pyrrolidine-2',4''-pyran]-5'-carboxylate [Formula 62]

[00142] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361) (48.7 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of tetrahydro-4H-pyran-4-one (22.4 µL, 0.24 mmol), glycine ethyl ester (20 µL, 0.20 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N ,N-Dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was stirred vigorously to separate a layer organic. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and all organic layers were combined and washed with water three times (2.5 mL each). The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (74.9 mg, yield: 96%, ratio of diastereomers: 75 (title compound):20:5, optical purity of the title compound: 98% ee) as a oily compound. 1H NMR (500 MHz, CDCl3): δ = 1.19 (t, J=7.3 Hz, 3H), 1.31-1.41 (m, 1H), 1.42-1.50 (m, 1H), 1.85-1.98 (m, 2H), 3.18-3.38 (m, 1H), 3.67-3.77 (m, 2H), 3.84-3.92 ( m, 1H), 3.88-4.06 (m, 1H), 4.08-4.20 (m, 2H), 4.56 (d, J = 9.5 Hz, 1H), 4.78 (d, J = 9.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 7 .34 (dd, J = 8.3, 2.3 Hz, 1H), 7.49-7.54 (m, 1H), 8.06 (d, J = 5.0 Hz, 1H), 8, 43 (s, 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK IC 4.6 mm x 250 mm, 5 μm Mobile phase: 10 mM AcOH buffer solution : MeCN = 40:60 Flow rate: 1.0 min/min column: 27°C Detection wavelength: 220 nm Injection amount: 5 μL Retention time: title compound = 26.2 min, enantiomer = 22.8 min [Example 7] (3'R,4'S,5 'R)-6-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-3',3'-dimethyl-2-oxo-1,2-dihydrospiro[indole-3,3 Ethyl '-pyrrolidine]-5'-carboxylate [Formula 63]

[00143] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361) (51 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), an acetone solution ( 17.8 µL, 0.24 mmol), glycine ethyl ester (20 µL, 0.20 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was stirred vigorously to separate a layer organic. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and all organic layers were combined and washed with water three times (2.5 mL each). The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (68.9 mg, yield: 92%, ratio of diastereomers: 87 (title compound):13, optical purity of the title compound: 98% ee) as an oily compound . 1H NMR (500 MHz, CDCl3): δ = 1.08 (s, 3H), 1.20 (t, J =7.0 Hz, 3H), 1.46 (s, 3H), 3.40-3 .65 (m, 1H), 4.09-4.26 (m, 2H), 4.54 (d, J = 9.5 Hz, 1H), 4.89 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 1.5 Hz, 1H), 7.07 (dd, J = 8.5, 2.0 Hz, 1H), 7.36 (dd, J = 8.0 , 1.5 Hz, 1H), 7.49-7.55 (m, 1H), 7.86 (s, 1H), 8.07 (d, J = 5.0 Hz, 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK AS-RH 4.6 mm x 150 mm, 5 μm Mobile phase: 10 mM AcOH buffer solution : MeCN = 60:40 Flow rate: 1.0 min/min Column temperature: 40°C Detection wavelength: 254 nm Injection amount: 5 μL Retention time: title compound = 8.4 min, enantiomer = 7.1 min [Example 8] (3'R,4'S ,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxo-1'',2''-dihydrospiro[cyclopentane-1,2'- Ethyl pyrrolidine-3',3''-indole]-5'-carboxylate [Formula 64]

[00144] To a mixture of (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one (WO2006/091646) ( 52.1 mg, 0.17 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of cyclopentanone (28.7 µL, 0.32 mmol), glycine ethyl ester (26.4 µL, 0.26 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under an atmosphere of nitrogen, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was stirred vigorously to separate a layer organic. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and all organic layers were combined and washed with water three times (2.5 mL each). The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 100:50:1.5 (v/v)] and dried under reduced pressure at 40°C. °C to obtain a mixture of the title compound and diastereomers (69 mg, yield: 86%, ratio of diastereomers: 84 (title compound):14:2, optical purity of the title compound: 99% ee) as a oily compound. 1H NMR (500 MHz, CDCl3): δ = 1.17 (t, J=7.3 Hz, 3H), 1.22-1.30 (m, 1H), 1.32-1.42 (m, 1H), 1.50-1.60 (m, 2H), 1.66-1.83 (m, 2H), 1.86-1.97 (m, 1H), 2.07-2.15 ( m, 1H), 3.25-3.64 (m, 1H), 4.07-4.23 (m, 2H), 4.53 (d, J = 9.5 Hz, 1H), 4.76 (d, J = 9.0 Hz, 1H), 6.72-6.77 (m, 1H), 6.80 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.0, 1.5 Hz, 1H), 7.08-7.13 (m, 1H), 7.38 (dd, J = 8.0, 2.0 Hz, 1H), 7.43-7 .50 (m, 1H), 8.68 (s, 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK IC 4.6 mm x 250 mm, 5 μm Mobile phase: HCOOH aq. 0.1% : MeCN = 50:50 Flow rate: 1.0 min/min Column temperature: 27°C Detection wavelength: 220 nm Injection quantity: 5 μL Retention time: title compound = 6.0 min, enantiomer = 5.6 min [Example 9] (3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-2''Ethyl-oxo-1'',2''-dihydrospiro[cyclopentane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [Formula 65]

[00145] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361) (50.9 mg, 0.16 mmol), (R)-BINAP (6.1 mg, 0.01 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of cyclopentanone (21.6 µL, 0.24 mmol), glycine ethyl ester (20 µL, 0.20 mmol), and triethylamine (3.4 µL, 0.024 mmol) in N,N-dimethylacetamide (1.0 mL) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 42 hours. To the reaction mixture, ethyl acetate (1 mL), water (0.5 mL), and a 20% aqueous ammonium chloride solution (0.5 mL) were added, and the mixture was stirred vigorously to separate a layer organic. The aqueous layer was subjected to extraction with ethyl acetate twice (1 mL each), and all organic layers were combined and washed with water three times (2.5 mL each). The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and diastereomers (69.1 mg, yield: 88%, ratio of diastereomers: 87 (title compound):13, optical purity of the title compound: 98% ee) as an oily compound . 1H NMR (500 MHz, CDCl3): δ = 1.19 (t, J=7.3 Hz, 3H), 1.22-1.30 (m, 1H), 1.32-1.43 (m, 1H), 1.48-1.60 (m, 2H), 1.66-1.82 (m, 2H), 1.86-1.96 (m, 1H), 2.02-2.09 ( m, 1H), 3.40-3.62 (m, 1H), 4.08-4.24 (m, 2H), 4.53 (d, J=9.0 Hz, 1H), 4.73 (d, J = 9.0 Hz, 1H), 6.82 (d, J = 1.5 Hz, 1H), 7.07 (dd, J = 8.3, 1.8 Hz, 1H), 7 .36 (dd, J = 8.3, 2.3 Hz, 1H), 7.50-7.54 (m, 1H), 8.04 (d, J = 5.5 Hz, 1H), 8, 60 (s, 1H). (HPLC conditions for measuring optical purity) Column: CHIRALPAK IC 4.6 mm x 250 mm, 5 μm Mobile phase: HCOOH aq. 0.1% : MeCN = 50:50 Flow rate: 1.0 min/min Column temperature: 27°C Detection wavelength: 220 nm Injection quantity: 5 μL Retention time: title compound = 6.7 min, enantiomer = 13.3 min [Example 10] (3'R,4'S,5'R)-N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide [Formula 66]

[Step 1] (4'S,5'R)-6''-Chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2' acid '-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylic

[00146] To a solution of the compound (5.00 g, 9.61 mmol) obtained in Example 4 in methanol (25 mL) and tetrahydrofuran (25 mL), an aqueous solution of 1 N sodium hydroxide (18, 3 ml, 18.3 mmol) was added under ice-cooling, and the mixture was stirred at 0°C for 41.5 hours. The reaction mixture was neutralized to pH 3 by the addition of concentrated hydrochloric acid under ice cooling. Water (75 ml) was added dropwise to the mixture, and the mixture was then stirred at room temperature for 4 hours. The deposited solid was filtered at 0°C and dried under reduced pressure at 40°C to obtain the title compound (4.52 g, yield: 96%) as a solid.

[Step 2] (3'R,4'S,5'R)-N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro-4'-(2-chloro- 3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3'' -indol]-5'-carboxamide

[00147] To a solution of the compound (2.00 g, 4.06 mmol) obtained in step 1 above in N,N-dimethylacetamide (20 mL), 1-hydroxybenzotriazole monohydrate (310 mg, 2.02 mmol) , (2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012/121361) (707 mg, 4.90 mmol), diisopropylethylamine (850 µL, 4.88 mmol), and 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (934 mg, 4.87 mmol) was added, and the mixture was stirred at 0°C for 47.5 hours. To the reaction mixture, ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (20 mL each), and all organic layers were combined and washed with water three times (20 mL each). The solvent was distilled off under reduced pressure. To the residue, acetonitrile (30 ml) was then added, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was allowed to cool, and the deposited solid was then filtered and dried under reduced pressure at 40°C to obtain the title compound (2.13 g, yield: 80%) as a solid. [Example 11] 11-1) Influence of various asymmetric catalysts [Formula 67]

[00148] To a solution of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), and triethylamine (15 mol%) in THF (10 times amount) , a catalyst solution separately prepared by stirring a Lewis acid (5 mol %), a chiral ligand (6 mol %), and THF (10 times amount) for 1 hour under a nitrogen atmosphere was added under an atmosphere of nitrogen, and the mixture was stirred at room temperature for 12 to 16 hours. Then, the optical purity and yield of the obtained trans-1 compound (((3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4 Ethyl ,4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate ) were measured by HPLC. (HPLC conditions for measuring optical purity) Column: CHIRALPAK OD-3R 4.6 mm x 150 mm, 3 μm Mobile phase: 10 mM phosphate buffer solution: MeCN = 40:60 Flow rate: 1.0 min/min Column temperature: 40°C Detection wavelength: 254 nm Injection amount: 5 μL Retention time: title compound = 13.8 min, enantiomer = 12.9 min

[00149] The main results are shown in Table 1 [Table 1-1] [Table 1-2] 11-2) Influence of the various solvents [Formula 68]

[00150] Acidos (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012 /121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol %), and a solvent (10 times amount), a Catalyst solution prepared separately by stirring CuOAc (5 mol %), (S)-BINAP (6 mol %), and a solvent (10 times amount) for 1 hour under a nitrogen atmosphere was added under a nitrogen atmosphere. of nitrogen, and the mixture was stirred at room temperature for 21.5 hours. Then, the yield and optical purity of the obtained trans-2 compound ((3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4, Ethyl 4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate) were measured by HPLC.

[00151] The main results are shown in Table 2. [Table 2] 11-3) Study on the Lewis acid of Cu(I) [Formula 69]

[00152] Acidos (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012 /121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol %), and N,N-dimethylacetamide (10 times amount ), a catalyst solution separately prepared by stirring Cu(I) Lewis acid (5 mol %), (S)-BINAP (6 mol %), and N,N-dimethylacetamide (10 times amount) for 1 hour under a nitrogen atmosphere, was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 to 21.5 hours. Then, the yield and optical purity by HPLC of the obtained trans-2 compound ((3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)- 4,4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate ethyl) were measured by HPLC.

[00153] The main results are shown in Table 3. [Table 3] 11-4) Study on Lewis acid of Cu(II) [Formula 70]

[00154] (3E/Z)-6-Chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one (WO2012/ 121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), Cu(II) Lewis acid (5 mol%), (R)-BINAP (6 mol %), and N,N-dimethylacetamide (20 times amount) were stirred at room temperature for 15 hours under a nitrogen atmosphere. Then, the yield and optical purity of the obtained trans-2 compound ((3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)- 4,4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate ethyl) were measured by UPLC and HPLC, respectively.

[00155] The main results are shown in Table 4. [Table 4] *:Sign "-" in column "ee" indicates that the compound trans-2 ((3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl )-4,4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'- ethyl carboxylate) was a major product. 11-5) Study using CuOAc and various chiral ligands [Formula 71]

[00156] To a solution of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), and triethylamine (15 mol%) in THF (10 times amount) , a catalyst solution separately prepared by stirring CuOAc (5 mol %), a chiral ligand (6 mol %), and THF (10 times amount) for 1 hour under an atmosphere of nitrogen was added under an atmosphere of nitrogen, and the mixture was stirred at room temperature for 12 to 16 hours. Then, the yield and optical purity of the obtained trans-1 compound ((3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4 Ethyl -dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate) were measured by HPLC.

[00157] The main results are shown in Table 5. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] *: Sign "-" in column "ee" indicates that the compound trans-2 ((3'S,4'R,5'S)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl )-4,4-dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'- ethyl carboxylate) was a major product. [Example 12] (3'R,4'S,5'R)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo - tert-butyl 1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylate [Formula 72]

[00158] To a mixture of (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2- one (WO2012/121361) (50.0 mg, 0.16 mmol), (R)-BINAP (6.0 mg, 0.009 mmol), and CuOAc (1.0 mg, 0.008 mmol), a solution of 4, 4-dimethylcyclohexanone (31.0 mg, 0.25 mmol), glycine tert-butyl ester (27.8 mg, 0.21 mmol), and triethylamine (3.4 µl, 0.024 mmol) in N,N -dimethylacetamide (1.0 ml) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 19.5 hours. To the reaction mixture, ethyl acetate (2.0 ml), water (0.5 ml), and a 20% aqueous ammonium chloride solution (0.5 ml) were added, and the mixture was vigorously stirred to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice (2.0 ml each), and all organic layers were combined and washed with water three times (2.0 ml each). The obtained organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [heptane:ethyl acetate:triethylamine = 50:50:1 (v/v)] and dried under reduced pressure at 40°C to obtain a mixture of the title compound and the diastereomer (61.0 mg, yield: 69%, ratio of diastereomers: 90 (title compound):10, optical purity of the title compound: 97% ee) as an oily compound . 1H NMR (500 MHz, CDCl3): δ = 0.67 (s, 3H), 0.92 (s, 3H), 1.10-1.25 (m, 3H), 1.33 (s, 9H) , 1.45-1.75 (m, 3H), 1.80-2.00 (m, 2H), 3.15-3.20 (m, 1H), 4.42 (d, J = 9, 0 Hz, 1H), 4.68 (d, J = 9.5 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 7.53-7.63 (m, 2H), 8.06 (d, J = 5 .0 Hz, 1H) (HPLC conditions for measuring optical purity) Column: CHIRALPAK OD-3R 4.6 mm x 150 mm, 3 μm Mobile phase: HCOOH aq. 0.1% (v/v):MeCN = 50:50 Flow rate: 1.0 ml/min Column temperature: 40°C Detection wavelength: 254 nm Injection quantity: 5 μL Retention time: compound of the titre = 9.4 min, enantiomer = 11.4 min [Reference Example 1] (2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide [Formula 73]

[Step 1] tert-Butyl N-(2-{[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]amino}-2-oxoethyl)carbamate

[00159] To a slurry of N-(tert-butoxycarbonyl)glycine (1.01 g, 5.77 mmol), (2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012/ 121361) (0.85 g, 5.90 mmol), and diisopropylethylamine (994 µl, 5.71 mmol) in tetrahydrofuran (40 ml), O-(7-azabenzotriazol-1-yl)-N hexafluorophosphate, N,N',N',-tetramethyluronium (2.21 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [ethyl acetate:methanol = 98:2 → 80:20 (v/v)]. To the obtained solid, ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 4 hours. The obtained slurry was filtered and dried under reduced pressure at 40°C to obtain the title compound (1.47 g, yield: 83%) as a white solid. 1H NMR (500 MHz, CDCl3): δ = 1.40-1.50 (m, 1H), 1.46 (s, 9H), 1.57-1.66 (m, 1H), 2.08- 2.16 (m, 1H), 2.22-2.28 (m, 1H), 3.09 (t, J = 10.5 Hz, 1H), 3.70-3.82 (m, 3H) , 3.90-4.02 (m, 1H), 4.16 (ddd, J = 10.9, 4.9, 1.9 Hz, 1H), 5.08-5.15 (m, 1H) , 5.38-5.46 (m, 1H), 5.95-6.05 (m, 1H), 6.43-6.53 (m, 1H)

[Step 2] (2S,5R)-5-[(2-Aminoacetyl)amino]tetrahydro-2H-pyran-2-carboxamide

[00160] To the compound (500 mg, 1.66 mmol) obtained in the preceding step 1, a solution of 4 N hydrogen chloride in cyclopentyl and methyl ether (5 ml, 20 mmol) was added, and the mixture was stirred at room temperature environment for 15 hours. The reaction mixture was filtered and washed with cyclopentyl and methyl ether (5 ml). To a solution of the obtained solid in methanol (5 ml), a 28% solution of sodium methoxide in methanol (810 µl, 3.32 mmol) was added, and the mixture was stirred at room temperature for 2 hours. To the obtained reaction mixture, neutral silica gel (500 mg) was added, and the mixture was concentrated under reduced pressure. To the residue, ethyl acetate (50 ml) and methanol (5 ml) were added, and the silica gel pad was filtered. The filtrate was concentrated under reduced pressure. To the residue, tetrahydrofuran (2.0 ml) was added, and the mixture was stirred at room temperature for 17 hours. The obtained slurry was filtered and dried under reduced pressure at 40°C to obtain the title compound (111 mg, yield: 33%) as a white solid. 1H NMR (500 MHz, CD3OD): δ = 1.50-1.61 (m, 2H), 2.00-2.18 (m, 2H), 3.16 (t, J = 10.8 Hz, 1H), 3.21 (d, J = 16.5 Hz, 1H), 3.25 (d, J = 17.0 Hz, 1H), 3.72-3.78 (m, 1H), 3, 80-3.90 (m, 1H), 4.07 (ddd, J = 10.9, 4.9, 1.9 Hz, 1H) [Example 13] (3'R,4'S,5'R)- N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4 -dimethyl-2''-oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide [Formula 74]

[00161] To a mixture of the compound (39.1 mg, 0.19 mmol) obtained in Reference Example 1, (3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1, 3-dihydro-2H-indol-2-one (WO2006/091646) (48.6 mg, 0.16 mmol), (R)-BINAP (6.6 mg, 0.011 mmol), and CuOAc (1. 2 mg, 0.010 mmol), a solution of 4,4-dimethylcyclohexanone (30.6 mg, 0.24 mmol) in N,N-dimethylacetamide (1.0 ml) was added under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 17 hours. The entire amount of the reaction mixture was diluted with methanol (100 ml) to obtain the title compound (ultra high performance liquid chromatography (UHPLC) yield: 65%, 96%de) as a solution in methanol. (UHPLC measurement conditions for UHPLC yield calculation) Column: CAPCELL CORE ADME 2.1 mm x 100 mm, 2.7 μm Mobile phase: HCOOH aq. 0.1% (v/v):MeCN Gradient: MeCN 20% ^ 92% Gradient Conditions: 0-2.5 min MeCN 20%, 2.5-7.3 min MeCN 20 ^ 92%, 7.3 -14 min 92% MeCN, 14.01-17 min 20% MeCN Flow rate: 0.6 ml/min Column temperature: 40°C Detection wavelength: 254 nm Injection quantity: 5 μl Retention time: compound titre length = 6.6 min (HPLC conditions for measurement) Column: CHIRALPAK OD-3R 4.6 x 150 mm, 3 μm Mobile phase: 0.1% (v/v) aq. HCOOH:MeCN = 60: 40 Flow rate: 1.0 ml/min Column temperature: 40°C Detection wavelength: 254 nm Injection amount: 10 μl Retention time: title compound =17.7 min, diastereomer = 8.5 min [ Example 14] (3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2''- oxo-1'',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide [Formula 75]

[Step 1] (4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2''-oxo-1'' acid, 2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5''-carboxylic

[00162] To a slurry of the compound (1.00 g, 2.04 mmol) obtained in Example 1 and methanol (10 ml), 25% (w/v) aqueous sodium hydroxide solution (1.0 ml , 6.25 mmol) was added under ice-cooling, and the mixture was stirred at 0°C for 27.5 hours. The reaction mixture was neutralized by adding 35% (w/w) concentrated hydrochloric acid (651 mg, 6.25 mmol) under ice cooling. Water (15 ml) was added dropwise to the mixture, and the mixture was then stirred at 0°C for 18 hours. The deposited crystals were filtered at 0°C and dried under reduced pressure at 40°C to obtain the title compound (0.90 g, yield: 95%, >99.5% ee) as a pale yellow solid. 1H NMR (500 MHz, CD3OD): δ = 1.10-1.30 (m, 2H), 1.50-1.68 (m, 1H), 1.70-2.13 (m, 5H), 2.18-2.28 (m, 1H), 2.50-2.62 (m, 1H), 4.81 (d, J = 10.0 Hz, 1H), 5.01 (d, J = 10.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 7.07-7.15 (m, 2H), 7.28-7.35 (m, 1H), 7.54 (dd, J = 8.0, 2.5 Hz, 1H), 7.60-7.68 (m, 1H) (HPLC conditions for measuring optical purity) Column: CHIRALPAK QN-AX 4 .6 mm x 150 mm, 3 µm Mobile phase: aq. 0.1% (v/v) :MeCN = 60:40 Flow rate: 1.0 ml/min Column temperature: 40°C Detection wavelength: 254 nm Injection quantity: 5 μL Retention time: compound of the titre = 7.5 min, enantiomer = 4.0 min

[Step 2] (3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-N-(trans-4-hydroxycyclohexyl)-2''-oxo-1 '',2''-dihydrospiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide

[00163] To a solution of the compound (501 mg, 1.08 mmol, 99% ee) obtained in step 1 above and trans-4-aminocyclohexanol (157 mg, 1.36 mmol) in N,N-dimethylacetamide ( 5 ml), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (392 mg, 1.42 mmol) was added under ice cooling, and the mixture was stirred at 0°C for 1 hour. To the reaction mixture, ethyl acetate (10 ml) and water (5 ml) were added, and the mixture was shaken to separate an organic layer. The aqueous layer was subjected to extraction with ethyl acetate (10 ml), and all organic layers were combined and washed with water three times (10 ml each). The solvent was distilled off under reduced pressure. To the residue, acetonitrile (15 ml) was then added, and the mixture was stirred at room temperature for 18 hours. The deposited crystals were filtered and dried under reduced pressure at 40°C to obtain the title compound (426 g, yield: 70%, >99.5% ee) as a white solid. 1H NMR (500 MHz, CD3OD): δ = 0.93 (td, J = 13.5, 4.2 Hz, 1H), 1.0-1.15 (m, 1H), 1.25-1, 45 (m, 4H), 1.5-2.05 (m, 12H), 3.5-3.65 (m, 2H), 4.49 (d, J=9.5 Hz, 1H), 4 .65 (d, J = 9.0 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 7.02 (td, J = 8.5, 2.0 Hz, 1H) , 7.20 (td, J = 15.0, 1.5 Hz, 1H), 7.39 (dd, J = 8.5, 2.5 Hz, 1H), 7.61 (td, J = 14 ,8, 1.3 Hz, 1H) (HPLC conditions for measuring optical purity) Column: CHIRALPAK OD-3R 4.6 mm x 150 mm, 3 μm Mobile phase: HCOOH aq. 0.1% (v/v) : MeCN = 60:40 Flow rate: 1.0 ml/min Column temperature: 40°C Detection wavelength: 254 nm Injection quantity: 5 μL Retention time: compound of the titre = 4.9 min, enantiomer = 4.2 min

Claims (7)

1. Compound, characterized by the fact that it presents the formula or a salt thereof wherein: R1 is hydrogen; R2 is a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; R3 and R4 together form a C4-C6 cycloalkyl ring, optionally having 1 to 8 substituents independently selected from halogen and C1-C6 alkyl; R5 is C1-C6 alkoxy, C3-C8 cycloalkoxy or C2-C6 alkenyloxy, wherein C1-C6 alkoxy and C3-C8 cycloalkoxy are each optionally having 1 to 3 substituents independently selected from the group E below; ring Z is a benzene ring optionally having 1 to 4 substituents independently selected from the group E below, a pyridine ring optionally having 1 to 3 substituents independently selected from the group E below, or a pyrimidine ring optionally having 1 or 2 substituents selected regardless of group E below; and E group: a halogen atom, a hydroxy group, a vinyl group, an ethynyl group, a cyano group, a C1-C6 alkoxy group, an aminocarbonyl group and a C1-C6 alkyl group optionally having 1 to 3 halogen atoms . 2. Compound according to claim 1, characterized in that R5 is C1-C6 alkoxy optionally with 1 to 3 substituents independently selected from a halogen atom, a hydroxy group, a vinyl group, an ethynyl group, a cyano group, a C1 -C6 alkoxy group, an aminocarbonyl group and a C1 -C6 alkyl group optionally having 1 to 3 halogen atoms. 3. Compound according to claim 2, characterized in that R 5 is C1-C6 alkoxy. 4. Compound, according to any one of claims 1 to 3, characterized in that it has the formula (XIX): , or a salt thereof wherein: M is N or CH; L is a single bond, an oxygen atom, CH2 , or C(CH3)2 ; and R53 is C1-C6 alkyl. 5. Compound, according to claim 4, characterized by the fact that M is N. 6. Compound of claim 4 or 5, characterized in that L is C(CH3)2. 7. Compound according to any one of claims 4 to 6, characterized in that M is N; L is C(CH3^; and R53 is C1-C6 alkyl.