JP2011012024A - Indane compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound useful as a neurokinin receptor antagonist.SOLUTION: The compound is expressed by general formula (I) (wherein Ris optionally substituted phenyl or the like; Ris optionally substituted phenyl or the like; Ris -Y-CHC(=O)-N(R)(CH)-N(R)-SO-R, -Y-CHC(=O)-N(R)(CH)-N(R)-C(=O)-Ror the like; Y is methylene, an oxygen atom or the like; and R, R, Rand Rare each alkyl or the like).

Description

The present invention relates to a novel indane derivative having an antagonistic action on neurokinin receptors (NK ₁ , NK ₂ and NK ₃ ).

Patent Document 1 discloses an indanol derivative that exhibits an antagonistic action on a neurokinin NK ₁ receptor, a neurokinin NK ₂ receptor, and a neurokinin NK ₃ receptor.

  Patent Document 1 describes, for example, a compound in which an amide group is bonded via a methylene group as a derivative in which the hydroxyl group of indanol is substituted. However, the compound described in the publication differs from the compound of the present invention in the substituent bonded to the nitrogen atom of the amide group. Patent Document 1 does not describe a compound in which a carbon atom or a nitrogen atom is bonded to the 2-position of indane.

US Pat. No. 7,365,067

As a result of intensive studies on neurokinin receptor antagonists for many years, the present inventors have shown that they have an antagonistic action on all of neurokinin NK ₁ , neurokinin NK ₂ and neurokinin NK ₃ receptors, and are persistent. The present invention was completed by finding a compound having a medicinal effect.

  Furthermore, another object of the present invention is to provide a novel pharmaceutical comprising the above compound as an active ingredient. Examples of diseases to which the pharmaceutical can be applied include anxiety, depression, psychiatric disease and schizophrenia. Central nervous system diseases including: dementia in AIDS, Alzheimer-type senile dementia, Alzheimer's disease, Down's syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy, and neuralgia Respiratory disease including chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma, cough; inflammatory bowel disease (IBD), psoriasis, connective tissue inflammation, osteoarthritis, degenerative arthritis, and rheumatoid arthritis Allergic diseases including eczema; and rhinitis; hypersensitivity diseases including hypersensitivity diseases to vines; conjunctivitis, spring conjunctivitis, spring catarrh, blood associated with various inflammatory eye diseases Ophthalmic diseases including destruction of aqueous humor barrier, increased intraocular pressure, miosis; skin diseases including contact dermatitis, atopic dermatitis, hives, and other eczema-like dermatitis; weakness including alcoholism Physical disease; reflex sympathetic dystrophy including shoulder-hand syndrome; mood modulation; unwanted immune response including graft rejection and immune enhancement including systemic lupus erythematosus or immunosuppression Diseases caused by abnormalities in the nerves that regulate the internal organs, colitis, ulcerative colitis, irritable bowel syndrome, gastrointestinal diseases including Crohn's disease; Postoperative disease, gastrointestinal obstruction, decreased gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure or vomiting induced by side effects associated with various drug administrations; cystitis, bladder function including urinary incontinence disease Eosinophilia due to collagen disease, scleroderma, liver cirrhosis infection; diseases caused by abnormal blood flow due to vasodilation or contraction including angina, migraine, and Raynaud's disease; Pain nociceptive pain, including sleep apnea syndrome. The novel medicament of the present invention can be used particularly as a preventive or therapeutic agent for respiratory diseases such as asthma, bronchitis and chronic obstructive pulmonary disease; allergic diseases such as rhinitis; and / or urinary incontinence. .

  The present invention relates to (1) general formula (I)

[Where:
R ¹ may be independently substituted with a group selected from substituent group A and may be independently substituted with 1 to 5 phenyl groups or a group selected from substituent group A and may be independently substituted with 1 to 3 A good heterocyclic group,
R ² may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A A good heterocyclic group,
R ³ represents any of the following groups:
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 5) -SO 2 -R 6,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 5) -C (= O) -R 7,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 5) -C (= O) -N (R 8) R 9,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -O-C (= O) -N (R 8) R 9,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -C (= O) -N (R 8) R 9,
^{_{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 8) R 9,
^{_{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -O-R 10,
^{_{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -C (= O) -R 10,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -CH (OH) -R 10,
-N ^(R 4) H,
_{^{-N (R 11) CH 2 C}} (= O) -N (R 4) (CH 2) n -O-R 10,
Y represents a methylene group, an oxygen atom or a group represented by the formula —NH—,
R ⁴ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a hydroxy group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₁₁ alkylcarbonyl group, a benzoyl group or a benzyloxycarbonyl. Group,
R ⁵ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a phenyl group or a benzyl group,
R ⁶ is a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a phenyl group which may be independently substituted with a group selected from the substituent group A, or a substituent group A A heterocyclic group optionally substituted with 1 to 3 groups independently selected from the above (provided that when R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl group is excluded);
R ⁷ _is, C 1 -C ₆ alkyl, _C 1 -C ₆ alkyl which is 1 to 3 substituents independently a group selected from substituent group _B, C 3 -C ₆ cycloalkyl groups, C _1- C ₆ alkoxy group, phenoxy group, phenyl group which may be independently substituted with 1 to 5 groups independently selected from substituent group A, 1 to 5 groups independently selected from substituent group A A naphthyl group which may be individually substituted or a heterocyclic group which may be independently substituted with 1 to 3 groups selected from the substituent group A (provided that when R ⁵ is a hydrogen atom, Except ₁ -C ₆ alkyl groups),
R ⁸ and R ⁹ are the same or different and are each selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ hydroxyalkyl group, a C ₃ -C ₆ cycloalkyl group, and a substituent group A. A phenyl group optionally substituted with 1 to 5 groups independently, a naphthyl group, an indanyl group or a substituent group A optionally substituted with 1 to 5 groups independently selected from the substituent group A A heterocyclic group which may be independently substituted with a group selected from 1 or 3 together, or together, including the nitrogen atom to which they are attached, selected from substituent group A A nitrogen-containing heterocyclic group which may be independently substituted with 1 to 3 groups,
R ¹⁰ is independently a hydrogen atom, a phenyl group which may be independently substituted with a group selected from the substituent group A, or a group selected from substituent group A; A C ₁ -C ₆ alkyl group substituted by one optionally substituted heterocyclic group or a C ₃ -C ₆ cycloalkyl group,
R ¹¹ represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a hydroxy group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₁₁ alkylcarbonyl group, a benzoyl group or a benzyloxycarbonyl group. ,
m represents an integer of 1 to 3,
n represents an integer of 1 to 6,
Substituent group A is a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ halogenated alkyl _group, C 1 -C ₆ hydroxyalkyl group, hydroxy _group, C 1 -C ₆ alkoxy group, _{C 1} - C ₆ halogenated alkoxy group, a cyano group, a carboxyl group, a carbamoyl _group, C 2 -C ₇ alkylcarbonyl _group, C 2 -C ₇ alkoxycarbonyl _group, C 2 -C ₇ alkylcarbonyloxy _group, C 2 -C ₇ alkoxy carbonyloxy _group, C 1 -C ₆ alkylsulfonyl group, a nitro group, an amino group, a mono _-C 1 -C ₆ alkylamino group, di - _(C 1 -C ₆ alkyl) amino group, N- _(C 2 -C ₇ alkoxycarbonyl) -N- _(C 1 -C ₆ alkyl) amino group, a group consisting of phenyl and pyridyl groups,
Substituent Group B represents a phenyl group, a hydroxy _group, C 1 -C ₆ alkoxy group, a phenoxy _group, C 2 -C ₇ alkylcarbonyloxy group and di - indicates a _(C 1 -C ₆ alkyl) group consisting of amino group . Or a pharmacologically acceptable salt thereof.

In the present invention, preferably,
(2) In (1),
The compound or its pharmacologically acceptable salt whose general formula (I) is general formula (Ia).

(3) In (1),
The compound whose general formula (I) is general formula (Ib), or its pharmacologically acceptable salt.

(4) In (1),
The compound whose general formula (I) is general formula (Ic), or its pharmacologically acceptable salt.

(5) In any one item selected from (1) to (4),
A compound or a pharmacologically acceptable salt thereof, wherein R ³ is any of the following groups:

_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -SO 2 -R 6,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -C (= O) -R 7,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -C (= O) -N (R 8) R 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -O-C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -N (R 8) R 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -O-R 10,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -C (= O) -R 10,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -CH (OH) -R 10,
—NH—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—R ¹⁰
(6) In (5),
R ⁵ is a hydrogen atom, methyl group, phenyl group or benzyl group, R ⁶ is a phenyl group, 4-trifluoromethylphenyl group or 8-quinolyl group, R ⁷ is a phenoxy group, 4-triol group A fluoromethylphenyl group, a 3,5-di (trifluoromethyl) phenyl group, a 2-naphthyl group or a 2-quinolyl group, and the group represented by the formula —N (R ⁸ ) R ⁹ is an anilino group, diethylamino group; Group, N-methyl-N-phenylamino group, 4-morpholinyl group or 1-piperidyl group, and the group represented by the formula -NHR ⁹ is isopropylamino group, butylamino group, t-butylamino group, cyclohexyl amino group, an anilino group, 2-phenylphenyl group, a 1-naphthylamino group or a 5-indanyl amino ^{group, R 10} is a hydrogen atom, a phenyl group or 2-pyridyl a group compound or a pharmacologically acceptable salt thereof.

(7) In any one item selected from (1) to (4),
A compound or a pharmacologically acceptable salt thereof, wherein R ³ is any of the following groups:

_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -SO 2 -R 6,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -C (= O) -R 7,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -O-C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -N (R 8) R 9,
R ⁵ is a hydrogen atom, methyl group, phenyl group or benzyl group, R ⁶ is a phenyl group, 4-trifluoromethylphenyl group or 8-quinolyl group, R ⁷ is a phenoxy group, 2-naphthyl group A group represented by the formula -N (R ⁸ ) R ⁹ is an anilino group, and a group represented by the formula -NHR ⁹ is a butylamino group or a t-butylamino group. , A cyclohexylamino group, an anilino group or a 2-phenylphenylamino group, or a pharmacologically acceptable salt thereof.

(8) In (1),
The general formula (I) is the general formula (Ib), and R ³ is the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N (R ⁵ ) —SO. A group represented by _2- R ⁶ or a group represented by the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N (R ⁵ ) —C (═O) —R ⁷ R ⁵ is a hydrogen atom, a methyl group, a phenyl group or a benzyl group, R ⁶ is a phenyl group, a 4-trifluoromethylphenyl group or an 8-quinolyl group, and R ⁷ is A compound or a pharmacologically acceptable salt thereof which is a phenoxy group, 4-trifluoromethylphenyl group, 3,5-di (trifluoromethyl) phenyl group, 2-naphthyl group or 2-quinolyl group.

(9) In (1),
The general formula (I) is the general formula (Ib), and R ³ is the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N (R ⁵ ) —SO. A group represented by _2- R ⁶ or a group represented by the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N (R ⁵ ) —C (═O) —R ⁷ R ⁵ is a hydrogen atom, a methyl group, a phenyl group or a benzyl group, R ⁶ is a phenyl group, a 4-trifluoromethylphenyl group or an 8-quinolyl group, and R ⁷ is The compound which is a phenoxy group, 2-naphthyl group or 2-quinolyl group, or a pharmacologically acceptable salt thereof.

(10) In (1),
The general formula (I) is the general formula (Ib) or the general formula (Ic), and R ³ is the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N. (R ⁵ ) —C (═O) —N (R ⁸ ) R ⁹ , wherein R ⁵ is a hydrogen atom, a methyl group, a phenyl group or a benzyl group, and the formula —N (R ⁸ ) A compound or a pharmacologically acceptable salt thereof, wherein the group represented by R ⁹ is an anilino group, diethylamino group, N-methyl-N-phenylamino group, 4-morpholinyl group or 1-piperidyl group.

(11) In (1),
The general formula (I) is the general formula (Ib), and R ³ is the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—C (═O). A group represented by —NHR ⁹ or a group represented by the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —C (═O) —NHR ⁹ , The group represented by —NHR ⁹ is an isopropylamino group, a butylamino group, a t-butylamino group, a cyclohexylamino group, an anilino group, a 2-phenylphenylamino group, a 1-naphthylamino group, or a 5-indanylamino group. Or a pharmacologically acceptable salt thereof.

(12) In (1),
The general formula (I) is the general formula (Ib), and R ³ is the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—C (═O). A group represented by —NHR ⁹ or a group represented by the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —C (═O) —NHR ⁹ , A compound or a pharmacologically acceptable salt thereof, wherein the group represented by —NHR ⁹ is a butylamino group, a t-butylamino group, a cyclohexylamino group, an anilino group or a 2-phenylphenylamino group.

(13) In (1),
The general formula (I) is the general formula (Ib), and R ³ is the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —N (R ⁸ ) R ^9. And the group represented by the formula —N (R ⁸ ) R ⁹ is an anilino group, diethylamino group, N-methyl-N-phenylamino group, 4-morpholinyl group or 1-piperidyl group. A compound or a pharmacologically acceptable salt thereof.

(14) In (1),
The general formula (I) is the general formula (Ib), and R ³ is represented by the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—R ^10. A group represented by the formula: —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —C (═O) —R ¹⁰ or a formula —O—CH ₂ C (= O) —N (CH ₃ ) — (CH ₂ ) ₃ —CH (OH) —R ¹⁰ is a group represented by the formula, and R ¹⁰ is a hydrogen atom, a phenyl group or a 2-pyridyl group, or a pharmacology thereof Top acceptable salt.

(15) In (1),
The general formula (I) is the general formula (Ia), and R ³ is represented by the formula —NH—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—R ^10. Or a pharmacologically acceptable salt thereof, wherein R ¹⁰ is a hydrogen atom, a phenyl group or a 2-pyridyl group.

(16) A compound having the general formula (I)
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl-2-naphthamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy] -N-methyl-N- {3- [methyl (phenylsulfonyl) amino] propyl} acetamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -4- (trifluoromethyl) benzamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -3,5-bis (trifluoromethyl Benzamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} quinoline-2-carboxamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- {3-[(quinolin-8-ylsulfonyl) amino] propyl} acetamide ,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [3-({[4- (trifluoromethyl) phenyl] sulfonyl} Amino) propyl] acetamide,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-phenylbutanamide,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N- (2,3-dihydro-1H-indene-5 -Yl) butanamide,

N-biphenyl-2-yl-4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3 4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butanamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-morpholin-4-ylbutyl) acetamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-piperidin-1-ylbutyl) acetamide,
N- (4-anilinobutyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4- Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide,

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-phenoxybutyl) acetamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [4- (pyridin-2-yloxy) butyl] acetamide,
N-benzyl-N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} benzamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-phenylbenzamide,
Phenyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine- 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-oxo-4-phenylbutyl) acetamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxy-4-phenylbutyl) -N-methylacetamide,

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl phenylcarbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl isopropyl carbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl 1-naphthylcarbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl tert-butylcarbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl cyclohexyl carbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl butyl carbamate,

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {3-[(diethylcarbamoyl) amino] propyl} -N-methylacetamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} morpholine-4-carboxamide,
2-{[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine- 5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (3- {methyl [methyl (phenyl) carbamoyl] amino } Propyl) acetamide,
^{N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2 , 3-dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylglycinamide, or
^{N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2 , 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylglycinamide or a pharmacologically acceptable salt thereof. Salt.

(17) A compound having the general formula (I)
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl-2-naphthamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy] -N-methyl-N- {3- [methyl (phenylsulfonyl) amino] propyl} acetamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} quinoline-2-carboxamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- {3-[(quinolin-8-ylsulfonyl) amino] propyl} acetamide ,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [3-({[4- (trifluoromethyl) phenyl] sulfonyl} Amino) propyl] acetamide,
N-biphenyl-2-yl-4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3 4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butanamide,
N- (4-anilinobutyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4- Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide,

N-benzyl-N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} benzamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-phenylbenzamide,
Phenyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine- 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid,

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl phenylcarbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl tert-butylcarbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl cyclohexyl carbamate, or
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl butyl carbamate or the pharmacology thereof Top acceptable salt.

The present invention further relates to a pharmaceutical composition (in particular, neurokinin NK) comprising as an active ingredient the compound described in any one of (1) to (17) or a pharmacologically acceptable salt thereof. ₁ , a pharmaceutical composition for treating or preventing a disease mediated by neurokinin NK ₂ and / or neurokinin NK ₃ receptor; a pharmaceutical composition for preventing or treating respiratory disease, allergic disease and / or urinary incontinence And a pharmaceutical composition for preventing or treating asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence), in particular, any one selected from (1) to (17) above Prevention of respiratory diseases (particularly asthma, bronchitis and / or chronic obstructive pulmonary disease) containing the compound according to one item or a pharmacologically acceptable salt thereof as an active ingredient Alternatively, it relates to a pharmaceutical composition for pulmonary administration for treatment.

The present invention further provides a pharmaceutical composition (in particular, a pharmaceutical composition for treating or preventing a disease mediated by neurokinin NK ₁ , neurokinin NK ₂ and / or neurokinin NK ₃ receptor; respiratory disease, allergy A pharmaceutical composition for preventing or treating disease and / or urinary incontinence; and a pharmaceutical composition for preventing or treating asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence) For use as an active ingredient of a compound described in any one of (1) to (17) above or a pharmacologically acceptable salt thereof, particularly for respiratory diseases (particularly asthma, Selected from the above (1) to (17) for producing a pharmaceutical composition for pulmonary administration for preventing or treating bronchitis and / or chronic obstructive pulmonary disease) This invention relates to the use of the compound described in any one of the above or a pharmacologically acceptable salt thereof as an active ingredient.

The present invention further comprises administering an effective amount of the compound described in any one of (1) to (17) above or a pharmacologically acceptable salt thereof to a mammal (particularly human). Causes neurokinin NK ₁ , neurokinin NK ₂ and / or neurokinin NK ₃ receptor mediated diseases (especially respiratory diseases, allergic diseases and / or urinary incontinence; and asthma, bronchitis, chronic obstructive lungs) With regard to a method for preventing or treating (disease, rhinitis and / or urinary incontinence), in particular, an effective amount of the compound described in any one of (1) to (17) above or a pharmacologically acceptable salt thereof The present invention relates to a method for preventing or treating respiratory diseases (particularly asthma, bronchitis and / or chronic obstructive pulmonary disease) by pulmonary administration of salt to mammals (particularly humans).

  In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom.

In the present invention, the “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl or hexyl group, preferably having 1 to 4 linear or branched alkyl groups (C ₁ -C ₄ alkyl groups). R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ are more preferably a methyl group or an ethyl group (C ₁ -C ₂ alkyl group), and even more preferably a methyl group. It is. R ⁸ and R ⁹ are more preferably a methyl group, an ethyl group, an isopropyl group, a butyl group or a t-butyl group, and even more preferably a butyl group or a t-butyl group.

In the present invention, the “C ₁ -C ₆ halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkyl group”. For example, it is a trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl or fluoromethyl group, and preferably the same or different 1 to 5 “halogen atoms” are the “C ₁ -C ₄ alkyl”. A group (C ₁ -C ₄ halogenated alkyl group) bonded to the “group”, and more preferably 1 to 5 of the same or different “halogen atoms” are attached to the “C ₁ -C ₂ alkyl group”. A bonded group (C ₁ -C ₂ halogenated alkyl group), and even more preferably a trifluoromethyl group.

In the present invention, the “C ₁ -C ₆ hydroxyalkyl group” is a group in which one hydroxy group is bonded to the “C ₁ -C ₆ alkyl group”. For example, a hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl group, preferably a group in which one hydroxy group is bonded to the “C ₁ -C ₄ alkyl group”, More preferably, one hydroxy group is a group bonded to the “C ₁ -C ₂ alkyl group”, and even more preferably a hydroxymethyl group or a 2-hydroxyethyl group.

In the present invention, the “C ₁ -C ₆ alkoxy group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, 2-methylbutoxy, 3-ethylpropoxy, neopentoxy, hexyloxy or 2,3-dimethylbutoxy group, Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms (C ₁ -C ₄ alkoxy group), and more preferred is a methoxy group or an ethoxy group (C ₁ -C ₂ alkoxy group). And even more preferred is a methoxy group.

In the present invention, the “C ₁ -C ₆ halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkoxy group”. For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-fluoroethoxy or A pentafluoroethoxy group, preferably a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₄ alkoxy group” (C ₁ -C ₄ halogenated alkoxy group) More preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C ₁ -C ₂ alkoxy group” (C ₁ -C ₂ halogenated alkoxy group), Even more preferred is a trifluoromethoxy group.

In the present invention, the “C ₂ -C ₇ alkylcarbonyl group” is a group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a carbonyl group. For example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group, and preferably a group (C ₂ -C ₅ alkyl) in which _one “C ₁ -C ₄ alkyl group” is bonded to a carbonyl group A carbonyl group), more preferably an acetyl group or a propionyl group (C ₂ -C ₃ alkylcarbonyl group), and even more preferably an acetyl group.

In the present invention, the “C ₂ -C ₇ alkoxycarbonyl group” is a group in which one of the above “C ₁ -C ₆ alkoxy groups” is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group, preferably one of the above-mentioned “C ₁ -C ₄ alkoxy” “Group” is a group bonded to a carbonyl group (C ₂ -C ₅ alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (C ₂ -C ₃ alkoxycarbonyl group), and even more preferably. Is a methoxycarbonyl group.

In the present invention, the “C ₂ -C ₇ alkylcarbonyloxy group” is a group in which one carbonyl group to which the “C ₁ -C ₆ alkyl group” is bonded is bonded to an oxygen atom. For example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, pivaloyloxy or valeryloxy group, and preferably a carbonyl group to which one of the above-mentioned “C ₁ -C ₄ alkyl groups” is bonded is an oxygen atom A group (C ₂ -C ₅ alkylcarbonyloxy group) bonded to, more preferably an acetoxy or propionyloxy group (C ₂ -C ₃ alkylcarbonyloxy group), and still more preferably an acetoxy group. It is.

In the present invention, the “C ₂ -C ₇ alkoxycarbonyloxy group” is a group in which one carbonyl group to which the “C ₁ -C ₆ alkoxy group” is bonded is bonded to an oxygen atom. For example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, s-butoxycarbonyloxy or t-butoxycarbonyloxy group, preferably one A carbonyl group to which the “C ₁ -C ₄ alkoxy group” is bonded is a group (C ₂ -C ₅ alkoxycarbonyloxy group) bonded to an oxygen atom, and more preferably a methoxycarbonyloxy group or an ethoxycarbonyloxy group a (C ₂ -C ₃ alkoxycarbonyl group), further preferably more, a methoxycarbonyloxy group.

In the present invention, the “C ₁ -C ₆ alkylsulfonyl group” is a group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a sulfonyl group, and is a straight chain or branched group having 1 to 6 carbon atoms. It is a branched alkylsulfonyl group. For example, a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl or pentylsulfonyl group, preferably a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms A group (C ₁ -C ₄ alkylsulfonyl group), more preferably a methylsulfonyl or ethylsulfonyl group (C ₁ -C ₂ alkylsulfonyl group), and even more preferably a methylsulfonyl group.

In the present invention, the “mono-C ₁ -C ₆ alkylamino group” is a group in which one “C ₁ -C ₆ alkyl group” is bonded to an amino group. For example, it is a methylamino, ethylamino, propylamino, isopropylamino or butylamino group, and preferably a group in which one of the aforementioned “C ₁ -C ₄ alkyl group” is bonded to an amino group (mono-C ₁ — a C ₄ alkylamino group), more preferably a methylamino group or an ethylamino group (mono--C ₁ -C ₂ alkylamino group), more preferably more, a methylamino group.

In the present invention, the “di- (C ₁ -C ₆ alkyl) amino group” is a group in which two identical or different “C ₁ -C ₆ alkyl groups” are bonded to an amino group. For example, dimethylamino, diethylamino, dipropylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino or N-butyl-N-methylamino group, preferably two identical or different Wherein the “C ₁ -C ₄ alkyl group” is a group bonded to an amino group (di- (C ₁ -C ₄ alkyl) amino group), more preferably a dimethylamino group, a diethylamino group or N-ethyl —N-methylamino group (di- (C ₁ -C ₂ alkyl) amino group), and even more preferably a dimethylamino group.

In the present invention, “N- (C ₂ -C ₇ alkoxycarbonyl) -N— (C ₁ -C ₆ alkyl) amino group” means one “C ₂ -C ₇ alkoxycarbonyl group” and one The “C ₁ -C ₆ alkyl group” is a group bonded to an amino group. For example, N-methoxycarbonyl-N-methylamino, N-ethoxycarbonyl-N-methylamino or N-ethyl-N-methoxycarbonylamino group, preferably one of the above-mentioned “C ₂ -C ₅ alkoxy” groups carbonyl group "and one of the" _C 1 -C ₄ alkyl group "is bonded to an amino group _(N- (C 2 -C _{5 alkoxycarbonyl)-N-(C} 1 -C ₄ alkyl) amino group) And more preferably N-methoxycarbonyl-N-methylamino group, N-ethoxycarbonyl-N-methylamino group, N-ethyl-N-methoxycarbonylamino group or N-ethoxycarbonyl-N-ethylamino group. a group _(N- (C 2 -C ₃ alkoxycarbonyl) -N- _(C 1 -C ₂ alkyl) amino group), more preferably, N- methoxy carbonylation Is -N- methylamino group.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. A cyclohexyl group is preferred.

  In the present invention, the “heterocyclic group” contains 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and may further contain 1 or 2 nitrogen atoms, and the sulfur atom contains 2 oxygen atoms. A 4- to 7-membered heterocyclic group to which atoms may be bonded. For example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, An `` aromatic heterocyclic group '' such as a pyrimidinyl or pyrazinyl group, or tetrahydropyranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, Thiazolinyl, thiazolidinyl, pyrazolidinyl, dioxolanyl, dioxanyl or 5,6-dihydro-4H-1,3- A “partially or fully reduced saturated heterocyclic group” such as a xazine group, and the heterocyclic group may be condensed with another cyclic group such as a benzene ring (“fused bicyclic ring”). Heterocyclic groups "), for example, quinolyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, 1,3-dihydroisobenzofuranyl, quinolyl, 1,3-benzodioxolanyl, 1,4- A benzodioxanyl, indolyl, isoindolyl or indolinyl group; Preferable is a pyridyl group, piperidyl group, morpholinyl group or quinolyl group, and more preferable is a 2-pyridyl group, 1-piperidyl group, 4-morpholinyl group, 2-quinolyl group or 8-quinolyl group.

In the present invention, the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted. R ¹ is preferably a 3,5-di (trifluoromethyl) phenyl group. R ² is preferably a 4-fluorophenyl group or a 3,4-dichlorophenyl group, and more preferably a 3,4-dichlorophenyl group. R ⁶ is preferably a phenyl group or a 4-trifluoromethylphenyl group. R ⁷ is preferably a 4-trifluoromethylphenyl group or a 3,5-di (trifluoromethyl) phenyl group. R ⁸ and R ⁹ are preferably a phenyl group or a 2-phenylphenyl group. R ¹⁰ is preferably a phenyl group.

In the present invention, “a naphthyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” refers to 1 to 5 independently with a naphthyl group or a group selected from the substituent group A. It is a naphthyl group substituted one by one. A naphthyl group is preferred. More preferably, R ⁷ is a 2-naphthyl group. R ⁸ and R ⁹ are 1-naphthyl groups.

In the present invention, the “heterocyclic group optionally substituted with 1 to 3 groups independently selected from the substituent group A” is independently 1 with a group selected from the heterocyclic group or the substituent group A. Thru | or 3 substituted heterocyclic groups. R ⁶ is preferably a quinolyl group, more preferably an 8-quinolyl group. R ⁷ is preferably a quinolyl group, and more preferably a 2-quinolyl group. In R ^10, it is preferably a pyridyl group, and more preferably a 2-pyridyl group.

  In the present invention, the “nitrogen-containing heterocyclic group optionally substituted by 1 to 3 groups independently selected from the substituent group A” means “heterocyclic group” or substituent containing at least one nitrogen atom. A “heterocyclic group” containing at least one nitrogen atom, independently substituted with 1 to 3 groups selected from group A; Preferred is a piperidyl group or morpholinyl group, and more preferred is a 4-morpholinyl group or 1-piperidyl group.

In the present invention, preferred R ¹ is a 3,5-di (trifluoromethyl) phenyl group.

In the present invention, preferred R ² is a 4-fluorophenyl group or a 3,4-dichlorophenyl group, and more preferred R ² is a 3,4-dichlorophenyl group.

  In the present invention, preferable general formula (I) is general formula (Ia), general formula (Ib) or general formula (Ic), and more preferable general formula (I) is general formula (Ib). .

In the present invention, R ³ is preferably a group represented by the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N (R ⁵ ) —SO ₂ —R ^6. A group represented by the formula: —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N (R ⁵ ) —C (═O) —R ⁷ , a formula —O—CH _{A group represented by 2} C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —N (R ⁵ ) —C (═O) —N (R ⁸ ) R ⁹ , a formula —O—CH ₂ A group represented by C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—C (═O) —NHR ⁹ , a formula —O—CH ₂ C (═O) —N (CH ₃ ); ) — (CH ₂ ) ₃ —C (═O) —NHR ⁹ group, the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —N (R ⁸ ) ) Group represented by R ⁹ , the formula —O—CH ₂ C (═O) —N (CH _{3) - (CH} 2) 4 group represented by ^{-O-R 10,} wherein _{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -C (= O) -R A group represented by formula ¹⁰ , a group represented by the formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₃ —CH (OH) —R ¹⁰ , or a formula —NH—CH ₂ A group represented by C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—R ¹⁰ , and more preferred R ³ is represented by the formula —O—CH ₂ C (═O) —N. ^{_{(CH 3) - (CH 2}} ) 3 -N (R 5) groups represented by _-SO 2 -R ^6, wherein _{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) A group represented by _3- N (R ⁵ ) —C (═O) —R ⁷ , a formula —O—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—C ( = O) group represented by -NHR ^9, wherein _-O-CH 2 C _{= O) -N (CH 3)} - (CH 2) 3 -C (= O) group represented by -NHR ⁹ or formula _{-O-CH 2 C (= O} ) -N (CH 3) - (CH ₂ ) A group represented by _4- N (R ⁸ ) R ⁹ .

  In the present invention, preferred Y is an oxygen atom or a group represented by the formula —NH—, and more preferred Y is an oxygen atom.

In the present invention, preferred R ⁴ is a methyl group.

In the present invention, preferred R ⁵ is a hydrogen atom, a methyl group, a phenyl group or a benzyl group.

In the present invention, R ⁶ is preferably a phenyl group, a 4-trifluoromethylphenyl group, or an 8-quinolyl group.

In the present invention, preferred R ⁷ is a phenoxy group, 4-trifluoromethylphenyl group, 3,5-di (trifluoromethyl) phenyl group, 2-naphthyl group or 2-quinolyl group, and more preferred R 7 ⁷ is a phenoxy group, 2-naphthyl group or 2-quinolyl group.

In the present invention, a preferred group represented by the formula —N (R ⁸ ) R ⁹ is an anilino group, diethylamino group, N-methyl-N-phenylamino group, 4-morpholinyl group or 1-piperidyl group, A more preferred group represented by the formula —N (R ⁸ ) R ⁹ is an anilino group.

In the present invention, preferable groups represented by the formula —NHR ⁹ are isopropylamino group, butylamino group, t-butylamino group, cyclohexylamino group, anilino group, 2-phenylphenylamino group, 1-naphthylamino group. Or a 5-indanylamino group, and a more preferable group represented by the formula —N (R ⁸ ) R ⁹ is a butylamino group, a t-butylamino group, a cyclohexylamino group, an anilino group, or 2-phenylphenyl. It is an amino group.

In the present invention, preferred R ¹⁰ is a hydrogen atom, a phenyl group or a 2-pyridyl group.

  In the present invention, preferable m is 1 or 2, and more preferable m is 2.

  In the present invention, n is preferably 3 or 4.

In the present invention, a preferred substituent group A is a halogen atom, a C ₁ -C ₆ halogenated alkyl group or a phenyl group, and a more preferred substituent group A is a fluorine atom or a chlorine atom, a trifluoromethyl group or It is a phenyl group.

  In the present invention, a preferred substituent group B is a phenyl group.

  The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.).

  The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers since an asymmetric carbon atom exists in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.

  For the stereoisomer as described above, an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound. Examples of atomic isotopes include deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), and the like. The compound may also be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

  The “pharmacologically acceptable salt” means that the compound having the general formula (I) of the present invention has a basic group such as an amino group, and is reacted with an acid, or a carboxyl group. In the case of having an acidic group such as, a salt can be obtained by reacting with a base, so that the salt is shown.

Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C ₁ -C ₆ alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine salt And amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.

  On the other hand, examples of the salt based on the acidic group 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 salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt, etc. Amine salts such as machine salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.

  The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the atmosphere or recrystallized, and adsorbs water, or hydrates. Such hydrates are also included in the salts of the present invention.

  The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also a solvate of the present invention. Included in the salt.

  The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably a compound having the general formula (I) of the present invention.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is useful as a medicament because it exhibits an antagonistic action on the neurokinin NK ₁ , neurokinin NK ₂ and neurokinin NK ₃ receptors. In particular, it is useful as a preventive or therapeutic agent for respiratory diseases such as asthma, bronchitis and chronic obstructive pulmonary disease; allergic diseases such as rhinitis; and / or urinary incontinence.

  The compound having the general formula (I) of the present invention can be produced according to the methods A to O described below.

  The solvent used in the reaction in each step of the following methods A to O is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example. Solvent groups include hydrocarbons such as pentane, hexane, heptane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N Amides such as methyl-2-pyrrolidinone, hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, i-propanol N-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve Such alcohols; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, carbonic acid Esters such as diethyl; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, chloroform, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene; acetic acid, formic acid, propionic acid, butyric acid, triflu Carboxylic acids such as roacetic acid; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine, picoline, 4 -Dimethylaminopyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona -5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), such as piperidine Amines; water; and a mixed solvent thereof.

  The base used in the reaction in each step of the following methods A to O is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxy Sodium-t-butoxide, potassium methoxide, potassium Alkali metal alkoxides such as um ethoxide, potassium tert-butoxide, lithium methoxide; alkali metal trialkylsiloxides such as sodium trimethylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; sodium thiomethoxide, sodium Mercaptan alkali metals such as thioethoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4- Pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine (4-DMAP), 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethyl Ruaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8 Organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU); organometallic bases such as n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide; or proline Is an amino acid such as

  The condensing agent used in the reaction in each step of the following methods A to O is, for example, azodicarboxylic acid di-lower alkyl ester-triphenylphosphine such as azodicarboxylic acid diethyl ester-triphenylphosphine; N, N ′ -Carbodiimide derivatives such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI); 2-halo-1-lower such as 2-chloro-1-methylpyridinium iodide Alkylpyridinium halides; diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA); phosphoryl chlorides such as diethylphosphoryl chloride; imidazole derivatives such as N, N'-carbodiimidazole (CDI); O- (7 -Azabe Zotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), (1H-benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP) Such benzotriazole derivatives.

  When a condensing agent is used in the reaction of each step of the following method A to method O, an additive for promoting dehydration condensation or suppressing side reactions may be added as necessary. The additive used is not particularly limited as long as it is generally known, but 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzo Triazole (HOAt), hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt), 4-dimethylaminopyridine (4-DMAP).

  In the reaction of each step of the following methods A to O, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.

  In the reaction in each step of the following methods A to O, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, distillation or a method commonly used for separation and purification of ordinary organic compounds (for example, silica gel, alumina, magnesium-silica gel-based Florisil). Such as adsorption column chromatography using such a carrier, Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) Separation by column chromatography using a suitable carrier, ion exchange chromatography, or normal phase / reverse phase column chromatography using silica gel or alkylated silica gel, preferably various high performance liquid chromatography (HPLC)). Can be purified. In addition, the target compound in each step can be directly used in the next reaction without purification.

  In addition, the amino group, hydroxy group and / or carboxyl group may be protected using a protecting group as necessary. Processes that require protection and deprotection are known methods (for example, the method described in “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication)). It is done accordingly.

In Method A, R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁵ ) —SO ₂ —R ^6. In which the compound having the general formula (Id) is a group represented by the formula:

In the present invention, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , Y, m, and n are as defined above, and R ^1a , R ^2a , R ^4a, and R ^6a are R ¹ R ¹ , R ² , R ⁴ and R ⁶ are amino groups, hydroxy groups and / or carboxyl groups which may be protected, and R ¹ , R ² , R ⁴ and R ⁶ are the same groups as defined above, and X represents a leaving group.

  The “leaving group” in the definition of X is usually a group leaving as a nucleophilic residue. For example, a halogen atom such as a fluorine atom, chlorine atom, bromine atom or iodine atom; a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy; a halogeno lower group such as trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy An alkanesulfonyloxy group; an arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, preferably a halogen atom, more preferably a bromine atom or iodine Is an atom. Further, it may be a leaving group activated (generated) in a reaction solution system represented by Mitsunobu reaction (for example, Bull. Chem. Soc. Jpn. 1967, 40, 935-939., Tetrahedron). Lett. 1993, 34, 1639-1642., Tetrahedron Lett. 1996, 37, 2459.).

Step A1 This step is a step of producing a compound having the general formula (Id).

In this step, a compound having the general formula (II) is reacted with a compound having the general formula (III) in a solvent in the presence or absence of a base, and then R ^1a , R ^2a , R ^{4a are} optionally reacted. And removal of amino, hydroxy and / or carboxyl protecting groups in R ^6a .

  The compound having the general formula (III) is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

  The solvent used in this step is preferably a halogenated hydrocarbon, ether, amide or a mixed solvent thereof, more preferably dichloromethane, N, N-dimethylformamide or a mixed solvent thereof. It is.

  The base used in this step is preferably an organic base, more preferably triethylamine, diisopropylethylamine or pyridine, and even more preferably triethylamine.

  The reaction temperature in this step is usually from −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C., more preferably 20 ° C. to 50 ° C.

  The reaction time in this step is usually 30 minutes to 24 hours, preferably 1 to 6 hours.

In the method B, R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁵ ) —C (═O). This is a method for producing a compound having the general formula (Ie) which is a group represented by —R ⁷ .

In the present invention, R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ , R ^1a , R ^2a , R ^4a , Y, m, and n are as defined above, and R ^7a is R ⁷ The amino group, hydroxy group and / or carboxyl group contained as a substituent in the group of R ⁷ is an amino group, hydroxy group and / or carboxyl group which may be protected, and is the same as the group in the definition of the group of R ⁷ Represents a group, and X ¹ represents a hydroxyl group or a group similar to the group in the definition of the group of X.

Step B1 This step is a step of producing a compound having the general formula (Ie), and is performed by the method (i), (ii) or (iii).

(I) (When X ¹ is a hydroxyl group) In this step, the halogen group or acid anhydride agent is used in a solvent to convert the carboxyl group of the compound having the general formula (IV) into an acid halide or mixed acid anhydride. After conversion to a compound, activation, reaction with a compound having the general formula (II) in the presence or absence of a base, and optionally an amino group in R ^1a , R ^2a , R ^4a and R ^7a , It is carried out by removing a protective group for a hydroxy group and / or a carboxyl group.

  The compound having the general formula (IV) is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

  The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.

  Examples of the halogenating agent or acid anhydride agent used in this step include acid halogenating agents such as thionyl chloride and oxalyl chloride; phosphate chlorides such as phosphorus trichloride and phosphorus pentachloride; Chloroformates such as ethyl and isobutyl chloroformate; acid halides such as acetyl chloride and pivaloyl chloride; acid anhydrides such as acetic anhydride and trifluoroacetic anhydride; or dichlorotriphenylphosphorane, dibromotriphenyl Phosphoranes such as phospholane, preferably oxalyl chloride, isobutyl chloroformate, pivaloyl chloride or trifluoroacetic anhydride, more preferably pivaloyl chloride.

  The base used in this step is preferably an organic base, more preferably triethylamine, diisopropylethylamine, pyridine or 4- (N, N-dimethylamino) pyridine, and even more preferably. , Triethylamine or diisopropylethylamine.

  The reaction temperature in this step is usually -10 ° C to 60 ° C, preferably 0 ° C to 30 ° C.

  The reaction time in this step is usually 10 minutes to 24 hours, preferably 1 hour to 12 hours.

(Ii) (when X ¹ is a hydroxyl group) This step is in a solvent in the presence of a condensing agent, the presence or absence of a base, a compound having the general formula (II) with a compound having the general formula (IV) After the reaction, the amino group, hydroxy group and / or carboxyl group protecting group in R ^1a , R ^2a , R ^4a and R ^7a is optionally removed.

  The solvent used in this step is preferably a halogenated hydrocarbon, ether, amide or a mixed solvent thereof, more preferably dichloromethane, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. It is a mixed solvent.

  The condensing agent used in this step is preferably DCC, EDCI, CDI, HATU or PyBOP, and more preferably EDCI.

  The base used in this step is preferably an organic base, more preferably triethylamine, diisopropylethylamine or pyridine, and even more preferably triethylamine.

  The additive used in this step is preferably 4-dimethylaminopyridine (4-DMAP).

  The reaction temperature in this step is usually from −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C., more preferably 20 ° C. to 50 ° C.

  The reaction time in this step is usually 10 minutes to 48 hours, preferably 1 hour to 24 hours.

(Iii) (when X ¹ is X) This step comprises reacting a compound having the general formula (II) with a compound having the general formula (IV) in a solvent in the presence or absence of a base. The method is carried out in the same manner as in step A1 of the method A, and is optionally performed by removing amino, hydroxy and / or carboxyl protecting groups in R ^1a , R ^2a , R ^4a and R ^7a . .

In the method C, R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁵ ) —C (═O). This is a method for producing a compound having the general formula (If) which is a group represented by —N (R ⁸ ) R ⁹ .

In the present invention, R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ^1a , R ^2a , R ^4a , Y, X ¹ , m and n are as defined above, R ^8a and R ^9a are amino groups, hydroxy groups and / or carboxyl groups which may be protected in the amino group, hydroxy group and / or carboxyl group contained as a substituent in the groups of R ⁸ and R ^9. , R ⁸ and R ⁹ are the same groups as defined in the definition of the group.

Step C1 This step is a step of producing a compound having the general formula (If), and is carried out by the method (i), (ii) or (iii).

(I) (When X ¹ is a hydroxyl group) In this step, the halogen group or acid anhydride agent is used in a solvent to convert the carboxyl group of the compound having the general formula (V) into an acid halide or mixed acid anhydride. After being converted into a product, etc., activated, and reacted in the presence or absence of a base with a compound having the general formula (II) in the same manner as in Step B1 (i) of Method B above If desired, the amino group, hydroxy group and / or carboxyl group protecting group in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a is removed.

  The compound having the general formula (V) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

(Ii) (When X ¹ is a hydroxyl group) In this step, a compound having the general formula (II) and a compound having the general formula (V) in a solvent in the presence of a condensing agent, in the presence or absence of a base Is carried out in the same manner as in step B1 (ii) of the above-mentioned method B, and if desired, the amino group, hydroxy group and / or carboxyl in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a This is done by removing the protecting group of the group.

(Iii) (when X ¹ is X) This step comprises reacting a compound having the general formula (II) with a compound having the general formula (V) in a solvent in the presence or absence of a base. After the same procedure as in Step A1 of Method A, the amino group, hydroxy group and / or carboxyl group protecting group in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a is optionally removed. It is done by.

In the method D, R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁵ ) —C (═O). This is a method for producing a compound having the general formula (Ig), which is a group represented by —N (R ⁸ ) R ⁹ , and R ⁹ is a hydrogen atom.

In the present invention, R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , R ^1a , R ^2a , R ^4a , R ^8a , Y, m and n have the same meaning as described above.

Step D1 This step is a step of producing a compound having the general formula (Ig).

In this step, a compound having the general formula (II) is reacted with a compound having the general formula (VI) in a solvent or non-solvent in the presence or absence of a base, and then R ^1a , R ^{2a is} optionally reacted. , R ^4a and R ^8a are carried out by removing the protecting group of the amino group, hydroxy group and / or carboxyl group.

  The compound having the general formula (VI) is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

  The solvent used in this step is preferably a halogenated hydrocarbon, ether, aromatic hydrocarbon or a mixed solvent thereof, more preferably dichloromethane, tetrahydrofuran, toluene or a mixed solvent thereof. It is.

  The base used in this step is preferably an organic base, more preferably triethylamine, diisopropylethylamine or pyridine, and even more preferably triethylamine (having the general formula (II) If the compound is an acid salt, it is added to make it free).

  The reaction temperature in this step is usually from −20 ° C. to 150 ° C., preferably 0 ° C. to 120 ° C., more preferably 50 ° C. to 80 ° C.

  The reaction time in this step is usually 10 minutes to 24 hours, preferably 30 minutes to 6 hours.

In the method E, R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —O—C (═O) —N (R ⁸⁾ a method for the preparation of a compound having the general formula is a group represented by R ⁹ and (Ih).

In the present invention, R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ^1a , R ^2a , R ^4a , R ^8a , R ^9a , Y, X ¹ , m and n are as defined above. Indicates.

Step E1 This step is a step of producing a compound having the general formula (Ih) and is carried out by the method (i), (ii) or (iii).

(I) (When X ¹ is a hydroxyl group) In this step, a halogen group or an acid anhydride agent is used in a solvent to convert the carboxyl group of the compound having the general formula (V) into an acid halide or mixed acid anhydride. After being converted into a product, etc., and activated in the same manner as in Step B1 (i) of Method B by reacting with a compound having the general formula (VII) in the presence or absence of a base If desired, the amino group, hydroxy group and / or carboxyl group-protecting group in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a is removed.

(Ii) (When X ¹ is a hydroxyl group) In this step, a compound having the general formula (VII) and a compound having the general formula (V) in a solvent in the presence of a condensing agent, in the presence or absence of a base Is carried out in the same manner as in step B1 (ii) of the above-mentioned method B, and if desired, the amino group, hydroxy group and / or carboxyl in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a This is done by removing the protecting group of the group.

(Iii) (When X ¹ is X) This step is performed by reacting a compound having the general formula (VII) with a compound having the general formula (V) in a solvent in the presence or absence of a base. After the same procedure as in Step A1 of Method A, the amino group, hydroxy group and / or carboxyl group protecting group in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a is optionally removed. It is done by.

In Method F, R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —O—C (═O) —N (R ⁸⁾ a group represented by R ^9, a method for the preparation of a compound having the general formula R ⁹ is a hydrogen atom (Ii).

In the present invention, R ¹ , R ² , R ⁴ , R ⁸ , R ^1a , R ^2a , R ^4a , R ^8a , Y, m and n have the same meaning as described above.

Step F1 This step is a step of producing a compound having the general formula (Ii).

This step comprises reacting the compound having the general formula (VII) with the compound having the general formula (VI) in a solvent or non-solvent, in the presence or absence of a base, in the step D1 of the method D ^Followed by removal of the amino, hydroxy and / or carboxyl protecting groups in R ^1a , R ^2a , R ^4a and R ^8a as desired.

In the method G, R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —C (═O) —N (R ⁸ ). This is a method for producing a compound having the general formula (Ij) which is a group represented by R ⁹ .

In the present invention, R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ^1a , R ^2a , R ^4a , R ^8a , R ^9a , Y, m and n have the same meaning as described above.

Step G1 This step is a step of producing a compound having the general formula (Ij) and is carried out by the method (i) or (ii).

(I) This step uses a halogenating agent or acid anhydride agent in a solvent to convert the carboxyl group of the compound having the general formula (VIII) into an acid halide or mixed acid anhydride, etc. Thereafter, the reaction is carried out in the same manner as in Step B1 (i) of Method B by reacting with a compound having the general formula (IX) in the presence or absence of a base, and then R ^1a , R ^{2a as} desired. , R ^4a , R ^8a and R ^9a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.

  The compound having the general formula (IX) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

(Ii) This step comprises reacting a compound having the general formula (VIII) with a compound having the general formula (IX) in a solvent in the presence of a condensing agent or in the presence or absence of a base. After carrying out in the same manner as in step B1 (ii) of the method, the amino, hydroxy and / or carboxyl protecting groups in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a are optionally removed It is done by.

In the method H, R ^{3 of the} compound having the general formula (I) is a group represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁸ ) R ^9. A method for producing a compound having the general formula (Ik).

In the present invention, R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ^1a , R ^2a , R ^4a , R ^8a , R ^9a , Y, X, m and n are as defined above. Show.

Step H1 This step is a step of producing a compound having the general formula (X) (converting a hydroxyl group to a leaving group).

  This step is performed by reacting a compound having the general formula (VII) in a solvent with a reagent (for example, a sulfonyloxylating agent) used for conversion from a hydroxyl group to a leaving group.

  The leaving group in this step is preferably a halogen atom such as chlorine atom or bromine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group or p-chlorobenzenesulfonyloxy group, more preferably methanesulfonyl. It is an oxy group.

  The solvent used in this step is preferably a halogenated hydrocarbon or an ether, more preferably dichloromethane, tetrahydrofuran or a mixed solvent thereof, and still more preferably dichloromethane.

  The base used in this step is preferably an organic base, more preferably triethylamine, diisopropylethylamine, pyridine or 4- (N, N-dimethylamino) pyridine, and even more preferably. , Triethylamine or diisopropylethylamine.

  The sulfonyloxylating agent used in this step is not particularly limited as long as it is used for conversion from a hydroxyl group to a leaving group. For example, lower alkanesulfonyloxylation such as methanesulfonyl chloride and ethanesulfonyl chloride. Agents; halogeno-lower alkanesulfonyloxygenating agents such as trifluoromethanesulfonyl anhydride, trifluoromethanesulfonyl chloride, pentafluoroethanesulfonyl chloride; or benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-chlorobenzenesulfonyl Arylsulfonyloxylating agents such as chloride, preferably methanesulfonyl chloride, trifluoromethanesulfonyl anhydride or p-chlorobenzenesulfonyl chloride There, more preferably a methanesulfonyl chloride.

  The reaction temperature in this step is usually −20 ° C. to 150 ° C., preferably −10 ° C. to 30 ° C.

  The reaction time in this step is usually 5 minutes to 6 hours, preferably 15 minutes to 3 hours.

Step H2 This step is a step of producing a compound having the general formula (Ik).

In this step, after reacting a compound having the general formula (X) with a compound having the general formula (IX) in a solvent in the presence or absence of a base, R ^1a , R ^2a , R ^4a , It is carried out by removing amino, hydroxy and / or carboxyl protecting groups in R ^8a and R ^9a .

  The solvent used in this step is preferably a nitrile or amide, more preferably acetonitrile, isobutylnitrile, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide. Even more preferred is N, N-dimethylformamide or acetonitrile.

  The base used in this step is preferably an inorganic base, more preferably potassium carbonate or sodium hydrogen carbonate, and even more preferably sodium hydrogen carbonate.

  The reaction temperature in this step is usually 0 ° C. to 150 ° C., preferably 50 ° C. to 100 ° C.

  The reaction time in this step is usually 10 minutes to 48 hours, preferably 1 hour to 24 hours.

In the method I, R ^{3 of the} compound having the general formula (I) is a group represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁸ ) R ^9. A method for producing a compound having the general formula (Ik).

In the present invention, R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ^1a , R ^2a , R ^4a , R ^8a , R ^9a , Y, m and n have the same meaning as described above.

Step I1 This step is a step of producing a compound having the general formula (XI).

  This step is performed by reacting a compound having the general formula (VII) with an oxidizing agent in a solvent.

  The solvent used in this step is preferably a halogenated hydrocarbon or an ether, more preferably dichloromethane, tetrahydrofuran or a mixed solvent thereof, and still more preferably dichloromethane.

The oxidizing agent used in this step is not particularly limited as long as it is used for ordinary alcohol oxidation reaction. For example, chromium such as pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC). Acids; combinations of various electrophiles such as DCC, trifluoroacetic anhydride, thionyl chloride, oxalyl chloride, chlorine, N-chlorosuccinimide (NCS), sulfur trioxide-pyridine complex; dimethyl sulfoxide; 2, 2, 6, 6-tetramethylpiperidine oxoammonium such as 1-oxyl (TEMPO); metal and metal complexes such as tetrapropylammonium perruthenate (TPAP), manganese dioxide; 1,1,1-triacetoxy-1 , 1-Dihydro-1,2-benziodoxol-3 (1H) -one ( Dess-Martin periodinane, Dess-Martin reagent), o-iodoxybenzoic acid (IBX), oxone _{^{(TM) (Oxone: 2KHSO 5}} · KHSO 4 · K2SO 4) an oxidizing agent such as, preferably, the parent Combination of electronic agent and dimethyl sulfoxide, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one or 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), more preferably a combination of sulfur trioxide-pyridine complex and dimethyl sulfoxide.

  The reaction temperature in this step is usually -80 ° C to 100 ° C, preferably -10 ° C to 30 ° C.

  The reaction time in this step is usually 10 minutes to 6 hours, preferably 30 minutes to 3 hours.

Step I2 This step is a step of producing a compound having the general formula (Ik).

In this step, a compound having the general formula (XI) is reacted in a solvent with a compound having the general formula (IX) under reducing conditions in the presence or absence of a base, and then optionally R ^1a , R ^It is carried out by removing amino, hydroxy and / or carboxyl protecting groups in ^2a , R ^4a , R ^8a and R ^9a .

  The solvent used in this step is preferably a halogenated hydrocarbon, alcohol, carboxylic acid, a mixed solvent of halogenated hydrocarbon and alcohol, or a mixture of alcohol and ether. A solvent, a mixed solvent of alcohols and water, or a mixed solvent of carboxylic acids and water, and more preferably methanol, ethanol, acetic acid, methanol or ethanol and diethyl ether. A mixed solvent of methanol, ethanol or ethanol and dichloromethane, a mixed solvent of methanol or ethanol and tetrahydrofuran, a mixed solvent of methanol or ethanol and water, or acetic acid and water. And a mixed solvent.

  The reducing conditions used in this step are not particularly limited as long as they are usually used for imine reduction. For example, (i) sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride Or (ii) catalytic reduction using a metal catalyst such as palladium or platinum with hydrogen, ammonium formate, or the like. The condition (i) is preferred.

  (I) The alkali metal borohydride used in this step is preferably sodium triacetoxyborohydride. If necessary, acetic acid, molecular sieves, Lewis acid, etc. may be added.

  The reaction temperature in this step is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C.

  The reaction time in this step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.

  (Ii) The catalyst used in this step is not particularly limited as long as it is usually used in a catalytic reduction reaction. Palladium carbon, palladium black, Raney-nickel, platinum oxide, platinum black, rhodium- Aluminum oxide, triphenylphosphine-rhodium chloride or palladium-barium sulfate, preferably platinum oxide or palladium carbon. The pressure during the catalytic reduction is not particularly limited, but is usually 1 to 10 atmospheres.

  The reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 20 ° C. to 70 ° C.

  The reaction time in this step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.

Method J is a group in which R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁸ ) R ^9. A method for producing a compound having the general formula (Ik).

In the present invention, R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ^1a , R ^2a , R ^4a , R ^8a , R ^9a , Y, X, m and n are as defined above. Show.

Step J1 This step is a step of producing a compound having the general formula (Ik).

This step is carried out in the same manner as Step H2 of Method H above by reacting the compound having the general formula (XII) with the compound having the general formula (XIII) in a solvent in the presence or absence of a base. Thereafter, the amino group, hydroxy group and / or carboxyl group protecting group in R ^1a , R ^2a , R ^4a , R ^8a and R ^9a is optionally removed.

  The compound having the general formula (XIII) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

Method K is a group in which R ^{3 of the} compound having the general formula (I) is represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —N (R ⁸ ) R ^9. A method for producing a compound having the general formula (Ik).

In the present invention, R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , R ^1a , R ^2a , R ^4a , R ^8a , Y, m and n are as defined above, and R ^9b is And the remaining group obtained by removing the methylene group from R ^9a described above (that is, the group represented by the formula R ^9a — is a group represented by the formula R ^9b —CH ₂ —).

Step K1 This step is a step of producing a compound having the general formula (Ik).

This step is performed in the same manner as in Step I2 of Method I above by reacting a compound having the general formula (XII) with a compound having the general formula (XIV) in a solvent in the presence or absence of a base. Thereafter, the amino group, hydroxy group and / or carboxyl group-protecting group in R ^1a , R ^2a , R ^4a , R ^8a and R ^9b is optionally removed.

  The compound having the general formula (XIV) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

In the method L, R ^{3 of the} compound having the general formula (I) is a group represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —O—R ¹⁰ A process for preparing a compound having the formula (Im).

In the present invention, R ¹ , R ² , R ⁴ , R ¹⁰ , R ^1a , R ^2a , R ^4a , Y, X, m and n are as defined above, and R ^10a represents R ¹⁰ The amino group, hydroxy group and / or carboxyl group contained as a substituent in the group is an amino group, hydroxy group and / or carboxyl group which may be protected, and the same group as the group in the definition of the group of R ¹⁰ Indicates.

Step L1 This step is a step of producing a compound having the general formula (Im).

In this step, a compound having the general formula (VII) is reacted with a compound having the general formula (XV) in a solvent in the presence or absence of a base, and then R ^1a , R ^2a , R ^4a and It is carried out by removing the protective group for amino group, hydroxy group and / or carboxyl group in R ^10a .

  The compound having the general formula (XV) is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

  The solvent used in this step is preferably ethers, amides, aromatic hydrocarbons, alcohols or amines, and more preferably tetrahydrofuran, N, N-dimethylformamide, benzene, 2,6-lutidine or a mixed solvent thereof, and still more preferably tetrahydrofuran or N, N-dimethylformamide.

  The base used in this step is preferably an alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydride or alkali metal alkoxide, and more preferably potassium carbonate, cesium carbonate, hydrogen carbonate. Sodium, sodium hydride or potassium tert-butoxide, even more preferably sodium hydride or potassium tert-butoxide.

  The reaction temperature in this step is usually −80 ° C. to 100 ° C., preferably 0 ° C. to 70 ° C.

  The reaction time in this step is usually 10 minutes to 24 hours, preferably 30 minutes to 6 hours.

In Method M, R ^{3 of the} compound having the general formula (I) is a group represented by the formula —Y—CH ₂ C (═O) —N (R ⁴ ) (CH ₂ ) _n —O—R ¹⁰ A process for preparing a compound having the formula (Im).

In the present invention, R ¹ , R ² , R ⁴ , R ¹⁰ , R ^1a , R ^2a , R ^4a , R ^10a , Y, X, m and n have the same meaning as described above.

Step M1 This step is a step of producing a compound having the general formula (Im).

This step is carried out in the same manner as in Step L1 of Method L above by reacting a compound having the general formula (X) with a compound having the general formula (XVI) in a solvent in the presence or absence of a base. Thereafter, the amino group, hydroxy group and / or carboxyl group-protecting group in R ^1a , R ^2a , R ^4a and R ^{10a is} optionally removed.

  The compound having the general formula (XVI) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

  Method N is a method for producing a compound having the general formula (XIX) used in the methods A to M.

In general formula (XIX), NH (R ⁵ ) in general formula (II) is Z, the hydroxy group in general formula (VII) is Z, the carboxyl group in general formula (VIII) is Z, NH (R ^8a ) in formula (XII) is Z, and X in general formula (X) is Z.

In the present invention, R ^1a , R ^2a , R ^4a , Y, m and n are as defined above, and Z is NH (R ⁵ ), a hydroxy group, a carboxyl group, NH (R ^8a ) or It is the same as X.

Step N1 This step is a step of producing a compound having the general formula (XIX) and is carried out by the method (i) or (ii).

  (I) In this step, the carboxyl group of the compound having the general formula (XVII) is converted into an acid halide or a mixed acid anhydride using a halogenating agent or an acid anhydride agent in a solvent, and activated. Thereafter, the reaction is carried out in the same manner as in Step B1 (i) of Method B by reacting with a compound having the general formula (XVIII) in the presence or absence of a base.

  The compound having the general formula (XVII) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

  The compound having the general formula (XVIII) is a known compound, or can be easily produced according to a known method or a method similar thereto by using the known compound as a starting material.

  (Ii) This step is carried out by reacting a compound having the general formula (XVII) with a compound having the general formula (XVIII) in a solvent in the presence of a condensing agent, in the presence or absence of a base. This is performed in the same manner as in the first B1 step (ii) of the method.

  The method O is a method for producing a compound having the general formula (XIX) used in the methods A to M.

In the present invention, R ^1a , R ^2a , R ^4a , Y, X, Z, m and n have the same meaning as described above.

Step O1 This step is a step of producing a compound having the general formula (XIX).

  This step is carried out in the same manner as Step H2 of Method H above by reacting a compound having the general formula (XX) with a compound having the general formula (XXI) in a solvent in the presence or absence of a base. It is.

  The compound having the general formula (XX) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

  The compound having the general formula (XXI) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.

In the above, “an amino group which may be protected”, “an hydroxy group which may be protected” and “a group which may be protected” in the definitions of R ^1a , R ^2a , R ^4a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a The protecting group of “optionally protected carboxyl group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and is generally used in organic synthetic chemistry. Protecting groups are indicated (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above, “protective group” of “hydroxy group which may be protected” in the definition of R ^1a , R ^2a , R ^4a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a is a field of synthetic organic chemistry. Although it is not particularly limited as long as it is a protecting group for hydroxy group used in the above, for example, formyl group; such as “C ₂ -C ₇ alkylcarbonyl group”, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc. “Alkylcarbonyl” such as halogenated alkylcarbonyl group, alkoxyalkylcarbonyl group such as methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl group such as (E) -2-methyl-2-butenoyl Group "; benzoyl, alpha-naphthoyl, arylcarbonyl groups such as β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl, C ₁ -C ₆ alkylation such as 2,4,6-trimethylbenzoyl, 4-toluoyl Arylcarbonyl groups, C ₁ -C ₆ alkoxylated arylcarbonyl groups such as 4-anisoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl and the like An “arylcarbonyl group” such as a C ₂ -C ₇ alkoxycarbonylated arylcarbonyl group, an arylated arylcarbonyl group such as 4-phenylbenzoyl; the above “C ₂ -C ₇ alkoxycarbonyl group”, 2,2,2 -Trichloroethoxycarbonyl, 2-trimethyl Halogen or tri like Le ethoxycarbonyl - (C ₁ -C ₆ alkyl) "alkoxycarbonyl group" of the C ₂ -C ₇ alkoxycarbonyl group substituted by a silyl group; tetrahydropyran-2-yl, 3-bromo A “tetrahydropyranyl or tetrahydrothiopyranyl group” such as tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; “Tetrahydrofuranyl or tetrahydrothiofuranyl group” such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t - butylsilyl, tri as triisopropylsilyl - _(C 1 -C ₆ alkyl) silyl group, diphenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, such as phenyl diisopropylsilyl _(C 1 -C ₆ alkyl) diarylsilyl Or a “silyl group” such as a di- (C ₁ -C ₆ alkyl) arylsilyl group; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t- (C ₁ -C ₆ alkoxy) methyl group such as butoxymethyl, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) methyl group such as 2-methoxyethoxymethyl, 2,2,2- Trichloroethoxymethyl, bis (2-chloroethoxy) methyl Such "alkoxymethyl group" such as _(C 1 -C ₆ halogenated alkoxy) methyl; 1-ethoxyethyl, 1- (isopropoxy) such as ethyl _(C 1 -C ₆ alkoxy) ethyl group, 2,2, “Substituted ethyl groups” such as halogenated ethyl groups such as 2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl; C ₁ -C ₆ alkyl group substituted with 1 to 3 aryl groups such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl _C 1 -C ₆ alkyl, such as _{4-cyanobenzyl,} C 1 -C ₆ alkoxy, nitro, halogen, a cyano group - Le ring of 1 to 3 substituted ants - C substituted with Le group “Aralkyl groups” such as _1- C ₆ alkyl groups; “alkenyloxycarbonyl groups” such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with one or two C ₁ -C ₆ alkoxy or nitro groups, such as 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; And preferably an alkylcarbonyl group, a silyl group or an aralkyl group.

In the above, the “protecting group” of the “optionally protected carboxyl group” in the definition of R ^1a , R ^2a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a is used in the field of synthetic organic chemistry. For example, the above-mentioned “C ₁ -C ₆ alkyl group”; “C 1 -propenyl, 2-propenyl, 1-methyl-2-propenyl” ₂ -C ₆ alkenyl group "; ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-like propynyl" _C 2 -C ₆ alkynyl group ";the" _C 1 -C ₆ halogenated alkyl group "; hydroxymethyl, 2- _C 1 -C ₆ hydroxyalkyl groups such as hydroxyethyl; such as acetyl methyl _(C 2 -C ₇ alkylcarbonyl) - _{(C 1} C ₆ alkyl group); the "aralkyl group"; a or the "silyl group", preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

In the above, “protecting group” of “amino group which may be protected” in the definition of R ^1a , R ^2a , R ^6a , R ^7a , R ^8a , R ^9a and R ^10a is used in the field of synthetic organic chemistry. There is no particular limitation as long as it is a protective group for an amino group, for example, “alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; “silyl group”; “Aralkyl group”; “alkenyloxycarbonyl group”; or a group similar to “aralkyloxycarbonyl group” or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5 -Chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenyl A like styrene "substituted methylene group forming a Schiff base", preferably, an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, more preferably an alkoxycarbonyl group.

  Processes that require protection and deprotection are known methods (for example, the method described in “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication), etc.) It is done accordingly.

The compound having the general formula (I) of the present invention and a pharmacologically acceptable salt thereof have an antagonistic action on neurokinin receptors (neurokinin NK ₁ , neurokinin NK ₂ and neurokinin NK ₃ receptors). So it can be used as a medicine. The medicament can be administered to diseases mediated by neurokinin NK ₁ , neurokinin NK ₂ and / or neurokinin NK ₃ receptors, such as anxiety, depression, psychiatric disorders and division. Central nervous system diseases including dystrophy; including dementia in AIDS, senile dementia of Alzheimer type, Alzheimer's disease, Down's syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy, and neuralgia Neurodegenerative diseases; chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma, respiratory diseases including cough; inflammatory bowel disease (IBD), psoriasis, connective tissue inflammation, osteoarthritis, degenerative arthritis, and Inflammatory diseases including rheumatoid arthritis; eczema; and allergic diseases including rhinitis; hypersensitivity diseases including hypersensitivity diseases to vines; conjunctivitis, spring conjunctivitis, spring catarrh Ophthalmic disorders including blood-aqueous humor barrier associated with various inflammatory eye diseases, elevated intraocular pressure, miosis; contact dermatitis, atopic dermatitis, hives, and other eczema-like dermatitis Skin disorders, including alcoholism; somatic disorders including stress; somatic disorders due to stress; reflex sympathetic dystrophy, including shoulder-hand syndrome; mood modulation; undesired immune response including graft rejection and systemic erythema Diseases related to immune enhancement or immunosuppression, including lupus; diseases caused by abnormalities in the nerves that control the internal organs, colitis, ulcerative colitis, irritable bowel syndrome, gastrointestinal diseases including Crohn's disease; Vomiting induced by side effects associated with chemotherapeutic agents, toxicants, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure, or administration of various drugs Vomiting including; Bladder dysfunction including cystitis and urinary incontinence; collagen disease, scleroderma, hypereosinophilia due to hepatic fistula infection; blood flow due to vasodilation or contraction including angina, migraine, and Raynaud's disease Illness due to abnormalities of pain; painful nociceptive pain including migraine, headache, toothache; sleep apnea syndrome. The medicament can be used in particular as a prophylactic or therapeutic agent for respiratory diseases such as asthma, bronchitis and chronic obstructive pulmonary disease; allergic diseases such as rhinitis; and / or urinary incontinence.

  The administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is, for example, oral administration by tablets, capsules, granules, powders or syrups, or injections or suppositories. Parenteral administration, etc. Furthermore, the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can be administered pulmonary as a powder, solution or suspension. Formulations for these are produced by well-known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.

  Excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbit, starch derivatives such as corn starch, potato starch, α-starch, dextrin or carboxymethyl starch, crystalline cellulose, low degree of substitution Organic excipients such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally cross-linked sodium carboxymethylcellulose sodium, gum arabic, dextran, or pullulan; or light anhydrous silicic acid, synthetic silicic acid Silicate derivatives such as aluminum or magnesium metasilicate aluminate, phosphates such as calcium phosphate, carbonates such as calcium carbonate, or It may be inorganic excipients such as sulfuric acid salts, such as calcium.

  Lubricants include, for example, stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or gay wax; boric acid; adipic acid; sulfuric acid such as sodium sulfate Salt; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid or silicic acid hydrate; or the above starch It can be a derivative.

  The binder may be, for example, polyvinyl pyrrolidone or macrogol, or a compound similar to the excipient.

  The disintegrant may be, for example, the same compound as the excipient, or a chemically modified starch / cellulose such as croscarmellose sodium, carboxymethyl starch sodium or crosslinked polyvinylpyrrolidone.

  Stabilizers include, for example, paraoxybenzoates such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; Dehydroacetic acid; or sorbic acid.

  The flavoring agent can be a commonly used sweetener, acidulant, fragrance or the like.

  When producing a solution or suspension for pulmonary administration of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, for example, the crystal of the present invention is mixed with water or water. It can be produced by dissolving or suspending it in a mixture of a co-solvent (for example, ethanol, propylene glycol, polyethylene glycol, etc.). Such solutions or suspensions may further comprise preservatives (eg benzauconium chloride), solubilizers (eg polysorbates such as Tween 80 or Span 80, or surfactants such as benzalkonium chloride), Buffers, isotonic agents (eg, sodium chloride), absorption enhancers and / or thickeners may be included. The suspension may further contain a suspending agent (for example, microcrystalline cellulose, sodium carboxymethyl cellulose, etc.).

  Compositions for pulmonary administration prepared as described above are administered directly to the nasal cavity or oral cavity by means common in the field of inhalants (eg, using a dropper, pipette, cannula or nebulizer). If a nebulizer is used, the crystals of the present invention are combined with a suitable propellant (eg, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide) in a pressurized pack. It can be sprayed as a shaped aerosol or administered using a nebulizer.

  The amount of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on symptoms, age, administration method, and the like. For example, in the case of oral administration, The lower limit is 0.1 mg (preferably 1 mg, more preferably 5 mg), and the upper limit is 1000 mg (preferably 100 mg, more preferably 50 mg), divided into 1 or several doses and administered according to symptoms It is desirable. In the case of intravenous administration, the lower limit is 0.01 mg (preferably 0.1 mg) and the upper limit is 100 mg (preferably 10 mg) per day for adults. Is desirable.

  In addition, the amount used in the case of pulmonary administration of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on symptoms, age, sex, etc. The lower limit is 0.01 μg / kg (preferably 0.05 μg / kg), and the upper limit is 1000 μg / kg (preferably 100 μg / kg, more preferably 20 μg / kg). It is desirable to administer accordingly.

  EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these.

Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, a silica gel 60F ₂₅₄ manufactured by Merck or TLC plates NH manufactured by Fuji Silysia is used as a TLC plate, and a solvent used as an elution solvent in column chromatography is used as a developing solvent. A UV detector was adopted. The silica gel for the column is also silica gel SK-85 (230-400 mesh), SK-34 (70-230 mesh) manufactured by Kishida Chemical, silica gel 60N (40-50 μm) manufactured by Kanto Chemical, Chromatorex manufactured by Fuji Silysia. NH DM1020 (100 to 200 mesh), DM2035SG (200 to 350 mesh) or silica gel FL100B manufactured by Fuji Silysia Chemical Ltd. was used. In addition to normal column chromatography, Yamazen's automated chromatography device (YFLC-prep4) and disposable columns (Mortex, Yamazen, Wako Pure Chemical Industries) were used as appropriate. The purification by preparative TLC manufactured by Merck silica gel _60F 254, 0.5 mm thick, was used plates 20 × 20 cm.

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H NMR) spectra are described with chemical shift values expressed as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, and br for broad lines.

  Mass spectrometry (hereinafter referred to as MS) was performed by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, APCI (Atmospheric Pressure Chemical Ionization) method or ESI (Electron Spray Ionization) method.

[Example 1]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N, 2-dimethylpropanamide hydrochloride

[Example 1a]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide {[(2S) -1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro 6.0 g (7.90 mmol) of [indene-1,4′-piperidin] -2-yl] oxy} acetic acid was dissolved in 50 mL of dichloromethane and stirred under ice cooling. Thereto were added dropwise 1.15 mL (8.30 mmol) of triethylamine and 924 μL (7.51 mmol) of pivaloyl chloride, and the mixture was stirred for 1 hour under ice cooling. The reaction solution was added dropwise to a solution of 2.42 g (23.7 mmol) of N, N′-dimethyl-1,3-propanediamine in dichloromethane (100 mL) over 1 hour under ice cooling. After completion of the dropwise addition, the mixture was stirred for 2 hours under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered through celite, the solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel chromatography (elution solvent: methanol / ethyl acetate = 0/1 to 1/9). 1.89 g (yield: 28%) of the title compound was obtained.
MS (FAB) m / z: 843 ((M + H) ⁺ , free form).
[Example 1b]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N, 2-dimethylpropanamide hydrochloride 2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide 70 mg (0.083 mmol) It was dissolved in dichloromethane (4 mL), and stirred at room temperature. Thereto were sequentially added 14 μL (0.100 mmol) of triethylamine and 10 μL (0.100 mmol) of isobutyryl chloride, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 72 mg of the free form of the title compound. A solution of free form (72 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 65 mg (yield: 82%) of the title compound.
IR νmax cm ^-1 (KBr): 3438, 2932, 1645, 1475, 1376, 1282, 1186, 1139, 1108, 681.
MS (FAB) m / z: 913 ((M + H) ⁺ , free body).

[Example 2]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylcyclopropanecarboxamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 1b was performed using 70 mg (0.083 mmol) and cyclopropanecarbonyl chloride 9.0 μL (0.100 mmol) to obtain 67 mg (yield: 85%) of the title compound.
IR νmax cm ^-1 (KBr): 3436, 2929, 1645, 1475, 1440, 1282, 1185, 1138, 1109, 681.
MS (FAB) m / z: 911 ((M + H) ⁺ , free body).

[Example 3]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylpyridine-2-carboxamide Dihydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide Using 70 mg (0.083 mmol) and picolinic acid hydrochloride 18 mg (0.100 mmol), the same reaction as in Example 1b was performed to obtain 64 mg (yield: 75%) of the title compound.
IR νmax cm ^-1 (KBr): 3436, 2930, 1649, 1475, 1442, 1376, 1167, 1138, 1107, 756, 681.
MS (FAB) m / z: 948 ((M + H) ⁺ , free body).

[Example 4]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylcyclohexanecarboxamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 1b was performed using 70 mg (0.083 mmol) and cyclohexanecarbonyl chloride 14 μL (0.100 mmol) to obtain 71 mg (yield: 86%) of the title compound.
IR νmax cm ^-1 (KBr): 3404, 2930, 2856, 1646, 1440, 1376, 1281, 1185, 1139, 1109, 681.
MS (FAB) m / z: 953 ((M + H) ⁺ , free form).

[Example 5]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyltetrahydro-2H-pyran- 4-Carboxamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 1b was performed using 70 mg (0.083 mmol) and tetrahydropyrancarbonyl chloride 15 mg (0.10 mmol) to obtain 71 mg (yield: 86%) of the title compound.
IR νmax cm ^-1 (KBr): 3406, 2953, 2928, 1646, 1474, 1441, 1376, 1282, 1185, 1137, 1107, 1030, 758, 681.
MS (FAB) m / z: 955 ((M + H) ⁺ , free body).

[Example 6]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {3-[(methoxyacetyl) (methyl) amino] propyl} -N-methylacetamide hydrochloric acid salt

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 1b was carried out using 50 mg (0.059 mmol) and 8 μL (0.089 mmol) of methoxyacetyl chloride to obtain 43 mg (yield: 76%) of the title compound.
IR νmax cm ^-1 (KBr): 3441, 2930, 1649, 1475, 1440, 1376, 1282, 1185, 1138, 1108, 681.
MS (FAB) m / z: 915 ((M + H) ⁺ , free body).

[Example 7]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- {3- [methyl (phenoxyacetyl) amino] propyl} acetamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide Using 50 mg (0.059 mmol) and 12 μL (0.089 mmol) of phenoxyacetyl chloride, the same reaction as in Example 1b was performed to obtain 40 mg (yield: 67%) of the title compound.
IR νmax cm ^-1 (KBr): 3432, 2930, 1650, 1476, 1440, 1376, 1282, 1185, 1138, 756, 681.
MS (FAB) m / z: 977 ((M + H) ⁺ , free form).

[Example 8]
2-[{3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} (methyl) amino] -2-oxoethyl Acetic acid hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide Using 75 mg (0.089 mmol) and acetoxyacetyl chloride 14 μL (0.133 mmol), the same reaction as in Example 1b was carried out to obtain 84 mg (yield: 99%) of the title compound free form. Of these, 40 mg was dissolved in dichloromethane (2 mL), and 2N diethyl ether solution (0.1 mL) was added dropwise with stirring at room temperature. The solvent was distilled off under reduced pressure to obtain 27 mg (yield: 62%) of the title compound.
IR νmax cm ^-1 (KBr): 3438, 2934, 1748, 1651, 1475, 1439, 1376, 1282, 1238, 1186, 1138, 681.
MS (FAB) m / z: 943 ((M + H) ⁺ , free form).

[Example 9]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {3- [glycoloyl (methyl) amino] propyl} -N-methylacetamide hydrochloride

2-[{3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} (methyl) amino] -2-oxoethyl To a solution of 44 mg (0.047 mmol) of acetic acid in methanol / water (4 mL / 2 mL), 19 mg (0.140 mmol) of potassium carbonate was added and stirred at room temperature for 1 hour. Methanol was distilled off under reduced pressure, and water (4 mL) and dichloromethane (4 mL) were added to the residue for extraction. The aqueous layer was extracted once more with dichloromethane (2 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 26 mg of the free form of the title compound. A solution of free form (26 mg) in dichloromethane (2 mL) was stirred under ice-cooling, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 22 mg (yield: 50%) of the title compound.
IR νmax cm ^-1 (KBr): 3419, 2930, 1649, 1475, 1440, 1376, 1282, 1185, 1138, 1097, 1029, 905, 758, 681.
MS (FAB) m / z: 901 ((M + H) ⁺ , free body).

[Example 10]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -4- (dimethylamino) -N— Methylbenzamide dihydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 1b was carried out using 50 mg (0.059 mmol) and dimethylaminobenzoyl chloride 16 mg (0.089 mmol) to obtain 34 mg (yield: 54%) of the title compound.
IR νmax cm ^-1 (KBr): 3429, 2929, 2425, 1644, 1476, 1376, 1282, 1185, 1137, 905, 681.
MS (FAB) m / z: 990 ((M + H) ⁺ , free body).

[Example 11]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylbenzamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 1b was carried out using 50 mg (0.059 mmol) and 10 μL (0.089 mmol) of benzoyl chloride to obtain 38 mg (yield: 65%) of the title compound.
IR νmax cm ^-1 (KBr): 3437, 2929, 1645, 1476, 1440, 1376, 1282, 1185, 1138, 1098, 681.
MS (FAB) m / z: 947 ((M + H) ⁺ , free body).

[Example 12]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylquinoline-2-carboxamide Dihydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide Using 40 mg (0.047 mmol) and quinolinecarbonyl chloride 14 mg (0.071 mmol), the same reaction as in Example 1b was carried out to obtain 32 mg (yield: 63%) of the title compound.
IR νmax cm ^-1 (KBr): 3429, 2929, 2552, 1649, 1476, 1439, 1376, 1282, 1185, 1138, 1098, 761, 681.
MS (FAB) m / z: 998 ((M + H) ⁺ , free body).

[Example 13]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl-2-naphthamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide Using 40 mg (0.047 mmol) and naphthoyl chloride 13 mg (0.071 mmol), the same reaction as in Example 1b was carried out to obtain 29 mg (yield: 59%) of the title compound.
IR νmax cm ^-1 (KBr): 2929, 1646, 1476, 1439, 1376, 1185, 1138, 1098, 758, 681.
MS (FAB) m / z: 997 ((M + H) ⁺ , free body).

[Example 14]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylbiphenyl-4-carboxamide Hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide Using 40 mg (0.047 mmol) and biphenylcarbonyl chloride 15 mg (0.071 mmol), the same reaction as in Example 1b was carried out to obtain 38 mg (yield: 75%) of the title compound.
IR νmax cm ^-1 (KBr): 3427, 2929, 1646, 1478, 1439, 1376, 1281, 1185, 1139, 1098, 752, 681.
MS (FAB) m / z: 1023 ((M + H) ⁺ , free form).

[Example 15]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N, N ² , N ² -trimethylglycine Amide dihydrochloride

N, N-dimethylglycine was dissolved in 12 mg (0.119 mmol) of dichloromethane (2 mL), and 33 μL (0.237 mmol) of triethylamine and 15 μL (0.119 mmol) of pivaloyl chloride were sequentially added while stirring at room temperature. After stirring at room temperature for 30 minutes, 2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 1a was added to the reaction solution. ] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- A solution of [3- (methylamino) propyl] acetamide 50 mg (0.059 mmol) in dichloromethane (2 mL) was added dropwise. After stirring at room temperature for 1 hour, the solvent was distilled off, and the residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 1/1) to obtain 43 mg of a free form. A solution of the free form of the title compound (43 mg) in dichloromethane (2 mL) was stirred at room temperature, and 0.1 mL of 2N hydrochloric acid diethyl ether solution was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 44 mg (yield: 74%) of the title compound.
IR νmax cm ^-1 (KBr): 3429, 2931, 1651, 1475, 1376, 1282, 1185, 1139, 1029, 905, 757, 681.
MS (FAB) m / z: 928 ((M + H) ⁺ , free form).

[Example 16]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl-5-phenylpyridine-2 -Carboxamide dihydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 15 was carried out using 40 mg (0.047 mmol) and 14 mg (0.071 mmol) of 5-phenylpicolinic acid to obtain 10 mg (yield: 19%) of the title compound.
IR νmax cm ^-1 (KBr): 3430, 2930, 1647, 1471, 1439, 1376, 1281, 1185, 1139, 1099, 758, 681.
MS (FAB) m / z: 1024 ((M + H) ⁺ , free body).

[Example 17]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-pyridin-3-ylbutanamide dihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 40 mg (0.048 mmol) in dichloromethane (2 mL) Was stirred at room temperature, and 17 mg (0.089 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 25 μL (0.179 mmol) of triethylamine, and 6 mg (0.067 mmol) of 3-aminopyridine were successively added. And stirred for 15 hours. Water was added to the reaction solution, and extraction was performed 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 15 mg of the free form of the title compound. A solution of free form (15 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 12 mg (yield: 27%) of the title compound.
IR νmax cm ^-1 (KBr): 2932, 2678, 2577, 1699, 1648, 1550, 1459, 1376, 1282, 1185, 1138, 1098, 1029, 905, 808, 758, 681.
MS (FAB) m / z: 934 ((M + H) ⁺ , free body).

[Example 18]
tert-Butyl 4-[{3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [inden-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} (methyl) carbamoyl] piperidine- 1-carboxylic acid

123 mg (0.539 mmol) of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid was dissolved in 5 mL of dichloromethane and stirred at room temperature. Thereto, 87 μL (0.623 mmol) of triethylamine and 77 μL (0.623 mmol) of pivaloyl chloride were sequentially added and stirred at room temperature for 1 hour. To the reaction solution was added 2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 3) obtained in Example 1a. 4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) A solution of 350 mg (0.415 mmol) of propyl] acetamide in dichloromethane (3 mL) was added dropwise, and the mixture was further stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/1) to give 323 mg (yield: free) of the title compound. 73%).
IR νmax cm ^-1 (KBr): 2928, 1690, 1645, 1475, 1428, 1375, 1281, 1174, 1140, 1095, 1030, 905, 757, 681.
MS (FAB) m / z: 1054 ((M + H) ⁺ , free form).

[Example 19]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylpiperidine-4-carboxamide Hydrochloride

[Example 19a]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylpiperidine-4-carboxamide Tert-Butyl 4-[{3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl]-] obtained in Example 18 2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [inden-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} ( Methyl) carbamoyl ] To a solution of piperidine-1-carboxylic acid 320 mg (0.303 mmol) in dichloromethane (10 mL) was added 5 mL of trifluoroacetic acid at room temperature and stirred for 2 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the resulting residue, and extraction was performed 3 times with dichloromethane (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered through celite, and the solvent was evaporated under reduced pressure to obtain 288 mg (yield: 99%) of the title compound.
[Example 19b]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylpiperidine-4-carboxamide Hydrochloride N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2] obtained in Example 19a -(3,4-Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [inden-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N -Methylpiperidine-4-ca Dichloromethane (2 mL) solution of Bokishiamido 60 mg (0.062 mmol) was stirred at room temperature, it was added dropwise 2N hydrochloric acid solution in diethyl ether (0.1 mL). The solvent was distilled off under reduced pressure to obtain 56 mg (yield: 88%) of the title compound.
IR νmax cm ^-1 (KBr): 3402, 2931, 2711, 1645, 1474, 1439, 1376, 1282, 1185, 1139, 1097, 1029, 905, 759, 681.
MS (FAB) m / z: 954 ((M + H) ⁺ , free form).

[Example 20]
1-acetyl-N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [inden-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylpiperidine-4 -Carboxamide hydrochloride

N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- () obtained in Example 19a 3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl To a solution of piperidine-4-carboxamide 50 mg (0.052 mmol) in dichloromethane (3 mL), 6 μL (0.079 mmol) of acetyl chloride and 15 μL (0.105 mmol) of triethylamine were added dropwise at room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/0) to obtain the free form (53 mg) of the title compound. It was. A solution of free form (53 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 45 mg (yield: 83%) of the title compound.
IR νmax cm ^-1 (KBr): 3422, 2928, 2554, 1644, 1475, 1440, 1375, 1282, 1185, 1139, 1108, 1029, 905, 758, 681.
MS (FAB) m / z: 996 ((M + H) ⁺ , free body).

[Example 21]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl-1- (methylsulfonyl) Piperidine-4-carboxamide hydrochloride

N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- () obtained in Example 19a 3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl To a solution of piperidine-4-carboxamide 50 mg (0.052 mmol) in dichloromethane (5 mL), 6 μL (0.079 mmol) of methanesulfonyl chloride and 15 μL (0.105 mmol) of triethylamine were added dropwise at room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/0) to obtain the free form (55 mg) of the title compound. It was. A solution of free form (55 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 47 mg (yield: 84%) of the title compound.
IR νmax cm ^-1 (KBr): 3415, 2929, 2500, 2474, 1449, 1376, 1326, 1282, 1185, 1140, 1108, 1029, 960, 932, 905, 774, 681, 518.
MS (FAB) m / z: 1032 (M + H) ⁺ , free form).

[Example 22]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N, 1-dimethylpiperidine-4-carboxy Amide dihydrochloride

N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- () obtained in Example 19a 3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl To a solution of piperidine-4-carboxyamide 60 mg (0.063 mmol) in tetrahydrofuran / dimethylformamide (2 mL / 0.5 mL), 4 μL (0.063 mmol) of methyl iodide and 41 mg (0.126 mmol) of cesium carbonate were added. Stir at 1 ° C. for 1 hour 30 minutes. After removing unnecessary substances by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5). To obtain a free form (26 mg) of the title compound. A solution of free form (26 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 20 mg (yield: 30%) of the title compound.
IR νmax cm ^-1 (KBr): 3426, 2932, 2507, 1644, 1472, 1440, 1376, 1282, 1185, 1138, 1097, 1029, 905, 757, 681.
MS (FAB) m / z: 968 (M + H) ⁺ , free body).

[Example 23]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy] -N-methyl-N- {3- [methyl (methylsulfonyl) amino] propyl} acetamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide 70 mg (0.083 mmol) was dissolved in dichloromethane (4 mL) and stirred at room temperature. Thereto were sequentially added 14 μL (0.100 mmol) of triethylamine and 8 μL (0.100 mmol) of methanesulfonyl chloride, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 74 mg of the free form of the title compound. A solution of free form (74 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 58 mg (yield: 76%) of the title compound.
IR νmax cm ^-1 (KBr): 3439, 3069, 1649, 1474, 1376, 1330, 1282, 1186, 1141, 965, 761, 681, 521.
MS (FAB) m / z: 921 ((M + H) ⁺ , free form).

[Example 24]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy] -N-methyl-N- {3- [methyl (phenylsulfonyl) amino] propyl} acetamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 23 was carried out using 70 mg (0.083 mmol) and benzenesulfonyl chloride 16 μL (0.13 mmol) to obtain 66 mg (yield: 78%) of the title compound.
IR νmax cm ^-1 (KBr): 3431, 2929, 1650, 1475, 1445, 1376, 1341, 1282, 1166, 1138, 1093, 757, 681, 580.
MS (FAB) m / z: 983 ((M + H) ⁺ , free form).

[Example 25]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- {3- [methyl (pyridin-3-ylsulfonyl) amino] propyl} Acetamide dihydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 23 was performed using 70 mg (0.083 mmol) and 3-pyridinesulfonyl chloride hydrochloride 27 mg (0.13 mmol) to obtain 76 mg of the title compound (yield: 86%).
ax cm ^-1 (KBr): 3434, 2929, 2558, 1648, 1458, 1376, 1361, 1282, 1169, 1138, 1109, 761, 681, 581.
MS (FAB) m / z: 984 ((M + H) ⁺ , free body).

[Example 26]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy] -N- {3-[(isopropylsulfonyl) (methyl) amino] propyl} -N-methylacetamide hydrochloric acid salt

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 23 was carried out using 70 mg (0.083 mmol) and 14 μL (0.13 mmol) of isopropylsulfonyl chloride to obtain 20 mg (yield: 24%) of the title compound.
IR νmax cm ^-1 (KBr): 2930, 1650, 1473, 1440, 1376, 1324, 1282, 1167, 1137, 1097, 758, 681.
MS (FAB) m / z: 949 ((M + H) ⁺ , free body).

[Example 27]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -2-methylpropanamide hydrochloride

[Example 27a]
tert-butyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid {[(2S) -1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro 6.0 g (7.90 mmol) of [indene-1,4′-piperidin] -2-yl] oxy} acetic acid was dissolved in 60 mL of dichloromethane and stirred under ice cooling. Triethylamine 1.21mL (8.69mmol) and pivaloyl chloride 1.02mL (8.29mmol) were dripped there, and it stirred under ice-cooling for 40 minutes. To the reaction solution, a solution of tert-butyl [3- (methylamino) propyl] carbamic acid 1.64 g (8.69 mmol) in dichloromethane (10 mL) was added dropwise under ice cooling. The reaction solution was warmed to room temperature and stirred for 40 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, the solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel chromatography (elution solvent: methanol / ethyl acetate = 0/1 to 1/9). To 4.98 g (yield: 68%) of the title compound.
MS (FAB) m / z: 929 ((M + H) ⁺ , free body).
[Example 27b]
N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoroacetate salt synthesized in Example 27a Tert-butyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) ) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid 450 mg (0.484 mmol) Was dissolved in dichloromethane (10 mL) and stirred at room temperature. To the reaction solution was added 5 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 6 hours. Thereafter, the solvent was distilled off under reduced pressure. To the obtained residue, 5 mL of dichloromethane and 5 mL of toluene were added, and azeotropic operation was performed 3 times to remove trifluoroacetic acid. This gave 569 mg of the crude title compound.
MS (FAB) m / z: 829 ((M + H) ⁺ , free form).
[Example 27c]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -2-methylpropanamide hydrochloride Examples N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2 obtained in 27b -(3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoroacetate 80mg (0.076mm ol) was dissolved in dichloromethane (4 mL) and stirred at room temperature. Thereto were sequentially added 42 μL (0.301 mmol) of triethylamine and 12 μL (0.113 mmol) of isobutyryl chloride, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 65 mg of the free form of the title compound. A solution of free form (65 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 54 mg (yield: 76%) of the title compound.
IR νmax cm ^-1 (KBr): 3314, 2933, 1648, 1473, 1441, 1376, 1282, 1168, 1140, 905, 758, 682.
MS (FAB) m / z: 899 ((M + H) ⁺ , free body).

[Example 28]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} pyridine-2-carboxamide dihydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 80 mg (0.076 mmol) of acetate, 20 mg (0.113 mmol) of picolinic acid hydrochloride and 53 μL (0.378 mmol) of triethylamine, and 53 mg (yield: 70%) of the title compound. )
IR νmax cm ^-1 (KBr): 3382, 2930, 1648, 1521, 1439, 1376, 1282, 1167, 1139, 1108, 905, 755, 681.
MS (FAB) m / z: 934 ((M + H) ⁺ , free body).

[Example 29]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} cyclohexanecarboxamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 80 mg (0.076 mmol) of acetate and 15 μL (0.113 mmol) of cyclohexanecarbonyl chloride to obtain 57 mg (yield: 77%) of the title compound.
IR νmax cm ^-1 (KBr): 3302, 2931, 2857, 1649, 1442, 1376, 1282, 1169, 1140, 1109, 905, 758, 681.
MS (FAB) m / z: 939 ((M + H) ⁺ , free form).

[Example 30]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} tetrahydro-2H-pyran-4-carboxamide Hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 80 mg (0.076 mmol) of acetate and 17 mg (0.113 mmol) of tetrahydropyrancarbonyl chloride to obtain 48 mg (yield: 65%) of the title compound.
IR νmax cm ^-1 (KBr): 3315, 2930, 1650, 1442, 1376, 1282, 1169, 1139, 905, 681.
MS (FAB) m / z: 941 ((M + H) ⁺ , free form).

[Example 31]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} cyclopropanecarboxamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 80 mg (0.076 mmol) of acetate and 10 μL (0.113 mmol) of cyclopropanecarbonyl chloride to obtain 21 mg (yield: 30%) of the title compound.
IR νmax cm ^-1 (KBr): 3290, 2930, 1650, 1474, 1440, 1376, 1282, 1186, 1139, 1109, 905, 759, 681.
MS (FAB) m / z: 897 ((M + H) ⁺ , free form).

[Example 32]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} benzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was performed using 80 mg (0.076 mmol) of acetate and 13 μL (0.113 mmol) of benzoyl chloride to obtain 45 mg (yield: 61%) of the title compound.
IR νmax cm ^-1 (KBr): 3358, 2930, 1650, 1538, 1475, 1440, 1376, 1282, 1169, 1139, 1109, 1029, 905, 758, 707, 681.
MS (FAB) m / z: 933 ((M + H) ⁺ , free body).

[Example 33]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- {3-[(phenylacetyl) amino] propyl} acetamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 9.4 μL (0.071 mmol) of phenylacetyl chloride and 26 μL (0.189 mmol) of triethylamine, and 24 mg of the title compound (yield: 52%) )
IR νmax cm ^-1 (KBr): 3277, 2929, 1651, 1474, 1439, 1376, 1281, 1185, 1139, 1108, 1029, 905, 757, 681.
MS (FAB) m / z: 947 ((M + H) ⁺ , free body).

[Example 34]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -4-methoxybenzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 12 mg (0.071 mmol) of 4-methoxybenzoyl chloride and 26 μL (0.189 mmol) of triethylamine, and 32 mg (yield: 45%) of the title compound. )
IR νmax cm ^-1 (KBr): 3348, 2931, 1649, 1504, 1441, 1376, 1282, 1256, 1184, 1139, 1109, 1029, 905, 848, 760, 681.
MS (FAB) m / z: 963 ((M + H) ⁺ , free body).

[Example 35]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -3-methoxybenzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 12 mg (0.071 mmol) of 3-methoxybenzoyl chloride and 26 μL (0.189 mmol) of triethylamine, and 33 mg (yield: 46%) of the title compound. )
IR νmax cm ^-1 (KBr): 3336, 2931, 1650, 1537, 1476, 1439, 1376, 1282, 1185, 1139, 1109, 1030, 905, 756, 682.
MS (FAB) m / z: 963 ((M + H) ⁺ , free body).

[Example 36]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -2-methoxybenzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 12 mg (0.071 mmol) of 2-methoxybenzoyl chloride and 26 μL (0.189 mmol) of triethylamine, and 35 mg (yield: 49%) of the title compound. )
IR νmax cm ^-1 (KBr): 3396, 2931, 1648, 1537, 1483, 1440, 1376, 1282, 1185, 1139, 1109, 1028, 905, 758, 681.
MS (FAB) m / z: 963 ((M + H) ⁺ , free body).

[Example 37]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -4-chlorobenzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 9.0 μL (0.071 mmol) of 4-chlorobenzoyl chloride and 26 μL (0.189 mmol) of triethylamine, and 28 mg (yield: 59%).
IR νmax cm ^-1 (KBr): 3290, 2930, 1651, 1539, 1485, 1439, 1376, 1281, 1185, 1139, 1108, 905, 849, 758, 681.
MS (FAB) m / z: 967 ((M + H) ⁺ , free body).

[Example 38]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -4-methylbenzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 9.4 μL (0.071 mmol) of p-toluoyl chloride and 26 μL (0.189 mmol) of triethylamine, and 28 mg (yield: 60) of the title compound. %).
IR νmax cm ^-1 (KBr): 3335, 2927, 1645, 1549, 1475, 1441, 1376, 1282, 1186, 1140, 905, 755, 681.
MS (FAB) m / z: 947 ((M + H) ⁺ , free body).

[Example 39]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -4- (trifluoromethyl) benzamide hydrochloride salt

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 10.5 μL (0.071 mmol) of 4- (trifluoromethyl) benzoyl chloride and 26 μL (0.189 mmol) of triethylamine, and 12 mg of the title compound. (Yield: 24%) was obtained.
IR νmax cm ^-1 (KBr): 3302, 2930, 1651, 1545, 1474, 1440, 1376, 1328, 1282, 1167, 1137, 1068, 905, 758, 682.
MS (FAB) m / z: 1001 ((M + H) ⁺ , free form).

[Example 40]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -3,5-bis (trifluoromethyl ) Benzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The reaction was conducted in the same manner as in Example 27c using 50 mg (0.047 mmol) of acetate, 13 μL (0.071 mmol) of 3,5-bis (trifluoromethyl) benzoyl chloride, and 26 μL (0.189 mmol) of triethylamine. 15 mg (yield: 29%) was obtained.
IR νmax cm ^-1 (KBr): 3334, 2931, 1653, 1546, 1473, 1440, 1281, 1184, 1137, 906, 759, 704, 682.
MS (FAB) m / z: 1069 ((M + H) ⁺ , free form).

[Example 41]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} thiophene-2-carboxamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 7.6 μL (0.071 mmol) of 2-thiophenecarbonyl chloride and 26 μL (0.189 mmol) of triethylamine, and 32 mg (yield: 69%).
IR νmax cm ^-1 (KBr): 3290, 2930, 1646, 1545, 1475, 1440, 1376, 1282, 1185, 1139, 1108, 1029, 905, 756, 720, 681.
MS (FAB) m / z: 939 ((M + H) ⁺ , free form).

[Example 42]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -1-benzothiophene-2-carboxamide Hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 14 mg (0.071 mmol) of 2-benzothiophenecarbonyl chloride and 26 μL (0.189 mmol) of triethylamine, and 31 mg (yield: 64) of the title compound. %).
IR νmax cm ^-1 (KBr): 3277, 2929, 1649, 1542, 1474, 1438, 1376, 1281, 1185, 1139, 1108, 1029, 905, 758, 681.
MS (FAB) m / z: 989 ((M + H) ⁺ , free form).

[Example 43]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} quinoline-2-carboxamide dihydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 14 mg (0.071 mmol) of 2-quinolinecarbonyl chloride and 33 μL (0.236 mmol) of triethylamine, and 15 mg of the title compound (yield: 30%) )
IR νmax cm ^-1 (KBr): 3394, 2929, 2552, 1650, 1529, 1475, 1439, 1376, 1281, 1185, 1139, 1109, 905, 849, 759, 681.
MS (FAB) m / z: 984 ((M + H) ⁺ , free body).

[Example 44]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -2-naphthamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The reaction was conducted in the same manner as in Example 27c using 50 mg (0.047 mmol) of acetate, 14 mg (0.071 mmol) of 2-naphthoyl chloride and 33 μL (0.236 mmol) of triethylamine, and 32 mg of the title compound (yield: 66%) )
IR νmax cm ^-1 (KBr): 3348, 2929, 1650, 1535, 1474, 1438, 1376, 1281, 1185, 1139, 1108, 905, 761, 681.
MS (FAB) m / z: 983 ((M + H) ⁺ , free form).

[Example 45]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} biphenyl-4-carboxamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 15 mg (0.071 mmol) of biphenyl 4-carbonyl chloride and 33 μL (0.236 mmol) of triethylamine, and 23 mg (yield: 46%) of the title compound. )
IR νmax cm ^-1 (KBr): 3303, 2929, 1651, 1542, 1485, 1439, 1376, 1281, 1186, 1139, 1108, 905, 752, 681.
MS (FAB) m / z: 1009 ((M + H) ⁺ , free form).

[Example 46]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -4-tert-butylbenzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 14 μL (0.071 mmol) of 4-tert-butylbenzoyl chloride and 26 μL (0.189 mmol) of triethylamine, and 24 mg (yield: 49%).
IR νmax cm ^-1 (KBr): 3333, 2962, 1651, 1474, 1439, 1376, 1282, 1186, 1140, 1109, 905, 757, 681.
MS (FAB) m / z: 989 ((M + H) ⁺ , free form).

[Example 47]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -3-fluoro-4- (trifluoro Methyl) benzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 11 μL (0.071 mmol) of 3-fluoro-4- (trifluoromethyl) benzoyl chloride and 26 μL (0.189 mmol) of triethylamine. Compound 27 mg (yield: 54%) was obtained.
IR νmax cm ^-1 (KBr): 3291, 2931, 1652, 1474, 1439, 1376, 1325, 1282, 1184, 1138, 905, 759, 681.
MS (FAB) m / z: 1019 ((M + H) ⁺ , free form).

[Example 48]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -3,5-dimethylbenzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro A solution of 50 mg (0.047 mmol) of acetate in dichloromethane (2 mL) was stirred at room temperature, 14 mg (0.071 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 33 μL (0.236 mmol) of triethylamine. Then, 11 mg (0.071 mmol) of 3,5-dimethylbenzoyl chloride was sequentially added and stirred for 17 hours. Water was added to the reaction solution, and extraction was performed 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 20 mg of the free form of the title compound. A solution of free form (20 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 13 mg (yield: 27%) of the title compound.
IR νmax cm ^-1 (KBr): 3347, 2926, 1650, 1473, 1439, 1376, 1281, 1185, 1139, 1108, 905, 758, 682.
MS (FAB) m / z: 961 ((M + H) ⁺ , free form).

[Example 49]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -3,5-di-tert-butyl Benzamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate and 17 mg (0.071 mmol) of 3,5-di-tert-butylbenzoic acid to obtain 14 mg (yield: 27%) of the title compound. Obtained.
IR νmax cm ^-1 (KBr): 3393, 2962, 1651, 1475, 1438, 1375, 1281, 1141, 1030, 905, 756, 681.
MS (FAB) m / z: 1045 ((M + H) ⁺ , free form).

[Example 50]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- {3-[(phenylsulfonyl) amino] propyl} acetamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro 80 mg (0.076 mmol) of acetate was dissolved in 5 mL of dichloromethane and stirred at room temperature. Thereto were sequentially added 42 μL (0.303 mmol) of triethylamine and 14 μL (0.113 mmol) of benzenesulfonyl chloride, and the mixture was stirred at room temperature for 1 hour. After concentration of the reaction solution, the residue was purified by silica gel chromatography (eluent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 62 mg of the free form of the title compound. A solution of free form (62 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 55 mg (yield: 72%) of the title compound.
IR νmax cm ^-1 (KBr): 3358, 2931, 1645, 1446, 1377, 1326, 1282, 1162, 1140, 1097, 905, 757, 682, 586.
MS (FAB) m / z: 969 ((M + H) ⁺ , free body).

[Example 51]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} -N-methyl-N- {3-[(pyridin-3-ylsulfonyl) amino] propyl} acetamide Dihydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 50 was carried out using 80 mg (0.076 mmol) of acetate and 24 mg (0.113 mmol) of 3-pyridinesulfonyl chloride hydrochloride to obtain 17 mg (yield: 21%) of the title compound.
IR νmax cm ^-1 (KBr): 3414, 2931, 1647, 1459, 1441, 1376, 1282, 1170, 1139, 905, 757, 681, 589.
MS (FAB) m / z: 970 ((M + H) ⁺ , free body).

[Example 52]
N- {3-[(biphenyl-4-ylsulfonyl) amino] propyl} -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) ) Benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide Hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 50 was performed using 50 mg (0.047 mmol) of acetate and 18 mg (0.071 mmol) of 4-biphenylsulfonyl chloride to obtain 37 mg (yield: 72%) of the title compound.
IR νmax cm ^-1 (KBr): 3428, 2929, 1649, 1478, 1439, 1376, 1328, 1281, 1160, 1140, 1099, 764, 681, 592.
MS (FAB) m / z: 1045 ((M + H) ⁺ , free form).

[Example 53]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- {3-[(quinolin-8-ylsulfonyl) amino] propyl} acetamide Dihydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 50 was carried out using 50 mg (0.047 mmol) of acetate and 16 mg (0.071 mmol) of quinoline-8-sulfonyl chloride to obtain 27 mg (yield: 52%) of the title compound.
IR νmax cm ^-1 (KBr): 3429, 2929, 1648, 1474, 1439, 1376, 1330, 1282, 1165, 1142, 1108, 905, 836, 792, 761, 707, 681, 590.
MS (FAB) m / z: 1020 ((M + H) ⁺ , free form).

[Example 54]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [3-({[4- (trifluoromethyl) phenyl] sulfonyl} Amino) propyl] acetamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 50 was performed using 50 mg (0.047 mmol) of acetate and 17 mg (0.071 mmol) of 4-trifluoromethylbenzenesulfonyl chloride to obtain 27 mg (yield: 53%) of the title compound.
IR νmax cm ^-1 (KBr): 3414, 2932, 1650, 1474, 1440, 1376, 1325, 1282, 1166, 1137, 1108, 1063, 905, 848, 757, 710, 681, 604.
MS (FAB) m / z: 1037 ((M + H) ⁺ , free form).

[Example 55]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-isopropylbutanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 80 mg (0.089 mmol) was dissolved in 5 mL of dichloromethane. And stirred at room temperature. Thereto, 31 μL (0.225 mmol) of triethylamine and 17 μL (0.134 mmol) of pivaloyl chloride were sequentially added, and the mixture was stirred at room temperature for 30 minutes. To this was dropped 23 μL (0.268 mmol) of isopropylamine, and the mixture was further stirred at room temperature for 1 hour. After the reaction solution was concentrated, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 57 mg of the free form of the title compound. A solution of free form (57 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 53 mg (yield: 64%) of the title compound.
IR νmax cm ^-1 (KBr): 3288, 2968, 2930, 1651, 1473, 1458, 1439, 1376, 1282, 1185, 1139, 1098, 905, 757, 681.
MS (FAB) m / z: 899 ((M + H) ⁺ , free body).

[Example 56]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-morpholin-4-yl-4-oxobutyl) acetamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 80 mg (0.089 mmol) and morpholine 23 μL (0. 268 mmol) was used to carry out the same reaction as in Example 55, to obtain 65 mg (yield: 75%) of the title compound.
IR νmax cm ^-1 (KBr): 3422, 2926, 1649, 1438, 1376, 1282, 1185, 1138, 1116, 1030, 905, 758, 681.
MS (FAB) m / z: 927 ((M + H) ⁺ , free body).

[Example 57]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-oxo-4-piperidin-1-ylbutyl) acetamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 80 mg (0.089 mmol) and piperidine 18 μL (0. 179 mmol) was used to carry out the same reaction as in Example 55 to obtain 55 mg (yield: 64%) of the title compound.
IR νmax cm ^-1 (KBr): 3421, 2934, 1647, 1441, 1376, 1282, 1185, 1139, 1098, 905, 757, 681.
MS (FAB) m / z: 925 ((M + H) ⁺ , free body).

[Example 58]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [4- (4-methylpiperazin-1-yl) -4-oxobutyl Acetamide dihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 80 mg (0.089 mmol), 1-methylpiperazine 15 μL (0.134 mmol) and triethylamine 50 μL (0.358 mmol) were used to carry out the same reaction as in Example 55 to obtain 65 mg of the title compound (yield: 74%).
IR νmax cm ^-1 (KBr): 3430, 2929, 2574, 1650, 1440, 1376, 1282, 1185, 1139, 1097, 1029, 978, 905, 758, 681.
MS (FAB) m / z: 940 ((M + H) ⁺ , free body).

[Example 59]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [4-oxo-4- (4-phenylpiperazin-1-yl) Butyl] acetamide dihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 80 mg (0.089 mmol), 1-methylpiperazine 20 μL (0.134 mmol) and triethylamine 50 μL (0.358 mmol) were used to carry out the same reaction as in Example 55 to obtain 62 mg (yield: 64%) of the title compound.
IR νmax cm ^-1 (KBr): 3411, 2927, 2526, 1650, 1440, 1376, 1281, 1185, 1139, 1029, 905, 759, 681.
MS (FAB) m / z: 1002 ((M + H) ⁺ , free form).

[Example 60]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [4-oxo-4- (4-pyridin-2-ylpiperazine- 1-yl) butyl] acetamide trihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 70 mg (0.078 mmol), 1-pyridine-2 -Reaction was carried out in the same manner as in Example 55 using 18 μL (0.117 mmol) of ylpiperazine, 14 μL (0.117 mmol) of pivaloyl chloride and 43 μL (0.313 mmol) of triethylamine, and 60 mg (yield: 69%) of the title compound were obtained. Obtained.
IR νmax cm ^-1 (KBr): 3412, 2926, 1643, 1606, 1437, 1376, 1282, 1184, 1138, 1108, 1028, 905, 762, 681.
MS (FAB) m / z: 1003 ((M + H) ⁺ , free form).

[Example 61]
N- [4- (4-acetylpiperazin-1-yl) -4-oxobutyl] -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (tri Fluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N— Methylacetamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 70 mg (0.078 mmol), 1-acetylpiperazine 19 mg (0.117 mmol), 14 μL (0.117 mmol) of pivaloyl chloride and 43 μL (0.313 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 34 mg (yield: 43%) of the title compound.
IR νmax cm ^-1 (KBr): 3404, 2926, 1646, 1437, 1376, 1282, 1169, 1138, 1097, 1029, 996, 905, 758, 681.
MS (FAB) m / z: 968 ((M + H) ⁺ , free body).

[Example 62]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-cyclohexylbutanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 70 mg (0.078 mmol), cyclohexylamine 13 μL (0 117 mmol), 14 μL (0.117 mmol) of pivaloyl chloride and 43 μL (0.313 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 44 mg (yield: 58%) of the title compound.
IR νmax cm ^-1 (KBr): 3288, 2932, 2856, 1651, 1475, 1440, 1376, 1281, 1185, 1139, 1109, 1029, 905, 757, 681.
MS (FAB) m / z: 939 ((M + H) ⁺ , free form).

[Example 63]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-cyclopropylbutanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), cyclopropylamine 9 μL ( 0.134 mmol), 12 μL (0.101 mmol) of pivaloyl chloride and 37 μL (0.268 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 44 mg (yield: 70%) of the title compound.
IR νmax cm ^-1 (KBr): 3267, 2929, 1651, 1475, 1439, 1376, 1281, 1185, 1139, 1098, 1029, 905, 757, 681.
MS (FAB) m / z: 897 ((M + H) ⁺ , free form).

[Example 64]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-cyclopentylbutanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), cyclopentylamine 13 μL (0 .134 mmol), pivaloyl chloride 12 μL (0.101 mmol) and triethylamine 37 μL (0.268 mmol) were used to carry out the same reaction as in Example 55 to obtain 50 mg (yield: 77%) of the title compound.
IR νmax cm ^-1 (KBr): 3289, 2955, 1651, 1475, 1440, 1376, 1281, 1185, 1139, 1109, 1029, 905, 757, 681.
MS (FAB) m / z: 925 ((M + H) ⁺ , free body).

[Example 65]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N- (2-morpholin-4-ylethyl) butanamide dihydrochloride salt

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), 2-morpholine-4 -Ile Ethamineamine 18 μL (0.134 mmol), pivaloyl chloride 12 μL (0.101 mmol), triethylamine 37 μL (0.268 mmol) were used for the same reaction as in Example 55, and the title compound 58 mg (yield: 83%) was obtained. Obtained.
IR νmax cm ^-1 (KBr): 3266, 2929, 2581, 1648, 1541, 1441, 1376, 1282, 1137, 1102, 1028, 905, 761, 681.
MS (FAB) m / z: 970 ((M + H) ⁺ , free body).

[Example 66]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N- (2-hydroxyethyl) -N-methylbutanamide Hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), 2- (methylamino ) Ethanol 11 μL (0.134 mmol), pivaloyl chloride 12 μL (0.101 mmol) and triethylamine 37 μL (0.268 mmol) were used for the same reaction as in Example 55 to obtain 46 mg (yield: 72%) of the title compound. It was.
IR νmax cm ^-1 (KBr): 3375, 2930, 1647, 1475, 1439, 1376, 1282, 1185, 1139, 905, 758, 681.
MS (FAB) m / z: 915 ((M + H) ⁺ , free body).

[Example 67]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {4- [4- (hydroxymethyl) piperidin-1-yl] -4-oxobutyl} -N-methylacetamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), 2-piperidine-4 The reaction was carried out in the same manner as in Example 55 using 15 mg (0.134 mmol) of ylethanol, 12 μL (0.101 mmol) of pivaloyl chloride and 37 μL (0.268 mmol) of triethylamine, and 52 mg (yield: 78%) of the title compound was obtained. Obtained.
IR νmax cm ^-1 (KBr): 3403, 2927, 1646, 1474, 1441, 1376, 1282, 1185, 1138, 1097, 1029, 905, 758, 681.
MS (FAB) m / z: 955 ((M + H) ⁺ , free body).

[Example 68]
Ethyl 1- {4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butanoyl} piperidine-4-carboxylic acid hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), ethyl isonipecotate 21 μL ( 0.134 mmol), 12 μL (0.101 mmol) of pivaloyl chloride and 37 μL (0.268 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 49 mg (yield: 70%) of the title compound.
IR νmax cm ^-1 (KBr): 3434, 2931, 1729, 1648, 1473, 1441, 1376, 1282, 1184, 1138, 1040, 905, 758, 681.
MS (FAB) m / z: 997 ((M + H) ⁺ , free body).

[Example 69]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {4-[(3S) -3-hydroxypyrrolidin-1-yl] -4-oxobutyl } -N-methylacetamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), (3S) -pyrrolidine The reaction was carried out in the same manner as in Example 55 using 11 μL (0.134 mmol) of 3-ol, 12 μL (0.101 mmol) of pivaloyl chloride and 37 μL (0.268 mmol) of triethylamine, and 39 mg of the title compound (yield: 60%) Got.
IR νmax cm ^-1 (KBr): 3388, 2931, 1646, 1440, 1376, 1282, 1185, 1138, 1107, 1029, 905, 757, 681.
MS (FAB) m / z: 927 ((M + H) ⁺ , free body).

[Example 70]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N- (4-methoxyphenyl) butanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 60 mg (0.067 mmol), 4-methoxyaniline 12 mg (0.101 mmol), 12 μL (0.101 mmol) of pivaloyl chloride and 37 μL (0.268 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 31 mg (yield: 46%) of the title compound.
IR νmax cm ^-1 (KBr): 2932, 1651, 1512, 1472, 1441, 1376, 1282, 1242, 1139, 1030, 905, 832, 757, 681.
MS (FAB) m / z: 963 ((M + H) ⁺ , free body).

[Example 71]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-phenylbutanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 50 mg (0.056 mmol), aniline 7.6 μL ( 0.084 mmol), pivaloyl chloride 10 μL (0.084 mmol) and triethylamine 31 μL (0.224 mmol) were used to carry out the same reaction as in Example 55 to obtain 37 mg (yield: 68%) of the title compound.
IR νmax cm ^-1 (KBr): 2931, 1650, 1601, 1543, 1476, 1442, 1376, 1281, 1185, 1139, 1098, 1029, 905, 757, 681.
MS (FAB) m / z: 933 ((M + H) ⁺ , free body).

[Example 72]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N- (4-chlorophenyl) butanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 50 mg (0.056 mmol), 4-chloroaniline 11 μL (0.084 mmol), 10 μL (0.084 mmol) of pivaloyl chloride and 31 μL (0.224 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 40 mg (yield: 71%) of the title compound.
IR νmax cm ^-1 (KBr): 2930, 1651, 1597, 1535, 1493, 1440, 1376, 1281, 1185, 1139, 1094, 905, 832, 757, 681.
MS (FAB) m / z: 969 ((M + H) ⁺ , free body).

[Example 73]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N- (4-methylphenyl) butanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 50 mg (0.056 mmol), 4-methylaniline 9 mg (0.084 mmol), 10 μL (0.084 mmol) of pivaloyl chloride and 31 μL (0.224 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 39 mg (yield: 71%) of the title compound.
IR νmax cm ^-1 (KBr): 3421, 2927, 1650, 1515, 1475, 1440, 1376, 1281, 1185, 1140, 1098, 905, 821, 757, 681.
MS (FAB) m / z: 947 ((M + H) ⁺ , free body).

[Example 74]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N-methyl-N-phenylbutanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 50 mg (0.056 mmol), N-methylaniline 9 μL (0.084 mmol), 10 μL (0.084 mmol) of pivaloyl chloride and 31 μL (0.224 mmol) of triethylamine were used to carry out the same reaction as in Example 55 to obtain 37 mg of the title compound (yield: 67%).
IR νmax cm ^-1 (KBr): 3424, 2929, 1652, 1596, 1475, 1440, 1376, 1282, 1185, 1138, 1098, 1029, 905, 759, 704, 681.
MS (FAB) m / z: 947 ((M + H) ⁺ , free body).

[Example 75]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] -N- (2,3-dihydro-1H-indene-5 -Yl) butanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 50 mg (0.056 mmol), indan-5-amine 11 mg (0.084 mmol), pivaloyl chloride 10 μL (0.084 mmol), and triethylamine 31 μL (0.224 mmol) were used to carry out the same reaction as in Example 55 to obtain 42 mg (yield: 74%) of the title compound.
IR νmax cm ^-1 (KBr): 3289, 2933, 1651, 1541, 1491, 1440, 1376, 1281, 1185, 1139, 1098, 1029, 905, 757, 681.
MS (FAB) m / z: 973 ((M + H) ⁺ , free form).

[Example 76]
N-biphenyl-2-yl-4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3 4-Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butanamide hydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyric acid hydrochloride 50 mg (0.056 mmol), biphenyl-2-amine The same reaction as in Example 55 was carried out using 14 mg (0.084 mmol), pivaloyl chloride 10 μL (0.084 mmol), and triethylamine 31 μL (0.224 mmol) to obtain 31 mg (yield: 53%) of the title compound.
IR νmax cm ^-1 (KBr): 3417, 2929, 1650, 1519, 1438, 1376, 1281, 1185, 1139, 1097, 1029, 905, 756, 705, 681.
MS (FAB) m / z: 1009 ((M + H) ⁺ , free form).

[Example 77]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-morpholin-4-ylbutyl) acetamide dihydrochloride

[Example 77a]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl methanesulfonic acid 2-{[(2S) -1′- {2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene -1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 1.0 g (1.18 mmol) was dissolved in 10 mL of dichloromethane and stirred under ice cooling. . Triethylamine (101 μL, 1.30 mmol) and methanesulfonyl chloride (181 μL, 1.30 mmol) were sequentially added to the solution, and the mixture was warmed to room temperature and stirred for 2 hours. Water and saturated brine were added to the reaction solution, and extracted with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was evaporated under reduced pressure to obtain 1.17 g of the unpurified title compound.
MS (FAB) m / z: 922 ((M + H) ⁺ , free form).
[Example 77b]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-morpholin-4-ylbutyl) acetamide dihydrochloride In Example 77a 4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine obtained 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl methanesulfonic acid 100 mg (0.108 mmol) in acetonitrile 2 It melt | dissolved in mL, 18 mg (0.217 mmol) of sodium hydrogencarbonate, 36 mg (0.217 mmol) of potassium iodide, and 19 microliters (0.217 mmol) of morpholines were added in order, and it heated at 60 degreeC, and stirred for 3 hours. After cooling the reaction solution to room temperature and concentrating, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 2/5/5), and the resulting amorphous was further treated with NH. Purification by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/1) gave 31 mg of the free form of the title compound. A solution of free form (31 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 31 mg (yield: 29%) of the title compound.
IR νmax cm ^-1 (KBr): 3432, 2928, 2563, 2648, 1474, 1440, 1376, 1282, 1186, 1138, 1107, 905, 758, 586.
MS (FAB) m / z: 913 ((M + H) ⁺ , free body).

[Example 78]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {4- [butyl (methyl) amino] butyl} -N-methylacetamide dihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4) obtained in Example 77a. -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl methanesulfonic acid 100 mg (0. 108 mmol) was dissolved in 2 mL of dimethylformamide, 30 mg (0.217 mmol) of potassium carbonate and 26 μL (0.217 mmol) of N-methylbutan-1-amine were sequentially added thereto, heated to 60 ° C. and stirred for 5 hours. After cooling the reaction solution to room temperature, 3 mL of ethyl acetate was added, and unnecessary substances were removed by filtration. After concentrating the filtrate, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane / triethylamine = 0/5/5 / 0.1-2 / 5/5 / 0.1) 23 mg of a free form of the compound was obtained. A solution of free form (23 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 19 mg (yield: 17%) of the title compound.
IR νmax cm ^-1 (KBr): 3433, 2935, 2576, 1648, 1474, 1376, 1282, 1185, 1138, 1107, 1029, 905, 757, 586.
MS (FAB) m / z: 913 ((M + H) ⁺ , free body).

[Example 79]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-piperidin-1-ylbutyl) acetamide dihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4) obtained in Example 77a. -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl methanesulfonic acid 100 mg (0. 108 mmol) was dissolved in 3 mL of acetonitrile, 27 mg (0.325 mmol) of sodium bicarbonate and 21 μL (0.217 mmol) of piperidine were sequentially added thereto, heated to 60 ° C. and stirred for 5 hours. After cooling the reaction solution to room temperature, 3 mL of ethyl acetate was added, and unnecessary substances were removed by filtration. After concentrating the filtrate, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane / triethylamine = 0/5/5 / 0.1-2 / 5/5 / 0.1) to give the title compound. 56 mg of a free form of was obtained. A solution of free form (56 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 53 mg (yield: 50%) of the title compound.
IR νmax cm ^-1 (KBr): 3429, 2934, 2541, 1648, 1474, 1440, 1376, 1282, 1185, 1138, 1108, 905, 758, 586.
MS (FAB) m / z: 911 ((M + H) ⁺ , free body).

[Example 80]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- [4- (isopropylamino) butyl] -N-methylacetamide dihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4) obtained in Example 77a. -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl methanesulfonic acid 80 mg (0. 087 mmol) was dissolved in 2 mL of isopropylamine and stirred at room temperature for 9 hours. After concentrating the reaction solution, the residue was purified by NH silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/0/1 to 0/1/1 to 2/5/5) to give a free form of the title compound. 17 mg was obtained. A solution of free form (17 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 10 mg (yield: 12%) of the title compound.
IR νmax cm ^-1 (KBr): 3422, 2935, 2690, 1473, 1440, 1376, 1282, 1185, 1138, 1029, 905, 758, 586.
MS (FAB) m / z: 885 ((M + H) ⁺ , free form).

[Example 81]
N- (4-anilinobutyl) -2-{[(2S) -1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4- Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride

4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4) obtained in Example 77a. -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl methanesulfonic acid 100 mg (0. 108 mmol) was dissolved in 2 mL of aniline and stirred at 50 ° C. for 3 hours. The reaction solution was cooled to room temperature and purified by NH silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/0/1 to 0/1/1 to 2/5/5) to give the free form of the title compound. 27 mg was obtained. A solution of free form (27 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 21 mg (yield: 20%) of the title compound.
IR νmax cm ^-1 (KBr): 3413, 2930, 2606, 1649, 1475, 1439, 1376, 1281, 1185, 1139, 1109, 1029, 905, 758, 586.
MS (FAB) m / z: 919 ((M + H) ⁺ , free body).

[Example 82]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-phenoxybutyl) acetamide hydrochloride

To a solution of phenol 23 mg (0.244 mmol) in dimethylformamide (1 mL) was added 11 mg (0.244 mmol) of sodium hydride under ice cooling, and the mixture was stirred for 15 minutes. Thereto 4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3) obtained in Example 77a. , 4-Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl methanesulfonic acid 150 mg ( A solution of 0.163 mmol) in dimethylformamide (1 mL) was added dropwise, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted 3 times with ethyl acetate / hexane (1/1). The obtained organic layer was dried over anhydrous sodium sulfate, filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 2/5/5) to obtain 109 mg of the free form of the title compound. A solution of free form (109 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 100 mg (yield: 64%) of the title compound.
MS (FAB) m / z: 920 ((M + H) ⁺ , free body).

[Example 83]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [4- (pyridin-2-yloxy) butyl] acetamide dihydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 300 mg (0.355 mmol) and 2-pyridinol To a solution of 37 mg (0.391 mmol) in toluene (10 mL) were added 1,1 ′-(azodicarbonyl) dipiperidine (107 mg, 0.426 mmol) and tributylphosphine (106 μl, 0.426 mmol), and at room temperature for 5 hours. Stir vigorously. The insoluble material was filtered off, and the filtrate was concentrated. The resulting residue was purified using NH silica gel chromatography (ethyl acetate / dichloromethane = 0% → 60%) to obtain 144 mg of the free form of the title compound. A solution of free form (144 mg) in dichloromethane (5 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.2 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 142 mg (yield: 40%) of the title compound.
IR νmax cm ^-1 (KBr): 3413, 2929, 2565, 1645, 1472, 1376, 1282, 1166, 1138, 1108, 1029, 905, 778, 762, 681.
MS (FAB) m / z: 921 ((M + H) ⁺ , free form).

[Example 84]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- [4- (cyclopropylmethoxy) butyl] -N-methylacetamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 200 mg (0.237 mmol) dimethylformamide ( 3 mL) solution was added with 32 mg (0.284 mmol) of sodium hydride and stirred at room temperature for 15 minutes. Cyclopropylmethyl bromide 46 microliters (0.474 mmol) was dripped there, and it stirred at 60 degreeC for 2 hours 30 minutes. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted 3 times with ethyl acetate / hexane (4/1). The obtained organic layer was dried over anhydrous sodium sulfate, filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to give 36 mg of the free form of the title compound. A solution of free form (36 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 24 mg (yield: 11%) of the title compound.
IR νmax cm ^-1 (KBr): 2933, 2865, 1650, 1475, 1439, 1376, 1281, 1186, 1138, 1109, 1029, 905, 757, 681.
MS (FAB) m / z: 898 ((M + H) ⁺ , free body).

[Example 85]
N-benzyl-N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} benzamide hydrochloride

[Example 85a]
N-Benzylbenzamide 0.50 mL (4.58 mmol) of benzylamine was dissolved in 3 mL of dichloromethane and stirred at room temperature. Thereto, triethylamine 0.64 mL (4.58 mmol) and benzoyl chloride 0.53 mL (4.58 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure to quantitatively obtain 1.01 g of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 4.66 (2H, d, J = 5.9 Hz), 6.37 (1H, br s), 7.27-7.52 (8H, m), 7.78-7.80 (2H, m).
[Example 85b]
N-allyl-N-benzylbenzamide 700 mg (3.31 mmol) of N-benzylbenzamide obtained in Example 85a was dissolved in 5 mL of dimethylformamide and stirred under ice cooling. To this, 144 mg (3.31 mmol) of sodium hydride was added and stirred for 20 minutes. After dropwise addition of 344 μL (3.98 mmol) of allyl bromide, the reaction temperature was raised to room temperature and stirred for 3 hours. Water was added to the reaction solution, extraction was performed 3 times with ethyl acetate / hexane (1/1), and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/1) to obtain 777 mg (yield: 93%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 3.76 (1H, br s), 4.11 (1H, br s), 4.50 (1H, br s), 4.77 (1H, br s), 5.15-5.26 (2H, m) , 5.71-5.88 (1H, m), 7.27-7.47 (10H, m).
[Example 85c]
N-benzyl-N- (3-hydroxypropyl) benzamide 777 mg (3.09 mmol) of N-allyl-N-benzylbenzamide obtained in Example 85b was dissolved in 7 mL of tetrahydrofuran and stirred at room temperature. Thereto, 12.4 mL (6.18 mmol) of 9-borabicyclo [3,3,1] nonane / tetrahydrofuran solution (0.5 M) was added dropwise and stirred for 1 hour. While cooling the reaction solution with ice, water (4 mL) was added dropwise, and after stirring for 20 minutes, 5N sodium hydroxide (3 mL) and 30% aqueous hydrogen peroxide (2 mL) were added. After stirring for 1 hour under ice cooling, 5N hydrochloric acid was added dropwise to neutralize the reaction solution, followed by extraction with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate, filtered through celite, and the solvent was distilled off under reduced pressure to obtain 656 mg (yield: 79%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.73-1.77 (2H, m), 3.64-3.70 (4H, m), 4.52 (2H, s), 7.19-7.46 (10H, m).
[Example 85d]
N-benzyl-N- [3- (methylamino) propyl] benzamide 320 mg (1.19 mmol) of N-benzyl-N- (3-hydroxypropyl) benzamide obtained in Example 85c was dissolved in 5 mL of dichloromethane, and And stirred. Thereto, 330 μL (2.38 mmol) of triethylamine and 111 μL (1.43 mmol) of methanesulfonyl chloride were sequentially added, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 2/3) to give 363 mg of 3- [benzoyl (benzyl) amino] propyl methanesulfonic acid. (Yield: 88%) was obtained.

To the obtained 363 mg (1.04 mmol) of 3- [benzoyl (benzyl) amino] propyl methanesulfonic acid was added 4 mL of a 9.8 M methylamine / methanol solution, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to give 216 mg of the title compound ( Yield: 74%).
¹ H-NMR (CDCl ₃ ) δ: 1.66-1.83 (2H, m), 2.28-2.62 (5H, m), 4.52-4.80 (2H, m), 7.16-7.42 (10H, m).
[Example 85e]
N-benzyl-N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} benzamide hydrochloride {[( 2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, A solution of 80 mg (0.105 mmol) of 3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetic acid in dichloromethane (4 mL) was stirred under ice-cooling, and 23 μL of N-methylmorpholine (0 .2 1mmol), were successively added ethyl chloroformate 10 [mu] L (0.105 mmol), and stirred for 20 minutes. To the reaction solution was added dropwise a solution of N-benzyl-N- [3- (methylamino) propyl] benzamide 59 mg (0.211 mmol) obtained in Example 85d in dichloromethane (2 mL), and the mixture was further stirred for 40 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to give a free form of the title compound. 62 mg was obtained. A solution of free form (62 mg) in dichloromethane (2 mL) was stirred under ice-cooling, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 55 mg (yield: 49%) of the title compound.
IR νmax cm ^-1 (KBr): 2929, 2495, 1645, 1472, 1439, 1376, 1281, 1185, 1138, 1098, 1029, 905, 756, 703, 681.
MS (FAB) m / z: 1023 ((M + H) ⁺ , free form).

[Example 86]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-phenylbenzamide hydrochloride

  393 μL (4.31 mmol) of aniline was dissolved in 3 mL of dichloromethane and stirred at room temperature. Thereto, 0.60 mL (4.31 mmol) of triethylamine and 0.50 mL (4.31 mmol) of benzoyl chloride were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure to obtain N-phenylbenzamide. The obtained N-phenylbenzamide was dissolved in 5 mL of dimethylformamide and stirred under ice cooling. Thereto, 188 mg (4.31 mmol) of sodium hydride was added and stirred for 20 minutes. After dropwise addition of 447 μL (5.17 mmol) of allyl bromide, the reaction temperature was raised to room temperature and stirred for 3 hours. Water was added to the reaction solution, extraction was performed 3 times with ethyl acetate / hexane (1/1), and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/1) to give 1.02 g (yield) of N-allyl-N-phenylbenzamide. : 100%).

  1.0 g (4.21 mmol) of the obtained N-allyl-N-phenylbenzamide was dissolved in 10 mL of tetrahydrofuran and stirred at room temperature. Thereto, 16.9 mL (8.43 mmol) of a 9-borabicyclo [3,3,1] nonane / tetrahydrofuran solution (0.5 M) was added dropwise and stirred for 1 hour. Water (4 mL) was added dropwise while cooling the reaction solution, and after stirring for 20 minutes, 5N sodium hydroxide (3 mL) and 30% aqueous hydrogen peroxide (2 mL) were added. After stirring for 1 hour under ice cooling, 5N hydrochloric acid was added dropwise to neutralize the reaction solution, followed by extraction with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 2/3) to obtain 875 mg (yield: 81%) of N-phenyl-N- (3-hydroxypropyl) benzamide. .

  400 mg (1.56 mmol) of the obtained N-phenyl-N- (3-hydroxypropyl) benzamide was dissolved in 10 mL of dichloromethane and stirred at room temperature. Thereto, 326 μL (2.35 mmol) of triethylamine and 363 mg (1.72 mmol) of 4-chlorobenzenesulfonyl chloride were sequentially added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/1) to give 3- [benzoyl (phenyl) amino] propyl 4-chlorobenzenesulfone. 207 mg of acid (yield: 31%) was obtained.

  To 200 mg (0.465 mmol) of the obtained 3- [benzoyl (phenyl) amino] propyl 4-chlorobenzenesulfonic acid, 4 mL of a 9.8 M methylamine / methanol solution was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1/1 to 1/1), and N-phenyl-N- [ 58 mg (yield: 46%) of 3- (methylamino) propyl] benzamide were obtained.

The obtained N-phenyl-N- [3- (methylamino) propyl] benzamide 57 mg (0.211 mmol) and {[(2S) -1 ′-{2-[(2R) -4- [3,5- Bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} The same reaction as in Example 85e was carried out using 80 mg (0.105 mmol) of acetic acid to obtain 55 mg (yield: 50%) of the title compound.
IR νmax cm ^-1 (KBr): 3414, 2929, 2400, 1648, 1596, 1474, 1440, 1376, 1281, 1185, 1138, 1107, 1029, 905, 758, 702, 681.
MS (FAB) m / z: 1009 ((M + H) ⁺ , free form).

[Example 87]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-isopropylbenzamide hydrochloride

  Isopropylamine (440 μL, 5.17 mmol) was dissolved in dichloromethane (5 mL) and stirred at room temperature. Thereto, 0.72 mL (5.17 mmol) of triethylamine and 0.60 mL (5.17 mmol) of benzoyl chloride were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure to obtain 987 mg of N-isopropylbenzamide. The obtained N-isopropylbenzamide was dissolved in 5 mL of dimethylformamide and stirred under ice cooling. Thereto, 226 mg (5.17 mmol) of sodium hydride was added and stirred for 20 minutes. After dropwise addition of 537 μL (6.20 mmol) of allyl bromide, the reaction temperature was raised to room temperature and stirred for 3 hours. Water was added to the reaction solution, extraction was performed 3 times with ethyl acetate / hexane (1/1), and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/1), and 861 mg (yield: 82) of N-allyl-N-isopropylbenzamide. %).

  860 mg (4.23 mmol) of the obtained N-allyl-N-isopropylbenzamide was dissolved in 7 mL of tetrahydrofuran and stirred at room temperature. Thereto, 16.9 mL (8.46 mmol) of a 9-borabicyclo [3,3,1] nonane / tetrahydrofuran solution (0.5 M) was added dropwise and stirred for 1 hour. Water (4 mL) was added dropwise while cooling the reaction solution, and after stirring for 20 minutes, 5N sodium hydroxide (3 mL) and 30% aqueous hydrogen peroxide (2 mL) were added. After stirring for 1 hour under ice cooling, 5N hydrochloric acid was added dropwise to neutralize the reaction solution, followed by extraction with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/1) to obtain 748 mg (yield: 80%) of N- (3-hydroxypropyl) -N-isopropylbenzamide. .

  400 mg (1.81 mmol) of the obtained N- (3-hydroxypropyl) -N-isopropylbenzamide was dissolved in 10 mL of dichloromethane and stirred at room temperature. Thereto, 503 μL (3.62 mmol) of triethylamine and 420 mg (1.99 mmol) of 4-chlorobenzenesulfonyl chloride were sequentially added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/1) to give 3- [benzoyl (isopropyl) amino] propyl 4-chlorobenzenesulfone. 198 mg (yield: 28%) of the acid was obtained.

  To 198 mg (0.50 mmol) of the obtained 3- [benzoyl (isopropyl) amino] propyl 4-chlorobenzenesulfonic acid, 2 mL of a 9.8 M methylamine / methanol solution was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1/1 to 1/1), and N-isopropyl-N- [ 49 mg (yield: 46%) of 3- (methylamino) propyl] benzamide were obtained.

The obtained N-isopropyl-N- [3- (methylamino) propyl] benzamide 49 mg (0.211 mmol) and {[(2S) -1 ′-{2-[(2R) -4- [3,5- Bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} The same reaction as in Example 85e was carried out using 80 mg (0.105 mmol) of acetic acid to obtain 32 mg (yield: 30%) of the title compound.
IR νmax cm ^-1 (KBr): 3430, 2932, 2398, 1649, 1471, 1442, 1376, 1281, 1185, 1139, 1098, 1029, 905, 757, 706, 681.
MS (FAB) m / z: 975 ((M + H) ⁺ , free body).

[Example 88]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-ethylbenzamide hydrochloride

  422 mg (5.17 mmol) of ethylamine hydrochloride was suspended in 5 mL of dichloromethane and stirred at room temperature. Thereto, 0.72 mL (5.17 mmol) of triethylamine and 0.60 mL (5.17 mmol) of benzoyl chloride were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure to obtain 533 mg of N-ethylbenzamide. The obtained N-ethylbenzamide was dissolved in 5 mL of dimethylformamide and stirred under ice cooling. Thereto, 226 mg (5.17 mmol) of sodium hydride was added and stirred for 20 minutes. After dropwise addition of 537 μL (6.20 mmol) of allyl bromide, the reaction temperature was raised to room temperature and stirred for 1 hour. Water was added to the reaction solution, extraction was performed 3 times with ethyl acetate / hexane (1/1), and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/1) to give 633 mg (yield:%) of N-allyl-N-ethylbenzamide. 65) was obtained.

  630 mg (3.33 mmol) of the obtained N-allyl-N-ethylbenzamide was dissolved in 10 mL of tetrahydrofuran and stirred at room temperature. Thereto, 13.3 mL (6.66 mmol) of a 9-borabicyclo [3,3,1] nonane / tetrahydrofuran solution (0.5 M) was added dropwise and stirred for 1 hour. Water (4 mL) was added dropwise while cooling the reaction solution, and after stirring for 20 minutes, 5N sodium hydroxide (3 mL) and 30% aqueous hydrogen peroxide (2 mL) were added. After stirring for 1 hour under ice cooling, 5N hydrochloric acid was added dropwise to neutralize the reaction solution, followed by extraction with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/1) to obtain 477 mg (yield: 69%) of N-ethyl-N- (3-hydroxypropyl) benzamide. .

  470 mg (2.27 mmol) of the obtained N-ethyl-N- (3-hydroxypropyl) benzamide was dissolved in 10 mL of dichloromethane and stirred at room temperature. Thereto, 630 μL (4.54 mmol) of triethylamine and 211 μL (2.72 mmol) of methanesulfonyl chloride were sequentially added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel chromatography (elution solvent: dichloromethane) to obtain 487 mg (yield: 75%) of 3- [benzoyl (ethyl) amino] propyl methanesulfonic acid.

  To 480 mg (1.68 mmol) of the obtained 3- [benzoyl (ethyl) amino] propyl methanesulfonic acid, 4 mL of a 9.8 M methylamine / methanol solution was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 1/1 to methanol / dichloromethane = 1/9), and N-ethyl-N— 269 mg (yield: 73%) of [3- (methylamino) propyl] benzamide was obtained.

The obtained N-ethyl-N- [3- (methylamino) propyl] benzamide 46 mg (0.211 mmol) and {[(2S) -1 ′-{2-[(2R) -4- [3,5- Bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} The same reaction as in Example 85e was carried out using 80 mg (0.105 mmol) of acetic acid to obtain 52 mg (yield: 50%) of the title compound.
IR νmax cm ^-1 (KBr): 3387, 2931, 1647, 1472, 1438, 1376, 1281, 1185, 1165, 1138, 1098, 1029, 905, 757, 706, 681.
MS (FAB) m / z: 961 ((M + H) ⁺ , free form).

[Example 89]
Isopropyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine- 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro Acetate 50 mg (0.047 mmol) was dissolved in 3 mL of dichloromethane and stirred at room temperature. Thereto, 33 μL (0.237 mmol) of triethylamine and 8 μL (0.071 mmol) of isopropyl chloroformate were sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. After the reaction solution was concentrated, the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 29 mg of the free form of the title compound. A solution of free form (29 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 25 mg (yield: 56%) of the title compound.
IR νmax cm ^-1 (KBr): 3332, 2931, 1710, 1649, 1473, 1440, 1375, 1282, 1185, 1139, 1110, 1029, 905, 758, 681.
MS (FAB) m / z: 915 ((M + H) ⁺ , free body).

[Example 90]
Phenyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine- 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro Acetate 60 mg (0.057 mmol) was dissolved in 4 mL of dichloromethane and stirred under ice cooling. Thereto, 39 μL (0.284 mmol) of triethylamine and 11 μL (0.085 mmol) of phenyl chloroformate were sequentially added, followed by stirring for 30 minutes under ice cooling. After the reaction solution was concentrated, the residue was purified by silica gel chromatography (eluent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to obtain 40 mg of the free form of the title compound. A solution of free form (40 mg) in dichloromethane (2 mL) was stirred under ice-cooling, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 36 mg (yield: 64%) of the title compound.
IR νmax cm ^-1 (KBr): 3303, 2930, 1735, 1649, 1479, 1440, 1376, 1282, 1207, 1187, 1139, 1109, 1029, 905, 758, 681.
MS (FAB) m / z: 949 ((M + H) ⁺ , free body).

[Example 91]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-oxo-4-phenylbutyl) acetamide hydrochloride

[Example 91a]
tert-butyl {4- [methoxy (methyl) amino] -4-oxobutyl} methylcarbamic acid 4-[(tert-butoxycarbonyl) (methyl) amino] butyric acid (600 mg, 2.76 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Stir. There, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 794 mg (4.14 mmol), N-methylmorpholine 1.52 mL (13.8 mmol), 1-hydroxybenzotriazole 559 mg (4.14 mmol) , 404 mg (4.14 mmol) of N, O-dimethylhydroxylamine hydrochloride were sequentially added and stirred for 5 hours. Water was added to the reaction solution, and extraction was performed 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/1) to obtain 658 mg (yield: 92%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.80-1.88 (2H, m), 2.42 (2H, t, J = 7.5 Hz), 2.85 (3H, s), 3.18 (3H, s ), 3.27 (2H, t, J = 6.9 Hz), 3.67 (3H, s).
[Example 91b]
tert-Butyl methyl (4-oxo-4-phenylbutyl) carbamic acid 141 μL (1.34 mmol) of bromobenzene was dissolved in 5 mL of tetrahydrofuran and stirred at −78 ° C. There, 851 microliters (1.34 mmol) of 1.58M n-butyllithium / n-hexane solution was dripped, and it stirred for 30 minutes at the same temperature. A tetrahydrofuran solution of 350 mg (1.34 mmol) of tert-butyl {4- [methoxy (methyl) amino] -4-oxobutyl} methylcarbamic acid obtained in Example 91a was added dropwise over 5 minutes, and the temperature was naturally raised to room temperature. Thereafter, the mixture was stirred for 15 hours. 10 mL of water was added to the reaction solution, and extraction was performed 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate / n-hexane = 0/1 to 1/1) to obtain 81 mg (yield: 22%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.95-1.99 (2H, m), 2.87 (3H, m), 2.98 (2H, t, J = 7.2 Hz), 3.33 (2H, t , J = 6.8 Hz), 7.46 (2H, t, J = 7.4 Hz), 7.56 (1H, t, J = 7.4 Hz), 7.96 (2H, d, J = 8.6 Hz).
[Example 91c]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-oxo-4-phenylbutyl) acetamide hydrochloride In Example 91b 80 mg (0.292 mmol) of the obtained tert-butyl methyl (4-oxo-4-phenylbutyl) carbamic acid was dissolved in 4 mL of dichloromethane and stirred under ice cooling. Thereto, 1 mL of trifluoroacetic acid was added, and the temperature was raised to room temperature. After stirring at room temperature for 4 hours, the reaction solution was concentrated to obtain 4- (methylamino) -1-phenylbutan-1-one trifluoroacetate.

{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} A solution of 222 mg (0.292 mmol) of -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetic acid in dichloromethane (3 mL) was stirred at room temperature, and 81 μL (0. 584 mmol) and 36 μL (0.292 mmol) of pivaloyl chloride were sequentially added and stirred for 1 hour. To the reaction solution was added dropwise a solution of 4- (methylamino) -1-phenylbutan-1-one trifluoroacetate and 81 μL (0.584 mmol) of triethylamine in dichloromethane (2 mL), and the mixture was further stirred for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5) to give a free form of the title compound. 135 mg (yield: 50%) was obtained. A solution of free form (75 mg) in dichloromethane (2 mL) was stirred under ice-cooling, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 69 mg of the title compound.
IR νmax cm ^-1 (KBr): 3420, 2930, 2410, 1649, 1475, 1440, 1376, 1281, 1185, 1138, 1098, 1029, 905, 756, 681.
MS (FAB) m / z: 918 ((M + H) ⁺ , free body).

[Example 92]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxy-4-phenylbutyl) -N-methylacetamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 91c ) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (4-oxo-4-phenylbutyl) A solution of 60 mg (0.060 mmol) of acetamide in methanol (2 mL) was stirred at room temperature, and 6.8 mg (0.180 mmol) of sodium borohydride was added thereto and stirred for 1 hour. Several drops of water were added to the reaction solution, the solvent was distilled off, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5). 54 mg of a free form of the compound was obtained. A free form (54 mg) solution in dichloromethane (2 mL) was stirred under ice-cooling, and 2N diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 49 mg (yield: 85%) of the title compound.
IR νmax cm ^-1 (KBr): 3392, 2929, 2557, 1649, 1474, 1440, 1376, 1281, 1186, 1139, 1107, 1029, 905, 758, 704, 681.
MS (FAB) m / z: 920 ((M + H) ⁺ , free body).

[Example 93]
N- {3-[(biphenyl-4-ylsulfonyl) (methyl) amino] propyl} -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis ( Trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N -Methylacetamide hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide The same reaction as in Example 23 was carried out using 40 mg (0.047 mmol) and biphenyl-4-sulfonyl chloride 18 mg (0.071 mmol) to obtain 31 mg (yield: 60%) of the title compound.
IR νmax cm ^-1 (KBr): 3430, 2928, 2497, 1650, 1478, 1440, 1376, 1341, 1281, 1185, 1162, 1139, 1095, 905, 764, 725, 681, 586.
MS (FAB) m / z: 1059 ((M + H) ⁺ , free form).

[Example 94]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -5-phenylpyridine-2-carboxamide Dihydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 14 mg (0.071 mmol) of 5-phenylpicolinic acid and 33 μL (0.236 mmol) of triethylamine, and 15 mg (yield: 29%) of the title compound. )
IR νmax cm ^-1 (KBr): 3392, 2929, 2553, 1650, 1525, 1471, 1439, 1375, 1281, 1185, 1139, 1108, 1029, 905, 758, 703, 681.
MS (FAB) m / z: 1010 ((M + H) ⁺ , free form).

[Example 95]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} nicotinamide dihydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 27b] -2- (3,4-Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide ditrifluoro The same reaction as in Example 27c was carried out using 50 mg (0.047 mmol) of acetate, 12 mg (0.095 mmol) of nicotinic chloride and 33 μL (0.236 mmol) of triethylamine, and 12 mg (yield: 25%) of the title compound was obtained. Obtained.
IR νmax cm ^-1 (KBr): 3403, 2930, 2677, 2576, 1646, 1537, 1473, 1440, 1376, 1282, 1185, 1139, 1109, 905, 758, 681.
MS (FAB) m / z: 934 ((M + H) ⁺ , free body).

[Example 96]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl phenylcarbamate hydrochloride

[Example 96a]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl phenylcarbamate 2-{[(2S) -1 ′-{ 2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene- 1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 100 mg (0.118 mmol) was dissolved in toluene (2.0 mL) and phenyl isocyanate 4.2μL (0.130mmol) and heated for 1 hour stirring at 80 ° C. by adding. After allowing to cool, the reaction solution was concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel (eluent: n-hexane / ethyl acetate / methanol = 7/3 / 0-0 / 10 / 100-0 / 8/2). To obtain 78 mg (yield 68%) of the title compound.
MS (APCI) m / z: 963 (M + H) ⁺ .
[Example 96b]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl phenylcarbamate hydrochloride 4- [obtained in Example 96a ({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl } -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl phenylcarbamate (free form) 78 mg (0.0809 mmol) of dichroic Methane (2 mL) was added 4 N hydrochloric acid - After dropwise dioxane (0.2 mL), and the solvent was evaporated under reduced pressure. N-Hexane and diisopropyl ether were added to the obtained residue and the mixture was collected by filtration to obtain 73 mg (yield 90%) of the title compound as a white solid.
IR νmax cm ^-1 (KBr): 3425, 2932, 1724, 1649, 1444, 1281, 1138, 1029, 905, 757, 681.
MS (APCI) m / z: 963 ((M + H) ⁺ , free body).

[Example 97]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl isopropylcarbamate hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide (100 mg, 0.118 mmol) was added to tetrahydrofuran (1. 0 mL), 14 μL (0.142 mmol) of isopropyl isocyanate and 5 μL of pyridine were added, and the mixture was heated and stirred at 80 ° C. for 1 hour. 60 μL (0.611 mmol) of isopropyl isocyanate was added, and the mixture was further heated and stirred at 80 ° C. for 1.5 hours. After allowing to cool, the reaction solution is concentrated under reduced pressure, and the resulting residue is chromatographed on silica gel (eluent: n-hexane / ethyl acetate / methanol = 7/3 / 0-0 / 10 / 100-0 / 8/2). To obtain 104 mg of the free form of the title compound. 4N Hydrochloric acid-dioxane solution (0.2 mL) was added dropwise to a solution of 104 mg of the resulting free form in dichloromethane (2 mL), and the solvent was evaporated under reduced pressure. N-Hexane and diisopropyl ether were added to the resulting residue, and the residue was collected by filtration to obtain 101 mg (yield 88%) of the title compound as a white solid.
IR νmax cm ^-1 (KBr): 2967, 1710, 1648, 1282, 1138, 1029, 905, 758, 681.
MS (APCI) m / z: 929 ((M + H) ⁺ , free body).

[Example 98]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl biphenyl-4-ylcarbamate hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide (100 mg, 0.118 mmol) was added to tetrahydrofuran (1. (0 mL), 46.2 mg (0.237 mmol) of 4-biphenyl isocyanate was added, and the mixture was stirred with heating at 80 ° C. for 1 hour. After allowing to cool, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 to 0/10) to give 107 mg of the free form of the title compound. Obtained. A 4N hydrochloric acid-dioxane solution (0.20 mL) was added dropwise to an acetone solution (2 mL) of 107 mg of the obtained free product, and then the solvent was distilled off under reduced pressure. N-Hexane and diisopropyl ether were added to the obtained residue and the mixture was collected by filtration to obtain 93 mg (yield 73%) of the title compound as a white solid.
IR νmax cm ^-1 (KBr): 2930, 1723, 1649, 1533, 1485, 1376, 1281, 1223, 1138, 764, 681.
MS (APCI) m / z: 1039 ((M + H) ⁺ , free body).

Example 99
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl 1-naphthylcarbamate hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 100 mg (0.118 mmol) and 1-naphthyl isocyanate According to the method described in Example 98 using 34 μL (0.237 mmol), 98 mg (yield 79%) of the title compound was obtained as a white solid.
IR νmax cm ^-1 (KBr): 2932, 1721, 1648, 1281, 1138, 1029, 905, 681.
MS (APCI) m / z: 1013 ((M + H) ⁺ , free body).

[Example 100]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl tert-butylcarbamate hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 100 mg (0.118 mmol) and t-butyl isocyanate 135 μL (1.18 mmol) was added, and the mixture was heated and stirred at 80 ° C. for 4 hours. Further, 135 μL (1.18 mmol) of t-butyl isocyanate was added and stirred with heating at 80 ° C. for 4 hours. After allowing to cool, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-85 / 15) to give a free form of the title compound. Using the obtained free form, the title compound (93 mg, yield 80%) was obtained as a white solid according to the method described in Example 96b.
IR νmax cm ^-1 (KBr): 2966, 1718, 1649, 1475, 1376, 1281, 1139, 1029, 905, 759, 681.
MS (APCI) m / z: 943 ((M + H) ⁺ , free body).

[Example 101]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl cyclohexyl carbamate hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 100 mg (0.118 mmol) and cyclohexyl isocyanate 200 μL ( According to the method described in Example 98 using 1.59 mmol), 109 mg (92% yield) of the title compound was obtained as a white solid.
IR νmax cm ^-1 (KBr): 2933, 1710, 1649, 1475, 1376, 1281, 1139, 1029, 905, 757, 681.
MS (APCI) m / z: 969 ((M + H) ⁺ , free body).

[Example 102]
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl butylcarbamate hydrochloride

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide 100 mg (0.118 mmol) and n-butyl isocyanate According to the method described in Example 98 using 200 μL (1.59 mmol), 103 mg (yield 89%) of the title compound was obtained as a white solid.
IR νmax cm ^-1 (KBr): 2933, 1712, 1649, 1475, 1376, 1282, 1138, 1029, 905, 757, 681.
MS (APCI) m / z: 943 ((M + H) ⁺ , free body).

[Example 103]
Methyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine- 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamate hydrochloride

[Example 103a]
N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [inden-1,4'-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride obtained in Example 27a tert-butyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid 1.23 g (1.32 mmol) ) Dichlorometa 7.0 mL (28 mmol) of 4N hydrochloric acid-dioxane solution was added to 30 mL of the solution and stirred at room temperature for 2.5 hours. To the reaction solution, 20 mL of toluene and 10 mL of methanol were added, and the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of dichloromethane and 10 mL of toluene were added and subjected to azeotropic operation twice, followed by drying to obtain 1.20 g (yield 100%) of the crude title compound as a white solid.
IR νmax cm ^-1 (KBr): 3429, 2934, 1643, 1475, 1376, 1281, 1138, 1129, 905, 758, 682.
MS (FAB) m / z: 829 ((M + H) ⁺ , free body).
[Example 103b]
Methyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine- 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamate hydrochloride N obtained in Example 103a -(3-Aminopropyl) -2-{[(2S) -1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4- Dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride 100 mg (0.111 mmol) dichlorome Triethylamine 77μL of (0.554 mmol) was added to the emissions (1.0 mL) solution. Under ice cooling, 9.0 μL (0.116 mmol) of methyl chloroformate was added dropwise and stirred for 20 minutes. The reaction solution was purified by NH silica gel chromatography (eluent: n-hexane / ethyl acetate = 9/1 to 0/10) to obtain 60 mg of the free form of the title compound. Using the obtained free form, the title compound (57 mg, yield 55%) was obtained as a white solid according to the method described in Example 96b.
IR νmax cm ^-1 (KBr): 3333, 2932, 1717, 1646, 1475, 1440, 1376, 1282, 1138, 1029, 905, 759, 681.
MS (APCI) m / z: 887 ((M + H) ⁺ , free body).

[Example 104]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {3-[(dimethylcarbamoyl) amino] propyl} -N-methylacetamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 103a] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride According to the method described in Example 103b using 100 mg (0.111 mmol), triethylamine 77 μL (0.554 mmol) and dimethylcarbamoyl chloride 15.3 μL (0.166 mmol), 96 mg (92% yield) of the title compound was obtained as a white solid Got as.
IR νmax cm ^-1 (KBr): 3374, 2932, 1645, 1537, 1476, 1441, 1376, 1282, 1138, 1029, 905, 759, 681.
MS (APCI) m / z: 900 ((M + H) ⁺ , free body).

[Example 105]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {3-[(diethylcarbamoyl) amino] propyl} -N-methylacetamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 103a] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride To a solution of 110 mg (0.122 mmol) in dichloromethane (1.0 mL) was added 77 μL (0.554 mmol) of triethylamine. At room temperature, 46.3 μL (0.366 mmol) of diethylcarbamoyl chloride was added and stirred for 20 minutes. The reaction solution was purified by silica gel chromatography (elution solvent: ethyl acetate / methanol = 10 / 0-7 / 3) to obtain a free form of the title compound. Using the obtained free form, the title compound (99 mg, yield 84%) was obtained as a white solid according to the method described in Example 96b.
IR νmax cm ^-1 (KBr): 2932, 1645, 1531, 1476, 1439, 1377, 1281, 1139, 905, 158, 681,
MS (APCI) m / z: 928 ((M + H) ⁺ , free body).

[Example 106]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {3-[(diisopropylcarbamoyl) amino] propyl} -N-methylacetamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 103a] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride According to the method described in Example 105 using 110 mg (0.122 mmol), triethylamine 77 μL (0.554 mmol) and diisopropylcarbamoyl chloride 60 mg (0.366 mmol), 104 mg (yield 86%) of the title compound was obtained as a white solid. It was.
IR νmax cm ^-1 (KBr): 2969, 2934, 1777, 1647, 1376, 1282, 1138, 1109, 1029, 964, 905, 758, 681.
MS (APCI) m / z: 956 ((M + H) ⁺ , free body).

[Example 107]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} piperidine-1-carboxamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 103a] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride According to the method described in Example 105 using 115 mg (0.127 mmol), triethylamine 71 μL (0.510 mmol) and 1-piperidinecarbonyl chloride 24 μL (0.191 mmol), 110 mg (yield 88%) of the title compound was obtained as a white solid. Got as.
IR νmax cm ^-1 (KBr): 3403, 2935, 1646, 1476, 1442, 1376, 1282, 1138, 1028, 905, 758, 681.
MS (APCI) m / z: 940 ((M + H) ⁺ , free body).

[Example 108]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} morpholine-4-carboxamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 103a] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride According to the method described in Example 105 using 120 mg (0.133 mmol), triethylamine 93 μL (0.665 mmol) and 4-morpholinecarbonyl chloride 46.5 μL (0.399 mmol), 118 mg (yield 91%) of the title compound was obtained. Obtained as a white solid.
IR νmax cm ^-1 (KBr): 3384, 2926, 1646, 1536, 1441, 1376, 1280, 1138, 905, 759, 681.
MS (APCI) m / z: 942 ((M + H) ⁺ , free body).

[Example 109]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- {3-[(diphenylcarbamoyl) amino] propyl} -N-methylacetamide hydrochloride

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 103a] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride 110 mg (0.122 mmol), 77 μL (0.554 mmol) of triethylamine and 85 mg (0.366 mmol) of diphenylcarbamoyl chloride were used to obtain 112 mg (yield 87%) of the title compound as a white solid according to the method described in Example 105. It was.
IR νmax cm ^-1 (KBr): 3438, 2927, 1656, 1491, 1280, 1137, 1101, 758, 697.
MS (APCI) m / z: 1024 ((M + H) ⁺ , free body).

[Example 110]
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (3-{[methyl (phenyl) carbamoyl] amino} propyl) acetamide hydrochloride salt

N- (3-aminopropyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] obtained in Example 103a] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide dihydrochloride According to the method described in Example 105 using 110 mg (0.122 mmol), triethylamine 84.9 μL (0.607 mmol) and N-methyl-N-phenylcarbamoyl chloride 62 mg (yield) 61%) was obtained as a white solid.
IR νmax cm ^-1 (KBr): 2931, 1648, 1516, 1496, 1476, 1280, 1136, 1028, 759.
MS (APCI) m / z: 962 ((M + H) ⁺ , free body).

[Example 111]
Ethyl 4-[({4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4- Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butoxy} carbonyl) amino] benzoate

2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N- (4-hydroxybutyl) -N-methylacetamide (1.00 g, 1.18 mmol) was dissolved in toluene ( (4.0 mL), 272 mg (1.42 mmol) of ethyl 4-isocyanate benzoate was added, and the mixture was heated to reflux for 1 hour. After allowing to cool, the reaction solution was concentrated under reduced pressure, and the resulting oil was purified by silica gel chromatography (elution solvent: ethyl acetate / methanol = 10 / 0-9 / 1) to give 1.22 g of the title compound (yield 99). %) As a white solid.
IR νmax cm ^-1 (KBr): 2929, 1712, 1645, 1281, 1222, 1175, 1139, 1108, 771, 681.
MS (APCI) m / z: 1035 ((M + H) ⁺ , free body).

[Example 112]
2-{[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine- 5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- (3- {methyl [methyl (phenyl) carbamoyl] amino } Propyl) acetamide hydrochloride

[Example 112a]
(5R) -3- [3,5-Bis (trifluoromethyl) benzoyl] -5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (4-fluorophenyl) -1 , 3-oxazolidine (2R) -1-amino-4-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-fluorophenyl) butan-2-ol (128.92 g, 0.411 mol) benzene Paraformaldehyde (18.50 g, 0.617 mol) was added to the (1000 mL) solution, a water separator was attached, and the mixture was stirred and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to give a crude product of (5R) -5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (4-fluorophenyl) -1,3-oxazolidine 139. 43 g were obtained as a brown oil.

  Crude (5R) -5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (4-fluorophenyl) -1,3-oxazolidine (139.43 g), triethylamine obtained (69 mL, 0.495 mol), 4- (dimethylamino) pyridine (5.02 g, 0.041 mol) in dichloromethane (1000 mL) under ice-cooling, 3,5-bis (trifluoromethyl) benzoyl chloride (100 g). 0.434 mol) was added dropwise and stirred at room temperature for 18 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% ethyl acetate / n-hexane) to give 131.76 g (yield 62%) of the title object compound as a pale yellow oil.

[Example 112b]
2-[(5R) -3- [3,5-Bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethanol Obtained in Example 112a (5R) -3- [3,5-Bis (trifluoromethyl) benzoyl] -5- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (4-fluorophenyl) -1 , 3-oxazolidine (131.76 g, 0.254 mol) in tetrahydrofuran (500 mL) was added tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 508 mL) and acetic acid (70 mL, 1.27 mol). Stir for hours. Ethyl acetate (1000 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane: 30% -50%) to obtain 102.11 g (yield 99%) of the title object compound as a colorless oil.

[Example 112c]
2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethyl methanesulfonate Obtained in Example 112b 2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethanol (102.11 g, 0.226 mol), triethylamine (63 mL, 0.452 mol), 4- (dimethylamino) pyridine (2.76 g, 0.0273 mol) in dichloromethane (1000 mL) in methanesulfonyl chloride (26 mL, 0.336 mol) under ice-cooling. ) Was added dropwise and stirred for 1 hour under ice-cooling. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 30% → 50%) to obtain 108.21 g (yield 90%) of the title object compound as a white solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.30-2.50 (2H, m), 2.91 (3H, brs), 3.80-4.21 (3H, m), 4.25-4.35 (1H, m), 4.90-5.10 (1H , m), 5.20-5.40 (1H, m), 7.11 (2H, brs), 7.20-7.47 (2H, m), 7.91 (2H, s), 8.00 (1H, s).
IR νmax cm ^-1 (ATR): 1734, 1646, 1356, 1278, 1171, 1129, 957, 906, 837, 681, 527.
MS (FAB) m / z: 530 (M + H) ⁺ .

[Example 112d]
tert-butyl (2S) -2- (allyloxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate tert-butyl (2S) -2-hydroxy -2,3-dihydro-1'H-spiro [indene-1,4'-piperidine] -1'-carboxylate (50.0 g, 164.8 mmol) in dimethylformamide (150 mL) under ice-cooling and stirring. Sodium hydride (55% content, 10.79 g, 247.2 mmol) was added in portions. After the addition, allyl bromide (28.5 mL, 329.6 mmol) was added dropwise and stirred for 1 hour under ice cooling. Water (400 mL) was added dropwise, followed by extraction with ethyl acetate (300 mL, 80 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane, 0% → 20%) to give 57.15 g of the title object compound as a colorless oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.45 (9H, s), 1.65-1.75 (2H, m), 2.05-2.12 (1H, m), 2.95-3.25 (4H, m), 3.80-4.20 (5H , m), 5.13-5.31 (2H, m), 5.86-5.98 (1H, m), 7.11-7.25 (4H, m).
IR νmax cm ^-1 (liquid film): 2976,2929,1694,1479,1425,1366,1278,1237,1171,1080,759 cm ^-1 .
MS (FAB +) m / z: 344 ((M + H) ⁺ ).

Example 112e tert-Butyl (2S) -2- (2-oxoethoxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate Example Tert-Butyl (2S) -2- (allyloxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate obtained in 112d (57.15 g) Is dissolved in a mixed solvent of acetone (400 mL), t-butanol (200 mL) and water (200 mL), and N-methylmorpholine N-oxide (21.2 g, 181 mmol) and osmium tetroxide (2.5 wt. % T-butanol solution, 8.39 g, 0.825 mmol) was added, and the mixture was stirred at room temperature for 4 hours. A sodium thiosulfate aqueous solution (26 g, 100 mL) was added to the reaction solution, followed by stirring for 10 minutes, and the organic solvent was distilled off under reduced pressure. Ethyl acetate was added for extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude tert-butyl (2S) -2- (2,3-dihydroxypropoxy) -2,3-dihydro-1′H—. Spiro [indene-1,4′-piperidine] -1′-carboxylate (69.58 g) was obtained as a pale yellow amorphous.

The obtained crude product was dissolved in a mixed solvent of tetrahydrofuran (400 mL) and water (400 mL), and sodium periodate (52.87 g, 247 mmol) was added little by little while stirring on ice. After the addition, the mixture was stirred at room temperature for 1.5 hours. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300, 150, 100 mL). The organic layers were combined and washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 59.52 g of the crude title object compound as a colorless amorphous.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.50 (9H, s), 1.62-1.85 (2H, m), 2.15-2.24 (1H, m), 2.92-4.25 (10H, m), 7.19-7.26 (4H , m), 9.74 (1H, s).
IR νmax cm ^-1 (liquid film): 2976,2931,1686,1479,1428,1367,1239, 1010,756.
MS (FAB +) m / z: 346 ((M + H) ⁺ ).

[Example 112f]
{[(2S) -1 ′-(tert-butoxycarbonyl) -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetic acid Crude tert obtained in Example 112e -59.52 g of butyl (2S) -2- (2-oxoethoxy) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate in tetrahydrofuran (200 mL) And t-butanol (400 mL) were dissolved in 2-methyl-2-butene (87.3 mL). Under ice-cooling stirring, sodium dihydrogen phosphate dihydrate (64.27 g, 412 mmol) in water (100 mL) and sodium chlorite (44.7 g, 494 mmol) were sequentially added, followed by stirring under water cooling for 2.5 hours. did. The reaction mixture was ice-cooled, and 4N aqueous sodium hydroxide solution (206 mL) was added dropwise. After adding water (200 mL) and ethyl acetate (200 mL), the resulting white precipitate was filtered off and the residue was washed with water (100 mL) and ethyl acetate (100 mL). The filtrate was ice-cooled, and 4N hydrochloric acid aqueous solution (160 mL) was added for liquid separation extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 59.58 g of the crude title object compound as a pale yellow amorphous product. The obtained crude product was recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 50.64 g of the title object compound as a white solid.
¹ H NMR (CD ₃ OD, 400 MHz): δ 1.48 (9H, s), 1.52-1.64 (2H, m), 1.68-1.75 (1H, m), 2,12-2.20 (1H, m), 3.00 ( 1H, dd, J = 16.5, 3.0 Hz), 3.15 (1H, dd, J = 16.5, 5.4 Hz), 3.20-3.40 (1H, m), 3.41-3.60 (1H, m), 3.86-3.99 (2H, m), 4.15-4.17 (2H, m), 4.32-4.37 (1H, m), 7.10-7.20 (4H, m).
IR νmax cm ^-1 (KBr): 2976,2932,1756,1690,1643,1479,1430,1366,1279,1169,1119,759.
MS (FAB +) m / z: 362 ((M + H) ⁺ ).

[Example 112g]
Ethyl [(2S) -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yloxy] acetate obtained in Example 1g {[(2S) -1 ′-(tert-butoxycarbonyl) -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetic acid (28.20 g, 78.0 mmol) in ethanol solution (280 mL) under ice-cooling and stirring with thionyl chloride (12 3 mL, 156 mol) was added dropwise and heated to reflux for 2 hours. After allowing to cool, ethanol in the reaction solution was distilled off under reduced pressure. Ethyl acetate was added to the obtained yellow oil, and then washed with an aqueous sodium hydrogen carbonate solution. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue for dissolution, and then the solvent was distilled off under reduced pressure to obtain 32.1 g of the crude title object compound as a pale yellow oil.
MS (FAB) m / z: 290 ((M + H) ^<+> ).

[Example 112h]
Ethyl {[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5 -Yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetate crude ethyl [(2S) -2,3-dihydro obtained in Example 112g Spiro [indene-1,4′-piperidin] -2-yloxy] acetate (32.1 g) and 2-[(5R) -3- [3,5-bis (trifluoromethyl) obtained in Example 112c To a solution of benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethyl methanesulfonate (37.6 g, 70.9 mmol) in acetonitrile (160 mL) at room temperature, Sodium hydrogen carbonate (7.15 g, 85.11 mmol) was added, and the mixture was stirred and refluxed for 14 hours under a nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, the organic solvent was distilled off under reduced pressure. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1-0 / 1, V / V) to obtain 47.8 g (yield 93%) of the title object compound as a white solid. .
¹ H NMR (CD ₃ OD, 400MHz): δ 1.26 (3H, t, J = 7.1 Hz), 1.45-1.95 (4H, m), 2.05-2.36 (4H, m), 2.37-2.53 (2H, m) , 2.57-2.80 (2H, m), 2.92-3.12 (2H, m), 3.75-3.93 (1H, m), 3.97-4.27 (6H, m), 4.84-5.10 (1H, m), 5.20-5.40 ( 1H, m), 7.02-7.43 (8H, m), 7.93 (2H, s), 7.95 (1H, s).
IR (KBr): 2927, 1755, 1650, 1431, 1359, 1281, 1182, 1137, 907, 845, 839, 758, 682 cm ^-1 .
MS (FAB) m / z: 723 ((M + H) ⁺ ).

[Example 112i]
{[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5 Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetic acid Ethyl {[(2S) -1 ′-{2- [ (5R) -3- [3,5-Bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine-5-yl] ethyl} -2,3-dihydrospiro [indene To a methanol solution (340 mL) of -1,4′-piperidin] -2-yl] oxy} acetate (34.1 g, 47.1 mmol), 1N aqueous sodium hydroxide solution (71 mL, 71 mmol) was added with stirring under ice cooling. Dripping, The mixture was stirred for 2 hours at temperature. Under ice-cooling and stirring, 1N hydrochloric acid (71 mL, 71 mmol) was added to neutralize, and then methanol was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and filtered through celite. The filtrate was distilled off under reduced pressure to obtain 32.6 g (yield 99%) of the title object compound as white amorphous.
¹ H NMR (CD ₃ OD, 400MHz): δ 1.70-2.08 (3H, m), 2.25-2.65 (3H, m), 2.82-3.03 (2H, m), 3.10-3.62 (5H, m), 3.85- 4.21 (5H, m), 4.25-4.40 (1H, m), 5.04-5.50 (2H, m), 7.05-7.25 (6H, m), 7.40-7.62 (2H, m), 7.97-8.20 (3H, m ),
IR νmax cm ^-1 (KBr): 2935,1651,1605,1511,1432,1360,1281,1179,1138,907,682.
MS (FAB) m / z: 695 ((M + H) ⁺ ).

[Example 112j]
2-{[(2S) -1 '-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine- 5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [3- (methylamino) propyl] acetamide Example 112i {[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3- Oxazolidin-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetic acid (800 mg, 1.15 mmol) is dissolved in methylene chloride (6 mL), Under ice-cooling, triethylamine (0.240 mL, 1.73 mmol) and pivaloyl chloride (0.156 mL, 1.27 mmol) were added, and 1 at room temperature was added. Stir for 5 minutes. The reaction solution was added dropwise to a methylene chloride solution (19 mL) of N, N′-dimethylpropanediamine (588 mg, 5.75 mmol) under ice-cooling, and stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was purified using NH silica gel column chromatography (ethyl acetate: methanol = 30: 1-10: 1, V / V) to give the title object compound (566 mg, yield 63). %) As a pale yellow solid.
IR νmax cm ^-1 (ATR): 2932, 1645, 1435, 1358, 1279, 1176, 1136, 907, 838, 757.
MS (ESI) m / z: 778 (M ⁺ ).

[Example 112k]
2-{[(2S) -1 '-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1,3-oxazolidine- 5-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} -N-methyl-N- (3- {methyl [methyl (phenyl) carbamoyl] amino } Propyl) acetamide hydrochloride 2-{[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5-] obtained in Example 112j (4-Fluorophenyl) -1,3-oxazolidine-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N— 72 mg (0.092 mmol) of [3- (methylamino) propyl] acetamide and 19.3 μL (0.139 mmol) of triethylamine were added. The title compound (69 mg, yield 79%) was obtained as a white solid according to the method described in Example 105 using 18.8 μL (0.111 mmol) of N-methyl-N-phenylcarbamoyl chloride under ice cooling.
IR νmax cm ^-1 (KBr): 3439, 2930, 1650, 1280, 1174, 1137, 1014, 906, 848, 761.
MS (APCI) m / z: 912 ((M + H) ⁺ , free body).

[Example 113]
N- {3-[({[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) -1 , 3-Oxazolidin-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methylpiperidine- 1-Carboxamide hydrochloride

2-{[(2S) -1 ′-{2-[(5R) -3- [3,5-bis (trifluoromethyl) benzoyl] -5- (4-fluorophenyl) obtained in Example 112j -1,3-oxazolidine-5-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [3- (methylamino) ) Propyl] acetamide 82 mg (0.105 mmol), triethylamine 22 μL (0.158 mmol) and 1-piperidinecarbonyl chloride 16 μL (0.126 mmol) and following the procedure described in Example 105, 72 mg (74% yield) ) Was obtained as a white solid.
IR νmax cm ^-1 (KBr): 3427, 2935, 1649, 1360, 1280, 1174, 1138, 907, 848, 759.
MS (APCI) m / z: 890 ((M + H) ⁺ , free body).

[Example 114]
N- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) octanamide

[Example 114a]
tert-butyl 2- (hydroxyimino) -2,3-dihydro-1′H-2-spiro [indene-1,4′-piperidine] -1′-carboxylic acid tert-butyl 2-oxo-2,3- Dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid 7.0 g (23.2 mmol) was dissolved in 50 mL of pyridine and stirred at room temperature. The hydroxylamine hydrochloride 3.23g (46.5mmol) was added there, and it stirred at 85 degree | times for 1 hour. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, 50 mL of toluene was added, and the solvent was distilled off again under reduced pressure. 50 mL of dichloromethane was added to the obtained residue, the precipitated white solid was removed by filtration, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 1/1) to obtain 7.26 g (yield: 99%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 1.73-1.77 (2H, m), 1.85-1.91 (2H, m), 3.46-3.57 (2H, br m), 3.89 (2H, s ), 3.95-4.12 (2H, m), 7.20-7.21 (1H, m), 7.24-7.30 (3H, m), 7.61 (1H, s).

[Example 114b]
tert-Butyl 2-amino-2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid tert-butyl 2- (hydroxyimino) obtained in Example 114a -2,3-Dihydro-1'H-2-spiro [indene-1,4'-piperidine] -1'-carboxylic acid 5.0 g (15.8 mmol) was dissolved in ethanol 50 mL and stirred at room temperature. Raney nickel was added there, and the inside of the container was replaced with hydrogen. After stirring the reaction solution at 40 degrees for 12 hours, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 1/1 to methanol / dichloromethane = 1/4) to obtain 3.30 g (yield: 69%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.53-1.66 (4H, m), 1.74-1.82 (1H, m), 1.90-1.96 (1H, m), 2.65 (1H, dd, J = 3.6, 16.1 Hz), 3.24-3.41 (3H, m), 3.59 (1H, dd, J = 3.5, 6.3 Hz), 3.79-3.88 (2H, m), 7.17-7.27 (4H, m).
MS (FAB) m / z: 303 ((M + H) ⁺ , free form).

[Example 114c]
tert-Butyl 2- (octanoylamino) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid tert-butyl 2-obtained in Example 114b 100 mg (0.331 mmol) of amino-2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid was dissolved in 3.0 mL of dichloromethane and stirred at room temperature. Thereto, 92 μL (0.662 mmol) of triethylamine and 85 μL (0.496 mmol) of octanoyl chloride were added and stirred for 20 minutes. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 1/2) to obtain 139 mg (yield: 98%) of the title compound. .
¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 6.7 Hz), 1.20-1.32 (9H, br m), 1.47 (9H, s), 1.51-1.63 (5H, m), 1.68- 1.74 (1H, m), 1.89-1.96 (1H, m), 2.03-2.17 (2H, m), 2.68 (1H, d, J = 16.9 Hz), 3.12 (1H, t, J = 11.4 Hz), 3.36 -3.43 (1H, m), 4.92-4.97 (1H, m), 5.46 (1H, d, J = 11.2 Hz), 7.20-7.31 (4H, m).
MS (FAB) m / z: 429 ((M + H) ⁺ , free body).

[Example 114d]
N- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) octanamide hydrochloride tert-butyl 2- (octanoylamino) -2,3-dihydro-1′H obtained in Example 114c A solution of 135 mg (0.315 mmol) of spiro [indene-1,4′-piperidine] -1′-carboxylic acid in dichloromethane (6 mL) was stirred at room temperature, and trifluoroacetic acid (2 mL) was added thereto. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added thereto for extraction. The aqueous layer was separated and further extracted twice with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent of the obtained solution was distilled off under reduced pressure to obtain crude N-(-2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) octanamide (107 mg). . The obtained crude N-(-2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) octanamide (107 mg) and 2-[(2R) -4- [3,5 -Bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl 4-chlorobenzenesulfonic acid (198 mg, 0.286 mmol) was dissolved in acetonitrile (10 mL) and stirred at room temperature. Thereto, 53 mg (0.630 mmol) of sodium hydrogen carbonate was added, and the mixture was stirred under reflux for 5 hours. After removing insolubles by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/5/5). As a result, 166 mg (yield: 70%) of the title compound was obtained.
IR νmax cm ⁻¹ (KBr): 3321, 2928, 1645, 1539, 1472, 1439, 1375, 1281, 1185, 1141, 905, 757, 682.

[Example 115]
Benzyl (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3 -Dihydrospiro [indene-1,4'-piperidin] -2-yl) carbamic acid

[Example 115a]
tert-Butyl 2-{[(Benzyloxy) carbonyl] amino} -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid Obtained in Example 114b tert-Butyl 2-amino-2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid (229 mg, 0.757 mmol) was dissolved in tetrahydrofuran (7 mL) and stirred at room temperature. did. Thereto, 7.0 mL of saturated aqueous sodium hydrogen carbonate solution and 215 μL (1.52 mmol) of benzyl formate were sequentially added and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 2/5) to obtain 319 mg (yield: 96%) of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.54-1.66 (2H, m), 1.76-1.80 (1H, m), 1.86-1.91 (1H, m), 2.77 (1H, dd, J = 16.6, 1.7 Hz), 3.17-3.41 (3H, m), 3.84-3.99 (2H, m), 4.59-4.62 (1H, m), 4.87 (1H, d, J = 10.3 Hz), 5.10 (2H , dd, J = 15.5, 12.0 Hz),), 7.21-7.25 (4H, m), 7.31-7.39 (5H, m).
MS (FAB) m / z: 437 ((M + H) ⁺ , free body).

[Example 115b]
Benzyl (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3 -Dihydrospiro [indene-1,4'-piperidin] -2-yl) carbamic acid tert-butyl 2-{[(benzyloxy) carbonyl] amino} -2,3-dihydro-1 obtained in Example 115a 315 mg (0.722 mmol) of 'H-spiro [indene-1,4'-piperidine] -1'-carboxylic acid was dissolved in 10 mL of dichloromethane and stirred at room temperature. Trifluoroacetic acid (4 mL) was added there, and it stirred at room temperature for 1 hour and 30 minutes. Thereafter, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added thereto for extraction. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered through celite. The solvent of the obtained solution was distilled off under reduced pressure to obtain crude benzyl 2,3-dihydrospiro [indene-1,4′-piperidin] -2-ylcarbamic acid (251 mg). The resulting crude 2,3-dihydrospiro [indene-1,4′-piperidin] -2-ylcarbamic acid (251 mg) and 2-[(2R) -4- [3,5-bis (trifluoro) Methyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl 4-chlorobenzenesulfonic acid 453 mg (0.656 mmol) was dissolved in acetonitrile 10 mL and stirred at room temperature. Thereto was added 109 mg (1.31 mmol) of sodium hydrogen carbonate, and the mixture was stirred for 15 hours under reflux. The insoluble material was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0 / 1-3 / 2) to give 537 mg of the title compound ( Yield: 98%).
IR νmax cm ^-1 (KBr): 3333, 2931, 1719, 1646, 1513, 1473, 1439, 1375, 1281, 1185, 1139, 1029, 904, 754, 705, 681.
MS (FAB) m / z: 834 ((M + H) ⁺ , free form).

[Example 116]
1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydro Spiro [indene-1,4'-piperidine] -2-amine

Benzyl (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] obtained in Example 115b ] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) carbamic acid 1.20 g (1.44 mmol) is dissolved in 15 mL of dichloromethane and stirred at −5 to −9 degrees. did. 2.88 mL (2.88 mmol) of a 1.0 M solution of boron tribromide in dichloromethane was added dropwise and stirred at the same temperature for 30 minutes. Then, after stirring for 2 hours under ice cooling, water and saturated brine were sequentially added to the reaction solution, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / dichloromethane = 0/1 to 1/4). 802 mg of compound (yield: 80%) was obtained.
IR νmax cm ^-1 (KBr): 3423, 2926, 1646, 1473, 1439, 1375, 1281, 1185, 1139, 905, 757, 706, 681.
MS (FAB) m / z: 700 ((M + H) ⁺ , free form).

[Example 117]
^{N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2 , 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylglycinamide dihydrochloride

[Example 117a]
2-Bromo-N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl) -N-methylacetamide 300 mg (2.91 mmol) of 4- (methylamino) butan-1-ol was dissolved in 10 mL of dichloromethane. And stirred under ice cooling. Thereto, 485 μL (3.49 mmol) of triethylamine and 10 mg of dimethylaminopyridine were sequentially added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent of the obtained solution was distilled off under reduced pressure to obtain crude 4-{[tert-butyl (dimethyl) silyl] oxy} -N-methylbutan-1-amine. The obtained solution of 4-{[tert-butyl (dimethyl) silyl] oxy} -N-methylbutan-1-amine in dichloromethane (2 mL) was added to a solution of bromoacetyl chloride 117 μL (1.40 mmol) in dichloromethane (4 mL) on ice. It was added dropwise over 5 minutes under cooling. Then, after stirring at the same temperature for 30 minutes, water was added to the reaction solution, extraction was performed 3 times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/4) to obtain 430 mg (yield: 44%) of the title compound. .
¹ H-NMR (CDCl ₃ ) δ: 0.05-0.06 (6H, m), 0.89-0.90 (9H, m), 1.48-1.65 (3H, m), 1.68-1.76 (1H, m), 2.95-3.07 ( 3H, m), 3.35-3.43 (2H, m), 3.61-3.67 (2H, m), 3.85-3.87 (2H, m).
MS (FAB) m / z: 338 ((M + H) ⁺ , free form).

[Example 117b]
^{N 2 - [(2S) -1} '- {2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl) -N-methylglycinamide 1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl obtained in Example 116 } -2,3-dihydrospiro [indene-1,4′-piperidine] -2-amine 40 mg (0.057 mmol) and 2-bromo-N- (4-{[tert] obtained in [Example 117a] -Butyl (dimethyl) Lyl] oxy} butyl) -N-methylacetamide 19 mg (0.057 mmol) was dissolved in 2 mL of acetonitrile and stirred at room temperature. Thereto, 10 mg (0.114 mmol) of sodium hydrogen carbonate was added, the temperature was raised to 60 degrees, and the mixture was stirred for 3 hours 30 minutes. After removing insolubles by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2). 29 mg (yield: 53%) of the title compound was obtained.
MS (FAB) m / z: 957 ((M + H) ⁺ , free body).

[Example 117c]
^{N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2 , 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylglycinamide dihydrochloride N ² -[( 2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, 3-dihydrospiro [indene-1,4′-piperidin] -2-yl] -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl) -N-methylglycinamide 29 mg (0.030 mmol) ) Tetrahi It melt | dissolved in 4 mL of drofurans, and stirred under ice-cooling. Thereto was added dropwise 61 μL (0.061 mmol) of a tetrabutylammonium fluoride / tetrahydrofuran solution (1.0 M), and the mixture was heated to 40 degrees and stirred for 5 hours. Thereafter, water was added to the reaction solution, extraction was performed three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2) to give 21 mg (yield) of the free form of the title compound. Rate: 82%). A solution of free form (21 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 18 mg (yield: 65%) of the title compound.
IR νmax cm ^-1 (KBr): 3402, 2960, 2935, 2875, 2566, 1651, 1473, 1440, 1376, 1282, 1185, 1139, 1029, 905, 759, 681.
MS (FAB) m / z: 843 ((M + H) ⁺ , free form).

[Example 118]
N ² - Acetyl ^{-N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl ] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylglycinamide hydrochloride

N ² -[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 117b ) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl ) -N-methylglycinamide 45 mg (0.047 mmol) was dissolved in 3 mL of dichloromethane and stirred at room temperature. Thereto, 13 μL (0.094 mmol) of triethylamine and 5 μL (0.071 mmol) of acetyl chloride were successively added dropwise and stirred for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/4/4), and N ² -acetyl. ^{-N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} - 2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl) -N-methylglycinamide 44 mg (yield) Rate: 94%).

The resulting ^{N 2} - Acetyl ^{-N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine - 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl) -N -44 mg (0.044 mmol) of methylglycinamide was dissolved in 4 mL of tetrahydrofuran and stirred at room temperature. Thereto, 88 μL (0.088 mmol) of a tetrabutylammonium fluoride / tetrahydrofuran solution (1.0 M) was added dropwise and stirred at room temperature for 5 hours. Thereafter, water was added to the reaction solution, extraction was performed three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2). Rate: 92%). A solution of free form (36 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 29 mg (yield: 71%) of the title compound.
IR νmax cm ^-1 (KBr): 3415, 2930, 1651, 1473, 1438, 1376, 1282, 1185, 1139, 905, 758, 681.
MS (FAB) m / z: 885 ((M + H) ⁺ , free form).

[Example 119]
N- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- {2-[(4-hydroxybutyl) (methyl) amino] -2-oxoethyl} hexanamide hydrochloride

N ² -[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 117b ) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl ) -N-methylglycinamide 50 mg (0.052 mmol) was dissolved in 4 mL of dichloromethane and stirred at room temperature. Thereto, 14 μL (0.104 mmol) of triethylamine and 11 μL (0.078 mmol) of hexanoyl chloride were sequentially added dropwise and stirred for 1 hour. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/4/4), and N- (1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [Indene-1,4′-piperidin] -2-yl) -N- {2-[(4-{[tert-butyl (dimethyl) silyl] oxy} butyl) (methyl) amino] -2-oxoethyl} hexane 39 mg (yield: 71%) of amide were obtained.

Obtained N- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl) -N- {2-[(4-{[tert-butyl (dimethyl) silyl] oxy} butyl) (methyl) amino ] 39 mg (0.037 mmol) of 2-oxoethyl} hexanamide was dissolved in 4 mL of tetrahydrofuran and stirred at room temperature. Thereto, 74 μL (0.074 mmol) of a tetrabutylammonium fluoride / tetrahydrofuran solution (1.0 M) was added dropwise and stirred at room temperature for 15 hours. Thereafter, water was added to the reaction solution, extraction was performed three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2) to give 26 mg (yield) of the free form of the title compound. (Rate: 75%). A solution of free form (26 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 22 mg (yield: 61%) of the title compound.
IR νmax cm ^-1 (KBr): 3401, 2932, 1650, 1471, 1459, 1438, 1376, 1282, 1185, 1139, 1098, 905, 757, 706, 681.
MS (FAB) m / z: 941 ((M + H) ⁺ , free form).

[Example 120]
N- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- {2-[(4-hydroxybutyl) (methyl) amino] -2-oxoethyl} benzamide hydrochloride

N ² -[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 117b ) Morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl ) -N-methylglycinamide 45 mg (0.047 mmol) was dissolved in 4 mL of dichloromethane and stirred at room temperature. Thereto, 13 μL (0.094 mmol) of triethylamine and 8 μL (0.071 mmol) of benzoyl chloride were successively added dropwise and stirred for 1 hour. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/4/4), and N- (1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [Indene-1,4′-piperidin] -2-yl) -N- {2-[(4-{[tert-butyl (dimethyl) silyl] oxy} butyl) (methyl) amino] -2-oxoethyl} benzamide 44 mg (yield: 88%) was obtained. Obtained N- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl) -N- {2-[(4-{[tert-butyl (dimethyl) silyl] oxy} butyl) (methyl) amino ] 44 mg (0.041 mmol) of 2-oxoethyl} hexanamide was dissolved in 4 mL of tetrahydrofuran and stirred at room temperature. Thereto, 83 μL (0.083 mmol) of a tetrabutylammonium fluoride / tetrahydrofuran solution (1.0 M) was added dropwise and stirred at room temperature for 15 hours. Thereafter, water was added to the reaction solution, extraction was performed three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2), and 30 mg (yield) of the free form of the title compound. (Rate: 76%). A solution of free form (30 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 24 mg (yield: 59%) of the title compound.
IR νmax cm ^-1 (KBr): 3419, 2932, 1649, 1472, 1457, 1440, 1375, 1282, 1185, 1139, 1029, 905, 757, 704, 681.
MS (FAB) m / z: 947 ((M + H) ⁺ , free body).

[Example 121]
Benzyl (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3 -Dihydrospiro [indene-1,4'-piperidin] -2-yl) carbamic acid

[Example 121a]
tert-Butyl 2-{[(Benzyloxy) carbonyl] amino} -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid Obtained in Example 114b 1.50 g (4.96 mmol) of tert-butyl 2-amino-2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid was dissolved in 10 mL of tetrahydrofuran, and And stirred. Thereto, 10 mL of a saturated aqueous sodium hydrogen carbonate solution and 1.06 mL (7.44 mmol) of benzyl formate were sequentially added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 2/5) to obtain 2.15 g (yield: 99%) of the title compound. It was. HPLC separation of the obtained racemic tert-butyl 2-amino-2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylic acid (Daicel Chemical CHIRALCEL OD) -H developing solvent: isopropanol / hexane = 3%) Less polar body 195 mg (Daicel Chemical CHIRALCEL OD-H retention time: 8.7 minutes developing solvent: isopropanol / hexane = 3% optical purity: 99% ee) and More polar body 200 mg (Daicel Chemical CHIRALCEL OD-H retention time: 13.2 minutes developing solvent: isopropanol / hexane = 3% optical purity: 83% ee) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.54-1.66 (2H, m), 1.76-1.80 (1H, m), 1.86-1.91 (1H, m), 2.77 (1H, dd, J = 16.6, 1.7 Hz), 3.17-3.41 (3H, m), 3.84-3.99 (2H, m), 4.59-4.62 (1H, m), 4.87 (1H, d, J = 10.3 Hz), 5.10 (2H , dd, J = 15.5, 12.0 Hz),), 7.21-7.25 (4H, m), 7.31-7.39 (5H, m).
MS (FAB) m / z: 437 ((M + H) ⁺ , free body).

[Example 121b]
Benzyl (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3 —Dihydrospiro [indene-1,4′-piperidin] -2-yl) carbamic acid Less polar tert-butyl 2-{[(benzyloxy) carbonyl] amino} -2,3 obtained in Example 121a -Dihydro-1'H-spiro [indene-1,4'-piperidine] -1'-carboxylic acid (195 mg, 0.447 mmol) was dissolved in 6 mL of dichloromethane and stirred under ice cooling. Trifluoroacetic acid (2 mL) was added there, and it stirred at room temperature for 4 hours. Thereafter, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added thereto for extraction. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered through celite. The solvent of the obtained solution was distilled off under reduced pressure to obtain crude benzyl 2,3-dihydrospiro [indene-1,4′-piperidin] -2-ylcarbamic acid (162 mg). The resulting crude 2,3-dihydrospiro [indene-1,4′-piperidin] -2-ylcarbamic acid (162 mg) and 2-[(2R) -4- [3,5-bis (trifluoro) 294 mg (0.426 mmol) of methyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl 4-chlorobenzenesulfonic acid was dissolved in 10 mL of acetonitrile and stirred at room temperature. Thereto, 72 mg (0.852 mmol) of sodium hydrogen carbonate was added and stirred for 15 hours under reflux. The insoluble material was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0/1 to 3/2) to give 278 mg of the title compound ( Yield: 78%) was obtained.
IR νmax cm ^-1 (KBr): 3334, 2930, 1719, 1646, 1513, 1473, 1439, 1375, 1281, 1185, 1139, 1029, 905, 754, 705, 681.
MS (FAB) m / z: 834 ((M + H) ⁺ , free form).

[Example 122]
1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydro Spiro [indene-1,4'-piperidine] -2-amine

Benzyl (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] obtained in Example 121b ] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) carbamic acid 260 mg (0.312 mmol) was dissolved in 10 mL of dichloromethane and stirred at −5 to −9 degrees. 623 μL (0.623 mmol) of a 1.0 M solution of boron tribromide in dichloromethane was added dropwise and stirred at the same temperature for 15 minutes. Then, after stirring for 2 hours under ice cooling, water and saturated brine were sequentially added to the reaction solution, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / dichloromethane = 0/1 to 1/4). 188 mg (yield: 86%) of the compound was obtained.
IR νmax cm ^-1 (KBr): 3402, 2927, 1645, 1474, 1441, 1376, 1281, 1186, 1139, 905, 757, 706, 682.
MS (FAB) m / z: 700 ((M + H) ⁺ , free form).

[Example 123]
^{N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2 , 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylglycinamide dihydrochloride

1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl obtained in Example 122 } -2,3-dihydrospiro [indene-1,4′-piperidine] -2-amine 165 mg (0.236 mmol) and 2-bromo-N- (4-{[tert-butyl (dimethyl) silyl] oxy} 80 mg (0.236 mmol) of (butyl) -N-methylacetamide was dissolved in 3 mL of acetonitrile and stirred at room temperature. Thereto, 40 mg (0.471 mmol) of sodium hydrogen carbonate was added, the temperature was raised to 60 degrees, and the mixture was stirred at 80 degrees for 4 hours. After removing insolubles by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2). Then, 61 mg of the raw material and 50 mg of the title compound in which de-t-butyldimethylsilylation had proceeded were obtained. The obtained title compound (50 mg) was purified by NH silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2) to give 16 mg (yield: 8) of the free form of the title compound. %). A solution of free form (16 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 14 mg (yield: 7%) of the title compound.
MS (FAB) m / z: 843 ((M + H) ⁺ , free form.

[Example 124]
Benzyl (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3 -Dihydrospiro [indene-1,4'-piperidin] -2-yl) carbamic acid

More polar tert-butyl 2-{[(benzyloxy) carbonyl] amino} -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1 obtained in Example 121a 200 mg (0.458 mmol) of '-carboxylic acid was dissolved in 6 mL of dichloromethane and stirred under ice cooling. Trifluoroacetic acid (3 mL) was added there, and it stirred at room temperature for 4 hours. Thereafter, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added thereto for extraction. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered through celite. The solvent of the obtained solution was distilled off under reduced pressure to obtain crude benzyl 2,3-dihydrospiro [indene-1,4′-piperidin] -2-ylcarbamic acid (161 mg). The resulting crude 2,3-dihydrospiro [indene-1,4′-piperidin] -2-ylcarbamic acid (161 mg) and 2-[(2R) -4- [3,5-bis (trifluoro) Methyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl 4-chlorobenzenesulfonic acid (301 mg, 0.436 mmol) was dissolved in 10 mL of acetonitrile and stirred at room temperature. Thereto was added 73 mg (0.872 mmol) of sodium hydrogen carbonate, and the mixture was stirred for 8 hours under reflux. After removing insolubles by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 0 / 1-3 / 2) to give 330 mg of the title compound ( Yield: 91%) was obtained.
IR νmax cm ^-1 (KBr): 3333, 2931, 1720, 1646, 1513, 1473, 1439, 1375, 1281, 1185, 1139, 1029, 905, 755, 705, 681.
MS (FAB) m / z: 834 ((M + H) ⁺ , free form).

[Example 125]
1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydro Spiro [indene-1,4'-piperidine] -2-amine

Benzyl- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2-] obtained in Example 124 Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) carbamic acid 310 mg (0.371 mmol) was dissolved in 10 mL of dichloromethane and stirred at −8 to −10 degrees. . 743 μL (0.743 mmol) of a 1.0 M solution of boron tribromide in dichloromethane was added dropwise and stirred at the same temperature for 15 minutes. Then, after stirring for 1 hour and 30 minutes under ice cooling, water and saturated brine were sequentially added to the reaction solution, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered through celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / dichloromethane = 0/1 to 1/4). 218 mg (yield: 84%) of compound were obtained.
IR νmax cm ^-1 (KBr): 3412, 2926, 1645, 1474, 1440, 1376, 1282, 1186, 1139, 905, 758, 707, 682.
MS (FAB) m / z: 700 ((M + H) ⁺ , free form).

[Example 126]
^{N 2 - (1 '- {} 2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2 , 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylglycinamide dihydrochloride

1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl obtained in Example 125 } -2,3-dihydrospiro [indene-1,4′-piperidine] -2-amine 60 mg (0.086 mmol) and 2-bromo-N- (4-{[tert-butyl (dimethyl) silyl] oxy} (Butyl) -N-methylacetamide (29 mg, 0.086 mmol) was dissolved in acetonitrile (3 mL) and stirred at room temperature. Thereto, 22 mg (0.257 mmol) of sodium hydrogen carbonate was added, and the temperature was raised to 75 degrees and stirred for 6 hours. After removing insolubles by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2). N ² -[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl) -N-methyl 37 mg (yield: 45%) of glycinamide was obtained. The resulting ^{N 2 - [(2S) -1} '- {2 - [(2R) -4- [3,5- bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2 -Yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] -N- (4-{[tert-butyl (dimethyl) silyl] oxy} butyl) -N- 37 mg (0.039 mmol) of methyl glycinamide was dissolved in 4 mL of tetrahydrofuran and stirred under ice cooling. Thereto, 77 μL (0.077 mmol) of a tetrabutylammonium fluoride / tetrahydrofuran solution (1.0 M) was added dropwise and stirred at room temperature for 6 hours. Thereafter, water was added to the reaction solution, extraction was performed three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 1/2/2) to give 28 mg (yield) of the free form of the title compound. (Rate: 79%). A solution of free form (28 mg) in dichloromethane (2 mL) was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain 24 mg (yield: 75%) of the title compound.
IR νmax cm ^-1 (KBr): 3313, 2961, 2935, 2874, 1642, 1472, 1383, 1281, 1185, 1139, 1028, 904, 756, 707, 681.
MS (FAB) m / z: 843 ((M + H) ⁺ , free form).

[Example 127]
3- (1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, 3-Dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylpropanamide hydrochloride

[Example 127a]
Ethyl 1H-inden-2-yl acetate A solution of 18.66 g (83.2 mmol) of triethyl phosphonoacetate in tetrahydrofuran (83 mL) was ice-cooled under a nitrogen atmosphere. 79.5 mL of 1.0 M hexamethyldisilazane lithium / tetrahydrofuran solution was added dropwise while maintaining the internal temperature at 10 ° C. or lower, and the mixture was stirred for 15 minutes. Furthermore, a tetrahydrofuran solution (80 mL) of 10.0 g (75.7 mmol) of 2-indanone was added dropwise under ice-cooling and stirred at room temperature for 3 hours. After adding 50 mL of saturated aqueous ammonium chloride solution to the reaction solution, the mixture was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting brown oil was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 10 / 1-7 / 1) to give 10.4 g (68% yield) of the title compound as a yellow oil. It was.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.28 (3H, t, J = 7.0 Hz), 3.45 (2H, s), 3.52 (2H, s), 4.17 (2H, q, J = 7.0 Hz), 6.70 (1H, s), 7.11-7.32 (3H, m), 7.40 (1H, d, J = 7.4 Hz).
IR νmax cm ^-1 (KBr): 2981, 1736, 1462, 1393, 1369, 1174, 1030, 754, 717.
MS (EI) m / z: 202 (M ^{+ ・} ).

[Example 127b]
2- (1H-inden-2-yl) ethanol In a nitrogen atmosphere, 67 mL of tetrahydrofuran was added to 2.55 g (67.2 mmol) of lithium aluminum hydride. The mixture was stirred under ice-cooling, and 38 mL of a tetrahydrofuran solution of 7.70 g (38.1 mmol) of ethyl 1H-inden-2-yl acetate obtained in Example 127a was added dropwise, followed by stirring at room temperature for 30 minutes. The mixture was stirred again on ice, 40 g of sodium sulfate decahydrate was added little by little, 380 mL of diisopropyl ether was added, and the mixture was stirred at room temperature for 3 hours. Insoluble material was removed by filtration through Celite, and the filtrate was distilled off under reduced pressure to obtain 6.48 g of crude 2- (1H-inden-2-yl) ethanol as a colorless oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.78 (2H, t, J = 6.3 Hz), 3.37 (2H, s), 3.88 (2H, t, J = 6.3 Hz), 6.64 (1H, s), 7.11 -7.32 (3H, m), 7.40 (1H, d, J = 7.3 Hz).
IR νmax cm ^-1 (KBr): 3341, 2883, 1610, 1461, 1391, 1047, 911, 849, 751, 717, 557 cm ^-1 .
MS (EI) m / z: 160 (M ^{+ ・} ).

[Example 127c]
tert-Butyl [2- (1H-inden-2-yl) ethoxy] dimethylsilane To 60 mL of a dimethylformamide solution of 6.48 g of crude 2- (1H-inden-2-yl) ethanol obtained in Example 127b 5.18 g (76.1 mmol) and tert-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for 15 minutes. An n-hexane-ethyl acetate mixture (1: 1, 250 mL) was added to the reaction solution, and the mixture was washed with 10% brine and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting yellow oil was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 10/0 to 10/1) to give 10.2 g (yield 98%) of the title compound as a yellow oil. It was.
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.06 (6H, s), 0.90 (9H, s), 2.71 (2H, t, J = 7.0 Hz), 3.35 (2H, s), 3.86 (2H, t, J = 7.0 Hz), 6.55 (1H, s), 7.08-7.30 (3H, m), 7.39 (1H, d, J = 7.0 Hz).
IR νmax cm ^-1 (KBr): 2954, 2928, 2857, 1462, 1390, 1255, 1098, 837, 776, 750, 716, cm ^-1 .
MS (FAB) m / z: 275 (M + H) ^<+> .

[Example 127d]
tert-Butyl 2- (2-{[tert-Butyl (dimethyl) silyl] oxy} ethyl) -1'H-spiro [indene-1,4'-piperidine] -1'-carboxylate 1.0M hexamethyldi A silazane lithium / tetrahydrofuran solution (76.5 mL, 76.5 mmol) was cooled to −10 ° C., and 10.0 g of tert-butyl [2- (1H-inden-2-yl) ethoxy] dimethylsilane obtained in Example 127c was used. 24 mL of a tetrahydrofuran solution (36.4 mmol) was added and stirred for 20 minutes. To the reaction solution, 28 mL of tetrahydrofuran of 8.82 g (36.4 mmol) of tert-butyl bis (2-chloroethyl) carbamate was added dropwise and stirred at room temperature for 1 hour. A 10% saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (× 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 10/0 to 4/1) to give 15.6 g (yield 96%) of the title compound as a pale yellow oil. It was.
¹ H NMR (CDCl ₃ , 400 MHz): δ 0.09 (6H, s), 0.91 (9H, s), δ1.19 (2H, brd, 13.7 Hz), 1.52 (9H, s), 1.97 (2H, dt, J = 4.9, 5.4 Hz), 2.46 (2H, t, J = 7.3 Hz), 3.40-3.51 (2H, brt), 3.89 (2H, t, J = 7.3 Hz), 4.20-4.44 (2H, br), 6.47 (1H, s), 7.10 (1H, brt, J = 7.3 Hz), 7.25-7.30 (2H, m), 7.70 (1H, d, J = 7.8 Hz).
IR νmax cm ^-1 (KBr): 2929, 1697, 1472, 1417, 1365, 1240, 1169, 1100, 1045, 946, 838, 776, 748.
MS (FAB) m / z: 444 (M + H) ⁺ .

[Example 127e]
tert-Butyl 2- (2-hydroxyethyl) -1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate tert-Butyl 2- (2-{[ tert-Butyl (dimethyl) silyl] oxy} ethyl) -1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate 1.0 M in 107 mL tetrahydrofuran solution Tetrabutylammonium fluoride in tetrahydrofuran was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 4/1 to 1/1) to give 5.68 g (yield 72%) of the title compound. Obtained as a pale yellow oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ1.21 (2H, brd, 13.2 Hz), 1.52 (9H, s), 1.97 (2H, dt, J = 4.9, 5.4 Hz), 2.53 (2H, t, J = 6.4 Hz), 3.48-3.55 (2H, br), 3.95 (2H, dt, J = 6.3, 6.3 Hz), 4.01-4.29 (2H, br), 6.55 (1H, s), 7.13 (1H, m) , 7.23-7.32 (2H, m), 7.71 (1H, d, J = 7.3 Hz).
IR νmax cm ^-1 (KBr): 3438, 2933, 1693, 1424, 1241, 1167, 1119, 1042, 946,750 cm ^-1 .
MS (FAB) m / z: 330 (M + H) ⁺ .

[Example 127f]
tert-Butyl 2- (2-hydroxyethyl) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate tert-Butyl obtained in Example 127e 2 -(2-hydroxyethyl) -1'H-spiro [indene-1,4'-piperidine] -1'-carboxylate (4.81 g, 14.6 mmol) in methanol (146 mL) was added 10% palladium-carbon (400 mg). The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere.
The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (4.52 g, yield 93%) as a colorless oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ1.37-1.62 (2H, m), 1.49 (9H, s), 1.64-1.84 (3H, m), 2.32-2.40 (1H, m), 2.65 (1H, d, J = 5.9, 15.6 Hz), 3.06 (2H, d, J = 7.0, 15.6 Hz), 3.36-3.44 (1H, m), 3.50-3.65 (2H, m), 3.66-3.74 (1H, m) , 3.75-3.83 (2H, m), 7.13-7.23 (3H, m), 7.28-7.33 (1H, m).
IR νmax cm ^-1 (KBr): 3422, 2932, 1693, 1426, 1240, 1170, 1124, 1055, 758 cm ^-1 .
MS (FAB) m / z: 332 (M + H) ^<+> .

[Example 127g]
tert-Butyl 2- (2-cyanoethyl) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate tert-Butyl obtained in Example 127f 2- (2-Hydroxyethyl) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate 4.51 g (13.6 mmol) in 41 mL of toluene solution and triethylamine 2. 28 mL (16.4 mmol) was added. Under ice-cooling, 1.16 mL (15.0 mmol) of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and crude tert-butyl 2- {2-[(methylsulfonyl) oxy] ethyl} -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1 5.89 g of '-carboxylate was obtained. The obtained crude product was dissolved in 60 mL of dimethylformamide, 1.07 g (16.4 mmol) of potassium cyanide and 18-crown-6 (10 mg) were added, and the mixture was stirred at 80 ° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: n-hexane / ethyl acetate = 9/1 to 0/10) to give 2.85 g (yield 61%) of the title compound. Obtained as a pale yellow oil.
¹ H NMR (CDCl ₃ , 400 MHz): δ1.50 (9H, s), 1.45-1.78 (5H, m), 1.86-1.96 (1H, m), 2.31-2.42 (2H, m), 2.44-2.53 ( 1H, m), 2.62 (1H, dd, J = 5.9, 15.6 Hz), 3.13 (1H, dd, J = 7.3, 15.6 Hz), 3.32-3.42 (1H, m), 3.48-3.57 (1H, m) , 3.62-3.70 (1H, m), 3.85-3.96 (1H, m), 7.16-7.33 (4H, m).
IR νmax cm ^-1 (liquid film): 2932, 2247, 1691, 1478, 1425, 1365, 1240, 1171, 1124, 916, 760, 731cm ^-1 .
MS (EI) m / z: 340 (M ^{+ ・} ).

[Example 127h]
3- [1 ′-(tert-Butoxycarbonyl) -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] propionic acid tert-Butyl 2- (2 obtained in 127 g of Example -Cyanoethyl) -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate 2.63 g (7.73 mmol) in ethanol 77 mL solution and 5N aqueous sodium hydroxide solution 15.5 mL (77.3 mmol) was added, and the mixture was heated to reflux for 5.5 hours. The reaction solution was ice-cooled, 28.7 mL of a 2N aqueous hydrochloric acid solution (77.4 mmol) was added, and the organic solvent was distilled off under reduced pressure. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent: n-hexane / ethyl acetate = 9/1 to 0/10) to obtain 2.31 g (yield 83%) of the title compound as a white solid.
MS (FAB) m / z: 360 (M + H) ^<+> .

[Example 127i]
tert-butyl 2- {3-[(4-hydroxybutyl) (methyl) amino] -3-oxopropyl} -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1 '-Carboxylate 3- [1'-(tert-Butoxycarbonyl) -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] propionic acid obtained in Example 127h (0 mg .835 mmol) was dissolved in 8 mL of dichloromethane, and 140 μL (1.00 mmol) of triethylamine was added. Under ice-cooling and stirring, 139 μL (0.918 mmol) of pivaloyl chloride was added dropwise and stirred for 15 minutes. To the reaction solution, 258 mg (2.5 mmol) of 4- (methylamino) butan-1-ol was added dropwise and stirred at room temperature for 10 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 377 mg (yield 99%) of the title compound as a white solid.
MS (ESI) m / z: 345 ((M-Boc) ⁺ , de-Boc form).

[Example 127j]
3- (1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl} -2, 3-dihydrospiro [indene-1,4'-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylpropanamide hydrochloride tert-butyl 2- {3 obtained from Example 127i -[(4-Hydroxybutyl) (methyl) amino] -3-oxopropyl} -2,3-dihydro-1′H-spiro [indene-1,4′-piperidine] -1′-carboxylate in dichloromethane 8 Dissolved in 0.0 mL, added 1.0 mL of trifluoroacetic acid, and stirred at room temperature for 35 minutes. After adding 15 mL of toluene to the reaction solution, the solvent was distilled off under reduced pressure. The resulting residue was dissolved by adding 15 mL of toluene and 1.0 mL of triethylamine, and then the solvent was distilled off again under reduced pressure. The obtained residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate / methanol = 10/0 to 10/1) to give 3- (2,3-dihydrospiro [indene-1,4′-piperidine]- 287 mg (quantitative) of 2-yl) -N- (4-hydroxybutyl) -N-methylpropanamide were obtained as a white solid.

287 mg (0.835 mmol) of 3- (2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl) -N- (4-hydroxybutyl) -N-methylpropanamide obtained, 2 -[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl methanesulfonate 518 mg (0.750 mmol) and sodium hydrogen carbonate Acetonitrile 3.0mL was added to 82 mg (0.974 mmol), and it stirred at 80 degreeC for 12 hours. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent: ethyl acetate / methanol = 10/0 to 10/1) to obtain 351 mg of the crude title compound as a white solid. The obtained crude product was subjected to reverse phase preparative chromatography (column: Waters X Bridge Prep C18, 5 μm, 30φ × 150 mm, elution solvent: 0.1 v / v% ammonium formate aqueous solution-acetonitrile = 50: 50 → 25: 75) To obtain a free form of the title compound. The obtained free form was dissolved in 2.0 mL of dichloromethane, and 0.10 mL of 4N hydrochloric acid-dioxane solution was added. The solvent was distilled off under reduced pressure, and the resulting white solid was suspended in a mixed solution of diisopropyl ether and n-hexane and collected by filtration to obtain 228 mg (yield 37%) of the title compound as a white solid.
IR νmax cm ^-1 (KBr): 3401, 2932, 1639, 1376, 1281, 1138, 905, 681.
MS (APCI) m / z: 842 ((M + H) ⁺ , free body).

[Example 128]
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl-4- (methylamino) Benzamide dihydrochloride

  2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) obtained in Example 1a ) Morpholin-2-yl] ethyl] -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy] -N-methyl-N- [3- (methylamino) propyl] acetamide Using 65 mg (0.077 mmol) and 4-[(t-butoxycarbonyl) (methyl) amino] benzoic acid 23 mg (0.092 mmol), the same reaction as in Example 15 was carried out, and tert-butyl {4-[{3 -[({[(2S) -1 '-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl ] Ethyl}- To give 3-dihydro-spiro [indene-1,4-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} (methyl) carbamoyl] phenyl} methylcarbamate.

To a solution of 56 mg (0.052 mmol) of the obtained compound in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was added at room temperature and stirred for 2 hours. The solvent was distilled off, and the residue was purified by silica gel chromatography (eluent: methanol / ethyl acetate / dichloromethane = 0/1/1 to 2/5/5) to give a free form of the title compound. A free form of dichloromethane (2 mL) solution was stirred at room temperature, and 2N hydrochloric acid diethyl ether solution (0.1 mL) was added dropwise thereto. The solvent was distilled off under reduced pressure to obtain the title compound.
IR νmax cm ^-1 (KBr): 3420, 2929, 2654, 2576, 1645, 1475, 1440, 1376, 1282, 1184, 1138, 1099, 760, 681.
MS (FAB) m / z: 976 ((M + H) ⁺ , free body).

(Test Example 1)
[Human NK ₁ receptor binding test]
(A) Preparation of crude membrane specimen A cryopreserved cell solution of human NK ₁ receptor-expressing COS cells was diluted with buffer (1) (50 mM Tris-HCl, pH 7.4 containing 0.04% BSA) to give 5.0 × 10 ⁶ cells / mL was used as a crude membrane specimen.
(B) Receptor binding test
[ ³ H] substance P with 50 mM Tris-HCl (pH 7.4), 6 mM manganese chloride, 800 μg / mL BSA, 8 μg / mL chymostatin, 8 μg / mL leupeptin, 80 μg / mL bacitracin, 20 μg / Dilute with mL phosphoramidon mixture. A test substance and 250 μL of a crude membrane sample solution were added to 250 μL of this mixed solution, and incubated at room temperature for 60 minutes ([ ³ H] substance P is a final concentration of 1 nM). After the reaction, membrane components were collected on a GF / B glass fiber filter (Whatman, Biomedical Research and Development Laboratories, Inc.) using an automatic filtration device (Brandel, Biomedical Research and Development Laboratories, Inc.). The glass filter was pretreated with 0.1% polyethyleneimine solution for about 4 hours in order to keep nonspecific binding low. The membrane component recovery filter was transferred to a mini plastic vial containing 3 mL of Picoflow, and the radioactivity was measured with a liquid scintillation counter (Perkin Elmer, Tri-Carb 2300TR).
NK ₁ receptor binding action, 50% binding dose (IC ₅₀₎ and NK ₁ The affinity of ^[3 H] substance P to the receptor than (Kd), affinity for NK ₁ receptors of the test substance (Ki ).

The results are shown in Table 1.
(Table 1)
------------
Example Ki (nM)
------------
40 7.2
49 19
54 3.7
93 7.8
96 2.3
97 0.91
99 2.9
------------.

From the above results, the compound of the present invention has an excellent neurokinin NK ₁ receptor binding action.

(Test Example 2)
[Human NK ₂ receptor binding test]
(A) Preparation of crude membrane specimen A cryopreserved cell solution of human NK ₂ receptor-expressing COS cells was diluted with buffer (1) (50 mM Tris-HCl, pH 7.4 containing 0.04% BSA) to give 5.0 × 10 ⁶ cells / mL was used as a crude membrane specimen.
(B) Receptor binding test
[ ³ H] SR-48968 with 50 mM Tris-HCl (pH 7.4), 6 mM manganese chloride, 800 μg / mL BSA, 8 μg / mL chymostatin, 8 μg / mL leupeptin, 80 μg / mL bacitracin, 20 μg Dilute with / mL phosphoramidon mixture. To this mixed solution 250 μL, a test substance and 250 μL of a crude membrane sample solution were added and incubated at room temperature for 35 minutes ([ ³ H] SR-48968 was a final concentration of 1 nM). After the reaction, membrane components were collected on a GF / B glass fiber filter (Whatman, Biomedical Research and Development Laboratories, Inc.) using an automatic filtration device (Brandel, Biomedical Research and Development Laboratories, Inc.). The glass filter was pretreated with 0.1% polyethyleneimine solution for about 4 hours in order to keep nonspecific binding low. The membrane component recovery filter was transferred to a mini plastic vial containing 3 mL of Picoflow, and the radioactivity was measured with a liquid scintillation counter (Perkin Elmer, Tri-Carb 2300TR).
NK ₂ receptor binding activity is 50% bound dose (IC ₅₀₎ and the affinity of ^[3 H] SR-48968 against NK ₂ receptors than (Kd), affinity for NK ₂ receptors of the test substance ( Ki).

The results are shown in Table 2.
(Table 2)
---------------
Example Ki (nM)
---------------
40 2.1
49 0.93
54 0.63
93 1.9
96 0.89
97 0.42
99 0.49
--------------.

From the above results, the compound of the present invention has an excellent neurokinin NK ₂ receptor binding action.

(Test Example 3)
[Human NK ₃ receptor binding test]
(A) Preparation of crude membrane specimen A cryopreserved cell solution of human NK ₃ receptor-expressing CHO cells was diluted with buffer (1) (50 mM Tris-HCl, pH 7.4 containing 0.04% BSA) to give 1.0 × 10 ⁷ cells / mL was used as a crude membrane specimen.
(B) Receptor binding test
[ ³ H] senktide 50 mM Tris-HCl (pH 7.4), 6 mM manganese chloride, 800 μg / mL BSA, 8 μg / mL chymostatin, 8 μg / mL leupeptin, 80 μg / mL bacitracin, 20 μg / mL Dilute with phosphoramidon mixture. A test substance and 250 μL of a crude membrane sample solution were added to 250 μL of this mixed solution, and incubated at room temperature for 60 minutes ([ ³ H] senktide was a final concentration of 2.5 nM). After the reaction, membrane components were collected on a GF / B glass fiber filter (Whatman, Biomedical Research and Development Laboratories, Inc.) using an automatic filtration device (Brandel, Biomedical Research and Development Laboratories, Inc.). The glass filter was pretreated with 0.1% polyethyleneimine solution for about 4 hours in order to keep nonspecific binding low. The membrane component recovery filter was transferred to a mini plastic vial containing 3 mL of Picoflow, and the radioactivity was measured with a liquid scintillation counter (Perkin Elmer, Tri-Carb2300TR).
The NK ₃ receptor binding action is determined by the affinity of the test substance to the NK ₃ receptor (Ki) from the 50% binding dose (IC ₅₀ ) and the affinity of [ ³ H] senktide for the NK ₃ receptor (Kd). Calculated as

The results are shown in Table 3.
(Table 3)
---------------
Example Ki (nM)
---------------
40 10.8
49 9.8
54 5.8
93 8.9
96 5.3
97 2.9
99 6.2
--------------.

From the above results, the compound of the present invention has an excellent neurokinin NK ₃ receptor binding action.

Formulation Example (Formulation Example 1) Powder A powder can be obtained by mixing 5 g of the compound of Example 40, 895 g of lactose and 100 g of corn starch with a blender.

(Formulation example 2) Granules After mixing 5 g of the compound of Example 40, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.

(Formulation example 3) Tablet After mixing 5 g of the compound of Example 96, lactose 90 g, corn starch 34 g, crystalline cellulose 20 g and magnesium stearate 1 g with a blender, tablets are obtained by tableting with a tablet machine.

(Formulation example 4) Solution 1 for inhalation
The compound of Example 40 was 10% (W / W), benzalkonium chloride was 0.04% (W / W), phenethyl alcohol was 0.40% (W / W), and purified water was 89.56% ( W / W) is prepared.

(Formulation example 5) Inhalation solution 2
The compound of Example 96 was 10% (W / W), benzalkonium chloride was 0.04% (W / W), polyethylene glycol was 10% (W / W), and propylene glycol was 30% (W / W). The solution is prepared so that purified water is 39.96% (W / W) (Formulation Example 6) Powder for inhalation 40% (W / W) of the compound of Example 40, 60% (W / W) of lactose A powder is prepared so as to be W).

(Formulation Example 7) Aerosol The compound of Example 96 was 10% (W / W), lecithin was 0.5% (W / W), Freon 11 was 34.5% (W / W), and Freon 12 was 55. An aerosol agent is prepared so that it may become% (W / W).

The indane derivative of the present invention has an antagonistic action on all of the neurokinin NK ₁ , neurokinin NK ₂ and neurokinin NK ₃ receptors, is less toxic and has excellent pharmacokinetics, and thus is useful as a medicine. In particular, it is useful as a prophylactic or therapeutic agent for respiratory diseases such as asthma, bronchitis and chronic obstructive pulmonary disease; allergic diseases such as rhinitis; and / or urinary incontinence.

Claims (29)

Formula (I)

[Where:
R ¹ may be independently substituted with a group selected from substituent group A and may be independently substituted with 1 to 5 phenyl groups or a group selected from substituent group A and may be independently substituted with 1 to 3 A good heterocyclic group,
R ² may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A A good heterocyclic group,
R ³ represents any of the following groups:
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 5) -SO 2 -R 6,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 5) -C (= O) -R 7,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 5) -C (= O) -N (R 8) R 9,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -O-C (= O) -N (R 8) R 9,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -C (= O) -N (R 8) R 9,
^{_{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -N (R 8) R 9,
^{_{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -O-R 10,
^{_{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -C (= O) -R 10,
_{^{-Y-CH 2 C (= O}} ) -N (R 4) (CH 2) n -CH (OH) -R 10,
-N ^(R 4) H,
_{^{-N (R 11) CH 2 C}} (= O) -N (R 4) (CH 2) n -O-R 10,
Y represents a methylene group, an oxygen atom or a group represented by the formula —NH—,
R ⁴ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a hydroxy group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₁₁ alkylcarbonyl group, a benzoyl group or a benzyloxycarbonyl. Group,
R ⁵ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a phenyl group or a benzyl group,
R ⁶ is a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a phenyl group which may be independently substituted with a group selected from the substituent group A, or a substituent group A A heterocyclic group optionally substituted with 1 to 3 groups independently selected from the above (provided that when R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl group is excluded);
R ⁷ _is, C 1 -C ₆ alkyl, _C 1 -C ₆ alkyl which is 1 to 3 substituents independently a group selected from substituent group _B, C 3 -C ₆ cycloalkyl groups, C _1- C ₆ alkoxy group, phenoxy group, phenyl group which may be independently substituted with 1 to 5 groups independently selected from substituent group A, 1 to 5 groups independently selected from substituent group A A naphthyl group which may be individually substituted or a heterocyclic group which may be independently substituted with 1 to 3 groups selected from the substituent group A (provided that when R ⁵ is a hydrogen atom, Except ₁ -C ₆ alkyl groups),
R ⁸ and R ⁹ are the same or different and are each selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ hydroxyalkyl group, a C ₃ -C ₆ cycloalkyl group, and a substituent group A. A phenyl group optionally substituted with 1 to 5 groups independently, a naphthyl group, an indanyl group or a substituent group A optionally substituted with 1 to 5 groups independently selected from the substituent group A A heterocyclic group which may be independently substituted with a group selected from 1 or 3 together, or together, including the nitrogen atom to which they are attached, selected from substituent group A A nitrogen-containing heterocyclic group which may be independently substituted with 1 to 3 groups,
R ¹⁰ is independently a hydrogen atom, a phenyl group which may be independently substituted with a group selected from the substituent group A, or a group selected from substituent group A; A C ₁ -C ₆ alkyl group substituted by one optionally substituted heterocyclic group or a C ₃ -C ₆ cycloalkyl group,
R ¹¹ represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a hydroxy group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₁₁ alkylcarbonyl group, a benzoyl group or a benzyloxycarbonyl group. ,
m represents an integer of 1 to 3,
n represents an integer of 1 to 6,
Substituent group A is a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ halogenated alkyl _group, C 1 -C ₆ hydroxyalkyl group, hydroxy _group, C 1 -C ₆ alkoxy group, _{C 1} - C ₆ halogenated alkoxy group, a cyano group, a carboxyl group, a carbamoyl _group, C 2 -C ₇ alkylcarbonyl _group, C 2 -C ₇ alkoxycarbonyl _group, C 2 -C ₇ alkylcarbonyloxy _group, C 2 -C ₇ alkoxy carbonyloxy _group, C 1 -C ₆ alkylsulfonyl group, a nitro group, an amino group, a mono _-C 1 -C ₆ alkylamino group, di - _(C 1 -C ₆ alkyl) amino group, N- _(C 2 -C ₇ alkoxycarbonyl) -N- _(C 1 -C ₆ alkyl) amino group, a group consisting of phenyl and pyridyl groups,
Substituent Group B represents a phenyl group, a hydroxy _group, C 1 -C ₆ alkoxy group, a phenoxy _group, C 2 -C ₇ alkylcarbonyloxy group and di - indicates a _(C 1 -C ₆ alkyl) group consisting of amino group . Or a pharmacologically acceptable salt thereof. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ia).

The compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ib).

The compound or pharmacologically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ic).

The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein R ³ is any one of the following groups.
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -SO 2 -R 6,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -C (= O) -R 7,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -C (= O) -N (R 8) R 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -O-C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -N (R 8) R 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -O-R 10,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -C (= O) -R 10,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -CH (OH) -R 10,
—NH—CH ₂ C (═O) —N (CH ₃ ) — (CH ₂ ) ₄ —O—R ¹⁰ In Claim 5, R ⁵ is a hydrogen atom, a methyl group, a phenyl group or a benzyl group, R ⁶ is a phenyl group, a 4-trifluoromethylphenyl group or an 8-quinolyl group, and R ⁷ is a phenoxy group. Group, 4-trifluoromethylphenyl group, 3,5-di (trifluoromethyl) phenyl group, 2-naphthyl group or 2-quinolyl group, and a group represented by the formula —N (R ⁸ ) R ⁹ is , Anilino group, diethylamino group, N-methyl-N-phenylamino group, 4-morpholinyl group or 1-piperidyl group, and the group represented by the formula -NHR ⁹ is isopropylamino group, butylamino group, t- butylamino group, cyclohexylamino group, an anilino group, 2-phenylphenyl group, a 1-naphthylamino group or a 5-indanyl amino group, R ¹⁰ is hydrogen Child, phenyl group or compound or a pharmacologically acceptable salt thereof is a 2-pyridyl group. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein R ³ is any one of the following groups.
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -SO 2 -R 6,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -N (R 5) -C (= O) -R 7,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -O-C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 3 -C (= O) -NHR 9,
_{-O-CH 2 C (= O} ) -N (CH 3) - (CH 2) 4 -N (R 8) R 9;
R ⁵ is a hydrogen atom, methyl group, phenyl group or benzyl group, R ⁶ is a phenyl group, 4-trifluoromethylphenyl group or 8-quinolyl group, R ⁷ is a phenoxy group, 2-naphthyl group A group represented by the formula -N (R ⁸ ) R ⁹ is an anilino group, and a group represented by the formula -NHR ⁹ is a butylamino group or a t-butylamino group. , A cyclohexylamino group, an anilino group or a 2-phenylphenylamino group, or a pharmacologically acceptable salt thereof. A compound having the general formula (I)
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-methyl-2-naphthamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy] -N-methyl-N- {3- [methyl (phenylsulfonyl) amino] propyl} acetamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl] -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} quinoline-2-carboxamide,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- {3-[(quinolin-8-ylsulfonyl) amino] propyl} acetamide ,
2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholin-2-yl] Ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methyl-N- [3-({[4- (trifluoromethyl) phenyl] sulfonyl} Amino) propyl] acetamide,
N-biphenyl-2-yl-4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3 4-dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butanamide,
N- (4-anilinobutyl) -2-{[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4- Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} -N-methylacetamide,
N-benzyl-N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 -Dichlorophenyl) morpholin-2-yl] ethyl} -2,3-dihydrospiro [indene-1,4'-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} benzamide,
N- {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine -2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} -N-phenylbenzamide,
Phenyl {3-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine- 2-yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] propyl} carbamic acid,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl phenylcarbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl tert-butylcarbamate,
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- Yl] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl cyclohexyl carbamate, or
4-[({[(2S) -1 ′-{2-[(2R) -4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) morpholine-2- [Il] ethyl} -2,3-dihydrospiro [indene-1,4′-piperidin] -2-yl] oxy} acetyl) (methyl) amino] butyl butyl carbamate Top acceptable salt.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. Neurokinin NK ₁ , neurokinin NK ₂ and / or neurokinin NK ₃ receptor comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient A pharmaceutical composition for treating or preventing a disease mediated by the body.   In order to prevent or treat respiratory diseases, allergic diseases and / or urinary incontinence comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. Pharmaceutical composition.   Asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence containing the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient A pharmaceutical composition for the prevention or treatment of.   A pharmaceutical composition for preventing or treating a respiratory disease, comprising as an active ingredient the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof.   9. Preventing or treating asthma, bronchitis and / or chronic obstructive pulmonary disease comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient Pharmaceutical composition for   15. A composition according to claim 13 or 14 for pulmonary administration.   Use of the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient for producing a pharmaceutical composition. Any one selected from 1 to 8 for producing a pharmaceutical composition for treating or preventing a disease mediated by neurokinin NK ₁ , neurokinin NK ₂ and / or neurokinin NK ₃ receptor. Or a pharmacologically acceptable salt thereof as an active ingredient.   The compound according to any one of claims 1 to 8, or a pharmacologically acceptable product thereof, for producing a pharmaceutical composition for preventing or treating respiratory diseases, allergic diseases and / or urinary incontinence Used as an active ingredient.   9. The method according to any one of claims 1 to 8, for producing a pharmaceutical composition for preventing or treating asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis and / or urinary incontinence. Use of a compound or a pharmacologically acceptable salt thereof as an active ingredient.   As an active ingredient of a compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating respiratory diseases use.   The compound according to any one of claims 1 to 8, or a pharmacologically thereof, for producing a pharmaceutical composition for preventing or treating asthma, bronchitis and / or chronic obstructive pulmonary disease Use of acceptable salts as active ingredients.   The use according to claim 20 or 21, wherein the pharmaceutical composition is a composition for pulmonary administration. Neurokinin NK ₁ , Neurokinin NK ₂ and / or by administering an effective amount of the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof to a mammal A method for preventing or treating a disease mediated by a neurokinin NK ₃ receptor.   By administering an effective amount of the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof to a mammal, respiratory diseases, allergic diseases and / or urinary incontinence can be obtained. How to prevent or treat.   Asthma, bronchitis, chronic obstructive pulmonary disease, rhinitis by administering an effective amount of the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof to a mammal And / or a method of preventing or treating urinary incontinence.   A method for preventing or treating a respiratory illness by administering an effective amount of the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof to a mammal.   Asthma, bronchitis and / or chronic obstructive pulmonary disease by administering an effective amount of the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof to a mammal How to prevent or treat   27. The method according to claim 25 or 26, wherein the compound having the general formula (I) or a pharmacologically acceptable salt thereof is administered by pulmonary administration.   29. A method according to any one of claims 23 to 28, wherein the mammal is a human.