KR20070015639A - Nitrogenous cyclic compounds and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention provides novel compounds having good calcium antagonism, in particular neuroselective calcium antagonism. That is, the compound or its salt or its hydrate which are represented by following formula is provided:

In formula, Ar represents the 5-14 membered aromatic ring group etc. which may be substituted; Ring A represents any one ring selected from piperazine, homopiperazine, piperidine and the like; Ring B represents a hydrocarbon ring such as C _{3 -14} which may be substituted; E represents a single bond, a group represented by the formula -CO-, and the like; X represents a single bond, an oxygen atom, or the like; R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, or the like; D ^1, D ^2, W ¹ and W ² represents a C _{1 -6} alkylene chain which may be substituted with the same or different and are each a single bond or.

Calcium, Calcium Channel, Antagonism, Nerve Selection, Neuronal Death, Analgesic Drug, Aromatic Ring

Description

Nitrogen-containing compounds and pharmaceutical compositions containing them {NITROGENOUS CYCLIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME}

1 shows the HPLC chart in Reference Example 97.

Fig. 2 shows the HPLC charts in Reference Examples 100 and 101, wherein the spectrum of No. 1 in the drawings shows the spectrum in Reference Example 100, and the spectrum of No. 2 shows the spectrum in Reference Example 101, respectively.

3 shows the HPLC chart in Reference Example 103.

The present invention relates to novel compounds useful as calcium antagonists, salts thereof, their hydrates, preparations thereof and pharmaceutical compositions thereof, in particular neuroselective calcium antagonists, inter alia, having P / Q type calcium channels and / or N type calcium channel inhibitory activity. Novel compounds and the like.

The annual number of strokes in Japan is more than 1.4 million, and the medical expenses are estimated at about 2 trillion yen. Stroke is the second leading cause of death after malignant tumors, and it is the largest cause of a state in which many serious sequelae remain and thus do not occur. The key to the treatment of stroke is the response of the acute phase, the treatment of the acute phase determines the life and function prognosis, and also has a great effect on the sequelae. For the purpose of improving blood flow, Ozagrel Sodium (Tromoxane Synthase Inhibitor), Argatroban (Antithrombin Agent) for Chronic Arterial Occlusion, and T-PA (Alteplase: Tissue Plasma) Several kinds of chemicals, such as a minogen activator and limited to within 3 hours after the onset), have been used or applied outside of adaptation. However, conventional treatment with a medicament is a complicated method as described in [1] to [6] below, and requires careful judgment by a specialist based on sufficient knowledge and experience. In other words, [1] thrombotic cerebral infarction is first performed by respiratory management, blood pressure management, and fluid management. [2] Periodically measure the choke and blood pressure of blood gases. Reactive hypertension can be seen in the acute phase, but if no complications such as heart and kidneys are seen, no coercion is performed. [4] Next, thrombolytic release "urokinase" is used as a case of a superacute phase in which low absorption zone is not identified in CT. [5] In case of inadequate adaptation or in cases more than 24 hours after onset, "ozagrerel sodium" is administered. However, argatroban is not adapted for lacunar infarction. [6] Properly administer "glycerine" or "mannitol" to prevent the development of cerebral edema.

In addition, the therapeutic effects of these drugs, which have been conventionally used, have never been satisfactory, and there is also a risk of bleeding caused by the main drug effect, which is difficult to use other than an experienced specialist.

On the other hand, compounds having an N-type and / or P / Q-type calcium channel inhibitory effect are useful as neuronal cell death inhibitors, neuronal cell protective agents, and neurological diseases treatment / improvement agents, and also have acute stages of cerebrovascular disorders, head trauma, brain neuronal cell death and Alzheimer's disease. , Circulatory metabolic disorder, brain dysfunction or pain treatment / improvement agent, anticonvulsant, schizophrenia treatment / improvement agent, migraine, epilepsy, manic-depressive disease, neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, muscular dystrophy, Huntington's disease), Prevention, treatment and improvement of cerebral ischemia, epilepsy, head trauma, AIDS dementia complex, swelling, anxiety disorder or diabetic neuropathy, further edema, anxiety disorder, schizophrenia, diabetic neuropathy or migraine The following publications have been reported about the prophylaxis, treatment, and improvement.

(1) Cerebrovascular Acute Stage: Annj. Rev. Physiol., 52, 543-559, 1990.

(2) Head trauma: SCRIP, No 2203, 24, 1997.

(3) ischemia-brain neuronal cell death: Advances in Phamacology, 22, 271-297, 1991.

(4) Alzheimer's Disease: Trends in Neuroscience, 16, 409, 1993.

(5) Cerebral Circulatory Metabolic Disorders: Nishi-Ri 誌, 85, 323-328, 1985.

(6) Brain dysfunction: Acta Neurol. Scand., 78: 2, 14-200, 1998.

(7) Analgesic: Drug of the Future, 23 (2), 152-160, 1998.

(8) Cerebral Ischemia, Migraine, Epilepsy, Manic Disease: Casopis Lekau Ceskych., 130 (22-23), 625-630, 1991.

(9) Neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease), cerebral ischemia, epilepsy, head trauma, AIDS dementia complications: Revista de Neurologia., 24 (134), 1199-1209, 1996.

(10) Edema: Brain Research, 776, 140-145, 1997.

(11) Anxiety Disorders, Schizophrenia: Circulation Control, 14 (2), 139-145, 1993.

(12) Diabetic Neuropathy: Neurology, 50, 423-428, 1999.

(13) Migraine: Neurology, 50 (4), 1105-1110, 1998.

As mentioned above, although the provision of the calcium antagonist useful as a medicine, especially the neuroselective calcium antagonist is anticipated, it shows the outstanding calcium antagonistic action, and also satisfy | fills the point of pharmacological activity, dosage, safety, etc. as a medicine, and also clinically No drug has been found to work effectively in. That is, the object of the present invention is to search and find such excellent calcium channel antagonists.

In view of the above circumstances, the present inventors have obtained a highly stable drug which has an excellent treatment and improvement effect against acute ischemic stroke in which there is no useful drug yet, and does not cause a bleeding tendency. Careful attention has been paid to attention to neuroselective, translocation-dependent calcium channel antagonists that act directly on cells and inhibit the progression of infarcts. (3 PAGE middle)

As a result, it succeeds in synthesizing the novel nitrogen-containing cyclic compounds represented by the following formula (I), salts and hydrates thereof, and surprisingly, these compounds or salts or hydrates thereof are P / Q type calcium channels or N It has excellent neuronal cell death inhibitory effect and neuroprotective effect based on type calcium channel antagonism, and it is found that the cellular disorder and toxicity are significantly reduced compared to conventional calcium antagonists, and excellent in safety, and completed the present invention. .

Wherein Ar is

(1) a C _6-14 aromatic hydrocarbon ring group which may be substituted,

(2) a 5 to 14 membered aromatic heterocyclic group which may be substituted,

(3) a C _1-6 alkyl group substituted with a C _6-14 aromatic hydrocarbon ring which may be substituted or

(4) a C _1-6 alkyl group substituted with a 5-14 membered aromatic heterocyclic group which may be substituted;

Ring A represents a piperazine, homopiperazine, piperidine, homopiperidine, pyrrolidine or diazabicyclo [2,2,1] heptane ring, each of which may be substituted;

Ring B is

(1) a C _3-14 hydrocarbon ring which may be substituted or

(2) represents a 5 to 14 membered heterocycle which may be substituted;

E is

(1) a single bond,

(2) Formula -CO- or

(3) represents a group represented by -CH (OH)-;

X is

(1) a single bond,

(2) an oxygen atom,

(3) sulfur atoms,

(4) a C _1-6 alkylene chain which may be substituted,

(5) Formula -NR ^2- (wherein R ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, a C _3-8 cycloalkyl group, a lower acyl group or a C _1-6 alkylsulfonyl group) ,

(6) -CO-,

(7) -COO-,

(8) -OOC-,

(9) -CONR ^3- (wherein R ³ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(10) -NR ⁴ CO- (wherein R ⁴ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(11) -SO-,

(12) -SO _2- ,

(13) -SONR ^5- (wherein R ⁵ represents a hydrogen atom or a optionally substituted C _1-6 alkyl group),

(14) -NR ⁶ SO- (wherein R ⁶ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(15) -SO ₂ NR ^7- (wherein R ⁷ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(16) -NR ⁸ SO _2- (wherein R ⁸ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(17)> C = N-OR ⁹ (wherein R ⁹ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(18) -NR ¹⁰ -W ³ -O- wherein R ¹⁰ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, C _3-8 cycloalkyl group, lower acyl group or C _1-6 alkylsulphate A phenyl group; W ³ represents a C _1-6 alkylene chain which may be substituted),

(19) -NH-CO-NH-,

(20) -NH-CS-NH-,

(21) -C (= NR ¹⁵ ) NR ^16- (wherein R ¹⁵ and R ¹⁶ are the same or different and represent a hydrogen atom, a nitrile group, a C _1-6 alkyl group, a C _2-6 alkenyl group, C _3-8 Cycloalkyl group or C _3-8 cycloalkenyl group),

(22) -NHC (= NH)-,

(23) -O-CO-S-,

(24) -S-CO-O-,

(25) -OCOO-,

(26) -NHCOO-,

(27) -OCONH-,

(28) -CO (CH ₂ ) _m O- (wherein m represents 0 or an integer of 1 to 6),

(29) -CHOH- or

(30) represents a group represented by -CHOH (CH ₂ ) _n O-, wherein n represents 0 or an integer of 1 to 6;

R ¹ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) hydroxyl,

(4) a C _1-6 alkyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(5) a C _2-6 alkenyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(6) a C _2-6 alkynyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(7) a C _3-8 cycloalkyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(9) a C _1-6 alkoxy-C _1-6 alkyl group,

(10) an amino-C _1-6 alkyl group in which the nitrogen atom may be substituted;

(11) a group represented by the formula -N (R ¹¹ ) R ¹² (wherein R ¹¹ and R ¹² are the same or different and represent a hydrogen atom or a C _1-6 alkyl group),

(12) an aralkyl group,

(13) morpholinyl group,

(14) thiomorpholinyl group,

(15) piperidyl,

(16) pyrrolidinyl groups or

(17) piperazinyl group;

D ¹ , D ² , W ¹ and W ² are the same or different, respectively

(1) single bond or

(2) represents a C _1-6 alkylene chain which may be substituted;

With the proviso that 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] Piperazine, 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (3-fluorophenoxy) ethyl] piperazine and 1 -[4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-fluorophenoxy) ethyl] piperazine is excluded.

That is, the 1st characteristic of this invention is

[1] a compound represented by the formula (I) or a salt thereof or a hydrate thereof;

[2] In the above [1], Ar may be a C _6-14 aromatic hydrocarbon ring or a 5-14 membered aromatic heterocycle, which may be substituted, respectively;

[3] In the above [1], Ar may be a thiophene ring or a benzene ring which may be substituted, respectively,

[4] In the above [1], Ar may be a C _6-14 aromatic hydrocarbon ring or a 5-14 membered aromatic heterocycle, which may be substituted with any one or more groups selected from a nitrile group and a halogen atom, respectively.

[5] In the above [1], Ar may be a thiophene ring or a benzene ring which may be substituted with any one or more groups selected from a nitrile group and a halogen atom, respectively.

[6] In the above [1], Ring A may be a piperazine, homopiperazine or piperidine ring,

[7] In the above [1], Ring A may be a piperazine ring,

[8] In the above [1], the ring A may be a hydroxyl group, a halogen atom, a cyano group, a substituted C _1-6 alkyl group, a substituted C _2-6 alkenyl group, or a substituted C. _2-6 alkynyl group, C _1-6 alkoxy group which may be substituted, C _2-6 alkenyloxy group which may be substituted, C _1-6 alkylcarbonyl group which may be substituted, C ₂ which may be substituted _-6 alkenylcarbonyl group, optionally substituted C _1-6 alkoxycarbonyl group and optionally substituted C _2-6 alkenyloxycarbonyl group, piperazine, homopiperazine which may be substituted with any one or more groups Or piperidine ring,

[9] In the above [1], the ring B may be a C _6-14 aromatic hydrocarbon ring or a 5-14 membered aromatic heterocyclic ring which may be substituted, respectively.

[10] In the above [1], ring B is benzene, thiophene, pyridine, 1,4-benzodioxane, indole, benzothiazole, benzoxazole, benzimidazole, 2- which may each be substituted. Keto-1-benzimidazole, thiazole, oxazole, isoxazole, 1,2,4-oxadiazole, indanone, benzofuran, quinoline, 1,2,3,4-tetrahydroquinoline, naphthalene or 1 Or a 2,3,4-tetrahydronaphthalene ring,

* [11] In the above [1], ring B is substituted with any one or more groups selected from halogen atom, nitrile group, C _1-6 alkyl group, lower acyl group, C _1-6 alkylsulfonyl group and aralkyl group, respectively Or a C _6-14 aromatic hydrocarbon ring or a 5 to 14 membered aromatic heterocycle,

[12] The above [1], wherein D ¹ and D ² are the same or different and include (1) a single bond or (2) a hydroxyl group, a halogen atom, a nitrile group, a C _1-6 alkyl group, a C _2-6 alkenyl group, and Or a C _1-6 alkylene chain which may be substituted with any one or more groups selected from C _1-6 alkoxy groups,

[13] In the above [1], E may be a single bond,

[14] the above-mentioned [1], wherein D ¹ and D ² are C _1-6 alkylene chains, and E may be a single bond,

[15] The above-mentioned [1], wherein the partial structure -D ¹ -ED ² -may be a C _1-4 alkylene group,

[16] The above [1], wherein W ¹ and W ² are the same or different and include (1) a single bond or (2) a hydroxyl group, a halogen atom, a nitrile group, a C _1-6 alkoxy group and a C _2-6 alkenyl jade. Or a C _1-6 alkylene chain which may be substituted with a hydrocarbon group which may be substituted with any one or more groups selected from time periods,

[17] The compound of [1], wherein W ¹ is any ^{one selected} from (1) a single bond or (2) (i) a nitrile group, (ii) a C _1-6 alkoxy group and a C _2-6 alkenyloxy group. C _1-6 alkyl group which may be substituted with at least two groups and (iii) C _1-6 alkylene chain which may be substituted with at least one group selected from C _2-6 alkenyl groups, and W ² is a single bond Maybe,

[18] The C _1-6 alkylene chain according to the above [1], wherein W ¹ and W ² are the same or different and are substituted with any one or more groups selected from a C _1-6 alkyl group and a C _2-6 alkenyl group. The C _1-6 alkyl group and / or C _2-6 alkenyl group may form a ring together by a bond, or the C _1-6 alkyl group or C _2-6 alkenyl group may be bonded to a ring B or X to form a ring. May be forming,

[19] The above [1], wherein X is (1) a single bond, (2) an oxygen atom, or (3) Formula -NR ^2- [wherein R ² is a hydrogen atom or C _1- which may be substituted; ₆ alkyl group, C _3-8 cycloalkyl group, lower acyl group or C _1-6 alkylsulfonyl group], (4) -NR ¹⁰ -W ³ -O-, wherein R ¹⁰ is a hydrogen atom, substituted A C _1-6 alkyl group, C _3-8 cycloalkyl group, lower acyl group or C _1-6 alkylsulfonyl group which may be substituted; W ³ represents a C _1-6 alkylene chain which may be substituted] or (5) a group represented by -NH-SO _2- ,

[20] In the above [1], X is (1) an oxygen atom, (2) formula -NR ^2- [wherein R ² is a hydrogen atom, a C _1-6 alkyl group which may be substituted, C _{3- An 8} cycloalkyl group, a lower acyl group, or a C _1-6 alkylsulfonyl group] or (3) a group represented by -NH-SO _2- ,

[21] In the above [1], the partial structure -W ¹ -XW ² -may be a C _1-6 alkylene group which may be substituted,

[22] The above [1], W ¹ is a C _1-6 alkylene chain which may be substituted, W ² is a single bond, and X is an oxygen atom or a formula -NR ^2- [wherein R ² Represents the definitions and synonyms of the foregoing].

[23] according to [22], it is (1) the substituent W ^1, a nitrile group, (2) C _1-6 alkoxy group or a C _2-6 C _1-6 alkyl group which may be substituted with an alkenyloxy and (3) any one or more groups selected from C _2-6 alkenyl groups, and may be a C _1-6 alkyl group in which R ² may be substituted,

[24] In the above [1], R ¹ may be a C _1-6 alkyl group,

[25] In the above [1], R ¹ may be a methyl group, an ethyl group, n-propyl group or iso-propyl group,

[26] The compound of [1], wherein

[Wherein, R ¹ represents the same meaning as the above definition;

R ¹³ and R ¹⁴ are the same or different

(1) a hydrogen atom,

(2) a halogen atom,

(3) hydroxyl,

(4) mercapto groups,

(5) a C _1-6 alkyl group which may be substituted with any one or more groups selected from hydroxyl groups and halogen atoms,

(6) a hydroxyl group, a halogen atom and C _1-6 C _1-6 which may be substituted with any one or more selected from an alkoxycarbonyl group the alkoxy group,

(7) nitro groups,

(8) an amino group which may be substituted;

(9) cyano groups,

(10) carboxyl groups,

(11) C _1-6 alkoxycarbonyl group,

(12) a C _1-6 thioalkoxy group,

(13) a C _1-6 alkylsulfonyl group,

(14) lower acyl,

(15) a C _6-14 aromatic hydrocarbon ring group which may be substituted,

(16) a 5 to 14 membered aromatic heterocyclic group which may be substituted,

(17) aryloxy group or

(18) represent an aralkyloxy group, or

(19) R ¹³ or R ¹⁴ may be bonded together to form (i) an optionally substituted alicyclic ring, (ii) an optionally substituted heterocycle, or (iii) an alkylenedioxy group. have;

n represents 0 or an integer of 1 to 3;

p represents an integer of 1 to 6;

q represents an integer of 1 to 6;

r represents 0 or an integer from 1 to 5;

Provided that 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] pipe Razine, 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (3-fluorophenoxy) ethyl] piperazine and 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-fluorophenoxy) ethyl] piperazine is excluded] may be used.

[27] The compound of [1], wherein

[Wherein, R ¹ and R ² have the same definition as the above definition;

R ¹³ and R ¹⁴ are the same or different

(1) a hydrogen atom,

(2) a halogen atom,

(3) hydroxyl,

(4) mercapto groups,

(5) a C _1-6 alkyl group which may be substituted with any one or more groups selected from hydroxyl groups and halogen atoms,

(6) a hydroxyl group, a halogen atom and C _1-6 C _1-6 which may be substituted with any one or more selected from an alkoxycarbonyl group the alkoxy group,

(7) nitro groups,

(8) an amino group which may be substituted;

(9) cyano groups,

(10) carboxyl groups,

(11) C _1-6 alkoxycarbonyl group,

(12) a C _1-6 thioalkoxy group,

(13) a C _1-6 alkylsulfonyl group,

(14) lower acyl,

(15) a C _6-14 aromatic hydrocarbon ring group which may be substituted,

(16) a 5 to 14 membered aromatic heterocyclic group which may be substituted,

(17) aryloxy group or

(18) represent an aralkyloxy group or

(19) R ¹³ or R ¹⁴ may be bonded to each other to form (i) an optionally substituted alicyclic ring, (ii) an optionally substituted heterocyclic ring, or (iii) an alkylenedioxy group;

n represents 0 or an integer of 1 to 3;

p represents an integer of 1 to 6;

q represents an integer of 1 to 6;

r may represent 0 or an integer of 1 to 5].

[28] The compound of [1], wherein the compound is

4-[(4-cyano-5-methyl-4-phenyl) hexyl] -N- (4-fluorophenyl) -N '-(2-methylpropyl) -1 (2H) -pyrazinecarboxyimidamid ;

1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino] -1-phenylbutyl cyanide;

1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [3- (5-cyano-2-thienyl) propyl] piperazine;

1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1- {4-cyano-5-methyl-4- [4- (2-cyano) -thienyl] hexyl} -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-benzoxazolyl) amino] piperidine;

1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl) -N-benzylamino] Pyrrolidine;

1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2-cyanoethyl) -N-benzylamino] Pyrrolidine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (benzothiazolyl) piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (6-methoxy) benzothiazolyl] piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-benzoxazolyl) piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-quinolinyl) piperazine;

4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepan-1-yl] -1-isopropyl-1-phenylbutylcyanide;

* 4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepan-1-yl] -1-isopropyl-1-phenylbutyl cyanide;

Ethyl 4- (4-cyano-5-methyl-4-phenylhexyl) -1- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate;

1-[(2-oxo-1,2-dihydro-3-quinolyl) methyl] -4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidine;

4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (methanesulfonylamino) phenyl] methyl} piperazine;

4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (methanesulfonylamino) phenyl] methyl} piperidine;

(S) -3-phenyl-2-amino-propanoic acid {1- [4-cyano-5-methyl-5- (2-thionyl) hexyl] piperazinyl} amide;

4- [4- (4-phenylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide;

4- [4- (4-cyano-4-phenylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide and

It may be any one selected from 4- [4- (4-benzylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide.

Moreover, the 2nd characteristic of this invention is

[29] expression

[Wherein Ar is

(1) a C _6-14 aromatic hydrocarbon ring group which may be substituted,

(2) a 5 to 14 membered aromatic heterocyclic group which may be substituted,

(3) a C _1-6 alkyl group substituted with a C _6-14 aromatic hydrocarbon ring which may be substituted or

(4) a C _1-6 alkyl group substituted with a 5-14 membered aromatic heterocyclic group which may be substituted;

Ring A represents a piperazine, homopiperazine, piperidine, homopiperidine, pyrrolidine or diazabicyclo [2,2,1] heptane ring, each of which may be substituted;

Ring B is

(1) a C _3-14 hydrocarbon ring which may be substituted or

(2) represents a 5 to 14 membered heterocycle which may be substituted;

E is

(1) a single bond,

(2) Formula -CO- or

(3) represents a group represented by -CH (OH)-;

X is

(1) a single bond,

(2) an oxygen atom,

(3) sulfur atoms,

(4) a C _1-6 alkylene chain which may be substituted,

(5) Formula -NR ^2- (wherein R ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, a C _3-8 cycloalkyl group, a lower acyl group or a C _1-6 alkylsulfonyl group) ,

(6) -CO-,

(7) -COO-,

(8) -OOC-,

(9) -CONR ^3- (wherein R ³ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(10) -NR ⁴ CO- (wherein R ⁴ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(11) -SO-,

(12) -SO2-,

(13) -SONR ^5- (wherein R ⁵ represents a hydrogen atom or a optionally substituted C _1-6 alkyl group),

(14) -NR ⁶ SO- (wherein R ⁶ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(15) -SO ₂ NR ^7- (wherein R ⁷ represents a hydrogen atom or a optionally substituted C _1-6 alkyl group),

(16) -NR ⁸ SO _2- (wherein R ⁸ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(17)> C = N-OR ⁹ (wherein R ⁹ represents a hydrogen atom or a substituted C _1-6 alkyl group),

(18) -NR ¹⁰ -W ³ -O- wherein R ¹⁰ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, a C _3-8 cycloalkyl group, a lower acyl group or a C _1-6 alkylsulfur A phenyl group; W ³ represents a C _1-6 alkylene chain which may be substituted),

(19) -NH-CO-NH-,

(20) -NH-CS-NH-,

(21) -C (= NR ¹⁵ ) NR ^16- (wherein R ¹⁵ and R ¹⁶ are the same or different and represent a hydrogen atom, a nitrile group, a C _1-6 alkyl group, a C _2-6 alkenyl group, C _3-8 Cycloalkyl group or C _3-8 cycloalkenyl group),

(22) -NHC (= NH)-,

(23) -O-CO-S-,

(24) -S-CO-O-,

(25) -OCOO-,

(26) -NHCOO-,

(27) -OCONH-,

(28) -CO (CH ₂ ) _m O- (wherein m represents 0 or an integer of 1 to 6),

(29) -CHOH- or

(30) represents a group represented by -CHOH (CH ₂ ) _n O-, wherein n represents 0 or an integer of 1 to 6;

R ¹ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) hydroxyl,

(4) a C _1-6 alkyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(5) a C _2-6 alkenyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(6) a C _2-6 alkynyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(7) a C _3-8 cycloalkyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(9) a C _1-6 alkoxy-C _1-6 alkyl group,

(10) an amino-C _1-6 alkyl group in which the nitrogen atom may be substituted;

(11) a group represented by the formula -N (R ¹¹ ) R ¹² (wherein R ¹¹ and R ¹² are the same or different and represent a hydrogen atom or a C _1-6 alkyl group),

(12) an aralkyl group,

(13) morpholinyl group,

(14) thiomorpholinyl group,

(15) piperidyl,

(16) pyrrolidinyl groups or

(17) piperazinyl group;

D ¹ , D ² , W ¹ and W ² are the same or different, respectively

(1) single bond or

(2) represents a C _1-6 alkylene chain which may be substituted;

With the proviso that 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] Piperazine, 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (3-fluorophenoxy) ethyl] piperazine and 1 -[4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-fluorophenoxy) ethyl] piperazine is excluded] or a salt thereof Or in a pharmaceutical composition comprising these hydrates,

[30] The composition of [29] may be a calcium antagonist,

[31] The composition of [29] may be a neuroselective calcium antagonist,

[32] The composition of [29] may be a P / Q type calcium channel and / or an N type calcium channel inhibitor,

[33] The composition of the above-mentioned [29] may be a treatment / prevention / improvement agent for diseases in which P / Q type calcium channel inhibitory action and / or N type calcium channel inhibitory action are effective.

[34] The composition of [29] may be a neuronal cell death inhibitor or a neuronal cell protective agent,

[35] The composition of the above-mentioned [29] may be a treatment, prevention or improvement agent for neurological diseases,

[36] The neurological disorders described in [35] include acute cerebrovascular disease, stroke, cerebral infarction, head trauma, cerebral neuronal cell death, Alzheimer's disease, Parkinson's disease, atrophic lateral sclerosis, Huntington's disease, cerebral circulatory metabolic disorder, and brain dysfunction. May be pain, cramps, schizophrenia, migraine, epilepsy, manic-depressive disorders, neurodegenerative disorders, cerebral ischemia, AIDS dementia complications, edema, anxiety disorders, diabetic neuropathy, cerebrovascular dementia or multiple sclerosis,

[37] The composition of [29] may be an analgesic drug.

The present invention provides a pharmacologically effective amount of a compound represented by the above formula (I) or a salt thereof or a hydrate thereof to a patient, thereby providing a disease in which calcium antagonism is effective, a disease in which neuroselective calcium antagonism is effective, or a P / Q type calcium channel. The present invention provides a method for preventing, treating, and improving a disease in which an inhibitory action and / or an N-type calcium channel inhibitory action is effective, a method for inhibiting neuronal cell death or protecting a brain nerve cell.

The present invention provides a method for preventing, treating and improving neurological diseases or pain.

In addition, the present invention is a compound represented by the formula (I) or a salt thereof or a hydrate thereof calcium antagonist, neuroselective calcium antagonist, P / Q type calcium channel and / or N type calcium channel inhibitor, P / Q type calcium channel The present invention provides a use for the treatment, prevention, improvement, neuronal cell death inhibitor or neuroprotective agent for the treatment of diseases in which inhibitory action and / or N-type calcium channel inhibitory action are effective.

Moreover, this invention provides the use which uses the compound represented by said Formula (I), its salt, or its hydrate for the treatment, prevention, improvement, or analgesic medicine of neurological diseases.

Neurological diseases include, for example, acute cerebrovascular disorders, strokes, cerebral infarction, head trauma, cerebral nerve cell death, Alzheimer's disease, Parkinson's disease, cerebral atrophic lateral sclerosis, Huntington's disease, cerebral metabolic disorders, brain dysfunction, pain, convulsions, Schizophrenia, migraine, epilepsy, manic illness, neurodegenerative disorders, cerebral ischemia, AIDS dementia, edema, anxiety disorders, diabetic neuropathy, cerebrovascular dementia and multiple sclerosis.

* Hereinafter, the meaning of symbols, terms, etc. which are described in this specification are demonstrated and this invention is demonstrated in detail.

In the present specification, although the structural formula of the compound may show a constant isomer for convenience, the present invention includes all geometric isomers, optical isomers based on sub-carbons, stereoisomers, tautomers and the like, and isomer mixtures. In addition, it is not limited to description of a formula for convenience, either isomer and mixture may be sufficient. Therefore, the compound of the present invention may contain an optically active substance and a racemate with a subsidiary carbon atom in the molecule, but is not limited in the present invention, and all are included. Moreover, although a crystal polymorph may exist, it is not limited to the same, Any one crystal form may be single or a crystalline mixture, or a hydrate may be sufficient as an anhydride. In addition, so-called metabolites, which are produced by decomposition of the compound according to the present invention in vivo, are also included in the claims of the present invention.

The phrase "and / or" in this specification is used in the sense including both the case of "and" and the case of "or". Therefore, for example, "A and / or B" includes both the case of "A and B" and the case of "A or B", and has shown that any case may be sufficient.

As used herein, the term "neuropathy" is mainly acute cerebrovascular disease, stroke, cerebral infarction, head trauma, cerebral neuronal cell death, Alzheimer's disease, Parkinson's disease, cerebral atrophic lateral sclerosis, Huntington's disease, brain circulation metabolic disorder, brain dysfunction, pain , Convulsions, schizophrenia, migraine, epilepsy, mood swings, neurodegenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorders, diabetic neuropathy, cerebrovascular dementia or multiple sclerosis.

As used herein, "analgesic" refers to a medicament that relieves or eliminates pain by changing the perception of invading receptor stimuli without causing anesthesia or loss of consciousness.

The "halogen atom" used in this specification represents atoms, such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., Preferably they are a fluorine atom, a chlorine atom, a bromine atom, More preferably, a fluorine atom, It is a chlorine atom.

The "C _1-6 alkyl group" used in the present specification refers to an alkyl group having 1 to 6 carbon atoms, preferably methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl Group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethyl Propyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl And linear or branched alkyl groups such as groups, 2-methylpentyl groups, and 3-methylpentyl groups.

The "C _2-6 alkenyl group" used in the present specification means an alkenyl group having 2 to 6 carbon atoms, preferably a vinyl group, an allyl group, a 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group And a linear or branched alkenyl group such as 1-pentenyl group, 1-hexenyl group, 1,3-hexanedienyl group, and 1,6-hexanedienyl group.

The "C _2-6 alkynyl group" used in the present specification refers to an alkynyl group having 2 to 6 carbon atoms, preferably an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2- Butynyl, 3-butynyl, 3-methyl-1-propynyl, 1-ethynyl-2-propynyl, 2-methyl-3-propynyl, 1-pentynyl, 1-hexynyl, 1,3- Linear or molecular chain alkynyl groups such as hexanediynyl group, 1,6-hexanediynyl group, and the like.

The "C _1-6 alkoxy group" used in this specification shows the "C _1-6 alkyloxy group" which the oxygen atom couple | bonded with the group which is synonymous with the C _1-6 alkyl group in the said definition, As a preferable group, For example, methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group , iso-pentyloxy group, sec-pentyloxy group, n-hexoxyoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyl jade Period, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,1,2-trimethylprop Fox group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2-ethylbutoxy group , 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group, hexyl ox And the like groups.

Used in the present specification, "C _1-6 alkenyloxy group" refers to the group of the C _1-6 alkenyl group in the definition agreed represents an oxygen atom is bound, a preferred group includes, for example vinyloxy, aryloxy Period, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group, 2-methyl-2- Propenyloxy group, 3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group, 1,3 -Hexanedienyloxy group, a 1, 6- hexanedienyloxy group, etc. are mentioned.

The "C _3-8 cycloalkyl group" used in the present specification refers to a cycloalkyl group in which a ring is formed with 3 to 8 carbon atoms, and preferred groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cyclohep Tyl group, cyclooctyl group, etc. are mentioned. In addition, the "C _3-8 cycloalkane" used in this specification shows the ring corresponding to the said C _3-8 cycloalkyl group.

The "C _3-8 cycloalkenyl group" used in the present specification refers to a C _3-8 cycloalkenyl group in which a ring is formed with 3 to 8 carbon atoms, for example, a formula

The group represented by is mentioned.

The "aromatic _ring group" used in this specification is a phrase which shows a C _6-14 aromatic hydrocarbon _ring group or a _5-14 membered aromatic heterocyclic group.

(1) As the "C _6-14 aromatic hydrocarbon _ring group", for example, a phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azurenyl group, heptarenyl group, biphenyl group, indasenyl group, acenaph And monocyclic, bicyclic or tricyclic C6-14 aromatic hydrocarbon ring groups such as a methyl group, a fluorenyl group, a penalenyl group, a penalenyl group, an anthracenyl group, a cyclopentacyclooctenyl group, a benzocyclooctenyl group, and the like. . In addition,

(2) The "5- to 14-membered aromatic heterocyclic group" includes a monocyclic, bicyclic or tricyclic 5- to 14-membered aromatic compound containing one or more of at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom Heterocycle can be mentioned, for example

(i) pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl, benzimidazolyl, Indolyl group, isoindolyl group, indolinyl group, furinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, Cynolinyl group, pterridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenantridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinyl group, phenna Nitrogen-containing aromatic heterocycles such as cynyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group, pyrazolopyridinyl group, and the like;

(ii) sulfur-containing aromatic heterocycles such as thienyl group and benzothienyl group;

(iii) oxygen-containing aromatic heterocycles such as furyl group, pyranyl group, cyclopentapyranyl group, benzofuranyl group, isobenzofuranyl group, and the like;

(iv) thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group, phenothiadinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, benz oxazolyl group Two or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as an oxadiazolyl group, a pyrazolooxazolyl group, an imidazothiazolyl group, a thienofuranyl group, a furypyrrolyl group, a pyridoxazinyl group, and the like The aromatic heterocyclic ring containing the is mentioned.

The "C _3-14 hydrocarbon ring" used in the present specification means C _3-8 cycloalkane, C _3-8 cycloalkene or C _6-14 aromatic hydrocarbon ring, and the significance of these rings is C in the above definition. _3-8 cycloalkanes, C _3-8 cycloalkenes and C _6-14 aromatic hydrocarbon rings are synonymous.

The "5-14 membered heterocycle" used in the present specification refers to a 5-14 membered heterocycle including any one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Aromatic heterocycles and non-aromatic heterocycles. From here,

(1) The said "5-14 membered aromatic heterocycle" means synonymous with the 5-14 membered aromatic heterocycle in the said definition. In addition,

(2) Preferred rings in the "5- to 14-membered non-aromatic heterocycle" include pyrrolidine, pyrroline, piperidine, piperazine, imidazoline, pyrazolidine, imidazolidine, morpholine, And condensed rings such as 5 to 14 membered non-aromatic heterocycles such as tetrahydrofuran, tetrahydropyran, aziridine, oxirane, oxathiolan, pyridone ring, phthalimide ring and succinimide ring.

The "hydrocarbon group" used in the present specification is specifically a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group or The C _6-14 aromatic hydrocarbon _ring group is represented, and the meaning of each is as described above.

[Significance of Ar]

In the compound represented by the formula (I) according to the present invention, Ar is (1) a substituted C _6-14 aromatic hydrocarbon ring group, (2) a substituted 5 to 14 membered aromatic heterocyclic group, 3 represents a C _1-6 alkyl group or (4) a C _1-6 alkyl group substituted by a 5- to 14-membered aromatic heterocyclic group which may be substituted with C _6-14 aromatic hydrocarbon ring group which may be substituted.

Preferable groups in the "C _6-14 aromatic hydrocarbon _ring group" include, for example, a phenyl group, pentalenyl group, indenyl group, naphthyl group, 1,2,3,4-tetrahydronaphthyl group, azulenyl group and heptale And a phenyl group, a benzocyclooctenyl group, a tetrayl group, a phenanthrenyl group, and the like, and more preferably a phenyl group and a naphthyl group.

Moreover, as a preferable ring in a "5-14 membered aromatic heterocycle", a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, Pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolinyl group, furinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthala group Chewy, naphthyridinyl, quinoxalyl, quinazolinyl, cinnaolinyl, pterdinyl, imidazotriazinyl, pyrazinopyridazinyl, acridinyl, phenanthridinyl, carbazolyl Group, carbazolinyl group, perimidinyl group, phenanthrolinyl group, phenacinyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group, pyrazolopyridinyl group, thienyl group, benzothienyl group, Furyl group, pyranyl group, cyclopentapyranyl group, benzofuranyl group, isobenzofu Neyl group, thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, benzoxazolyl group, An oxadiazolyl group, a pyrazolooxazolyl group, an imidazothiazolyl group, a thienofuranyl group, a propyrrolyl group, a pyridoxazinyl group, etc. are mentioned, More preferably, it is a thienyl group, a pyridyl group, etc., More preferably, Is a thienyl group.

Examples of the "substituent" when Ar is "C _6-14 aromatic hydrocarbon ring group which may be substituted" or "5 to 14 membered aromatic heterocyclic group which may be substituted" include, for example.

(i) hydroxyl groups,

(ii) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.),

(iii) nitrile groups,

(iv) C _1-6 alkyl group (preferably methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group , 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl Group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, etc.),

(v) C _2-6 alkenyl group (preferably vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group) , 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexane Dienyl group, 1,6-hexanedienyl group, etc.),

(vi) a C _2-6 alkynyl group (preferably an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl, 2-methyl-3-propynyl, 1-pentynyl, 1-hexynyl, 1,3-hexanediynyl, 1,6-hexanediynyl, etc.)

(vii) C _1-6 alkoxy group (preferably methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy Period, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2- Dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethyl Propoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxy group, 1, 3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group, hexyloxy group, etc.),

(viii) C _1-6 alkylthio group (preferably methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, n-butylthio group, iso-butylthio group, sec-butyl tea) Ogi, tert-butylthio group, n-pentylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group, 1-ethylpropylthio group, 2- Ethylpropylthio group, n-hexylthio group, 1-methyl-2-ethylpropylthio group, 1-ethyl-2-methylpropylthio group, 1,1,2-trimethylpropylthio group, 1-propylpropylthio group , 1-methylbutylthio group, 2-methylbutylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,3-dimethylbutylthio group , 2,3-dimethylbutylthio group, 2-ethylbutylthio group, 2-methylpentylthio group, 3-methylpentylthio group, etc.),

(ix) a C _1-6 alkoxycarbonyl group,

(x) a hydroxy C _1-6 alkyl group,

(xi) halogenated C _1-6 alkyl groups,

(xii) hydroxyimino C _1-6 alkyl group,

(xiii) nitro groups,

(xiv) an amino group in which a nitrogen atom may be substituted,

(xv) a carbamoyl group in which a nitrogen atom may be substituted,

(xvi) sulfamoyl groups in which a nitrogen atom may be substituted,

(xvii) lower acyl,

(xviii) aromatic acyl groups,

(xix) C _1-6 alkylsulfonyl groups, such as a methylsulfonyl group, etc. are mentioned, Preferably,

(a) hydroxyl group, (b) halogen atom, (c) nitrile group, (d) C _1-6 alkyl group, (e) C _1-6 alkylsulfonyl group, (f) C _1-6 alkoxy group, (g) A C _1-6 alkylthio group and the like, more preferably a nitrile group and a halogen atom (for example, a fluorine atom).

Moreover, as an example of the more preferable "substituted C _6-14 aromatic hydrocarbon ring group" or "substituted 5-14 membered aromatic heterocyclic group" in Ar, any one selected from a halogen atom and a cyano group A thiophene, pyridine, benzene or naphthalene ring which may be substituted by the above group is mentioned, The most preferable example is the thiophene ring which may be substituted by any 1 or more group chosen from a halogen atom and a cyano group, ie, a formula

In the formula, a ring represented by R ^13a , R ^13b and R ^13c is the same or different and represents a hydrogen atom, a halogen atom or a cyano group.

In the compound represented by the formula (I) according to the present invention, Ar is "C _1-6 alkyl group substituted with a C _6-14 aromatic hydrocarbon ring which may be substituted" or "5 to 5 may be substituted""C _6-14 aromatic hydrocarbon ring group which may be substituted" or "5 to 14 membered aromatic heterocyclic group which may be substituted" in the case of "C _1-6 alkyl group substituted with 14-membered aromatic heterocyclic group" The C _6-14 aromatic hydrocarbon ring group which may be substituted in the definition or the _5-14 membered aromatic heterocyclic group which may be substituted, respectively represents the group which is synonymous, and the C _1-6 alkyl group substituted by those groups is Substituted C _1-6 alkyl group. Herein, preferred groups in the "C _1-6 alkyl group" include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group and tert-butyl group , n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl -2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethyl Butyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methyl A pentyl group etc. are mentioned, Preferable group in a " _C1-6 alkyl group substituted by the aromatic group which may be substituted" includes a nitrile group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom). Etc.) may be substituted with one or more groups selected from Benzyl group, phenethyl group, phenylpropyl group, naphthylmethyl group, naphthylethyl group, naphthylpropyl group, pyridylmethyl group, pyrazinylmethyl group, pyrimidinylmethyl group, pyrrolylmethyl group, imidazolylmethyl group, pyrazolylmethyl group , Quinolylmethyl group, isoquinolylmethyl group, furfuryl group, thienylmethyl group, thiazolylmethyl group and the like.

Moreover, a preferable group in " _C1-6 alkoxycarbonyl group" in the definition of Ar is a methoxycarbonyl group, an ethoxycarbonyl group, n-propoxycarbonyl group, iso-propoxycarbonyl group, sec-propoxycarbonyl group, n-butoxy Carbonyl group, iso-butoxycarbonyl group, sec-butoxycarbonylcarbonyl group, tert-butoxycarbonylcarbonyl group, n-pentoxycarbonyl group, i-pentoxycarbonyl group, sec-pentoxycarbonyl group, tert-pentoxycarbonyl group, n- Hexooxycarbonyl group, iso-hexoxyoxycarbonyl group, 1,2-dimethylpropoxycarbonyl group, 2-ethylpropoxycarbonyl group, 1-methyl-2-ethylpropoxycarbonyl group, 1-ethyl-2-methylpropoxycarbonyl group, 1,1,2-trimethylpropoxycarbonyl group, 1,1,2-trimethylpropoxycarbonyl group, 1,1-dimethylbutoxycarbonyl group, 2,2-dimethylbutoxycarbonyl group, 2-ethylbutoxycarbonyl group, 1,3 -Dimethylbutoxycarbonyl group, 2-methylpentoxycarbono Group, a 3-methyl pentoxy group.

Preferred groups in the "hydroxy C _1-6 alkyl group" include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 3-hydroxy n-propyl group, hydroxy iso-propyl group, hydroxy- sec-propyl group, hydroxy-n-butyl group, hydroxy-iso-butyl group, hydroxy-sec-butyl group, hydroxy-tert-butyl group, hydroxy-n-pentyl group, hydroxy-iso- And linear or branched C _1-6 alkyl groups such as pentyl group, hydroxy-n-hexyl group and hydroxy-iso-hexyl group.

The "halogenated C _1-6 alkyl group" is, represents a combination of C _1-6 alkyl group in the definition of "C _1- 6 alkyl group" of the identical or different halogen atoms on one or more of motion, the preferred examples of the fluoroalkyl group, Difluoromethyl group, trifluoromethyl group, chloromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2-difluoro An ethyl group, a 2,2,2-trifluoroethyl group, and the like.

The "hydroxyimino C _1-6 alkyl group" refers to a group in which a hydroxyimino group is bonded to a group synonymous with a C _1-6 alkyl group in the above definition.

The "amino group in which the nitrogen atom may be substituted" is a formula -N (R ¹⁵ ) R ¹⁶ [wherein R ¹⁵ and R ¹⁶ are the same or different;

(1) a hydrogen atom,

(2) a C _1-6 alkyl group, C _1-6 , which may each be substituted with one or more groups selected from halogen atoms, C _3-8 cycloalkyl groups, C _3-8 cycloalkenyl groups, and C _1-6 alkoxy groups Alkenyl group or C _1-6 alkynyl group,

(3) a C _3-8 cycloalkyl group or C _3-8 cycloalkenyl group, each of which may be substituted with a halogen atom,

(4) C _1-6 alkyl group, C _1-6 alkenyl group, C _1-6 alkynyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _1-6 which may be substituted with halogen atoms, respectively A carbonyl group substituted with any one group selected from an alkoxy group, a C _6-14 aromatic hydrocarbon ring group, a _5-14 membered aromatic heterocyclic group, and a 5-10 membered non-aromatic heterocyclic group,

(5) may be substituted with any one group selected from C _1-6 alkyl group, C _1-6 alkenyl group, C _1-6 alkynyl group, C _6-14 aromatic hydrocarbon ring group and 5 to 14 membered aromatic heterocyclic group Carbamoyl or

(6) C _1-6 alkyl, C _1-6 alkenyl and C _1-6 alkynyl group in which one represents the like; substituted sulfonyl group selected from group or, or

(7) R ¹⁵ and R ¹⁶ may be bonded together to form a 3- to 10-membered non-aromatic heterocyclic group containing a nitrogen atom to be bonded together, and the heterocyclic group may also be a hydroxyl group, a halogen atom, C _{1 May} be substituted with one or more groups selected from _-6 alkoxy group and the like].

A preferred group of the above amino group is, for example, unsubstituted amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, methyl ethyl amino group, an acetamide group (CH ₃ CONH-), propionamide group, methanesulfonamide A group, an ethane sulfonamide group, a pyrrolidinyl group, a pyrazolinyl group, a piperidyl group, a piperazinyl group, a 4-morpholinyl group, a 4-thiomorpholinyl group, etc. are mentioned. More preferred groups in the "amino group which may be substituted" include C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group and C _3-8 cycloalkenyl group The amino group etc. which may be substituted by the 1 or 2 group chosen are mentioned.

The "carbamoyl group in which the nitrogen atom may be substituted" means a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, or the like. Carbamoyl group which the nitrogen atom, such as selected from the above, may be substituted. Moreover, the case where the nitrogen atom of a carbamoyl group is a part of cyclic amine is also included in the said carbamoyl group. Preferred groups in the "carbamoyl group in which the nitrogen atom may be substituted" include unsubstituted carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, N-ethylcarbamoyl group, N, N-diethylcarbamoyl group, N-methyl-N-ethylcarbamoyl group, 1-pyrrolidinylcarbonyl group, 1-pyrazolinylcarbonyl group, 1-piperidylcarbonyl group, 1-piperazinylcarbonyl group, 4-mor Polyyl carbonyl group, 4-thiomorpholinyl carbonyl group, etc. are mentioned.

The "sulfamoyl which may be substituted nitrogen atom is the parent group" is, C _1-6 alkyl, C _2- 6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 alkenyl group such as bicyclo The sulfamoyl group which the nitrogen atom may be substituted by the group chosen from is shown. In addition, the sulfamoyl group also includes the case where the nitrogen atom of a sulfamoyl group is a part of cyclic amine. Preferable groups in the "sulfamoyl group in which the nitrogen atom may be substituted" include unsubstituted sulfamoyl group (-SO ₂ NH ₂ ), N-methylsulfamoyl group (-SO ₂ NHCH ₂ ), N, N- Dimethylsulfamoyl group (-SO ₂ NH (CH ₃ ) ₂ ), N-ethylsulfamoyl group (-SO ₂ NHC ₂ H ₅ ), N, N-diethylsulfamoyl group-SO ₂ NH (C ₂ H ₅ ) ₂ ), N-methyl-N-ethylsulfamoyl group (-SO ₂ N (CH ₃ ) C ₂ H ₅ ), 1-pyrrolidinylsulfonyl group, 1-pyrazolinylsulfonyl group, 1-piperidyl Sulfonyl group, 1-piperazinylsulfonyl group, 4-morpholinylsulfonyl group, 4-thiomorpholinylsulfonyl group, etc. are mentioned.

The "lower acyl group" refers to a straight or molecular chain acyl group derived from C1-6 fatty acids, and preferred groups in the group include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, Valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, etc. are mentioned.

[Meaning of Ring A]

In the compound represented by the formula (I) according to the present invention, ring A is piperazine, homopiperazine, piperidine, homopiperidine, pyrrolidine and diazabicyclo [2,2,1] heptane The 1 type of ring chosen from a ring is shown. As a preferable ring in ring A, a piperazine, homopiperazine, a piperidine, a homopiperidine, a pyrrolidine ring is mentioned, More preferably, they are a piperidine ring and a piperazine ring, More preferably, It is a piperazine ring. In the case where ring A is piperazine, piperidine, pyrrolidine or diazabicyclo [2,2,1] heptane ring, preferred embodiments in which linking chains D ² and W ¹ are bonded to ring A are preferred. , Expression

The aspect represented by these is mentioned, More preferably, a formula

to be.

[Significance of ring B]

In the compound represented by the formula (I) according to the present invention, ring B represents (1) optionally substituted C _3-14 hydrocarbon ring or (2) optionally substituted 5 to 14 membered hetero ring. .

(1) The "C _3-14 hydrocarbon ring" in the definition of ring B represents a C _3-8 cycloalkane, C _3-8 cycloalkene or C _6-14 aromatic hydrocarbon ring. Preferred rings in the case where ring B is "C _3-8 cycloalkane" include _3-8 membered cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and more preferably. Are cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like. Preferred rings in the case where ring B is "C _3-8 cycloalkene" include _3-8 membered cycloalkenes such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and the like. And non-aromatic unsaturated hydrocarbon rings in which a carbon carbon double bond in an aromatic hydrocarbon ring is partially saturated, more preferably cyclopropene, cyclobutene, cyclopentene, cyclohexene and the like. Preferred rings in the case of ring B in the case of "C _6-14 aromatic hydrocarbon ring" include benzene, pentylene, indene, naphthalene, 1,2,3,4-tetrahydronaphthalene, azulene, heptalene, benzocyclo octene, phenanthrene and the like renhwan, a C _3-8 cycloalkyl ring and a condensed ring of an alkane and an aromatic hydrocarbon or, C _3-8 cycloalkyl fused ring thresher of alkenes and aromatic hydrocarbons, the "C _6-14 aromatic hydrocarbon ring" Included.

(2) "5-14 membered heterocycle" in the definition of ring B represents a 5-14 membered non-aromatic heterocycle or a 5-14 membered aromatic heterocycle. Preferred rings in the case of ring “5 to 14 membered non-aromatic heterocycle” include pyrrolidine, pyrroline, piperidine, piperazine, imidazoline, pyrazolidine, imidazolidine, mor And phosphine, tetrahydropyran, aziridine, oxirane ring, phthalimide, succinimide ring and the like. Preferred rings in the case of ring “5 to 14 membered aromatic heterocycle” include pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, indole, isoindoleyl, indolizin, furin, Indazole, quinoline-isoquinoline, quinolizine, phthalazine, nattilidine, quinoxaline, quinazoline, benzimidazole, cinnoline, pteridine, imidazotriazine, pyrazinopyridazine, acridine , Phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacine, thiophene, benzothiophene, furan, pyran, cyclopentapyran, benzofuran, isobenzofuran, thiazole, isothiazole , Benzthiazole, benzthiadiazole, phenothiazine, isoxazole, furazane, phenoxazine, pyrazolooxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, 1,4-benzodioxane , Benzoxazole, 2-keto-1-benzimidazole, oxazole, 1,2,4-oxadiazole, indanone, 1,2,3,4-tetrahydro And quinoline rings.

Examples of the "substituent" in "C _3-14 hydrocarbon ring which may be substituted" or "5- to 14-membered heterocycle which may be substituted" in ring B include, for example, (1) hydroxyl group, (2) Halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), (3) nitrile group, (4) optionally substituted C _1-6 alkyl group (e.g. hydroxyl group, halogen atom, nitrile group) , A C _1-6 alkyl group which may be substituted with one or more groups selected from a hydroxyimino group and the like, (5) a C _2-6 alkenyl group (eg, a hydroxyl group, a halogen atom, a nitrile group) which may be substituted , A C _2-6 alkenyl group which may be substituted with one or more groups selected from a hydroxyimino group, etc., (6) a C _1-6 alkoxy group which may be substituted (for example, a hydroxyl group, a halogen atom, a nitrile) One selected from group, hydroxy imino group, etc. Alkoxy groups on the C _1-6 which may be substituted), (7) C _1-6 alkylthio which may be substituted T, (8) C _1-6 alkoxycarbonyl group, (9) nitro group, (10) Amino group in which nitrogen atom may be substituted, (11) carbamoyl group in which nitrogen atom may be substituted, (12) sulfamoyl group in which nitrogen atom may be substituted, (13) lower acyl group, (14) aromatic acyl group (15) C _1-6 alkylsulfonyl groups (e.g., methylsulfonyl groups, ethylsulfonyl groups, etc.), (16) C _6-14 aromatic hydrocarbon _ring groups, (17) 5- to 14-membered aromatic heterocyclic groups, (18) And at least one group selected from an aralkyl group (e.g., a benzyl group, a phenethyl group, etc.) and the like, preferably (i) a hydroxyl group, (ii) a halogen atom (fluorine atom, chlorine atom, bromine atom, etc.) (iii) nitrile group, (iv) C _1-6 alkyl group (e.g. methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso- Butyl group, tert-butyl group, etc.), (v) C _6-14 aromatic hydrocarbon ring group, (vi) 5-14 membered aromatic heterocyclic group, etc., More preferably, they are a nitrile group, a fluorine atom, a chlorine atom, etc.

The most preferable aspect in ring B is the C _6-14 aromatic hydrocarbon ring which may be substituted or the _5-14 membered aromatic heterocycle which may be substituted, Specifically, a nitrile group, a halogen atom (for example, Fluorine atom, chlorine atom, bromine atom, etc.), C _6-14 aromatic hydrocarbon ring group (e.g., phenyl group, naphthyl group, etc.), 5-14 membered aromatic heterocyclic group (e.g. pyridyl group, thienyl group, furyl group, etc.) , C _1-6 alkyl group (eg methyl group, ethyl group, n-propyl group, iso-propyl group, iso-butyl group, etc.), lower acyl group and C _1-6 alkylsulfonyl group (eg methylsulfonyl group, Benzene, thiophene, pyridine, 1,4-benzodioxane, indole, benzothiazole, benzoxazole, benzimidazole, 2- which may each be substituted with one or more groups selected from an ethylsulfonyl group) Keto-1-benzimidazole, thiazole, oxazole, isoxazole, 1,2,4-oxa Azole, indanone, benzofuran, quinoline, 1,2,3,4-tetrahydroquinoline, a naphthalene, 1,2,3,4-tetrahydronaphthalene ring a naphthalene or the like.

[E significance]

In the compound represented by the formula (I) according to the present invention, the bond chain E represents a single bond, a group represented by the formula -CO- or -CH (OH)-. The most preferred aspect in E is a single bond.

[X's significance]

In the compound represented by the formula (I) according to the present invention, the bond chain X is (1) single bond, (2) oxygen atom, (3) sulfur atom, (4) C _1-6 which may be substituted Alkylene chain, (5) Formula -NR ^2- (wherein R ² is a hydrogen atom, a substituted C _1-6 alkyl group, a C _3-8 cycloalkyl group, a lower acyl group or a C _1-6 alkylsulfonyl Group), (6) -CO-, (7) -COO-, (8) -OOC-, (9) -CONR ^3- (wherein R ³ is a hydrogen atom or optionally substituted C _{1- 6} alkyl group), (10) -NR ⁴ CO- (wherein R ⁴ represents a hydrogen atom or optionally substituted C _1-6 alkyl group), (11) -SO-, (12) -SO _2- , (13) -SONR ^5- (wherein R ⁵ represents a hydrogen atom or a substituted C _1-6 alkyl group), (14) -NR ⁶ SO- (wherein R ⁶ Represents a hydrogen atom or a substituted C _1-6 alkyl group), (15) -SO ₂ NR ^7- (wherein R ⁷ represents a hydrogen atom or a substituted C _1-6 alkyl group), (16) -NR ⁸ SO _2- (wherein R ⁸ represents a hydrogen atom or a substituted C _1-6 alkyl group) (17)> C = N-OR ⁹ (wherein R ⁹ represents a hydrogen atom or a optionally substituted C _1-6 alkyl group), (18) -NR ¹⁰ -W ³ -O- ( In the formula, R ¹⁰ represents a hydrogen atom, optionally substituted C _1-6 alkyl group, C _3-8 cycloalkyl group, lower acyl group or C _1-6 alkylsulfonyl group; W ³ is substituted is represents a C _1-6 alkylene chain that may be), (19) -NH-CO -NH-, (20) -NH-CS-NH-, (21) -C (= NR 15) NR 16 - ( Wherein R ¹⁵ and R ¹⁶ are the same or different and represent a hydrogen atom, a nitrile group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-8 cycloalkyl group or a C _3-8 cycloalkenyl group), (22) -NHC (= NH)-, (23) -O-CO-S-, (24) -S-CO-O-, (25) -O COO-, (26) -NHCOO-, (27) -OCONH-, (28) -CO (CH ₂ ) _m O- (wherein m represents 0 or an integer from 1 to 6), (29)- CHOH- or (30) -CHOH (CH ₂ ) _n O- (wherein n represents an integer of 0 or 1 to 6).

"C _1-6 alkylene chain" in the case of "C _1-6 alkylene chain which may be substituted" refers to a chain derived from straight or branched C _1-6 alkanes, for example, methylene And ethylene, ethylidene, trimethylene-isopropylidene, propylene, tetramethylene, 1,2-butylene, 1,3-butylene, 2,3-butylene-isobutylene chain, and the like.

In the definition of X, the most preferable groups in the "substituted C _1-6 alkyl group" represented by R ² to R ¹⁰ include a hydroxyl group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, and iodine). Atoms, etc.), nitrile group, nitro group, C _1-6 alkoxy group (for example, methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, etc.), etc. C _1-6 alkyl group (for example, methyl group, ethyl group, n-propyl group, iso-propyl group etc.) which may exist is mentioned.

In the definition of X, preferred groups in the "C _3-8 cycloalkyl group" represented by R ² and R ¹⁰ include a cyclopropanyl group, a cyclobutanyl group, a cyclopentanyl group, a cyclohexanyl group, a cycloheptanyl group, and the like. More preferably, a cyclopropanyl group, a cyclobutanyl group, a cyclopentanyl group, a cyclohexanyl group, and the like.

In the definition of X, preferred groups in the "lower acyl group" represented by R ² and R ¹⁰ include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivalo. Diary, hexanoyl group, etc. are mentioned.

In the definition of X, preferred groups in the "C _1-6 alkylsulfonyl group" represented by R ² and R ¹⁰ include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, iso-propylsulfonyl group, sec- Propylsulfonyl group, n-butylsulfonyl group, iso-butylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, iso-pentylsulfonyl group, sec-pentylsulfonyl group, tert-pentylsulfo Nyl, n-hexylsulfonyl, iso-hexylsulfonyl, 1,2-dimethylpropylsulfonyl, 2-ethylpropylsulfonyl, 1-methyl-2-ethylpropylsulfonyl, 1-ethyl-2-methylpropylsulfo 1,1,2-trimethylpropylsulfonyl group, 1,1,2-trimethylpropylsulfonyl group, 1,1-dimethylbutylsulfonyl group, 2,2-dimethylbutylsulfonyl group, 2-ethylbutylsulfonyl group, 1 , 3-dimethylbutylsulfonyl group, 2-methylpentylsulfonyl group, 3-methylpentylsulfonyl group and the like.

In the definition of X, R ¹⁵ and R ¹⁶ are the same or different and represent a hydrogen atom, a nitrile group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-8 cycloalkyl group or a C _3-8 cycloalkenyl Although group is shown, when both are preferable, they are the same or different, and are a hydrogen atom, a nitrile group, a methyl group, an ethyl group, n-propyl group, an iso-propyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, etc., and more Preferably, R ¹⁵ is a nitrile group, an ethyl group, an n-propyl group, an iso-propyl group or a cyclohexyl group, and R ¹⁶ is a hydrogen atom, and the formula -C (= NR ¹⁵ ) NR ^16- As a most preferable aspect in, the chain represented by a formula -C (= NCN) NH- is mentioned.

But the significance of each group is shown in the above definition of X, (1) by a preferred embodiment of the X is a single bond, C _1-6 alkyl which may be an oxygen atom, a sulfur atom, an optionally substituted chain, formula -NR ² (Wherein, R ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, C _3-8 cycloalkyl group, lower acyl group or C _1-6 alkylsulfonyl group), -CO-,- NR ¹⁰ -W ³ -O- wherein R ¹⁰ is a hydrogen atom, optionally substituted C _1-6 alkyl group, C _3-8 cycloalkyl group, lower acyl group or C _1-6 alkyl Sulfonyl group; W ³ represents a C _1-6 alkylene chain which may be substituted], a chain represented by -NH-SO _2- , or the like, (2) More preferably, an oxygen atom or C _1-6 which may be substituted Alkylene chain, formula -NR ^2- [wherein R ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, a C _3-8 cycloalkyl group, a lower acyl group or a C _1-6 alkylsulfonyl group] , -CO-, -NR ¹⁰ -W ³ -O- wherein R ¹⁰ is a hydrogen atom, optionally substituted C _1-6 alkyl group, C _3-8 cycloalkyl group, lower acyl group Or a C _1-6 alkylsulfonyl group; W ³ represents a C _1-6 alkylene chain which may be substituted], a chain represented by -NH-SO _2- , (3) More preferably, an oxygen atom or C _1-6 alkyl which may be substituted Len chain, formula -NR ^2- [wherein, R ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, a C _3-8 cycloalkyl group, a lower acyl group, a C _1-6 alkylsulfonyl group], -CO-, -NH-SO ₂ -is a chain, and more preferably (4) is an oxygen atom, a formula -NR ^2- [wherein R ² is a hydrogen atom, optionally substituted C _{1- 6} alkyl group, C _3-8 cycloalkyl group, lower acyl group, or C _1-6 alkylsulfonyl group.

[R ^One Significance of

In the formula (I), the group represented by R ¹

(1) a hydrogen atom,

(2) a halogen atom,

(3) hydroxyl,

(4) a C _1-6 alkyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(5) a C _2-6 alkenyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(6) a C _2-6 alkynyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(7) a C _3-8 cycloalkyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom and nitrile group,

(9) a C _1-6 alkoxy-C _1-6 alkyl group,

(10) an amino-C _1-6 alkyl group in which the nitrogen atom may be substituted;

(11) a group represented by the formula -N (R ¹¹ ) R ¹² (wherein R ¹¹ and R ¹² are the same or different and represent a hydrogen atom or a C _1-6 alkyl group),

(12) an aralkyl group,

(13) morpholinyl group,

(14) thiomorpholinyl group,

(15) piperidyl,

(16) pyrrolidinyl groups or

(17) piperazinyl groups

Indicates.

Preferred atoms in the "halogen atom" include fluorine atom, chlorine atom and bromine atom, and more preferably fluorine atom and chlorine atom.

Preferable groups in the "C _1-6 alkyl group" in R ¹ include a methyl group, an ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group and tert-butyl group And the like, and more preferably methyl group, ethyl group, n-propyl group, iso-propyl group, more preferably n-propyl group and iso-propyl group, and most preferably iso-propyl group.

Preferable groups in the "C _2-6 alkenyl group" in R ¹ include a vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1 -Buten-3-yl group, 2-buten-1-yl group, 2-buten-2-yl group, etc. are mentioned, More preferably, they are a vinyl group, an allyl group, an isopropenyl group, etc.

Preferable groups in the "C _2-6 alkynyl group" in R ¹ include an ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group, hexynyl group and the like.

Preferable groups in the "C _3-8 cycloalkyl group" for R ¹ include a cyclopropanyl group, a cyclobutanyl group, a cyclopentanyl group, a cyclohexanyl group, and the like.

The "C _1-6 alkoxy-C _1-6 alkyl group" in R ¹ represents a C _1-6 alkyl group substituted with a group synonymous with a C _1-6 alkoxy group in the above definition, and preferred groups thereof are a methoxymethyl group, Ethoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 1-ethoxyethyl group, 2-methoxy-n-propyl group, 3-methoxy-n-propyl group, 2- (n-propoxy) Ethyl group etc. are mentioned.

Preferred groups in the "C _1-6 alkyl group substituted with a nitrile group" in R ¹ include a cyanomethyl group, 2-cyanoethyl group, 3-cyano-n-propyl group, and 2-cyano-iso-propyl group. , 2-cyano-n-butyl group, 2-cyano-sec-butyl group, 2-cyano-tert-butyl group, 2-cyano-n-pentyl group, 3-cyano-n-hexyl group Etc. can be mentioned.

Preferable groups in the "amino-C _1-6 alkyl group in which the nitrogen atom may be substituted" in R ¹ include aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, ethylaminomethyl group, diethylaminomethyl group, methylethylaminomethyl group And acetamide methyl group, pyrrolidinylmethyl group, 2-pyrazolinylethyl group, 1-piperidylethyl group, piperazinylmethyl group and the like.

Preferable groups in the "aralkyl group" in R ¹ include benzyl group, phenethyl group, phenylpropyl group, naphthylmethyl group, naphthylethyl group, naphthylpropyl group and the like.

But the significance of each group is shown in the above definition of R ^1, the preferred embodiment of the R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl group, C _3-8 cycloalkyl group, a hydroxy C _1-6 alkyl, C _1-6 alkoxy -C _1-6 alkyl, cyano, -C _1-6 alkyl, can be mentioned a halogen atom-substituted C _1-6 alkyl group More preferably, it is a halogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, More preferably, it is a C _1-6 alkyl group (especially a methyl group, an ethyl group, n-propyl). Group, iso-propyl group).

[D ^One , D ² , W ^One  And W ² Significance of

In the compound represented by the formula (I) according to the present invention, D ¹ , D ² , W ¹ and W ² are the same or different and may be (1) single bond or (2) substituted C _{1- 6} alkylene chain.

Preferred embodiments in the "C _1-6 alkylene chain" in the "C _1-6 alkylene chain which may be substituted" include methylene chain, ethylene chain, ethylidene chain, trimethylene chain-isopropylidene chain, Propylene chain, tetramethylene chain, 1,2-butylene chain, 1,3-butylene chain, 2,3-butylene chain-isobutylene chain, etc. are mentioned.

In addition, in these C _1-6 alkylene chains, the chains of right and left asymmetric are included, but in this case, the bonding direction is not limited, and any bonding direction is included in the "C _1-6 alkylene chain".

Preferred embodiments of the "substituent" in the "substituted C _1-6 alkylene chain" include (i) hydroxyl groups, (ii) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine) (Iii) nitrile group, (iv) C _1-6 alkyl group (methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, tert-butyl group, etc.), (v) C _2-6 Alkenyl group (for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1- propenyl group, 3-methyl-1- propenyl group, 2-methyl-2- (Vi) C _1-6 alkoxy groups (for example, methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, n-butoxy group, tert-butoxy group, etc.), such as a propenyl group, etc. are mentioned. have.

When the "substituent" is a C _1-6 alkyl group and / or a C _2-6 alkenyl group, these substituents may be bonded to each other to form a 5 to 14 membered ring, and in the case of W ¹ and W ² , those substituents It may combine with the ring B or X to form a 5-14 membered ring.

Preferred embodiments in D ¹ , D ² , W ¹ and W ² are the same or different and each may be substituted with one or more groups selected from (1) a single bond or (2) a hydroxyl group, a halogen atom and a nitrile group, respectively. Methylene chain, ethylene chain, ethylidene chain, trimethylene chain, isopropylidene chain, propylene chain, tetramethylene chain, 1,2-butylene chain, 1,3-butylene chain, 2,3-butylene chain, iso Butylene chain etc. are mentioned.

The above is significance of each of E, X, D ¹ , D ² , W ^1, and W ² . Here, the partial structure: -D ¹ -ED ² - In a preferred aspect of the in, the ethylene chain (-CH ₂ -CH ₂ -), ethyl Li denswae _{(-CH (CH 3) -)} , trimethylene chain (- ( CH ₂ ) _3- ), isopropylidene chain (-C (CH ₃ ) _2- ), propylene chain (-CH (CH ₃ ) CH _2- ), tetramethylene chain (-(CH ₂ ) _4- ), 1 , 2-butylene chain (-CH (C ₂ H ₅ ) CH _2- ), 1,3-butylene chain (-CH (CH ₃ ) CH ₂ CH _2- ), 2,3-butylene chain (-CH (CH ₃ ) CH (CH ₃ )-), isobutylene chain (-CH (CH ₃ ) ₂ CH _2- ), and the like, more preferably trimethylene chain (-(CH ₂ ) _3- ), isopropyl Leeden chain (-C (CH ₃ ) _2- ), propylene chain (-CH (CH ₃ ) CH _2- ), tetramethylene chain (-(CH ₂ ) _4- ), 1,2-butylene chain (-CH ( C ₂ H ₅ ) CH _2- ), and more preferably trimethylene chain (-(CH ₂ ) _3- ). The part structure -W ¹ -XW ² - a preferred embodiment of the is a single bond, a formula _{-CH 2 -CH 2 -O-, -CH 2} -CH 2 -NR 2 -, - (CH 2) 3 And a chain represented by -O- or-(CH ₂ ) ₃ -NR ^2- .

Aspect of which is denoted by the formula (I) according to the present invention compound is not particularly limited, if the skilled in the art, Ar, ring A, ring B, E, X, R ^1, D ^1, D ^2, W ¹ and W ² All compounds within that range can be implemented by freely combining the groups set forth in the definitions above for each. G. The preferred embodiment than in that, a 5 to 14-membered aromatic heterocyclic group which may be Ar is substituted, the ring A piperacillin jinhwan, piperidin to dinhwan or pyrrolidine dinhwan, C ₆ which may be the ring B is substituted with _-14 aromatic hydrocarbon ring or 5- to 14-membered aromatic heterocycle, wherein E is a single bond, and X is a single bond, an oxygen atom, a C _1-6 alkylene chain which may be substituted, or a formula -NR ^2- (where , R ² represents synonyms with the above definitions. In a preferred embodiment, the formula

or

The compound or its salt, or its hydrate represented by [each symbol in a formula represents the meaning of the said definition and a synonym respectively] is mentioned.

Preferred embodiments of the compound according to the present invention naturally include the example compounds shown later, and the following compounds are typical.

4-[(4-cyano-5-methyl-4-phenyl) hexyl] -N- (4-fluorophenyl) -N '-(2-methylpropyl) -1 (2H) -pyrazinecarboxyimidamid ;

1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino] -1-phenylbutyl cyanide;

1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [3- (5-cyano-2-thienyl) propyl] piperazine;

1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1- {4-cyano-5-methyl-4- [4- (2-cyano) -thienyl] hexyl} -4- [2- (3-cyanophenoxy) ethyl] piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-benzoxazolyl) amino] piperidine;

1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl) -N-benzylamino] Pyrrolidine;

1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2-cyanoethyl) -N-benzylamino] Pyrrolidine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (benzothiazolyl) piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (6-methoxy) benzothiazolyl] piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-benzoxazolyl) piperazine;

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-quinolinyl) piperazine;

4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepan-1-yl] -1-isopropyl-1-phenylbutyl cyanide;

4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepan-1-yl] -1-isopropyl-1-phenylbutyl cyanide;

Ethyl 4- (4-cyano-5-methyl-4-phenylhexyl) -1- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate;

1-[(2-oxo-1,2-dihydro-3-quinolyl) methyl] -4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidine;

4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (methanesulfonylamino) phenyl] methyl} piperazine;

4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (methanesulfonylamino) phenyl] methyl} piperidine;

(S) -3-phenyl-2-amino-propanoic acid {1- [4-cyano-5-methyl-5- (2-thionyl) hexyl] piperazinyl} amide;

4- [4- (4-phenylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide;

4- [4- (4-cyano-4-phenylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide;

4- [4- (4-benzylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide.

The compound represented by the formula (I) according to the present invention, or a salt thereof or a hydrate thereof can be produced by a known production method or a method similar thereto. As the known production method, for example, the production method described in Japanese Patent Application Laid-Open No. 2000-169462 (the production method described in paragraphs "0054" to "0065" in the above publication), or Japanese Patent Application No. 2000-12207 And the manufacturing methods described in Japanese Patent Application No. 2000-12208 and Japanese Patent Application No. 2000-12209.

In addition, the raw material compound in manufacture of compound (I) may form a salt and a hydrate, and if it does not inhibit a reaction, it will not specifically limit. Moreover, when the compound (I) which concerns on this invention is obtained as a free body, it can convert into the state of the salt which the said compound (I) may form according to a conventional method. In addition, when the compound which concerns on this invention is manufactured as a free body, it can convert into the state of a salt by a conventional method. In addition, various isomers (e.g., geometric isomers, optical isomers based on sub-carbons, stereoisomers, tautomers, etc.) obtained for the compound (I) according to the present invention may be ordinary separation means (for example, recrystallization). , Diasteromer salt method, enzymatic fractionation method, and various chromatography) can be purified and isolated.

The term "salt" in the present specification is not particularly limited as long as it forms a salt with the compound according to the present invention and is also pharmacologically acceptable, but is preferably a hydrochloride salt (for example, hydrofluoride, hydrochloride, hydrogen bromide). Acid salts, iodide hydrochloride, etc.), inorganic salts (e.g. sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.) organic carboxylates (e.g. acetate, trifluoroacetate, oxalate, maleate, tartarate) , Fumarates, citrates, etc., organic sulfonates (e.g. methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (e.g. Aspartic acid salts, glutamate salts, etc.), quaternary amine salts, alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (magnesium salt, calcium salt, etc.), etc. are mentioned. More preferably hydrochloride, oxalate, trifluoroacetate, and the like.

The compound represented by the formula (I) or a salt thereof or a hydrate thereof according to the present invention can be formulated by a conventional method, and preferred formulations are tablets, powders, granules, granules, coated tablets and capsules. , Syrups, torokis, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, popsing agents, lotions. For formulation, excipients, binders, disintegrants, lubricants, colorants, copulation agents, or stabilizers, emulsifiers, absorption accelerators, surfactants, pH adjusters, preservatives, antioxidants, and the like, which are commonly used, can be used. In addition, the component used as a raw material of a pharmaceutical formulation can be mix | blended and can be formulated by a conventional method. As these components, For example, animal and vegetable oils, such as soybean oil, tallow, synthetic glycerides; Hydrocarbons such as liquid paraffin, squalane and solid paraffin; Ester oils such as myristic acid octyldodecyl and myristic acid isopropyl; Higher alcohols such as cetostearyl alcohol and behenyl alcohol; Silicone resins; Silicone oil; Surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene polyoxypropylene block copolymer; Water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methyl cellulose; Lower alcohols such as ethanol and isopropanol; Polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; Sugars such as glucose and sucrose; Inorganic powders such as silicic anhydride, magnesium aluminum silicate, aluminum silicate, purified water and the like. Specifically, excipients include, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like; As a binder, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragant, gelatin, cellar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, poly Propylene glycol polyoxyethylene block polymer, meglumine, calcium citrate, dextrin, pectin and the like; Examples of disintegrating agents include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose and calcium; As a lubricant, For example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, etc .; As a coloring agent, what kind of thing may be used as long as it is permitted to add to a pharmaceutical product; Examples of copulation agents include cocoa powder, peppermint brain, aromatic acid, peppermint oil, green onion, cinnamon powder, and the like; As antioxidant, what is permitted to add to pharmaceuticals, such as ascorbic acid and (alpha) -tocopherol, is used, respectively.

For example, (1) oral preparations are prepared by conventional methods after adding the compounds or salts thereof, or their hydrates and excipients according to the invention, and, if necessary, binders, disintegrants, lubricants, colorants, colloids and the like. Powders, granules, granules, tablets, coated tablets, capsules and the like. (2) In the case of tablets and granules, of course, the coating of sugars, gelatin, and other necessities may be appropriate. (3) In the case of syrups, injectable preparations, eye drops, and the like, a pH adjusting agent, a dissolving agent, an isotonic agent, and the like, and a dissolution aid, stabilizer, buffer, suspending agent, antioxidant, and the like are added as necessary and formulated by a conventional method. do. In the case of the said formulation, it can also be made into a lyophilized thing, and injection can be administered intravenously, subcutaneously, and intramuscularly. Preferred examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragant powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like; Preferred examples of the dissolution aid include polyoxyethylene cured castor oil, polysorbate 80, niacinamide, polyoxyethylene sorbitan monolaurate and the like; Preferred examples of the stabilizer include sodium sulfite, sodium metasulfite, ether and the like; Preferred examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like. (4) Moreover, in the case of an external preparation, a manufacturing method is not specifically limited, It can manufacture by a normal method. As the base material to be used, various raw materials commonly used in medicines, quasi-drugs and cosmetics can be used. For example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, and surfactants Raw materials such as phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, and purified water, and if necessary, pH adjusters, antioxidants, chelating agents, preservatives, coloring agents, flavoring agents, and the like can be added. have. If necessary, a component having a differentiation-inducing action, a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell-activating agent, a vitamin, an amino acid, a humectant, a keratin soluble agent, or the like may be blended. The dosage of the medicament according to the present invention varies depending on the severity of symptoms, age, sex, weight, type of dosage form, salt, difference in sensitivity to drugs, and specific types of diseases. About 30 μg to 1000 mg, preferably 100 μg to 500 mg, more preferably 100 μg to 100 mg, and about 1 to 3000 μg / kg, preferably 3 to 1000 μg / kg each by injection or Administer in several portions.

The compound represented by the formula (I) according to the present invention, or a salt thereof or a hydrate thereof is useful as a calcium antagonist, particularly a neuroselective calcium antagonist. The compound according to the present invention has a P / Q type calcium channel inhibitory activity and an N type calcium channel inhibitory activity, and is useful as a treatment / improvement agent for diseases in which P / Q type calcium channel inhibitory activity or N type calcium channel inhibitory activity is effective. . Moreover, the compound represented by said Formula (I) which concerns on this invention, or its salt or its hydrate is a safe calcium antagonist with the remarkably low grade of cellular disorder, and the toxicity reduced compared with the conventional calcium antagonist. Therefore, the compound according to the present invention or a salt thereof or a hydrate thereof is useful as an inhibitor of neuronal cell death, an agent for protecting neuronal cells, a treatment / improvement agent for neurological diseases, and an analgesic agent, and in particular, a cerebrovascular disorder, a stroke, an infarction, Head trauma, Cranial nerve cell death, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Circulatory metabolic disorders, Brain dysfunction, Pain, Convulsions, Schizophrenia, Migraine, Epilepsy, Manic depression, Neurodegenerative diseases, Cerebral ischemia, AIDS dementia It is useful as a treatment / prevention / improvement agent for complications, edema, anxiety disorder, diabetic neuropathy, cerebrovascular dementia, multiple sclerosis, and the like.

As the best embodiment in the compound according to the present invention, examples are given below, but these reference examples, examples (also pharmacologically acceptable salts thereof, hydrates thereof or medicines comprising them) and test examples Exemplary, the compounds according to the invention in any case is not limited to the specific examples below. Those skilled in the art can make the present invention to the maximum by adding various changes to the claims according to the present specification as well as the examples shown below, and such changes are included in the claims according to the present specification.

In addition, the symbol "Z" used in the following reference examples or Examples shows the benzyloxycarbonyl group, the "Bn" the benzyl group, and "HPLC" shows the high performance liquid chromatography.

Reference Example 1; 2-[(4-cyano-5-methyl-4-phenyl) hexyl] -5-benzyl-2,5-diazabicyclo [2,2,1] heptane

According to the method described in Example 15, a pale yellow oily title compound was obtained (15%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.04-1.16 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.45-1.57 (m, 1H), 1.64 (dd, J = 9.6 Hz, J = 33.6 Hz, 2H), 1.94 (dt, J = 4.4 Hz, J = 12.4 Hz, 1H), 2.07-2.23 (m, 2H), 2.30-2.38 ( m, 1H), 2.50-2.71 (m, 5H), 3.19 (d, J = 14 Hz, 2H), 3.66 (q, J = 14 Hz, 2H), 7.19-7.40 (m, 10H).

Reference Example 2; 3-methyl-2- (2-naphthyl) butyronitrile

3.00 g (17.9 mmol) of 2-naphthyl acetonitrile was dissolved in 10 ml of dimethyl sulfoxide, 2.43 g (19.7 mmol) of 2-bromopropane, 330 mg (0.90 mmol, cat) of tetran-butylammonium iodide, 50 10 ml of% potassium hydroxide was added sequentially. After the reaction was completed, saturated brine was added and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with 150 g of silica gel (ethyl acetate: hexane = 1: 10) to obtain 2.42 g (11.6 mmol, 64.6%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.07 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 2.10-2.30 (m, 1H), 3.84 (d, J = 3.84 Hz, 1H), 7.38 (dd, J = 1.8 Hz, 8.6 Hz, 1H), 7.48-7.55 (m, 2H), 7.79-7.88 (m, 4H)

Reference Example 3; 4-cyano-5-methyl-4- (2-naphthyl) hexanol

1.00 g (4.78 mmol) of 3-methyl-2- (2-naphthyl) butyronitrile was dissolved in 20 ml of dimethylformamide, 191 mg (4.78 mmol, 60% wt) of sodium hydride was added and heated. After 30 minutes, the mixture was returned to room temperature, and 0.93 ml (4.00 mmol) of (3-bromopropoxy) -tert-butyldimethylsilane was added thereto. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 50 g of silica gel (ethyl acetate: hexane = 1:18) to obtain 1.40 g of a mixture of the target product, raw material, and impurities. This mixture was used for the next reaction without purification. That is, 1.40 g of the crude product 4-cyano-5-methyl-5- (2-naphthyl) hexaoxy-tert-butyldimethylsilane was dissolved in 20 ml of tetrahydrofuran and 5 ml (5 mmol) of tetraammonium fluorine was dissolved. Added. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with 50 g of silica gel (ethyl acetate: hexane = 1: 4) to give 590 mg (2.21 mmol, 46.2%, 2 steps) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.80 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 1.57-1.69 (m, 1H), 2.02-2.12 (m, 1H), 2.20-2.37 (m, 2H), 3.58 (t, J = 6.2 Hz, 2H), 7.38 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.48- 7.56 (m, 2H), 7.84-7.91 (m, 3H), 7.95 (brd-s, 1H)

Reference Example 4; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3-t-butoxycarbonylaminopyrrolidine

2.76 g (8.44 mmol) of 4-cyano-5-methyl-5-phenylhexyl iodide was dissolved in 50.0 ml of acetonitrile, 1.29 ml (9.28 mmol) of triethylamine and 3-tert-butoxycarbonylamino Pyrrolidine 1.88 g (10.1 mmol) was added and it heated to 60 degreeC. After the reaction was completed, the mixture was partitioned between ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. The crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate: hexane = 2: 1) to give 2.97 g (7.76 mmol, 91.3%) of the title compound as a pale yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.05-1.25 (m, 1H), 1.43 (s, 9H) , 1.50-1.65 (m, 2H), 1.88-2.00 (m, 1H), 2.00- 2.28 (m, 4H), 2.28-2.60 (m, 4H), 2.65-2.70 (m, 1H), 4.05-4.20 ( brd-s, 1H), 4.82-4.95 (brd-s, 1H), 7.26-7.59 (m, 5H)

Reference Example 5; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3-aminopyrrolidine

2.36 g (6.12 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3-tert-butoxycarbonylaminopyrrolidine was dissolved in a mixed solution of 5 ml of tetrahydrofuran and 10 ml of methanol. 4N hydrogen chloride-ethyl acetate solution was added. After completion of the reaction, the mixture was adjusted to alkaline with 2N sodium hydroxide solution, and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 1.66 g (5.82 mmol, 95.1%, orange syrup) of the crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.4, 3H), 1.20 (d, J = 6.8, 3H), 1.08-1.24 (m, 1H), 1.42-1.62 (m, 2H) , 1.84-2.00 (m, 3H), 2.08-2.28 (m, 4H), 2.32-2.48 (m, 3H), 2.58-2.67 (m, 2H), 3.42-3.51 (m, 1H), 7.26-7.40 ( m, 5H)

Reference Example 6; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) amino] pyrrolidine

700 mg (2.45 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3-aminopyrrolidine was dissolved in 15 ml of methanol, 0.19 mmol (2.85 mmol) of acrylonitrile was added, Heated under reflux. After completion of the reaction, the mixture was concentrated under reduced pressure to give a crude product. The crude product was treated with 20 g of Cromatorex NH silica gel (100% ethyl acetate) to give 775 mg (2.29 mmol, 93.5%) of the title compound as an orange syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.07-1.24 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.08-1.24 (m, 1H), 1.46-1.62 (m, 2H), 1.86-1.96 (m, 1H), 2.04-2.24 (m, 4H), 2.28-2.46 (m, 4H), 2.46-2.62 (m, 2H), 2.49 ( t, J = 6.8 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 3.22-3.30 (m, 1H), 7.26-7.40 (m, 5H)

Reference Example 7; 3-fluorophenoxyacetaldehyde

2.00 g (17.8 mmol) of m-fluorophenol was dissolved in 50 ml of dimethylformamide, followed by 785 mg (19.6 mmol, 60% wt, mineral) of sodium hydride, and 3.21 ml (21.3 mmol) of bromoacetaldehyde diethylacetal. After addition, it heated at 60 degreeC. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 105 g of Cromatorex NH silica gel (ethyl acetate: hexane = 1:40) to give 3.17 g (13.9 mmol, 78.1%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.25 (t, J = 7.0 Hz, 6H), 3.55-3.82 (m, 4H), 3.99 (d, J = 5.0 Hz, 2H), 4.82 (t, J = 5.0 Hz, 1H), 6.61-6.72 (m, 3H), 7.17-7.25 (m, 1H)

1.68 g (7.38 mmol) of the acetal was dissolved in 30 ml of acetone and 20 ml of 2.5N hydrochloric acid and heated. After completion of the reaction, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 800 mg of a crude product containing the following target compound. This crude product was used in the reaction described above without purification.

Reference Example 8; 1-benzyl-3- [N- (2-cyanoethyl) amino] pyrrolidine

4.00 g (22.7 mmol) of 1-benzyl-3-aminopyrrolidine was dissolved in 70 ml of methanol, 1.49 ml (22.7 mmol) of acrylonitrile were added and heated to 70 ° C. After the completion of the reaction, the crude product obtained by concentrating the reaction solution under reduced pressure was treated with 100 g of Cromatorex NH silica gel (100% ethyl acetate) to obtain 4.60 mg (20.1 mmol, 88.4%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.54-1.66 (m, 1H), 2.10-2.22 (m, 1H), 2.40-2.60 (m, 2H), 2.49 (t, J = 6.8 Hz, 2H), 2.67-2.78 (m, 2H), 2.86 (t, J = 6.8 Hz, 2H), 3.30-3.38 (m, 1H), 3.57-3.73 (m, 2H), 7.22-7.36 (m, 5H)

Reference Example 9; 1-benzyl-3- [N- (2-cyanoethyl) -N- {2- (4-cyanophenoxy) ethyl} amino] pyrrolidine

Dissolve 2.03 g (8.87 mmol) of 1-benzyl-3- [N- (2-cyanoethyl) amino] pyrrolidine in 50 ml of dichloroethane and separately synthesize 1.30 g (8.06 mmol) of 4-cyanophenoxyacetaldehyde. ), 1.02 ml (17.7 mmol) of acetic acid and 2.56 g (12.1 mmol) of sodium triacetoxyborohydride were added in this order. After completion of the reaction, the mixture was adjusted to alkaline using 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 250 g of Cromatorex NH silica gel (ethyl acetate: hexane = 2: 3) to give 2.39 g (6.38 mmol, 79.2%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.70-1.84 (m, 1H), 2.03-2.14 (m, 1H), 2.40-2.54 (m, 1H), 2.47 (t, J = 6.8 Hz, 2H), 2.55-2.68 (m, 2H), 2.76-2.88 (m, 1H), 2.91-3.09 (m, 4H), 3.48-3.68 (m, 2H), 3.64-3.74 (m, 1H), 4.03 (t, J = 5.6 Hz, 2H), 6.9 (t, J = 9.2 Hz, 2H), 7.24-7.40 (m, 5H), 7.57 (t, J = 9.2 Hz, 2H)

Reference Example 10; 3- [N- (2-cyanoethyl) -N- {2- (4-cyanophenoxy) ethyl} amino] pyrrolidine

1-benzyl-3- [N- (2-cyanoethyl) -N- {2- (4-cyanophenoxy) ethyl} amino] pyrrolidine was dissolved in dichloroethane and ACECl (0.84 ml, 7.66 mmol) was added and heated to reflux. After about 1 hour, ACECl (0.12 ml) was also added and heating continued. After the reaction was completed, the mixture was concentrated under reduced pressure, and 30 ml of methanol was added thereto, followed by heating to reflux. After 1 hour, the reaction solution was concentrated under reduced pressure. Extracted with 2N hydrochloric acid, washed with ether, adjusted to pH 11-12 with 5N sodium hydroxide, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate: methanol = 1: 0 to 3: 1) to obtain 1.12 g (3.93 mmol, 61.6%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.64-1.76 (m, 1H), 1.94-2.06 (m, 1H), 2.52 (t, J = 6.8 Hz, 2H), 2.56-2.70 (m, 2H), 2.77-2.86 (m, 1H), 2.91-3.20 (m, 5H), 3.36-3.51 (m, 1H), 4.08 (t, J = 5.6 Hz, 2H), 6.96 (t, J = 9.2 Hz, 2H) , 7.60 (t, J = 9.2 Hz, 2H)

Reference Example 11; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(methoxycarbonyl) methyl] piperazin

1.00 g (3.50 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine and 0.54 ml (3.85 mmol) of triethylamine were dissolved in 25 ml of tetrahydrofuran and bromo-cooled under ice-cooling. 0.35 ml (3.85 mmol) of methyl acetate were dripped. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate: hexane = 1: 2) to give 1.22 g (3.41 mmol, 97.5%) of the title compound as an orange oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.20 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.48-1.64 (m, 1H), 1.84-1.93 (m, 1H), 2.06-2.18 (m, 2H), 2.24-2.31 (m, 2H), 2.31-2.46 (m, 4H), 2.46-2.60 (m, 4H), 3.19 ( s, 2H), 3.71 (s, 3H), 7.24-7.39 (m, 5H)

Reference Example 12; 3-fluorobenzamide oxime

To a 200 ml solution of 10.0 g (82.6 mmol) of 3-fluorobenzcyanide, 8.61 g (124 mmol) of hydroxyamine hydrochloride and 22.8 g (165 mmol) of potassium carbonate were added and heated to reflux. After completion of the reaction, the mixture was concentrated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 100 g of silica gel (ethyl acetate: hexane = 1: 2-1: 4) to obtain 8.00 g (51.9 mmol, 62.8%) of the title compound as a yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.75-4.85 (m, 2H), 7.09-7.59 (m, 4H)

Reference Example 13; N-Z-4-piperidineethanol

4.70 g (36.4 mmol) of 4-piperidineethanol and 10.0 g (72.8 mmol) of potassium carbonate are dissolved in ether (50 ml) and water (50 ml), and ZCl (4.44 ml, 25.0 mmol) is dissolved in 30 ml of ether under ice cooling. Dropped by The physical properties of the title compound obtained are shown below. After completion of the reaction, saturated brine was added and the mixture was extracted with ether. The organic layer was washed with saturated brine and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 100 g of silica gel (ethyl acetate: hexane = 1: 2) to obtain 5.48 g (20.8 mmol, 57.2%) of the title compound as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.05-1.25 (m, 2H), 1.40-1.75 (m, 5H), 2.70-2.85 (m, 2H), 3.71 (t, J = 6.59 Hz, 2H), 4.10-4.25 (m, 2H), 5.12 (s, 2H), 7.28-7.39 (m, 5H)

Reference Example 14; 1-benzyloxycarbonyl-4- [2- (4-fluorophenoxy) ethyl] piperidine

2.00 g (7.60 mmol) of N-Z-4-piperidine ethanol, 1.70 g (15.2 mmol) of 4-fluorophenol, and 2.39 g (9.12 mmol) of triphenylphosphine were dissolved in 50 ml of tetrahydrofuran and ice-cooled. After 10 minutes, 1.44 ml (9.12 mmol) of diethyl azodicarboxylate was added dropwise, followed by stirring at room temperature. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with 100 g of silica gel (ethyl acetate: hexane = 1: 3) to obtain 2.19 g (6.12 mmol, 80.6%) of the title compound as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.10-1.30 (m, 2H), 1.65-1.80 (m, 5H), 2.70-2.90 (m, 2H), 3.96 (t, J = 6.0 HZ, 2H), 4.10-4.28 (m, 2H), 5.13 (s, 2H), 6.79-6.84 (m, 2H), 6.93-6.99 (m, 2H), 7.28-7.38 (m, 5H)

Reference Example 15; 4- [2- (4-fluorophenoxy) ethyl] piperidine

2.19 g (6.12 mmol) of 1-benzyloxycarbonyl-4- [2- (4-fluorophenoxy) ethyl] piperidine was dissolved in 40 ml of methanol, 300 mg of 10% palladium-carbon was added, and hydrogen substituted. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate: hexane = 1: 3 to ethyl acetate: methanol = 6: 1) to give 1.30 g (5.82 mmol, 95.1%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.10-1.23 (m, 2H), 1.60-1.77 (m, 5H), 2.59 (dt, J = 2.4 Hz, 12.2 Hz, 2H), 3.96 (t, J = 6.0HZ, 2H), 4.10-4.28 (m, 2H), 5.13 (s, 2H), 6.79-6.85 (m, 2H), 6.92-6.99 (m, 2H)

Reference Example 16; 1-benzyl-4-hydroxypropyl-1,2,5,6-tetrahydropyridine

5.00 g (36.4 mmol) of 3-pyridinepropanol was dissolved in 150 ml of acetonitrile, 4.55 ml (38.3 mmol) of benzyl bromide was added, and after 2 hours of heating to 70 DEG C, the heating was stopped, concentrated under reduced pressure, and then methanol It dissolved in 100 ml and cooled to 0 degreeC. To this was added 4.12 g (109 mmol) of sodium borohydride. After the reaction was completed, 50 ml of water was added, concentrated under reduced pressure, and then partitioned between ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. The crude product was treated with 150 g of Cromatorex NH silica gel (ethyl acetate: hexane = 1: 6 to 1: 1) to give 6.48 g (28.0 mmol, 77.0%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.65-1.74 (m, 2H), 2.02-2.13 (m, 4H), 2.55 (t, J = 6.0 Hz, 2H), 2.93-2.98 (m, 2H), 3.57 (s, 2H), 3.64 (t, J = 6.4Hz, 2H), 5.38-5.42 (m, 1H), 7.22-7.37 (m, 5H)

Reference Example 17; 1-benzyl-4-hydroxypropylpiperidine

6.48 g of 1-benzyl-4-hydroxypropyl-1,2,5,6-tetrahydropyridine was dissolved in 60 ml of methanol, 88 mg of PtO ₂ was added, and then hydrogen-substituted. After the reaction was completed, filtered and concentrated under reduced pressure to give 4.50 g (19.3 mmol, 68.9%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.16-1.33 (m, 5H), 1.33-1.41 (brd-s, 1H), 1.53-1.74 (m, 4H), 1.87-1.98 (m, 2H), 2.83 -2.90 (m, 2H), 3.48 (s, 2H), 3.62 (t, J = 6.4 Hz, 2H), 7.16-7.27 (m, 5H)

Reference Example 18; 1-benzyl-4-methanesulfonyloxypropylpiperidine

2.58 g (11.1 mmol) of 1-benzyl-4-hydroxypropylpiperidine and 3.26 ml (23.4 mmol) of triethylamine were dissolved in 50 ml of tetrahydrofuran, and 1.67 ml (21.6 mmol) of methanesulfonyl chloride were added dropwise thereto. . After completion of the reaction, the mixture was partitioned into ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. The crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate: hexane = 1: 1) to give 2.90 g (9.31 mmol, 83.9%) of the title compound as a yellow oil. Physical and chemical data of the title compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.18-1.37 (m, 5H), 1.58-1.68 (m, 2H), 1.71-1.80 (m, 2H), 1.88-1.97 (m, 2H), 2.84-2.90 (m, 2H), 3.00 (s, 3H), 3.48 (s, 2H), 4.21 (t, J = 6.8 Hz, 2H), 7.13-7.32 (m, 5H)

Reference Example 19; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidine

2.43 g (6.49 mmol) of 1-benzyl-4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidine was dissolved in 30 ml of 1,2-dichloroethane and 0.85 ml of ACE-Cl ( 7.79 mmol) was added and heated to reflux. After 45 minutes, concentrated under reduced pressure, 30 ml of methanol was added and heated to reflux again. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with water, and washed with ether. This aqueous layer was adjusted to alkaline, and then partitioned into ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to yield 1.62 g (5.69 mmol, 87.7%) of a yellow crude product. Physical and chemical data of the title compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 0.86-1.04 (m, 3H), 1.07-1.28 (m, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.29-1.44 (m, 1H), 1.48-1.58 (m, 2H), 1.74-1.85 (m, 1H), 2.04-2.14 (m, 2H), 2.49 (dt, J = 2.4 Hz, 12.0 Hz , 2H), 2.95-3.02 (m, 2H), 7.26-7.40 (m, 5H)

Reference Example 20; 3-cyano-3- (2-thienyl) propanol

In a nitrogen atmosphere, in a DMF solution (25 mL) in which thiophene-2-acetonitrile (1 g) and (3-bromopropoxy) -tert-butyldimethylsilane (2.06 g) were dissolved, sodium hydrogen was dissolved under hydrogen by an ice bath. 650 mg) was added. After 20 minutes, saturated aqueous ammonium chloride solution and ethyl acetate were added, and the organic layer was distributed. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered and concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (20 mL), 1M tetrabutylammonium fluoride / tetrahydrofuran solution (9.7 mL) was added, and the mixture was stirred at room temperature. After 18 hours, water and ethyl acetate were added, the organic layer was distributed, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid). Ethyl) to give the title compound (637 mg, 43%) as a red oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.08-2.16 (m, 1H), 3.08 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.0 Hz, 2H), 4.15-4.20 (m, 1H), 7.14 (dd, J = 3.8 Hz, 4.8 Hz, 1H), 7.65 (dd, J = 0.8 Hz, 4.8 Hz, 1H), 7.75 (dd, J = 0.8 Hz, 3.8 Hz, 1H).

Reference Example 21; 2-[(3-cyano-3-phenyl) propyl] -1,3-dioxolane

Sodium amide (1.11 g) was added to a tetrahydrofuran solution (25 mL) in which phenyl acetonitrile (3 g) was dissolved in a nitrogen atmosphere. After 30 minutes, a tetrahydrofuran solution (25 mL) in which 2- (2-bromoethyl) -1,3-dioxolane (4.64 g) was dissolved was added to the reaction solution with a dropping funnel. After stirring for 2 hours, saturated aqueous ammonium chloride solution and ethyl acetate were added, and the organic layer was distributed. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate system) to obtain the title compound (3.47 g, 62%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.75-1.90 (m, 2H), 1.95-2.10 (m, 2H), 3.80-4.00 (m, 5H), 4.91 (t, J = 4.4 Hz, 1H), 7.30-7.42 (m, 5H).

Reference Example 22; 4-Methyl-3-phenylpentanoic acid ethyl ester

Ethyl trimethylsilyl acetate (5.19 g) was added to tetrahydrofuran solution (100 mL) to which lithium diisopropylamide-tetrahydrofuran solution (1.5M, 21.6 mL) was added at nitrogen atmosphere. After 20 minutes, tetrahydrofuran solution (10 mL) in which isobutyrophenone (4.0 g) was dissolved was added, and the mixture was returned to room temperature naturally as it was. After stirring for 18 hours, sodium sulfite monohydrate (0.6 g) was added thereto, followed by stirring. After 10 minutes, 0.2N hydrogen chloride solution (250 mL) and ethyl acetate (200 mL) were added, and the organic layer was partitioned. The organic layer obtained was water and saturated brine. The mixture was washed with water, dried over anhydrous magnesium sulfate, and the drying agent was filtered off and concentrated under reduced pressure. In the obtained crude product (7.9 g), 756 mg was dissolved in methanol (5 mL), 10% palladium carbon (9.5 mg) was added in a catalytic amount, and the mixture was stirred under a hydrogen atmosphere. After 4 hours, the catalyst was filtered off and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate system) to obtain a title compound (350 mg) as colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.75 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H), 1.80-1.90 (m, 1H), 2.58 (dd, J = 10 Hz, 15.2 Hz, 1H), 2.77 (dd, J = 5.6 Hz, 15.2 Hz, 1H), 2.84-2.91 (m, 1H), 7.12-7.29 (m, 5H).

Reference Example 23; 4-methyl-3-phenylpentanol

Under nitrogen atmosphere, 4-methyl-3-phenylpentanoic acid ethyl ester (350 mg) was dissolved in tetrahydrofuran (10 mL), and a lithium aluminum hydride tetrahydrofuran solution (1.0 M, 1.58 mL) was added thereto. Stirred. After stirring, the mixture was returned to room temperature naturally, and after 1.5 hours, water (0.05 mL), 2N aqueous sodium hydroxide solution (0.05 mL) and water (0.15 mL) were added sequentially, followed by stirring and diethyl ether. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate system) to obtain a title compound of colorless oily (257 mg, 42%; 2 steps).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.73 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H), 1.78-1.88 (m, 2H), 2.04-2.14 (m, 1H), 2.36-2.46 (m, 1H), 3.34-3.54 (m, 2H), 7.20-7.16 (m, 2H), 7.17-7.22 (m, 1H), 7.25-7.31 (m, 2H).

Reference Example 24; 4-Methyl-3-phenylpentanoic acid

Sodium hydride (60%, 1.2 g) was added to a tetrahydrofuran solution (30 mL) to which t-butyldiethylphosphonoacetate (4.9 g) was added at 0 ° C under a nitrogen atmosphere. After 10 minutes, the mixture was returned to room temperature and stirred. After 1 hour, tetrahydrofuran solution (10 mL) in which isobutyrophenone (4.0 g) was dissolved was added. After stirring for 13 hours, water and ethyl acetate were added, and the organic layer was distributed, and the obtained organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered off and concentrated under reduced pressure. In the obtained crude product (6.1g), 5.48g was dissolved in methanol (30mL), 10% palladium carbon (250mg) was added with catalytic amount, and it reacted under hydrogen reduced pressure (3.9kg / cm <2>). After 1.3 hours, the catalyst was filtered off and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate system). The obtained product (3.0 g) was dissolved in acetone (50 mL) and 5N hydrochloric acid (20 mL) and stirred for 3 hours under reflux conditions. Concentration under reduced pressure afforded the title compound as a reddish yellow oil (1.96 g, 58%; 3 steps).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.75 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 1.80-1.91 (m, 1H), 2.62 (dd, J = 10.0 Hz, 15.6 Hz, 1H), 2.80 (dd, J = 5.6 Hz, 15.6 Hz, 1H), 2.82-2.91 (m, 1H), 7.11-7.16 (m, 2H), 7.13-7.22 (m, 1H) , 7.23-7.29 (m, 2 H).

Reference Example 25; N-methyl-N-methoxy-4-methyl-3-phenylpentanamide

Tetrahydrofuran solution (24 mL) in which 4-methyl-3-phenylpentanoic acid (1.96 g), N, O-dimethylhydroxyamine hydrochloride (1.18 g), and triethylamine (1.63 mL) were dissolved at 0 ° C. under a nitrogen atmosphere. ), Dimethylformamide solution in which cyanophosphonic acid diethyl ester (1.97 g) and triethylamine (1.63 mL) was dissolved was added. After 19 hours, diethyl ether and saturated aqueous ammonium chloride solution were added to distribute the organic layer, and the obtained organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate system) to obtain the title compound (1.13 g, 47%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.84-1.96 (m, 1H), 2.74-2.86 (m, 2H), 2.97-3.05 (m, 1H), 3.06 (s, 3H), 3.57 (s, 3H), 7.15-7.21 (m, 3H), 7.24-7.29 (m, 2H).

Reference Example 26; 4-methyl-3-phenylpentanal

N-methyl-N-methoxy-4-methyl-3-phenylpentanamide (215 mg) was dissolved in tetrahydrofuran (9.1 mL) at -78 ° C under a nitrogen atmosphere, and diisobutylaluminum hydride / toluene solution. (1.5M, 1.2 mL) was added. After 1 hour, methanol (3 mL) was added to the reaction system, and after foaming was stabilized, the mixture was returned to room temperature and stirring was continued. Diethyl ether, water and 1N hydrochloric acid were added, and the organic layer was distributed, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure to give a colorless oily title compound (200 mg). . The obtained compound was used for the next reaction as it was without purification.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 1.82-1.92 (m, 1H), 2.70-2.84 (m, 2H), 2.90-2.98 (m, 1H), 7.13-7.32 (m, 5H), 9.59-9.61 (m, 1H).

Reference Example 27; 4-methyl-3-phenylhexanal

To a tetrahydrofuran solution of (methoxymethyl) triphenylphosphonium chloride (627 mg) at -78 ° C under a nitrogen atmosphere, n-butyllithium tetrahydrofuran solution (1.53M, 1.2 mL) was added, followed by 0 ° C. Raised to. After 20 minutes, after the external temperature was lowered to -78 ° C, 4-methyl-3-phenylpentanal (200 mg) was added together with tetrahydrofuran (4 mL). After 45 minutes, the mixture was returned to room temperature and stirred for 20 minutes. Diethyl ether and saturated aqueous ammonium chloride solution were added and the organic layer was partitioned. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure to give a colorless oily title compound (200 mg). . The obtained compound was dissolved in isopropanol (2 mL) / water (2 mL) and p-toluenesulfonic acid (6 mg) was added and then reacted under reflux conditions for 8.5 hours. Diethyl ether and saturated aqueous sodium hydrogen carbonate were added thereto, and the organic layer was distributed. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off, concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane It was purified by ethyl acetate) to give a colorless oily title compound (103 mg, 59%, 3 steps).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.72 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 1.76-1.90 (m, 2H), 2.12-2.28 (m, 4H), 7.07-7.10 (m, 2H), 7.18-7.22 (m, 1H), 7.26-7.35 (m, 2H), 9.63-9.65 (m, 1H).

Reference Example 28; 1- [2-vinyl2- (4-fluorophenoxy) ethyl] piperazine

The title compound was synthesized in accordance with the method of Example 104 described in JP-A 11-206862.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.50-2.60 (m, 4H), 2.59 (dd, J = 4.0 Hz, 13.6 Hz, 1H), 2.77 (dd, J = 7.5 Hz, 13.6 Hz, 1H), 2.86-2.90 (m, 4H), 4.70-4.76 (m, 1H), 5.22 (brd, J = 10.6 Hz, 1H), 5.27 (brd, J = 17.2 Hz, 1H), 5.87 (ddd, J = 5.7 Hz , 10.6 Hz, 17.2 Hz, 1H), 6.82-6.89 (m, 2H), 6.89-6.97 (m, 2H).

Reference Example 29; 4-bromo-2-thiophencaraldehyde dimethylacetal

(90%) 4-Bromo-2-thiophenecaraldehyde (10.0 g) was dissolved in methanol (50 ml) and ion exchange resin Amberlite IR120B (5 g) was added. After heating to reflux for 10 hours, the mixture was allowed to cool to room temperature and the ion exchange resin was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by (NH) silica gel column chromatography (hexane) to obtain the title compound (8.93 g, 72%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.36 (s, 6H), 5.59 (d, J = 0.8 Hz, 1H), 7.00 (dd, J = 0.8 Hz, J = 1.6 Hz, 1H), 7.20 (d , J = 1.6 Hz, 1H).

Reference Example 30; 3-cyano-5-thiophencarboaldehyde

Method 1) 4-Bromo-2-thiophencaraldehyde dimethylacetal (6.82 g) was dissolved in DMF (50 ml), and copper cyanide (4.29 g) was added. After heating to reflux for 3 hours, the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with aqueous ammonia, water, 0.1N hydrochloric acid, and saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give an oil. This residue was dissolved in 80% acetic acid water (100 ml) and stirred at 60 ° C for 1 hour. Washed with brine. After cooling to room temperature, ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate water and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate system), and then recrystallized from ethyl acetate-hexane to give the title compound (2.44 g, 62%) as light yellow white crystals. .

Method 2) 4-Bromo-2-thiophenecaraldehyde (5.00 g) was dissolved in DMF (40 ml), and copper cyanide (3.52 g) was added. After heating to reflux for 3 hours, the mixture was allowed to cool to room temperature, ethyl acetate was added, and the mixture was washed with aqueous ammonia, water, 0.1N hydrochloric acid, and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate system), and then recrystallized from ethyl acetate-hexane to give the title compound (2.30 g, 71%) as light yellow white crystals. .

Physical and chemical data of the title compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 1.2 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H), 9.95 (d, J = 1.2 Hz, 1H).

Reference Example 31; 3-cyano-5- (1-hydroxy-2-methylpropyl) thiophene

3-cyano-5-thiophencarboaldehyde (2.00 g) was dissolved in anhydrous ether (100 ml) and anhydrous THF (20 ml), and (2.0 M) isopropyl magnesium chloride ether solution (10.9 ml) was added at 0 ° C. Added. After stirring at 0 ° C. for 2 hours, ethyl acetate was added, followed by washing with a saturated aqueous ammonium chloride solution and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (1.25 g, 47%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 1.99 (sext, J = 6.8 Hz, 1H), 2.42 (d , J = 4 Hz, 1H), 4.68 (dd, J = 4 Hz, J = 6 Hz, 1H), 7.08-7.10 (m, 1H), 7.85 (d, J = 1.6 Hz, 1H).

Reference Example 32; 3-cyano-5- (1-oxo-2-methylpropyl) thiophene

After dissolving oxalyl chloride (0.70 ml) in methylene chloride (10 ml), the mixture was cooled to -60 to -50 deg. C, dimethyl sulfoxide (0.57 ml) was added, and the mixture was stirred for 2 minutes. Further, a solution of methylene chloride (6 ml) of 3-cyano-5- (1-hydroxy-2-methylpropyl) thiophene (1.21 g) was added at -60 to -50 ° C, followed by stirring for 15 minutes, followed by triethyl Amine (4.65 ml) was added and the temperature was raised to room temperature. Ethyl acetate was added, and the mixture was washed with water and brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was recrystallized from ethanol, the title compound (0.59 g) as light yellow-white crystals was purified, and the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate system). 0.41 g). (Total yield: 1.00g, 84%)

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.27 (d, J = 6.8 Hz, 6H), 3.36 (qui, J = 6.8 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 8.18 (d , J = 0.8 Hz, 1H).

Reference Example 33; [1-cyano-1- (3-cyano-5-thienyl) -2-methylpropyl] diethylphosphate

3-Cyano-5- (1-oxo-2-methylpropyl) thiophene (0.90 g) was dissolved in THF (50 ml), (0.5 M) lithium cyanide DMF solution (30.1 ml) and (90%) digital Ethylcyanophosphonate (2.29 ml) was added. After stirring at room temperature for 30 minutes, ethyl acetate and hexane were added, and the mixture was washed with water and brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain a pale yellow oily title compound (1.72 g, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.96 (d, J = 6.8 Hz, 3H), 1.27-1.34 (m, 9H), 2.49 (qui, J = 6.8 Hz, 1H), 4.00-4.21 (m, 4H), 7.56 (d, J = 1.2 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H).

Reference Example 34; 3-cyano-5- (1-cyano-2-methylpropyl) thiophene

[1-Cyano-1- (3-cyano-5-thienyl) -2-methylpropyl] diethylphosphate (45 mg) was dissolved in ethyl acetate (5 ml) and (10%) palladium carbon (20 mg) Was added and hydrogenated at room temperature and atmospheric pressure for 2 hours. The catalyst was separated by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by preparative thin layer silica gel column chromatography (hexane / ethyl acetate system) to obtain a pale yellow oily title compound (22 mg, 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.09 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 2.20 (sext, J = 6.8 Hz, 1H), 3.96 (d , J = 6.8 Hz, 1H), 7.26 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H).

Reference Example 35; 4-Cyano-4- (3-cyano-5-thienyl) -5-methylhexanoate

Potassium tert-butoxide (35 mg) was suspended in DMF (5 ml) and a solution of DMF (5 ml) of 3-cyano-5- (1-cyano-2-methylpropyl) thiophene (0.60 g) was added. After stirring at room temperature for 3.5 hours, ethyl acetate was added, and the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate system) to give the title compound (0.55 g, 60%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.94 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 6.8 Hz, 3H), 2.04-2.15 (m, 3H), 2.45-2.60 (m, 2H), 4.04-4.17 (m, 2H), 7.30 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H).

Reference Example 36; 4-cyano-4- (3-cyano-5-thienyl) -5-methylhexanol

4-Cyano-4- (3-cyano-5-thienyl) -5-methylhexanoate (0.55 g) was dissolved in THF (10 ml), lithium borohydride (46 mg) was added, and 1.5 Heated to reflux. After cooling to room temperature, 1N hydrochloric acid and water were added at 0 ° C, extracted with ethyl acetate, and washed with saturated brine again. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (1.25 g, 47%) as a pale yellow oil. The catalyst was separated by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by preparative thin layer silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (0.39 g, 83%) as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.19-1.41 (m, 1H), 1.45-1.70 (m, 1H), 1.65-1.77 (m, 1H), 1.88 (dt, J = 4 Hz, J = 13.2 Hz, 1H), 2.09 (qui, J = 6.8 Hz, 1H), 2.30 (dt, J = 4 Hz, J = 12.4 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 7.30 (d, J = 1.2 Hz, 1H), 7.92 (s, 1H).

Reference Example 37; N- (2-cyanoethyl) -N- (2-iodineethyl) aniline

2.00 g (10.5 mmol) of N- (2-cyanoethyl) -N- (2-hydroxyethyl) aniline is dissolved in 60.0 ml of acetonitrile, 2.20 ml (15.8 mmol) of triethylamine, 0.90 mesyl chloride under ice-cooling ml (11.6 mmol) was added sequentially. After completion of the reaction, saturated brine was added, and the target product was extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This crude product was dissolved in acetone and 12.0 g (80.1 mmol) of sodium iodide was added. After the reaction was completed, saturated brine was added, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 1: 3) to give 2.78 g (9.26 mmol, 88.2%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.62 (t, J = 7.0 Hz, 2H), 3.26 (t, J = 8.0 Hz, 2H), 3.71-3.81 (m, 4H), 6.66-6.72 (m, 2H), 6.81-6.86 (m, 1H), 7.25-7.32 (m, 2H)

Reference Example 38; 1- {2- [N- (2-cyanoethyl) anilino] ethyl} piperazine

2.78 g (9.26 mmol) of the iodide was dissolved in 50.0 ml of acetonitrile, 2.5 g (13.4 mmol) of 1-tert-butoxycarbonylpiperazine and 1.29 ml (13.4 mmol) of triethylamine were added sequentially, and 60 It heated at degreeC, and after completion | finish of reaction, saturated brine was added and the target was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This crude product was dissolved in 40 ml of methanol and 30 ml of 4N hydrogen chloride-ethyl acetate solution was added. After the completion of the reaction, water and 10 ml of 5N HCl were added, washed with ethyl acetate, and then the aqueous layer was adjusted to pH 11 with 5N aqueous sodium hydroxide solution, and then the desired product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure to yield 1.81 g (7.01 mmol, 75.7%) of the title compound as a yellow syrup as a crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.00-2.10 (brd-s, 1H), 2.45-2.58 (m, 4H), 2.54 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.92 (t, J = 5.0 Hz, 4H), 3.51 (t, J = 6.8 Hz, 2H), 3.71 (t, J = 7.2 Hz, 2H), 6.65-6.72 (m, 2H), 6.73-6.79 (m, 1 H), 7.22-7.29 (m, 2 H)

Reference Example 39; 3- (1,3-dioxolan-2-yl) thiophene

20.3 g (181 mmol) of 3-thiophenealdehyde, 50 ml of ethylene glycol, and 2.00 g (7.96 mmol) of PPTS were dissolved in 230 ml of toluene and dehydrated using Dean-stark. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 1: 10) to give 12.1 g (77.3 mmol, 86.7%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.97-4.15 (m, 4H), 5.91 (s, 2H), 7.16 (ddd, J = 0.4 Hz, 1.2 Hz, 5.2 Hz, 1H), 7.32 (dd, J = 2.8 Hz, 5.2 Hz, 1H), 7.42 (ddd, J = 0.4 Hz, 1.2 Hz, 2.8 Hz, 1H)

Reference Example 40; 3- (1,3-dioxolan-2-yl) -2-thiophenecaraldehyde

5.00 g (32.0 mmol) of 3- (1,3-dioxolan-2-yl) thiophene were dissolved in 100 ml of THF. 24.5 ml of n-butyllithium (1.5 mol / l) was dripped here. After stirring for 0.5 hour, the mixture was cooled to -70 ° C, and thereto was added 3.10 ml (40.0 mmol) of DMF, and then transferred to an ice bath. After stirring for about 2 hours, saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 1: 2) to give 3.68 g (20.0 mmol, 62.4%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.97-4.15 (m, 4H), 5.91 (s, 2H), 7.16 (ddd, J = 0.4 Hz, 1.2 Hz, 5.2 Hz, 1H), 7.32 (dd, J = 2.8 Hz, 5.2 Hz, 1H), 7.42 (ddd, J = 0.4 Hz, 1.2 Hz, 2.8 Hz, 1H)

Reference Example 41; 3- (1,3-dioxolan-2-yl) -2-thiophenacetonitrile

4.49 g (40.0 mmol) of potassium tert-butoxide (KTB) 20 ml solution of THF was cooled to -45--30 ° C, TOSmic 3.90 g (20.0 mmol) solution of 20 ml THF, 3- (1,3-dioxolane A solution of 3.68 g (20.0 mmol) of THF 20 ml of 2--2-yl) -2-thiophenecaraldehyde was added sequentially. After 40 minutes, 60 ml of methanol was added at -15 ° C, heated to reflux for 15 minutes, and then saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with Cromatorex NH silica gel (eluted with ethyl acetate: hexane = 1: 4) to give 1.43 g (7.32 mmol, 36.6%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.00-4.15 (m, 4H), 4.04 (s, 2H), 5.91 (s, 1H), 7.06 (d, J = 5.6 Hz, 2H), 7.21 (d, J = 5.6Hz, 2H)

Reference Example 42; 2- [3- (1,3-dioxolan-2-yl) -2-thienyl] -4-methylbutyronitrile

1.43 g (7.32 mmol) of 3- (1,3-dioxolan-2-yl) -2-thiophenacetonitrile was dissolved in 2 ml of dimethyl sulfoxide, 1.08 g (8.78 mmol) of 2-bromopropane, tetra n 100 mg (cat) of butylammonium iodide was added followed by 3 ml of 50% potassium hydroxide. After 25 minutes, 300 mg of 2-bromopropane, and after 50 minutes, 1 ml of 50% potassium hydroxide and 2 ml of DMSO were added. After the reaction was completed, saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a crude product. The crude product was treated with 100 g of silica gel (ethyl acetate: hexane = 1: 8) to obtain 853 g (3.59 mmol, 49.1%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.03 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 2.17-2.27 (m, 1H), 3.97-4.13 (m, 4H), 4.31 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 5.2 Hz, 2H), 7.24 (d, J = 5.2 Hz, 2H)

Reference Example 43; 2- (3-formyl-2-thienyl) -4-methylbutyronitrile

2.16 g (9.10 mmol) of 2- [3- (1,3-dioxolan-2-yl) -2-thienyl] -4-methylbutyronitrile was dissolved in 40 ml of acetone, and 15 ml of 5N HCl was added thereto for 3 minutes. Heated to 70 ° C. After the reaction was completed, saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with 75 g of silica gel (ethyl acetate: hexane = 1: 2) to obtain 1.66 g (8.58 mmol, 94.3%) of the title compound as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.12 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 2.18-2.29 (m, 1H), 4.97 (d, J = 6.4 Hz, 1H), 7.34 (d, J = 5.2 Hz, 2H), 7.44 (d, J = 5.2 Hz, 2H), 10.01 (s, 1H)

Reference Example 44; 2- (3-cyano-2-thienyl) -4-methylbutyronitrile

1.66 g (8.58 mmol) of 2- (3-formyl-2-thienyl) -4-methylbutyronitrile was dissolved in 40 ml of ethanol, and 894 mg (12.9 mmol) of hydroxylamine hydrochloride and 1.41 g of sodium acetate were added thereto. 10 ml of an aqueous solution containing (17.2 mmol) was added, followed by heating to 80 ° C. After the reaction was completed, saturated brine was added, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give the crude product of the oxime. This oxime was dissolved in 50 ml of dimethylformamide, and 5.56 g (34.3 mmol) of carbodiimidazole were added. Then, it heated to 60 degreeC and after 50 minutes, 2.40 ml (17.2 ml) of triethylamines were added. After completion of the reaction, saturated brine was added under cooling, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 1: 9) to give 1.07 mg (5.47 mmol, 63.7%) of the title compound as an orange oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.10 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 2.27-2.38 (m, 1H), 4.20 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 5.6 Hz, 2H), 7.40 (d, J = 5.6 Hz, 2H)

Reference Example 45; Ethyl4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexanolate

1.07 g (5.47 mmol) of 2- (3-cyano-2-thienyl) -4-methylbutyronitrile and 0.71 ml (6.56 mmol) of ethyl acrylate were dissolved in 30 ml of tetrahydrofuran. To this solution was added 123 mg of potassium tert-butoxide (1.09 mmol, cat.) In small portions at room temperature. After completion of the reaction, saturated brine, saturated aqueous ammonium chloride solution and 2N HCl were added sequentially, and the target product was extracted with ethyl acetate. The organic layer was washed sequentially with saturated brine and water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 1: 9) to give 904 mg (3.11 mmol, 56.9%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.94 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 2.04-2.26 (m, 1H), 2.46-2.74 (m, 4H), 4.07-4.16 (m, 2H), 7.29 (d, J = 5.3 Hz, 2H), 7.31 (d, J = 5.3 Hz, 2H)

Reference Example 46; 4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexanol

500 mg (1.72 mmol) of ethyl 4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexanolate are dissolved in 10 ml of THF, and 37.5 mg (1.72 mmol) of lithium borohydride are dissolved. It was added and heated to reflux. After 1 h 20 min heating was stopped and 2N HCl was added under ice cooling. The mixture was extracted with ethyl acetate, washed sequentially with saturated brine and water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 35: 65) to give 244 mg (0.98 mmol, 57.1%) of the title compound as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.94 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H), 1.24-1.39 (m, 1H), 1.68-1.82 (m, 1H), 2.28-2.48 (m, 2H), 2.59-2.70 (m, 1H), 3.64-3.72 (m, 2H), 7.28-7.29 (m, 2H)

Reference Example 47; 4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexyl iodide

244 mg (0.98 mmol) of 4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexanol was dissolved in 10 ml of acetonitrile and 0.16 ml (1.18 mmol) of triethylamine. 83.6 µl (1.08 mmol) of mesyl chloride was added thereto. After about 5 minutes 1.47 g (9.80 mmol) of sodium iodide was added. After completion of the reaction, saturated brine and ethyl acetate were added, the ethyl acetate layer was washed with an aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 1: 10) to give 334 mg (0.93 mmol, 95.1%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J = 6.8 Hz, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.49-1.62 (m, 1H), 1.98-2.10 (m, 1H), 2.27-2.36 (m, 1H), 2.42-2.52 (m, 1H), 2.60-2.71 (m, 1H), 3.12-3.22 (m, 2H), 7.29-7.31 (m, 2H)

Reference Example 48; 4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl iodide

1.05 g (4.23 mmol) of 4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexanol was dissolved in 40 ml of acetonitrile and 0.80 ml (5.71 mmol) of triethylamine. 0.39 ml (5.07 mmol) of mesyl chloride was added thereto. After about 10 minutes, 6.34 g (42.3 mmol) of sodium iodide was added. After completion of the reaction, saturated brine and ethyl acetate were added, the ethyl acetate layer was washed with an aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 1: 2) to give 1.39 g (3.88 mmol, 91.7%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J = 6.8 Hz, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.49-1.62 (m, 1H), 1.98-2.10 (m, 1H), 2.27-2.36 (m, 1H), 2.42-2.52 (m, 1H), 2.60-2.71 (m, 1H), 3.12-3.22 (m, 2H), 7.29-7.31 (m, 2H)

Reference Example 49; Methyl 3- (5-bromo-2-thienyl) propanoate

J. Med. 3.85 g (20.6 mmol) of methyl 3- (2-thienyl) propanoate synthesized according to the method described in Chem., 1992, 35 (21), 3870, dissolved in 20 ml of DMF and 3.85 g of NBS dissolved in 10 ml of DMF ( 21.6 mmol) was added and heated to 80 ° C. After 2 hours, saturated saline was added and extracted with ether. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with silica gel (ethyl acetate: hexane = 1: 9) to give 4.62 g (18.6 mmol, 90.1%) of the title compound as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.65 (t, J = 7.4 Hz, 2H), 3.08 (t, J = 7.4 Hz, 2H), 3.69 (s, 3H), 6.58 (d, J = 3.6 Hz , 1H), 6.85 (d, J = 3.6 Hz, 1H)

Reference Example 50; Methyl 3- (5-cyano-2-thienyl) propanoate

4.62 g (18.6 mmol) of methyl 3- (5-bromo-2-thienyl) propanoate, 1.75 g (14.9 mmol) of Zn (CN) ₂ , 516 mg (0.93 mmol) of DPPF, 100 ml of DMF and 1 ml of water After suspended in, 341 mg (0.37 mmol) of Pd ₂ dba ₃ was added and heated to 120 ° C. After 2 hours, the mixture was allowed to cool and extracted with ether. The organic layer was washed with saturated brine, 2N HCl, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with silica gel (ethyl acetate: hexane = 1: 9) to give 2.96 g (18.6 mmol, 100%) of the title compound as a green oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.71 (t, J = 7.4 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H), 3.71 (s, 3H), 6.85 (d, J = 3.6 Hz , 1H), 7.46 (d, J = 3.6 Hz, 1H)

Reference Example 51; 3- (2-thienyl) propanol

1.32 g (7.75 mmol) of methyl 3- (2-thienyl) propanoate were dissolved in 50 ml of THF, cooled to -20 ° C, and 6.00 ml of LiAlH ₄ (1.0 M solution) was added. After completion of the reaction, the mixture was quenched with water and 5N NaOH and filtered through Celite. The filtrate was concentrated and the crude product obtained was treated with silica gel (ethyl acetate: hexane = 1: 1) to give 1.05 g (7.38 mmol, 95.2%) of the title compound as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.29 (t, J = 6.0 Hz, 1H), 1.90-2.00 (m, 2H), 2.95 (t, J = 7.6 Hz, 2H), 3.72 (q, J = 6.0 Hz, 2H), 6.80-6.83 (m, 1H), 6.91-6.94 (m, 1H), 7.11-7.14 (m, 1H)

Reference Example 52; 3- (5-cyano-2-thienyl) propanol

2.96 g (18.6 mmol) of methyl 3- (5-cyano-2-thienyl) propanoate was dissolved in 100 ml of THF, and 450 mg (18.6 mmol) of lithium borohydride were added and heated to reflux. After 1 hour, heating was stopped and 2N HCl was added under ice cooling. The mixture was extracted with ethyl acetate, washed sequentially with saturated brine and water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. The crude product was treated with silica gel (eluted with ethyl acetate: hexane = 25: 75 to 50:50) to give 1.37 g (8.19 mmol, 44.0%) of the title compound as a green oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.32-1.37 (m, 1H), 1.90-2.00 (m, 2H), 2.99 (t, J = 7.6 Hz, 2H), 3.68-3.76 (m, 2H), 6.84 (d, J = 3.6 Hz, 1H), 7.47 (d, J = 3.6 Hz, 1H)

Reference Example 53; tert-butyl 4- [3- (2-thienyl) propyl] -1-piperazinecarboxylate

1.05 g (7.38 mmol) of 3- (2-thienyl) propanol was dissolved in 60 ml of acetonitrile, and 2.58 ml (18.5 mmol) of triethylamine and 0.63 ml (8.12 mmol) of mesyl chloride were added to the solution. After 25 minutes, 2.07 g (11.1 mmol) of tert-butyl 1-piperazinecarboxylate, 3.32 g (22.7 mmol) of sodium iodide, and 6 ml of water were added and heated to 60 ° C. After the reaction was completed, saturated brine was added, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This crude product was treated with Cromatorex NH silica gel (eluted with ethyl acetate: hexane = 2: 8) to give 1.94 g (6.25 mmol, 84.7%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 1.83-1.91 (m, 2H), 2.35-2.42 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 3.40- 3.46 (m, 4H), 6.77-6.80 (m, 1H), 6.91 (dd, J = 3.2 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 5.2 Hz, 1H)

Reference Example 54; tert-butyl 4- [3- (5-cyano-2-thienyl) propyl] -1-piperazinecarboxylate

The title compound was synthesized according to the procedure for tert-butyl 4- [3- (2-thienyl) propyl] -1-piperazinecarboxylate in Reference Example 53 (yield 74.2%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 1.83-1.91 (m, 2H), 2.34-2.41 (m, 6H), 2.91 (t, J = 7.6 Hz, 2H), 3.41- 3.46 (m, 4H), 6.81 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 4.0 Hz, 1H)

Reference Example 55; 1- [3- (2-thienyl) propyl] piperazine

1.94 g (6.25 mmol) of tert-butyl4- [3- (2-thienyl) propyl] -1-piperazinecarboxylate was dissolved in 20 ml of methanol and 15 ml of 4N hydrogen chloride-ethyl acetate solution was added. After the completion of the reaction, the mixture was concentrated under reduced pressure, adjusted to pH 11 with 2N aqueous sodium hydroxide solution, and then the target product was extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to yield 1.23 g (5.85 mmol, 93.6%) of the title compound as a yellow oil as a crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.84-1.92 (m, 2H), 2.35-2.48 (m, 6H), 2.83-2.93 (m, 6H), 6.77-6.80 (m, 1H), 6.91 (dd) , J = 3.2 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 5.2 Hz, 1H)

Reference Example 56; 1- [3- (5-cyano-2-thienyl) propyl] piperazine

The title compound was synthesized according to the procedure for 1- [3- (2-thienyl) propyl] piperazine in Reference Example 55 (yield 96.0%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.83-1.91 (m, 2H), 2.33-2.44 (m, 6H), 2.87-2.94 (m, 6H), 6.81 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 4.0 Hz, 1H)

Reference Example 57; 2- (chloromethyl) benzoxazole

The title compound was prepared according to the method described in SYNTHTIC COMMUNICATION, 19 (16), 2921-2924 (1989) (yield; quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.77 (s, 2H), 7.34-7.43 (m, 2H), 7.54-7.58 (m, 1H), 7.73-7.77 (m, 1H)

Reference Example 58; Benzyl 4-[(2-benzooxazoyl) methyl] -1-piperazinecarboxylate

2.00 g (11.9 mmol) of 2- (chloromethyl) benzoxazole was dissolved in 50 ml of acetonitrile, 1.66 ml (11.9 mmol) of triethylamine and 3.15 g (14.3 mmol) of benzyl 1-piperazinecarboxylate were added, It stirred at 80 degreeC. After 2 hours, the reaction solution was concentrated, saturated brine was added, and the desired product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This was treated with Cromatorex NH silica gel (ethyl acetate: hexane = 25:75) to give 3.57 g (10.2 mmol, 85.7%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.56-2.68 (brd-s, 4H), 3.56-3.62 (m, 4H), 3.89 (s, 2H), 5.12 (s, 2H), 7.28-7.37 (m , 7H), 7.52-7.55 (m, 1H), 7.70-7.74 (m, 1H)

Reference Example 59; 1-[(2-benzoxazoyl) methyl] piperazine

3.57 g (10.2 mmol) of benzyl4-[(2-benzooxazoyl) methyl] -1-piperazinecarboxylate was dissolved in 50 ml of methanol and 400 mg of 10% Pd-C was added. After hydrogen replacement, the mixture was stirred. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to yield 2.15 g (9.89 mmol, 97.0%) of the title compound as a yellow oil as a crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.56-2.66 (m, 4H), 2.93-2.98 (m, 4H), 3.87 (s, 2H), 7.31-7.36 (m, 2H), 7.51-7.56 (m , 1H), 7.69-7.74 (m, 1H)

Reference Example 60; 2- (chloromethyl) -5-cyanobenzoxazole

The title compound was prepared according to the method described in SYNTHTIC COMMUNICATION, 19 (16), 2921-2924 (1989) (yield: 79.8%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.78 (s, 2H), 7.66-7.73 (m, 2H), 8.08-8.10 (m, 1H)

Reference Example 61; Benzyl4-[{2- (5-cyanobenzooxazoyl)} methyl] -1-piperazinecarboxylate

The title compound was synthesized according to the preparation of benzyl 4-[(2-benzooxazoyl) methyl] -1-piperazinecarboxylate in Reference Example 58 (yield: 85.6%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.57-2.70 (brd-s, 4H), 3.56-3.63 (m, 4H), 3.92 (s, 2H), 5.13 (s, 2H), 7.30-7.38 (m , 5H), 7.62-7.68 (m, 2H), 8.04-8.05 (m, 1H)

Reference Example 62; 1-[{2- (5-cyanobenzooxazoyl)} methyl] piperazine

The title compound was synthesized according to the method described in Reference Example 59 (yield: 58.0%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.59-2.66 (m, 4H), 2.93-3.00 (m, 4H), 3.90 (s, 2H), 7.62-7.67 (m, 2H), 8.03-8.05 (m , 1H)

Reference Example 63; Ethyl 4-cyano-5-methyl-4- (3-thienyl) hexanoate

3-methyl-2- (3-thienyl) butanenitrile (6.23 g) and ethyl acryl obtained by using 3-thienyl acetonitrile as starting materials according to the method of Example 114 described in Japanese Patent Application Laid-Open No. 11-206862 The rate (4.53 g) was dissolved in dimethylformamide (15 ml) and added to a dimethylformamide solution (60 ml) in which potassium-tert-butoxide (423 mg) was dissolved at room temperature. After stirring for 5 hours, an aqueous saturated ammonium chloride solution and diethyl ether were added thereto, and the organic layer was distributed. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the residue was concentrated under reduced pressure. Purification by chromatography (hexane / ethyl acetate system) afforded the title compound (6.66 g, 67%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.85 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 2.00-2.18 (m, 3H), 2.38-2.50 (m, 2H), 4.02-4.14 (m, 2H), 6.94 (dd, J = 1.4 Hz, 5.0 Hz, 1H), 7.29 (dd, J = 1.4 Hz, 2.8 Hz , 1H), 7.37 (dd, J = 2.9 Hz, 5.0 Hz, 1H).

Reference Example 64; 4-cyano-5-methyl-4- (3-thienyl) hexanol

Tetrahydrofuran solution (35 ml) in which 4-cyano-5-methyl-4- (3-thienyl) ethyl hexanoate (6.66 g) was dissolved was added to a tetrahydrofuran solution (50 ml) of lithium aluminum hydride (668 mg). Dropped. After stirring for 2 hours, 2N NaOH water and water were added to treat the precipitate formed. The obtained filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to give the title compound (5.30 g, 95%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.85 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H), 1.18-1.22 (m, 1H), 1.22-1.36 (m, 1H), 1.56-1.72 (m, 1H), 1.90 (ddd, J = 4.6 Hz, 12.1 Hz, 13.4 Hz, 1H), 2.04-2.12 (m, 1H), 2.14-1.22 (m, 1H), 3.58- 3.65 (m, 2H), 6.95 (dd, J = 1.5 Hz, 5.1 Hz, 1H), 7.28 (dd, J = 1.5 Hz, 3.0 Hz, 1H), 7.35 (dd, J = 3.0 Hz, 5.1 Hz, 1H ).

Reference Example 65; 1-iodine-4-cyano-5-methyl-4- (3-thienyl) hexane

Methanesulfonyl chloride (0.20) in an acetonitrile solution (9.0 ml) of 4-cyano-5-methyl-4- (3-thienyl) hexanol (400 mg), triethylamine (0.75 ml) at room temperature under a nitrogen atmosphere. ml) was added and stirred. After 2 hours, water and ethyl acetate were added, the organic layer was distributed, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered off and concentrated under reduced pressure. The obtained residue was dissolved in acetone (18 ml), sodium iodide (2.68 g) was added, and the mixture was stirred at 40 ° C for 2 hours. Water and ethyl acetate were added, the organic layer was partitioned, and the obtained organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure to give the title compound (670 mg) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.85 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.46-1.60 (m, 1H), 1.86-2.00 (m, 1H), 2.02-2.20 (m, 2H), 3.05-3.20 (m, 2H), 6.95 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.28 (dd, J = 1.2 Hz, 2.8 Hz, 1H) , 7.37 (dd, J = 2.8 Hz, 5.2 Hz, 1H).

Reference Example 66; 4-Cyano-5-methyl-4- [4- (2-cyano) thienyl] ethyl hexanoate

Ethyl 4-cyano-5-methyl-4- (3-thienyl) hexanoate (1.8 g) was dissolved in dimethylformamide (7 mL) under a nitrogen atmosphere, and N-bromosuccinimide was added thereto at room temperature. (1.33 g) / dimethylformamide (7 mL) solution was added dropwise over 30 minutes. After stirring at 50 ° C. for 4.5 hours, water and diethyl ether were added to distribute the organic layer, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off, and concentrated under reduced pressure. -Cyano-5-methyl-4- [4- (2-bromo) thienyl] ethyl hexanoate (2.42 g) was obtained. The obtained bromide (2.42 g) was added to zinc cyanide (637 mg) and 1,1'-bis (diphenylphosphino) ferrocene (188 mg) in a mixed solvent of dimethylformamide (17 mL) / water (0.17 mL) under a nitrogen atmosphere. Dissolved. A palladium-dibenzylidene acetone complex (124 mg) was added, and after nitrogen-exchanging 3 times, it stirred at 120 degreeC for 5 hours. Water, diethyl ether and ammonia water were added, the organic layer was distributed, the organic layer obtained was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, followed by silica gel column chromatography (hexane: ethyl acetate system). The title compound (338 mg, 17%; 2 steps) was obtained as a yellow oil (Preference: PE Maligres et al. "Tetrahedron 40 (1999) 8193-8195").

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.86 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 1.95-2.15 (m, 3H), 2.40-2.53 (m, 2H), 4.04-4.14 (m, 2H), 7.48 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H).

Reference Example 67; 4-cyano-5-methyl-4- (2-cyano-4-thienyl) hexanol

According to the LiBH ₄ reduction, the title compound was obtained as a yellow oil (30%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.86 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.20-1.33 (m, 1H), 1.60-1.72 (m, 1H), 1.86-1.96 (m, 1H), 2.00-2.12 (m, 1H), 2.16-2.26 (m, 1H), 3.60-3.68 (m, 2H), 7.48 (d, J = 1.6 Hz, 1H) , 7.57 (d, J = 1.6 Hz, 1H).

Reference Example 68; 1-iodine-4-cyano-5-methyl-4- [4- (2-cyano) thienyl] hexane

According to the method described in Reference Examples 63, 64 and 65, a yellow oily title compound was synthesized (91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.86 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.20-1.30 (m, 1H), 1.40-1.55 (m, 1H), 1.90-2.00 (m, 1H), 2.00-2.12 (m, 1H), 2.16-2.26 (m, 1H), 3.06-3.17 (m, 1H), 3.17-3.23 (m, 1H), 7.48 ( d, J = 1.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H).

Reference Example 69; 2- (2-cyano-4-fluorophenoxy) ethylpiperazine

Potassium-tert-butoxide (869 mg) was added to a tetrahydrofuran solution (10 ml) of 4- (2-hydroxyethyl) -1-piperazinecarboxylic acid benzyl ester (1.86 g) in an ice bath under a nitrogen atmosphere. After stirring for 1 hour, the reaction system was transferred to a dry ice methanol cooling bath, and after 10 minutes, a 2,5-difluorobenzonitrile (1.09 g) tetrahydrofuran solution (5 ml) was added. After stirring for 2 hours while returning to room temperature naturally, saturated aqueous ammonium chloride solution and diethyl ether were added, and the organic layer was partitioned. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate system) to obtain a colorless oily intermediate (1.10 g, 46%). The intermediate (1.10 g) was dissolved in methanol (10 ml), 10% palladium-carbon (100 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 1.5 hours, the reaction catalyst was filtered through Celite, and the filtrate was concentrated under reduced pressure. The title compound (647 mg, 80%) obtained was used for the next reaction as it was.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.55-2.63 (m, 4H), 2.87 (t, J = 5.7 Hz, 2H), 2.89-2.92 (m, 4H), 4.19 (t, J = 5.7 Hz, 2H), 6.93 (dd, J = 4 Hz, 8.8 Hz, 1H), 7.21-7.29 (m, 2H).

Reference Example 70; 4-cyano-5-methyl-4- [4- (2,5-dibromo) thienyl] hexanol

In a nitrogen atmosphere, 4-cyano-5-methyl-4- (3-thienyl) hexanol (500 mg) was dissolved in dimethylformamide (5 mL), and N-bromosuccinimide (1.0) was added thereto at room temperature. g) was added. After stirring at 100 ° C. for 1 hour, water and diethyl ether were added to distribute the organic layer, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to give the title compound (670 mg, 78%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.31-1.44 (m, 1H), 1.60-1.74 (m, 1H), 2.08 (ddd, J = 4.3Hz, 12.1Hz, 13.6Hz, 1H), 2.43 (ddd, J = 4.6Hz, 12.3Hz, 13.6Hz, 1H), 2.59 (sept, J = 6.8Hz, 1H) , 7.05 (s, 1 H).

Reference Example 71; 2- (4-methylsulfonylphenoxy) ethylpiperazine

Under a nitrogen atmosphere, 4- (methylthio) phenol (4.2 g) and ethanol bromide (5.6 g) were dissolved in a dimethylformamide solution (60 ml), potassium carbonate (12.4 g) was added thereto, and the mixture was stirred at 100 ° C by heating. After returning to room temperature after 3 hours, diethyl ether and water were added to distribute the organic layer, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, and the residue was silica gel. Purification by column chromatography (hexane / ethyl acetate system) afforded white crystals (4-methylthiophenoxy) ethanol (3.55 g, 64%). This product (1.0 g) was dissolved in dichloromethane (50 ml), cooled with a methanol-dry ice cooling bath, and metachloroperbenzoate (3.6 g) was added and stirred. After naturally returning to room temperature for 2 hours, 1N sodium hydrogencarbonate water and 1N Na ₂ S ₂ O ₃ water were added and stirred, followed by extraction with dichloromethane, drying over anhydrous magnesium sulfate, and drying of the drying agent under reduced pressure after filtration. The residue was dissolved in acetonitrile (18 ml), triethylamine (2.3 ml) and methanesulfonyl chloride (0.5 ml) were added, followed by stirring at room temperature. After 1.5 hours, sodium iodide (4.9 g) and t-butyl 1 -piperazine carboxylate (1.2 g) were added, followed by heating and stirring at 60 占 폚. After stirring for 4.5 hours, ethyl acetate and water were added to distribute the organic layer, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / Ethyl acetate) to give white crystals tert-butyl-2- (4-methylsulfonylphenoxy) ethyl-1-piperazinecarboxylate (1.15 g). This product (1.15 g) was dissolved in methanol (10 ml) and added to a 4N hydrochloric acid-ethyl acetate solution (30 ml) in an ice bath. After stirring overnight at room temperature, the resulting white crystals were separated by filtration and washed with diethyl ether. 1N aqueous sodium hydroxide solution and dichloromethane were added to the crystals, and the organic layer was distributed. The obtained organic layer was concentrated under reduced pressure to obtain the title compound (820 mg, 53%; 3 steps) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.52-2.60 (m, 4H), 2.83 (t, J = 5.8 Hz, 2H), 2.93 (brt, J = 4.8 Hz, 4H), 3.03 (s, 3H) 4.18 (t, J = 5.8 Hz, 2H), 7.03 (brd, J = 9.0 Hz, 2H), 7.86 (brd, J = 9.0 Hz, 2H).

Reference Example 72; 2- (3-acetylphenoxy) ethylpiperazine

Under a nitrogen atmosphere, 3-hydroxyacetophenone (4.1 g) and ethanol bromide (5.6 g) were dissolved in a dimethylformamide solution (60 ml), potassium carbonate (12.4 g) was added, and the mixture was heated and stirred at 100 ° C. After returning to room temperature after 3 hours, diethyl ether and water were added to distribute the organic layer. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure, and the residue was concentrated under reduced pressure. Purification by chromatography (hexane / ethyl acetate system) afforded white crystals (3-acetylphenoxy) ethanol (3.28 g, 61%). This product (977 mg) was dissolved in acetonitrile (18 ml), triethylamine (2.3 ml) and methanesulfonyl chloride (0.5 ml) were added, followed by stirring at room temperature. After 1.5 hours, sodium iodide (4.9 g) and tert-butyl 1 -piperazinecarboxylate (1.2 g) were added, followed by heating and stirring at 60 占 폚. After stirring for 4.5 hours, ethyl acetate and water were added to distribute the organic layer, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / Ethyl acetate) to give tert-butyl-2- (3-acetylphenoxy) ethyl-1-piperazinecarboxylate (1.33 g) as a yellow oil. This product (1.33 g) was dissolved in methanol (10 ml) and added to a 4N hydrochloric acid-ethyl acetate solution (30 ml) in an ice bath. The mixture was stirred overnight at room temperature, and the resulting white crystals were separated by filtration and washed with diethyl ether. An aqueous 1N sodium hydroxide solution and dichloromethane were added to the crystals, and the organic layer was distributed. The obtained organic layer was concentrated under reduced pressure to give the title compound (830 mg, 62%; 2 steps) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.52-2.60 (m, 4H), 2.60 (s, 3H), 2.82 (t, J = 5.8 Hz, 2H), 2.93 (brt, J = 4.9 Hz, 4H) , 4.16 (t, J = 5.8 Hz, 2H), 7.12 (ddd, J = 1.1 Hz, 2.6 Hz, 8.2 Hz, 1H), 7.34-7.40 (m, 1H), 7.50 (dd, J = 1.5 Hz, 2.6 Hz, 1H), 7.54 (ddd, J = 1.1 Hz, 1.5 Hz, 7.5 Hz, 1H).

Reference Example 73; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] piperazine

To acetonitrile solution (11 ml) of 1-iodine-4-cyano-5-methyl-4- (2-thienyl) hexanoic acid (744 mg) and triethylamine (0.93 ml) synthesized according to Example 84, tert-butyl-1-piperazinecarboxylate (540 ml) was added and the mixture was stirred at 50 ° C. for 5 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and then the crude product was purified by silica gel column chromatography (ethyl acetate / hexane system) to give a colorless oily product (705 mg, 81%). The obtained product (705 mg) was dissolved in methanol (5 ml), 4N hydrochloric acid and ethyl acetate solution (15 ml) were added, and the mixture was stirred for 10 hours. Diethyl ether and ethyl acetate were added and stirred with an ice bath, and the resulting hydrochloride of the title compound was filtered off (white crystals, 490 mg, 75%). The hydrochloride of the obtained title compound was converted into a vitreous body by extraction with dichloromethane and saturated aqueous sodium hydrogen carbonate solution and used for the next reaction.

Hydrochloride;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.82 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.30-1.55 (m, 1H), 1.60-1.83 (m , 1H), 1.83-2.00 (m, 1H), 2.22-2.30 (m, 2H), 3.00-3.80 (m, 10H), 7.07 (dd, J = 5.1 Hz, 3.5 Hz, 1H), 7.11 (dd, J = 3.5 Hz, 1.3 Hz, 1H), 7.59 (dd, J = 5.1 Hz, 1.3 Hz, 1H), 9.30-9.70 (m, 2H).

ESI-MS (m / e): 292 (M + H).

Reference Example 74; 1- [3-cyano-4-methyl-3- (2-thienyl) pentyl] piperazine

The title compound was synthesized according to the preparation method of Reference Example 73.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.50-1.60 (m, 1H), 1.88-1.98 (m, 1H ), 2.20-2.18 (m, 2H), 2.28-2.52 (m, 6H), 2.83-2.90 (m, 4H), 6.94-6.98 (m, 1H), 7.10-7.13 (m, 1H), 7.25-7.30 (m, 1 H).

Reference Example 75; 4- (1,4-diazepane-1-yl) -1-isopropyl-1-phenylbutyl cyanide

According to Example 73, the title compound was synthesized from tert-butyl-1-homopiperazinecarboxylate.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.02-1.20 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.44-1.62 (m, 1H ), 1.64-1.74 (m, 2H), 1.85-1.95 (m, 1H), 2.06-2.20 (m, 2H), 2.36-2.48 (m, 2H), 2.50-2.59 (m, 4H), 2.80-2.86 (m, 2H), 2.89 (t, J = 6.1 Hz, 2H), 7.25-7.34 (m, 1H), 7.36-7.40 (m, 4H).

Reference Example 76; 1- (vinylsulfonyl) piperidine

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.47-1.60 (m, 2H), 1.60-1.70 (m, 4H), 3.07-3.18 (m, 4H), 5.99 (d, J = 9.9 Hz, 1H), 6.20 (d, J = 16.7 Hz, 1H), 6.41 (dd, J = 16.7 Hz, 9.9 Hz, 1H).

Reference Example 77; 1,2,3,4-tetrahydro-1-quinolinyl vinylsulfone

*

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.95-2.05 (m, 2H), 2.81 (t, J = 6.8 Hz, 2H), 3.75-3.85 (m, 2H), 5.91 (d, J = 10.4 Hz, 1H ), 6.23 (d, J = 16.4 Hz, 1H), 6.46 (dd, J = 16.4 Hz, 10.4 Hz, 1H), 7.00-7.20 (m 3H), 7.65 (d, J = 8.4 Hz, 1H).

Reference Example 78; 5- (2,5-Dihydro-1H-1-pyrrolyl) -2-isopropyl-5-oxo-2- (2- thienyl) pentanenitrile

Cyanophosphonic acid diethyl ester in a tetrahydrofuran solution (15 ml) of 3-pyrroline (262 mg) and 4-cyano-4- (2-thienyl) -5-methylhexanoic acid (692 mg) under nitrogen atmosphere at room temperature (618 mg) was added and stirred overnight. The reaction solution was concentrated under reduced pressure, and then the crude product was purified by silica gel column chromatography (ethyl acetate / hexane system) to give a yellow oily title compound (440 mg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 2.00-2.30 (m, 3H), 2.40-. 60 (m, 2H), 4.00-4.30 (m, 4H), 5.70-5.80 (m, 1H), 5.80-5.90 (m, 1H), 6.87-7.00 (m 1H), 7.15 (m, 1H), 7.23 -7.26 (m, 1 H).

In the physicochemical data of the following compounds, the values obtained by measuring the vitreous substance for NMR and the hydrochloride salt for ESI-MS are described. In addition, hydrochloride was manufactured according to the method of Unexamined-Japanese-Patent No. 11-206862.

Reference Example 79; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3-tert- butoxycarbonylaminopyrrolidine

867 mg (3.49 mmol) of 4-cyano-4- (5-cyano-2-thienyl) -5-methylhexanol was dissolved in 20 ml of acetonitrile. 0.58 ml (1.20 eq) of triethylamine and 0.30 ml (1.10 eq) of mesyl chloride were added to this solution. After 10 minutes, saturated brine was added and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This was dissolved in 30 ml of acetonitrile, 1.57 g (3.00 eq) of sodium iodide, 0.54 ml (1.10 eq) of triethylamine, and 845 mg (4.54 mmol) of (3R) -3-tert-butoxycarbonylaminopyrrolidine were added thereto. And it heated to 60 degreeC. After the reaction was completed, saturated brine was added, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This crude product was treated with 100 g of Cromatorex NH silica gel (ethyl acetate: hexane = ethyl acetate 25-35%) to give 1.34 g (3.21 mmol, 92.0%) of the title compound as a yellow oil. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.17-1.30 (m, 1H), 1.44 (s, 9H) , 1.50-1.70 (m, 1H), 1.72-1.84 (m, 1H), 2.00-2.12 (m, 1H), 2.15-2.30 (m, 3H), 2.31-2.49 (m, 4H), 2.49-2.55 ( m, 1H), 2.62-2.75 (m, 1H), 4.07-4.20 (m, 1H), 4.70-4.82 (brd-s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.52 (d, J = 3.6Hz, 1H)

Reference Example 80; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3-amino pyrrolidine

1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3-tert-butoxycarbonylaminopyrrolidine obtained in Reference Example 79 ( 1.34 g = 3.21 mmol) was dissolved in 10 ml of methanol and 10 ml of 4N hydrogen chloride-ethyl acetate solution was added. After completion of the reaction, the mixture was adjusted to alkaline with 5N sodium hydroxide solution and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 998 mg (3.15 mmol, 99.5%, red oil) of the crude product. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.18-1.32 (m, 1H), 1.39-1.71 (m, 2H), 1.75-1.85 (m, 1H), 2.01-2.19 (m, 2H), 2.19-2.29 (m, 2H), 2.32-2.41 (m, 2H), 2.42-2.51 (m, 1H), 2.57- 2.66 (m, 2H), 3.45-3.52 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.52 (d, J = 3.6 Hz, 1H)

Reference Example 81; Of 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2- cyanoethyl) amino] pyrrolidine Produce

998 mg (3.15 mmol) of 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3-aminopyrrolidine obtained in Reference Example 80 was methanol It was dissolved in 25 ml, 0.26 ml (3.94 mmol) of acrylonitrile was added and heated to reflux. After completion of the reaction, the mixture was concentrated under reduced pressure to give a crude product. The crude product was treated with 50 g of Cromatorex NH silica gel (100% ethyl acetate) to yield 1.01 g (2.73 mmol, 86.7%) of the title compound as an orange oil. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.20-1.31 (m, 1H), 1.48-1.71 (m, 2H), 1.76-1.86 (m, 1H), 2.02-2.15 (m, 2H), 2.18-2.29 (m, 1H), 2.30-2.39 (m, 3H), 2.43-2.56 (m, 4H), 2.56- 2.64 (m, 1H), 2.86 (t, J = 6.4Hz, 2H), 3.25-3.33 (m, 1H), 7.16 (d, J = 4.0Hz, 1H), 7.52 (d, J = 4.0Hz, 1H )

Reference Example 82; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] piperazine

According to the preparation of Example 77, 1- [4 from 4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl iodide and tert-butyl 1-piperazinecarboxylate -Cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] -4- (tert-butoxycarbonyl) piperazine was synthesized. This was subjected to deprotection of the Boc group in accordance with the preparation method of Reference Example 79 to obtain the title compound. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.20-1.32 (m, 1H), 1.59-1.83 (m, 2H), 2.01-2.11-1.80 (m, 1H), 2.17-2.40 (m, 7H), 2.80-2.92 (m, 4H), 7.15 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 4.0 Hz, 1H)

Reference Example 83; 1- [4-cyano-5-methyl-4- (4-fluorophenyl) hexyl] piperazine

It synthesize | combined according to the reference example 73.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.08-1.17 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H), 1.52-1.62 (m, 1H ), 1.81-1.89 (m, 1H), 2.04-2.18 (m, 2H), 2.22-2.29 (m, 6H), 2.83-2.87 (m, 4H), 7.04-7.08 (m, 2H), 7.32-7.36 (m, 2 H).

Reference Example 84; 1- [4-cyano-5-methyl-4- (3-fluorophenyl) hexyl] piperazine

It synthesize | combined according to the reference example 73.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.79 (d, J = 6.6 Hz, 3H), 0.81-1.19 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H), 1.54-1.59 (m, 1H ), 1.81-1.89 (m, 1H), 2.05-2.29 (m, 8H), 2.83-2.87 (m, 4H), 6.97-7.03 (m, 1H), 7.06-7.10 (m, 1H), 7.17-7.20 (m, 1 H), 7.32-7.37 (m, 1 H).

Reference Example 85; 1- [4-cyano-5-methyl-4- (2-fluorophenyl) hexyl] piperazine

It synthesize | combined according to the reference example 73.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.80 (d, J = 6.8 Hz, 3H), 1.10-1.16 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H), 1.55-1.64 (m, 1H ), 2.03-2.11 (m, 1H), 2.17-2.34 (m, 7H), 2.43-2.50 (m, 1H), 2.80-2.87 (m, 4H), 7.01-7.06 (m, 1H), 7.13-7.17 (m, 1 H), 7.26- 7.34 (m, 1 H), 7.56-7.61 (m, 1 H).

Reference Example 86; 1- [4-cyano-5-methyl-4- (2-tril) hexyl] piperazine

According to Reference Example 73, the title compound was obtained as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.86 (d, J = 6.8 Hz, 3H), 1.10-1.24 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.50-1.64 (m, 1H ), 2.02-2.14 (m, 1H), 2.14-2.30 (m, 1H), 2.20-2.40 (m, 6H), 2.36-2.54 (m, 1H), 2.50 (s, 3H), 2.78-2.90 (m , 4H), 7.10-7.24 (m, 3H), 7.46-7.56 (m, 1H).

Reference Example 87; 1- [4-cyano-5-methyl-4- (2-methoxyphenyl) hexyl] piperazine

According to Reference Example 73, the title compound was obtained as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.75 (d, J = 6.4 Hz, 3H), 1.00-1.20 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.45-1.60 (m, 1H ), 1.90-2.00 (m, 1H), 2.20-2.40 (m, 6H), 2.35-2.50 (m, 1H), 2.65-2.75 (m, 1H), 2.75-2.90 (m, 4H), 3.80 (s , 3H), 6.87 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 7.24-7.32 (m, 1H), 7.55 (d, J = 7.6 Hz, 1H).

Reference Example 88; 1- [4-cyano-5-methyl-4- (2-chlorophenyl) hexyl] piperazine

According to Reference Example 73, the title compound was obtained as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.02-1.18 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.45-1.60 (m, 1H ), 1.95-2.10 (m, 1H), 2.20-2.40 (m, 6H), 2.64-2.76 (m, 1H), 2.80-2.90 (m, 4H), 2.88-3.02 (m, 1H), 7.22-7.32 (m, 2H), 7.34-7.40 (m, 1H), 7.71-7.77 (m, 1H).

Reference Example 89; 1-benzyl-4- [3- [1- (4-fluorophenyl) cyclohexyl] -1-oxopropyl] piperazine

Methyl 4-fluorophenyl acetate (10.0 g) was dissolved in tetrahydrofuran (150 ml) and 60% sodium hydride (5.95 g) was added under ice cooling. After stirring for 10 minutes under ice-cooling, 1,5-dibromopentane (11.3 ml) was added dropwise over 1 hour. After stirring overnight at room temperature, ice water was added and extracted with ethyl acetate. After washing with saturated brine, drying with anhydrous magnesium sulfate and concentrating under reduced pressure, the residue obtained was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 7.37 g (53%) of oil.

The oil (7.35 g) was dissolved in tetrahydrofuran (100 ml), and 1.0 M lithium aluminum hydride-diethyl ether solution (18.7 ml) was added dropwise at -50 to -40 ° C. After stirring at this temperature for 20 minutes, water, 5N sodium hydroxide aqueous solution, and water were added under ice-cooling, and the insolubles were separated by filtration using celite. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 3.43 g (53%) of oil.

Oxalyl chloride (1.05 ml) was dissolved in methylene chloride (25 ml), and a methylene chloride (5 ml) solution of dimethyl sulfoxide (0.85 ml) was added dropwise at -60 to -50 ° C. After stirring for 2 minutes, a solution of methylene chloride (10 ml) of the oil (2.08 g) was added dropwise within 5 minutes. After stirring at this temperature for 15 minutes, triethylamine (6.96 ml) was added, and after stirring for 5 minutes, the temperature was raised to room temperature. The mixture was washed with water and brine sequentially, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.91 g (93%) of oil.

60% sodium hydride (0.55 g) was suspended in tetrahydrofuran (10 ml), and tetrahydrofuran (5 ml) of triethylphosphonoacetate (2.73 ml) was added dropwise under ice cooling. After stirring for 15 minutes under ice cooling, a tetrahydrofuran (15 ml) solution of the oil (1.89 g) was added dropwise. After 15 minutes of stirring at this temperature, the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. After washing with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the residue obtained was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 2.07 g (82%) of an oil.

The oil (1.02 g) was dissolved in ethanol (20 ml), 10% palladium carbon (0.2 g) was added, and hydrogenated at room temperature and normal pressure for 30 minutes. The catalyst was separated by filtration, and the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 0.97 g (94%) of oil.

The oil (9.03 g) was dissolved in ethanol (50 ml) and 2N aqueous sodium hydroxide solution (50 ml) was added. After heating to reflux for 2 hours, the residue obtained by cooling to room temperature and concentrating under reduced pressure was suspended in ethyl acetate and prepared at pH 2 with 5N hydrochloric acid. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was recrystallized from ethyl acetate / n-hexane to give 6.45 g (79%) of white crystals.

1-benzylpiperazine (2.82 g) was dissolved in N, N-dimethylformamide (40 ml), and the crystals (4.00 g) and 1-hydroxybenzotriazole (2.16 g) were added. Under ice-cooling, a solution of 1,3-dicyclohexylcarbodiimide (3.63 g) of N, N-dimethylformamide (30 ml) was added dropwise. After stirring at room temperature overnight, the insolubles were separated by filtration and the filtrate was extracted with ethyl acetate and 1N hydrochloric acid. After washing with 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to give the title compound as an oil, 6.23 g (95%). Got.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.29-1.50 (m, 4H), 1.50-1.63 (m, 4H), 1.80-1.94 (m, 4H), 1.99-2.07 (m, 2H), 2.27 (t , J = 4.8 Hz, 2H), 2.34 (t, J = 4.8 Hz, 2H), 3.10 (t, J = 4.8 Hz, 2H), 3.47 (s 2H), 3.54 (t, J = 4.8 Hz, 2H) , 6.96-7.02 (m, 2 H), 7.22-7.34 (m, 7 H).

ESI-Mass; 409 (MH ⁺ ).

Reference Example 90; 1-benzyl-4- [3- [1- (4-fluorophenyl) cyclohexyl] propyl] piperazine

Dissolve 1-benzyl-4- [3- [1- (4-fluorophenyl) cyclohexyl] -1-oxopropyl] piperazine (5.90 g) in tetrahydrofuran (100 ml) and hydrogenate 80% under ice cooling Lithium aluminum (1.03 g) was added. After heating at reflux for 1.5 hours, the mixture was allowed to cool to room temperature, and water, 1N aqueous sodium hydroxide solution and water were added under ice cooling, and the insolubles were filtered off. The residue obtained by concentrating the filtrate under reduced pressure was recrystallized from ethanol to obtain 4.48 g (79%) of the title compound as white crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.06-1.15 (m, 2H), 1.28-1.58 (m, 12H), 1.98-2.06 (m, 2H), 2.14 (t, J = 8 Hz, 2H), 2.20 -2.54 (m, 8H), 3.47 (s 2H), 6.93-7.00 (m, 2H), 7.20-7.32 (m, 7H).

ESI-Mass; 395 (MH ⁺ ).

Reference Example 91; 4- [3- [1- (4-fluorophenyl) cyclohexyl] propyl] piperazine

Dissolve 1-benzyl-4- [3- [1- (4-fluorophenyl) cyclohexyl] propyl] piperazine (4.00 g) in methanol (100 ml), and 20% palladium hydroxide (0.4 g) It added and hydrogenated at normal temperature and normal pressure for 6 hours. The catalyst was filtered off, and then concentrated under reduced pressure to obtain 3.09 g (quantitative) of the title compound as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.07-1.17 (m, 2H), 1.28-1.60 (m, 10H), 1.75 (bs, 1H), 1.99-2.07 (m, 2H), 2.12 (t, J = 8 Hz, 2H), 2.25 (bs, 4H), 2.82 (t, J = 4.8 Hz, 2H), 6.94-7.01 (m, 2H), 7.21-7.27 (m, 2H).

ESI-Mass; 305 (MH ⁺ ).

Reference Example 92; Ethyl 4- (4-cyano-5-methyl-4-phenylhexyl) -2-piperazinecarboxylate

Ethyl1-benzyl-4- (4-cyano-5-methyl-4-phenylhexyl) -2-piperazinecarboxylate (857 mg) was dissolved in ethanol (15 ml) and 770 mg of 10% Pd-C was added. After hydrogen replacement, the mixture was stirred. After completion of the reaction, the mixture was concentrated under reduced pressure to give 639 mg (93%) of the title compound as a crude product.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.6 Hz, 3H), 1.08-1.16 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.22-1.29 (m, 3H ), 1.53-1.64 (m, 1H), 1.86-1.95 (m, 1H), 2.05-2.33 (m, 6H), 2.41-2.49 (m, 1H), 2.74-2.83 (m, 2H), 2.97-3.04 (m, 1H), 3.47-3.52 (m, 1H), 4.14-4.21 (m, 2H), 7.26-7.31 (m, 1H), 7.34-7.39 (m, 4H).

Reference Example 93; Ethyl 4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate

Synthesized according to Example 241 below, ethyl 1-benzyl-4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate (977 mg) was dissolved in ethanol (15 ml) and 10% 210 mg of Pd-C was added. After hydrogen replacement, the mixture was stirred. After the completion of the reaction, the mixture was concentrated under reduced pressure to yield 752 mg (100%) of the title compound as a crude product.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24-1.28 (m, 3H), 2.33-2.34 (m, 1H), 2.48-2.50 (m, 1H), 2.72-2.91 (m, 4H), 3.04-3.10 ( m, 2H), 3.56-3.59 (m, 1H), 4.04-4.08 (m, 2H), 4.16-4.22 (m, 2H), 6.82-6.86 (m, 2H), 6.94-6.99 (m, 2H).

Among the manufacturing intermediates for producing the compound according to the present invention, the optically active can be prepared according to a known production method or a method similar thereto, and can also be produced according to the following method, for example.

Reference Example 94; 3-methyl-2- (2-thienyl) butanenitrile

47.6 g (0.39 mol) of 2-thiophene acetonitrile and 57.0 g (0.46 mol) of 2-bromopropane were dissolved in 100 ml of DMSO, and 50% KOH aqueous solution was dripped. After the reaction was completed, water was added, followed by extraction with toluene. After washing with saturated brine and saturated aqueous ammonium chloride solution, the mixture was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This crude product was treated with reduced pressure distillation (2-3mmHg: 132-137deg) to give 46.4g (0.28mol, 72.7%) of the title compound as a colorless oil. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.08 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 2.14-2.24 (m, 1H), 3.95 (d, J = 6.0 Hz, 1H), 6.99 (dd, J = 4.0 Hz, 5.20 Hz, 1H), 7.05-7.08 (m, 1H), 7.27 (dd, J = 1.2 Hz, 5.2 Hz, 1H)

Reference Example 95; Ethyl 4-cyano-5-methyl-4- (2-thienyl) hexanolate

1.49 g (13.3 mmol, cat.) Of potassium tert-butoxide was dissolved in 120 ml of DMF, and 43.9 g (0.27 mol) of 3-methyl-2- (2-thienyl) butanonitrile and 30.2 ml of ethyl acrylate were dissolved in this solution. (0.28 mol) was added in small portions at room temperature. (Ethyl acrylate and potassium tert-butoxide were added when the raw material remained.) During this time, the exotherm continued. After completion of the reaction, 100 ml of saturated saline solution and 200 ml of saturated ammonium chloride aqueous solution were added sequentially, and the desired product was extracted with 500 ml of hexane. The organic layer was washed with 400 ml of saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford 67.0 g of crude product of the ester (ethyl 4-cyano-5-methyl-4- (2-thienyl) hexanolate) as a yellow oil. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 2.01-2.19 (m, 3H), 2.41-2.58 (m, 2H), 4.01-4.15 (m, 2H), 6.96 (dd, J = 3.6 Hz, 5.1 Hz1H), 7.12 (dd, J = 1.2 Hz, 3.6 Hz, 1H ), 7.29 (dd, J = 1.2 Hz, 5.1 Hz, 1H)

Reference Example 96; dl-4-cyano-4- (2-thienyl) -5-methylhexanoic acid cyclohexylamine salt

67.0 g of the ester obtained in the Example was dissolved in 500 ml of tetrahydrofuran, and 200 ml of 5N NaOH and 50 ml of ethanol were added to the solution, followed by stirring. After completion of the reaction, the mixture was concentrated under reduced pressure, and the aqueous layer containing the target product was washed with 200 ml × 4 of toluene, 320 ml of 5N HCl was added thereto, adjusted to pH 1-2, and the target product was extracted with 750 ml of toluene. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give 55.6 g (yellow oily phase) as a crude product carboxylic acid. This carboxylic acid was dissolved in 150 ml of toluene, and 22.5 g (0.23 mol) of cyclohexylamine was added. The precipitated white crystals were filtered to give 55.6 g (0.17 mol) of the title compound. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.20-1.40 (m, 6H), 1.57-1.67 (m, 1H), 1.72-1.81 (m, 2H), 1.92-2.11 (m, 3H), 2.30-2.42 (m, 1H), 2.44-2.54 (m, 1H), 2.85-2.96 (m, 1H), 6.95 ( dd, J = 3.2Hz, 5.2Hz1H), 7.11 (dd, J = 1.2Hz, 3.2Hz, 1H), 7.25-7.28 (m, 1H)

Reference Example 97; 4-Cyano-4- (2-thienyl) -5-methylhexanoic acid (S) -1- (4-methylphenyl) ethylamine salt

55 g (0.16 mol) of dl-4-cyano-4- (2-thienyl) -5-methylhexanoic acid cyclohexylamine salt was suspended in 100 ml of 5N HCl and 50 ml of water, and extracted with 300 ml of toluene. After washing with 2N HCl and saturated brine, it was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 38.7 g as a crude carboxylic acid. 38.7 g of this dl-4-cyano-4- (2-thienyl) -5-methylhexanoic acid was dissolved in 120 ml of toluene. 18.8 g (0.14 mol, 0.85 eq) / toluene 40 ml of (S) -1- (4-methylphenyl) ethylamine was added to the solution containing this carboxylic acid, and seeded with crystals (6 mg) of the title compound prepared in advance. And left to cool. The precipitated diastereomeric salt (salt 1) was filtered. Salt 1 was dissolved in 250 ml of toluene by heating and allowed to cool to room temperature under stirring. The precipitated diastereomeric salt (salt 2: optical purity 90.5% ee HPLC) was filtered to give 21.3 g (57.2 mmol, 35.1%) of the title compound (optical purity 90.5% ee).

(Example 2) dl-4-cyano-4- (2-thienyl) -5-methylhexanoic acid (96.6 mmol) was crystallized as a salt according to the above-described dividing method, and then recrystallized twice to repeat the title compound. 14.5 g (38.9 mmol, 40.3%) (optical purity 95% ee <) was obtained. Physical and chemical data of the compound were as follows. Moreover, the conditions of HPLC analysis are shown below, and the analysis result (HPLC chart) is shown in FIG.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 1.95-2.11 (m, 3H), 2.33 (s, 3H), 2.30-2.50 (m, 2H), 3.74 (brd-s, 3H), 6.95 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.10 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.25-7.29 (m, 1H)

HPLC analysis conditions

Column: Daicel chemical industries, Ltd. CHIRALCEL OJ, 4.6x 250mm

Mobile phase: 20% (B)

(A) n-hexane / trifluoroacetic acid mixture (1000: 1)

(B) n-hexane / isopropanol / trifluoroacetic acid mixture (500: 500: 1)

Flow rate: 0.5ml / min

Detector: UV 231nm

Retention time: 15.5 minutes

Reference Example 98; 4-Cyano-4- (2-thienyl) -5-methylhexanoic acid (S) -1-phenylethylamine salt

(S) -1-phenylethylamine (67.4 g) toluene based on dl-4-cyano-4- (2-thienyl) -5-methylhexanoic acid (168.8 g) according to the method according to Reference Example 97 Even if (990 ml) was used, optically active 4-cyano-4- (2-thienyl) -5-methylhexanoic acid (S) -1-phenylethylamine salt (107.7 g, 39%) (white crystals) And optical purity 96.9% ee). Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CD ₃ OD) δ 0.94 (d, J = 7 Hz, 3H), 1.23 (d, J = 7 Hz, 3H ,, 1.65 (d, J = 7 Hz, 3H), 2.02 (ddd, J = 15 Hz, 12 Hz, 4 Hz, 1H), 2.14 (ddd, J = 14 Hz, 12 Hz, 4 Hz, 1H), 2.18 (qq, J = 7 Hz, 7 Hz, 1H), 2.33 (ddd, J = 15 Hz, 12 Hz, 4 Hz, 1H), 2.52 (ddd, J = 14Hz, 12Hz, 4Hz, 1H), 4.44 (q, J = 7Hz, 1H), 7.04 (dd, J = 5Hz, 3Hz, 1H), 7.14 (dd, J = 3Hz, 1 Hz, 1H), 7.44 (dd, J = 5 Hz, 1 Hz, 1H), 7.40-7.50 (m, 5H).

EI-Mass (m / z): 135, 177, 195, 273 (M ⁺ )

Melting Point: 136-144 ℃

HPLC analysis conditions

Column: Daiseru Kogyo, Tokyo: CHIRALCEL OJ

Mobile phase: 10% (B)

(A) n-hexane / trifluoroacetic acid (1000: 1)

(B) n-hexane / 2-propanol / trifluoroacetic acid (500: 500: 1)

Flow rate: 0.5ml / min

Detector: UV 231nm

Retention time: 26.2 minutes

Reference Example 99; 4-Cyano-4- (2-thienyl) -5-methylhexanoic acid (R) -1-phenylethylamine salt

The title compound was obtained as white crystals according to the method of Reference Example 98 using (R) -1-phenylethylamine and dl-4-cyano-4- (2-thienyl) -5-methylhexanoic acid.

Melting Point: 136-144 ℃

HPLC analysis conditions

Column: Daiseru Kogyo, Tokyo: CHIRALCEL OJ

Mobile phase: 10% (B)

(A) n-hexane / trifluoroacetic acid (1000: 1)

(B) n-hexane / 2-propanol / trifluoroacetic acid (500: 500: 1)

Flow rate: 0.5ml / min

Detector: UV 231nm

Retention time: 19.9 minutes

Reference Example 100; 4-Cyano-4- (3-thienyl) -5-methylhexanoic acid (S) -1- (4-methylphenyl) ethyl amine salt

Dl-4-cyano-4- (3-thienyl) -5-methylhexanoic acid (11.4 g) and (S) -1- (4-methylphenyl) ethylamine synthesized according to Reference Example 96 and Reference Example 97 From (5.45 g), 5.60 g (optical purity 86.7% ee) of the title compound were obtained as white crystals. Physical and chemical data of the compound were as follows. Moreover, the conditions of HPLC analysis are shown below, and the analysis result (HPLC chart) is shown in FIG.

Free body: 4-cyano-4- (3-thienyl) -5-methylhexanoic acid;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.85 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 2.02-2.18 (m, 3H), 2.38-2.58 (m, 2H), 6.94 (dd, J = 3.1 Hz, 1.5 Hz, 1H), 7.30 (dd, J = 3.1 Hz, 1.5 Hz, 1H), 7.38 (dd, J = 5.1 Hz, 3.1 Hz, 1H).

Salt: 4-cyano-4- (3-thienyl) -5-methylhexanoic acid. (S) -1- (4-methylphenyl) ethylamine salt;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.42 (d, J = 6.6 Hz, 3H), 1.80-2.10 (m, 3H), 2.27-2.42 (m, 2H), 2.33 (s, 3H), 4.14 (q, J = 6.8 Hz, 1H), 6.91 (dd, J = 5.1 Hz, 1.5 Hz, 1H), 7.13 (brd, J = 8.0 Hz, 2H), 7.20 (brd, J = 8.0 Hz, 2H). 7.24 (dd, J = 3.1 Hz, 1.5 Hz, 1H), 7.33 (dd, J = 5.1 Hz, 3.1 Hz, 1H).

Melting point: 140-143 ℃

HPLC analysis conditions

Column: Daiseru Kogyo, Tokyo: CHIRALCEL OJ

Mobile phase: Hexane: IPA: TFA (900: 100: 1)

Flow rate: 0.5ml / min

Detector: UV 235nm

Retention time: 15.7 minutes

Reference Example 101; Optically active 4-cyano-4- (3-thienyl) -5-methylhexanoic acid

Hydrochloric acid was dissolved in 4-cyano-4- (3-thienyl) -5-methylhexanoic acid (S) -1- (4-methylphenyl) ethylamine salt (5.6 g) by the method according to Reference Example 97. By treatment with the title vitreous (3.94 g). Physical and chemical data of the compound were as follows. Moreover, the conditions of HPLC analysis are shown below, and the analysis result (HPLC chart) is shown in FIG.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.85 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 2.02-2.18 (m, 3H), 2.38-2.58 (m, 2H), 6.94 (dd, J = 3.1 Hz, 1.5 Hz, 1H), 7.30 (dd, J = 3.1 Hz, 1.5 Hz, 1H), 7.38 (dd, J = 5.1 Hz, 3.1 Hz, 1H).

Reference Example 102; 4-Cyano-4- (3-thienyl) -5-methylhexanoic acid (R) -1- (4-methylphenyl) ethyl amine salt

(R) -1- (4-methylphenyl) ethylamine and dl-4-cyano-4- (3-thienyl) -5-methylhexanoic acid were used as white crystals according to the preparation method of the example (35). %, Optical purity 88.5% ee).

* Melting point: 140-143 ℃

HPLC analysis conditions

Column: Daiseru Kogyo, Tokyo: CHIRALCEL OJ

Mobile phase: Hexane: IPA: TFA (900: 100: 1)

Flow rate: 0.5ml / min

Detector: UV 235nm

Retention time: 12.8 minutes

Reference Example 103; 4-Cyano-4- (2-thienyl) -5-methylhexanoic acid (R) -1- (4-methylphenyl) ethyl amine salt

Using (R) -1- (4-methylphenyl) ethylamine and dl-4-cyano-4- (2-thienyl) -5-methylhexanoic acid, the title compound was prepared according to the preparation method of Reference Example 97. . The conditions of HPLC analysis are shown below, and the analysis result (HPLC chart) is shown in FIG.

HPLC analysis conditions

Column: Daicel chemical industries, Ltd. CHIRALCEL OJ, 4.6x 250mm

Mobile phase: 20% (B)

(A) n-hexane / trifluoroacetic acid mixture (1000: 1)

(B) n-hexane / isopropanol / trifluoroacetic acid mixture (500: 500: 1)

Flow rate: 0.5ml / min

Detector: UV 231nm

Retention time: 12.8 minutes

Reference Example 104; 4-cyano-4- (2-thienyl) -5-methylhexanol (optical activator)

The 4-cyano-4- (2-thienyl) -5-methylhexanoic acid (S) -1- (4-methylphenyl) ethylamine salt obtained in Reference Example 97 was returned to the carboxylic acid free body in accordance with Reference Example 97. . 8.31 g (35.0 mmol) of this was dissolved in 140 ml of tetrahydrofuran, and 3 drops of N, N-dimethylformamide were added with a Pasteur pipette, followed by ice cooling. After dropping 3.51 ml (40.3 mmol) of oxalyl chlorides to this reaction solution, it returned to room temperature and stirred for 1.5 hours. After concentrating the reaction solvent under reduced pressure, 80 ml of tetrahydrofuran was added, and ice-cooled again. 75 ml of methanol and 6.10 ml (43.8 mmol) of triethylamine were added thereto, and the temperature was raised to room temperature and stirred. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated aqueous hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the crude product obtained was adjusted by silica gel column chromatography (hexane / ethyl acetate system) to obtain 8.00 g (31.8 mmol, 90.9%) of a methyl ester. 8.00 g (31.8 mmol) of this ester was dissolved in 50 ml of tetrahydrofuran and added dropwise to a THF suspension of 845 mg (22.3 mmol) of lithium aluminum hydride cooled to -50 to -40 ° C, followed by 0.5 hour external temperature. The temperature was raised to 20 ° C. After the completion of the reaction, the mixture was cooled again, 0.9 ml of water, 0.9 ml of 5N sodium hydroxide, and 2.70 ml of water were added sequentially, followed by celite filtration. The filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane / Purification with ethyl acetate) gave 6.60 g (29.6 mmol, 93.1%) of the title compound as a colorless oil. Physical and chemical data of the compound were as follows.

Carboxylic Acid A: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 2.01-2.23 (m, 3H), 2.47-2.58 (m, 2H), 6.97 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.12 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.29 (dd, J = 1.2 Hz, 5.2 Hz, 1H)

Methyl ester obtained from carboxylic acid A: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 2.03-2.20 (m, 3H ), 2.43-2.58 (m, 2H), 3.64 (s, 3H), 6.96 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.12 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.29 ( dd, J = 1.2 Hz, 5.2 Hz, 1H)

Alcohol A: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.33-1.46 (m, 1H), 1.65-1.77 (m, 1H), 1.80-1.90 (m, 1H), 2.08 (sept, J = 6.8 Hz, 1H), 2.27 (ddd, J = 4.4 Hz, 12.0 Hz, 13.2 Hz, 1H), 3.63 (brd-s , 2H), 6.96 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11-7.14 (m, 1H), 7.27 (dd, J = 1.2 Hz, 5.2 Hz, 1H)

Reference Example 105; 4-cyano-4- (5-cyano-2-thienyl) -5-methylhexanol (optical activator)

Using alcohol A obtained in Reference Example 104 as a starting material, a bromolation reaction and a cyanoation reaction were then carried out in accordance with Example 80. That is, 4-cyano-4- (5-bromo-2-thienyl) -5-methylhexanol which is optically active by the bromolation reaction is synthesized, and the title compound is subjected to cyanoation reaction without purification. Yield was obtained in 77.9%. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.94 (d, J = 6.59 Hz, 3H), 1.22 (d, J = 6.78 Hz, 3H), 1.28-1.42 (m, 1H), 1.66-1.78 (m, 1H), 1.83-1.93 (m, 1H), 2.03-2.16 (m, 1H), 2.32 (ddd, J = 4.40 Hz, 12.4 Hz, 13.2 Hz, 1H), 3.58-3.74 (m, 2H), 7.16 ( d, J = 3.60 Hz, 1H), 7.52 (d, J = 3.60 Hz, 1H)

Example 1; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (3-acetylphenoxy) ethyl] piperazine

According to the method of Example 86-5) described in Japanese Patent Application Laid-Open No. 11-206862, the title compound was synthesized (61%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.20 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.50-1.60 (m, 1H), 1.80-1.95 (m, 1H), 2.05-2.20 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.48 (m, 4H), 2.48-2.65 (m, 4H), 2.59 ( s, 3H), 2.81 (t, J = 5.8 Hz, 2H), 4.13 (t, J = 5.8 Hz, 2H), 7.08-7.13 (m, 1H), 7.26-7.32 (m, 1H), 7.34-7.40 (m, 5H), 7.46-7.50 (m, 1H), 7.52-7.56 (m, 1H).

Furthermore, this vitreous body was processed according to the method of Example 20 described in Japanese Patent Application Laid-Open No. 11-206862 to obtain a hydrochloride salt of the title compound.

* ESI-Mass; 448 (MH ⁺ ).

Example 2; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(1-benzyl-2-pyrrolidine) methyl] piperazine

1-benzyl-2-pyrrolidinemethanol (83 mg) was dissolved in acetonitrile (3 ml), and triethylamine (0.18 ml) and mesyl chloride (0.037 ml) were added at room temperature. After stirring for 1 hour at room temperature, a solution of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (124 mg) in acetonitrile (3 ml) was added. After heating to reflux for 3 hours, the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by (NH) silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (58 mg, 29%) as a pale yellow oil. Furthermore, the hydrochloride of the title compound was obtained using the vitreous as hydrochloride in the usual manner.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.18 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.49-1.73 (m, 4H), 1.83-2.00 (m, 3H), 2.07-2.18 (m, 2H), 2.20-2.64 (m, 13H), 2.87-2.93 (m, 1H), 3.23 (d, J = 12.8 Hz, 1H) , 4.19 (d, J = 12.8 Hz, 1H), 7.19-7.39 (m, 10H).

Hydrochloride;

ESI-Mass; 459 (MH ⁺ ).

Example 3; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-benzofuranyl) methyl] piperazin

1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (0.19 g) is dissolved in 1,2-dichloroethane (6 ml) and benzofuran-2-carboaldehyde (0.11 g ), Acetic acid (0.095 ml) and sodium triacetoxy borohydride were added. After stirring at room temperature for 3 hours, ethyl acetate was added, and water was also washed with saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by (NH) silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (0.28 g, quantitative) as a pale yellow oil. Furthermore, the hydrochloride of the title compound was obtained using the vitreous as hydrochloride in the usual manner.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 1.05-1.18 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.48-1.60 (m, 1H), 1.87 (dt, J = 4.4 Hz, J = 12 Hz, 1H), 2.07-2.17 (m, 2H), 2.27 (t, J = 7.2 Hz, 2H), 2.38 (bs, 4H), 2.52 (bs , 4H), 3.66 (s, 2H), 6.57 (s, 1H), 7.17-7.30 (m, 3H), 7.32-7.37 (m, 4H), 7.44-7.53 (m, 2H).

Hydrochloride;

ESI-Mass; 416 (MH ⁺ ).

Example 4; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(1-methyl-2-benzimidazolyl) methyl] piperazine

The title compound of the pale yellow oily substance was obtained according to the method of Example 3 (86%). The vitreous was also made of hydrochloride in the usual manner.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.18 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.47-1.60 (m, 1H), 1.90 (dt, J = 4.4 Hz, J = 12.4 Hz, 1H), 2.05-2.38 (m, 8H), 2.50 (bs, 4H), 3.79 (s, 2H), 3.84 (s, 3H), 7.21-7.40 (m, 8 H), 7.71-7.75 (m, 1 H).

Hydrochloride;

ESI-Mass; 430 (MH ⁺ ).

Example 5; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(3-indolyl) methyl] piperazine

The title compound of the pale yellow oily substance was obtained according to the method of Example 3 (76%). In addition, the hydrochloride salt of the title compound was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 1.04-1.18 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.47-1.60 (m, 1H), 1.86 (dt, J = 4.4 Hz, J = 12.4 Hz, 1H), 2.03-2.16 (m, 2H), 2.22-2.32 (m, 2H), 2.33 (bs, 4H), 2.49 (bs, 4H ), 3.70 (s, 2H), 7.05-7.20 (m, 4H), 7.23-7.48 (m, 5H), 7.70 (d, J = 6.8 Hz, 1H), 8.25-8.40 (m, 1H).

Hydrochloride;

ESI-Mass; 415 (MH ⁺ ).

Example 6; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-quinolinyl) methyl] piperazine

The title compound of the pale yellow oily substance was obtained according to the method of Example 3 (62%). In addition, the hydrochloride salt of the title compound was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06-1.18 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.90 (dt, J = 4.4 Hz, J = 12 Hz, 1H), 2.07-2.18 (m, 2H), 2.24-2.35 (m, 2H), 2.38 (bs, 4H), 2.54 (bs, 4H) , 3.82 (s, 2H), 7.24-7.30 (m, 1H), 7.32-7.38 (m, 4H), 7.51 (d, J = 8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.66 -7.72 (m, 1H), 7.79 (d, J = 8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H).

Hydrochloride;

ESI-Mass; 427 (MH ⁺ ).

Example 7; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(4-phenyl3-pyridyl) methyl] piperazin

The title compound of the light yellow oily substance was obtained according to the method of Example 3 (47%). In addition, the hydrochloride salt of the title compound was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 1.04-1.18 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.47-1.59 (m, 1H), 1.87 (dt, J = 4 Hz, J = 12 Hz, 1H), 2.06-2.34 (m, 8H), 2.34 (bs, 4H), 3.39 (s, 2H), 7.18 (d, J = 4.8 Hz, 1H), 7.25-7.46 (m, 10H), 8.52 (d, J = 4.8 Hz, 1H), 8.63 (s, 1H).

Hydrochloride;

ESI-Mass; 453 (MH ⁺ ).

Example 8; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (1,2,3,4-tetrahydro-2 -naphthoyl) piperazine

Dissolve 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (150 mg) in N, N-dimethylformamide (5 ml) and add 1-hydroxybenzotriazole (71 mg) and 1 , 2,3,4-tetrahydro-2-heptalenic acid (93 mg) was added, followed by addition of a dicyclohexylcarbodiimide (120 mg) solution of N, N-dimethylformamide (2 ml). After stirring overnight at room temperature, the insolubles were separated by filtration, ethyl acetate was added to the filtrate, and a small amount of 1N hydrochloric acid was added and stirred, followed by washing with a saturated aqueous sodium carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by (NH) silica gel column chromatography (hexane / ethyl acetate system) to give the title compound (220 mg, 94%) as a pale yellow oil. In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.04-1.20 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.50-1.63 (m, 1H), 1.86-2.04 (m, 3H), 2.09-2.23 (m, 2H), 2.24-2.36 (m, 6H), 2.75-2.94 (m, 4H), 3.03-3.12 (m, 1H), 3.49 ( t, J = 4.8 Hz, 2H), 3.56-3.68 (m, 2H), 7.06-7.13 (m, 4H), 7.27-7.40 (m, 5H).

Hydrochloride;

ESI-Mass; 444 (MH ⁺ ).

Example 9; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(1,2,3,4-tetrahydro- 2-naphthyl) methyl] piperazine

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (1,2,3,4-tetrahydro-2-naphthoyl) piperidine (150 mg) was added to tetrahydrofuran ( 5 ml), and 1.0 M borane tetrahydrofuran complex (1.35 ml) was added under ice-cooling. After stirring at room temperature for 5 hours, the mixture was concentrated under reduced pressure, methanol (5 ml) and 2N hydrochloric acid (5 ml) were added, and the mixture was stirred at 80 ° C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by preparative thin layer silica gel column chromatography (methylene chloride / methanol) to give the title compound (72 mg, 50%) as a pale yellow oil. In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.04-1.20 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H), 1.29-1.43 (m, 2H), 1.51-1.63 (m, 2H), 1.65-1.73 (m, 1H), 1.90 (dt, J = 4.4 Hz, J = 12 Hz, 1H), 1.90-2.00 (m, 4H), 2.08-2.19 ( m, 2H), 2.25-2.48 (m, 7H), 2.77-2.92 (m, 3H), 7.04-7.10 (m, 4H), 7.26-7.48 (m, 5H).

Hydrochloride;

ESI-Mass; 430 (MH ⁺ ).

Example 10; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (1,4-benzodioxanoyl)] piperazine

The title compound of the pale yellow oily substance was obtained according to the method of Example 8 (86%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.08-1.20 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.51-1.63 (m, 1H), 1.92 (dt, J = 4.4 Hz, J = 12 Hz, 1H), 2.09-2.23 (m, 2H), 2.25-2.40 (m, 6H), 3.49-3.57 (m, 2H), 3.63-3.76 ( m, 2H), 4.30 (dd, J = 8 Hz, J = 12 Hz, 1H), 4.46 (dd, J = 2.8 Hz, J = 12 Hz, 1H), 4.79 (dd, J = 2.8 Hz, J = 8 Hz, 1H ), 6.83-6.91 (m, 4H), 7.27-7.40 (m, 5H).

Hydrochloride;

ESI-Mass; 448 (MH ⁺ ).

Example 11; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (1,4-benzodioxanyl) methyl ] piperazine

According to the method of Example 9, the title compound was obtained in light yellow oily form (56%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.16-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.89 (dt, J = 4.4 Hz, J = 12.8 Hz, 1H), 2.08-2.19 (m, 2H), 2.24-2.34 (m, 2H), 2.36 (bs, 4H), 2.52 (bs, 4H ), 2.61 (ddd, J = 5.6 Hz, J = 13.2 Hz, J = 40.4 Hz, 2H), 3.96 (dd, J = 7.6 Hz, J = 11.6 Hz, 1H), 4.24-4.31 (m, 2H), 6.79-6.89 (m, 4 H), 7.26-7.39 (m, 5 H).

Hydrochloride;

ESI-Mass; 434 (MH ⁺ ).

Example 12; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (1-methyl-2-indoyl) piperazin

The title compound of the pale yellow oily substance was obtained according to the method of Example 8 (82%). The hydrochloride of the vitreous (title compound) was obtained by a conventional method.

* Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.08-1.20 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.87-1.97 (m, 1H), 2.08-2.22 (m, 2H), 2.28-2.38 (m, 6H), 3.72 (bs, 4H), 3.81 (s, 3H), 6.56 (s, 1H) , 7.10-7.16 (m, 1 H), 7.25-7.39 (m, 7 H), 7.61 (d, J = 8 Hz, 1 H).

Hydrochloride;

ESI-Mass; 443 (MH ⁺ ).

Example 13; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(1-methyl-2-indolyl) methyl] piperazine

The title compound of the pale yellow oily substance was obtained according to the method of Example 9 (40%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06-1.20 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.49-1.62 (m, 1H), 1.89 (dt, J = 4.4 Hz, J = 12 Hz, 1H), 2.07-2.17 (m, 2H), 2.21-2.37 (m, 6H), 2.44 (bs, 4H), 3.60 (s, 2H) , 3.76 (s, 3H), 6.34 (s, 1H), 7.07 (t, J = 8Hz, 1H), 7.18 (t, J = 8Hz, 1H), 7.25-7.38 (m, 6H), 7.54 (d, J = 8 Hz, 1H).

Hydrochloride;

ESI-Mass; 429 (MH ⁺ ).

Example 14; 2-[(4-cyano-5-methyl-4-phenyl) hexyl] -5- [2- (4-fluorophenoxy) ethyl] -2,5-diazabicyclo [2,2,1 ] Heptane

2-[(4-cyano-5-methyl-4-phenyl) hexyl] -5-benzyl-2,5-diazabicyclo [2,2,1] heptane (37 mg) was dissolved in methanol (5 ml) , 20% palladium hydroxide carbon (10 mg) was added, and hydrogenated at room temperature and normal pressure for 8 hours. After the catalyst was separated by filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow oily residue (29 mg). This residue was dissolved in N, N-dimethylformamide (3 ml), and triethylamine (0.027 ml) and 2- (4-fluorophenoxy) ethyl bromide (25 mg) of N, N-dimethylformamide (2 ml ) Solution was added. After stirring at 50 degreeC overnight, it cooled to room temperature, ethyl acetate was added, and it wash | cleaned with water and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by preparative thin-layer silica gel column chromatography (methylene chloride / methanol system) to obtain the title compound (20 mg, 48%) as a pale yellow oil. In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.06-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.45-1.57 (m, 1H), 1.66-1.73 (m, 2H), 1.95 (dt, J = 4.4 Hz, J = 12 Hz, 1H), 2.11 (qui, J = 6.8 Hz, 1H), 2.14-2.23 (m, 1H), 2.32 -2.40 (m, 1H), 2.51-2.61 (m, 2H), 2.63-2.81 (m, 3H), 2.91 (dqui, J = 6 Hz, J = 40.4 Hz, 2H), 3.21 (s, 1H), 3.36 (s, 1H), 3.94-4.03 (m, 2H), 6.79-6.85 (m, 2H), 6.92-7.00 (m, 2H), 7.26-7.40 (m, 5H).

Hydrochloride;

ESI-Mass; 436 (MH ⁺ ).

Example 15; 8-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-phenyl-1,3,8-triazaspiro- [4,5] decan-4-one

4-cyano-5-methyl-4-phenylhexanol (120 mg) was dissolved in acetonitrile (6 ml), and triethylamine (0.23 ml) and mesyl chloride (0.051 ml) were added at room temperature. After stirring for 1 hour at room temperature, a solution of 1-phenyl-1,3,8-triazaspiro- [4,5] decan-4-one (140 mg) in acetonitrile (3 ml) was added. After heating to reflux for 2.5 hours, the mixture was allowed to cool to room temperature, ethyl acetate was added, and the mixture was washed with water and brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by preparative thin layer silica gel column chromatography (hexane / ethyl acetate system) to obtain a pale yellow oily title compound (61 mg, 26%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.79 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.26 (t, J = 7.2 Hz, 2H), 1.55-1.73 (m, 3H), 1.94-2.05 (m, 1H), 2.08-2.25 (m, 2H), 2.38-2.52 (m, 2H), 2.60-2.90 (m, 6H), 4.72 (s, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8 Hz, 2H), 7.24-7.31 (m, 2H), 7.33-7.41 (m, 4H), 7.62 (bs, 1H).

Hydrochloride;

ESI-Mass; 431 (MH ⁺ ).

Example 16; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-keto-1-benzimidisolinyl ) piperidine

The pale yellow oily title compound was obtained according to the method of Example 15 (23%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.79 (d, J = 6.8 Hz, 3H), 1.11-1.34 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H), 1.55-1.67 (m, 1H), 1.73-1.82 (m, 2H), 1.90-2.05 (m, 2H), 2.08-2.23 (m, 3H), 2.30-2.52 (m, 4H), 2.88-3.02 (m, 2H), 4.28- 4.38 (m, 1H), 7.00-7.07 (m, 2H), 7.09-7.13 (m, 1H), 7.22-7.32 (m, 2H), 7.33-7.43 (m, 4H), 10.12-10.30 (m, 1H ).

Hydrochloride;

ESI-Mass; 417 (MH ⁺ ).

Example 17; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-benzoxazolyl) amino] piperidine

The title compound of the pale yellow oily substance was obtained according to the method of Example 15 (30%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.08-1.19 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.47-1.62 (m, 3H), 1.75-1.83 (m, 1H), 1.89 (dt, J = 4.4 Hz, J = 13.6 Hz, 1H), 2.00 (bt, J = 12.4 Hz, 1H), 2.04-2.20 (m, 4H), 2.25-2.31 (m, 2H), 2.72 (bt, J = 11.6 Hz, 2H), 3.69-3.80 (m, 1H), 4.92-5.02 (m, 1H), 6.99-7.05 (m, 1H), 7.13- 7.17 (m, 1 H), 7.20-7.25 (m, 1 H), 7.25-7.32 (m, 1 H), 7.33-7.40 (m, 5H).

Hydrochloride;

ESI-Mass; 417 (MH ⁺ ).

Example 18; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-benzothiazolyl) aminopiperidine

The pale yellow oily title compound was obtained by following the method of Example 15 (52%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.06-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.46-1.62 (m, 3H), 1.77 (bs, 1H), 1.85-1.94 (m, 1H), 1.96-2.05 (m, 1H), 2.05-2.18 (m, 4H), 2.25-2.32 (m, 2H), 2.70 (bt, J = 12.4 Hz, 2H), 3.56-3.66 (m, 1H), 5.24 (bd, J = 6.8 Hz, 1H), 7.04-7.09 (m, 1H), 7.25-7.32 (m, 2H), 7.33-7.39 (m, 4H), 7.50-7.58 (m, 2H).

Hydrochloride;

ESI-Mass; 433 (MH ⁺ ).

Example 19; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-benzothiazolyl) (methyl) amino] piperidine

The title compound of the pale yellow oily substance was obtained according to the method of Example 15 (30%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.08-1.20 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.51-1.64 (m, 1H), 1.74-2.20 (m, 9H), 2.30 (t, J = 7.2 Hz, 2H), 2.82-2.93 (m, 2H), 3.05 (s, 3H), 3.94-4.05 (m, 1H), 7.01 -7.06 (m, 1 H), 7.24-7.33 (m, 2H), 7.34-7.40 (m, 4H), 7.51-7.59 (m, 2H).

Hydrochloride;

ESI-Mass; 447 (MH ⁺ ).

Example 20; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-benzothiazolyl) (2 -propyl) amino] piperidine

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-benzothiazolyl) amino] piperidine (50 mg) synthesized in Example 18 was diluted with N, N-dimethyl. It was dissolved in formamide (3 ml) and 60% sodium hydride (7 mg) was added. After stirring at 50 ° C for 1 hour, 2-bromopropane (0.012 ml) was added. After stirring overnight at 50 ° C., 2-bromopropane (0.012 ml) was added. After stirring at 50 ° C. for 6 hours, 60% sodium hydride (7 mg) was added. After stirring overnight at 50 ° C, the mixture was allowed to cool to room temperature, ethyl acetate was added, and the mixture was washed with water and brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by (NH) silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (31 mg, 57%) as a pale yellow oil. In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.4 Hz, 3H), 1.08-1.20 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.50 (d, J = 6.8 Hz, 6H), 1.69-2.34 (m, 13H), 2.63-2.74 (m, 2H), 2.81-2.90 (m, 1H), 6.86-6.91 (m, 1H), 6.96-7.02 (m, 1H) , 7.11-7.16 (m, 1H), 7.25-7.32 (m, 2H), 7.33-7.41 (m, 4H).

Hydrochloride;

ESI-Mass; 475 (MH ⁺ ).

Example 21; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(1-methyl-2-benzimidazolyl ) amino] piperidine

The title compound of the pale yellow oily substance was obtained according to the method of Example 15 (12%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.06-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.42-1.61 (m, 3H), 1.84-1.93 (m, 1H), 1.98-2.20 (m, 6H), 2.27 (t, J = 7.2 Hz, 2H), 2.69-2.76 (m, 2H), 3.45 (s, 3H), 3.86 -4.01 (m, 2H), 7.01-7.12 (m, 3H), 7.26-7.31 (m, 1H), 7.33-7.39 (m, 4H), 7.45 (d, J = 7.6 Hz, 1H).

Hydrochloride;

ESI-Mass; 430 (MH ⁺ ).

Example 22; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[[1- (2-propyl) -2-benzimidazolyl ] amino] piperidine

The pale yellow oily title compound was obtained by the method of Example 15 (54%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.08-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.40-1.55 (m, 3H), 1.57 (d, J = 6.8 Hz, 6H), 1.85-1.93 (m, 2H), 2.02-2.20 (m, 5H), 2.28 (t, J = 7.2 Hz, 2H), 2.67-2.75 (m , 2H), 3.85-4.00 (m, 2H), 4.33 (qui, J = 6.8 Hz, 1H), 6.97-7.10 (m, 2H), 7.20-7.32 (m, 2H), 7.34-7.39 (m, 4H ), 7.46-7.48 (m, 1 H).

Hydrochloride;

ESI-Mass; 458 (MH ⁺ ).

Example 23; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(5,6-dimethoxy-1-indanon ) -2-yl] methylpiperidine

The title compound of the pale yellow oily substance was obtained according to the method of Example 15 (30%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.08-1.36 (m, 4H), 1.20 (d, J = 6.8 Hz, 3H), 1.38-1.95 (m, 8H), 2.08-2.18 (m, 2H), 2.18-2.32 (m, 2H), 2.65-2.83 (m, 4H), 3.22 (dd, J = 8 Hz, J = 17.6 Hz, 1H), 3.90 (s, 3H), 3.96 (s, 3H), 6.86 (s, 1H), 7.16 (s, 1H), 7.26-7.41 (m, 5H).

Hydrochloride;

ESI-Mass; 489 (MH ⁺ ).

Example 24; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[[2- (4-fluorophenoxy) ethyl] (2-cyanoethyl) amino] piperidine

The pale yellow oily title compound was obtained by following the method of Example 35 (21%). In addition, the hydrochloride of the vitreous (title compound) was obtained by a conventional method.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06-1.18 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.42-1.61 (m, 3H), 1.66-1.80 (m, 3H), 1.83-1.92 (m, 2H), 2.08-2.17 (m, 2H), 2.19-2.32 (m, 2H), 2.43-2.53 (m, 1H), 2.44 ( t, J = 6.8 Hz, 2H), 2.78-2.94 (m, 6H), 3.92 (t, J = 6 Hz, 2H), 6.79-6.85 (m, 2H), 6.94-7.00 (m, 2H), 7.27- 7.39 (m, 5 H).

Hydrochloride;

ESI-Mass; 491 (MH ⁺ ).

Example 25; 1- [4-cyano-5-methyl-4- (2-naphthyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] piperazine

310 mg (1.16 mmol) of 4-cyano-5-methyl-4- (2-naphthyl) hexanol was dissolved in 5 ml of acetonitrile, 190 µl (1.36 mmol) of triethylamine and 105 µl (1.36 mmol) of mesyl chloride. Added. After the end of mesylation, 1.11 g (7.38 mmol) of sodium iodide, 255 mg (1.85 mmol) of potassium carbonate, 414 mg (1.85 mmol) of 1- [2- (4-fluorophenoxy) ethyl] piperazine, 5 ml of dimethylformamide, 1 ml of water was added and it heated to 60 degreeC. After the reaction was completed, saturated brine was added, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This crude product was treated with Cromatorex NH silica gel (eluted with ethyl acetate / hexane = 2/3) to give 384 mg (0.81 mmol, 69.9%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.79 (d, J = 6.8 Hz, 3H), 1.05-1.15 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 1.50-1.65 (m, 1H), 1.93-2.05 (m, 1H), 2.18-2.60 (m, 12H), 2.75 (t, J = 5.8 Hz, 1H), 4.02 (t, J = 5.8 Hz, 2H), 6.78-6.83 (m , 2H), 6.91-6.97 (m, 2H), 7.36 (dd, J = 2.0 Hz, 8.8 Hz, 1H), 7.48-7.54 (m, 2H), 7.81-7.88 (m, 3H), 7.94 (brd- s, 1 H)

ESI-MS: 474 (M + H) ⁺

Example 26; 1- [4-cyano-5-methyl-4- (1-naphthyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] piperazine

According to the method of Example 25, the title compound was obtained as a colorless oil (yield 57.8%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.70-0.90 (m, 3H), 0.95-1.10 (m, 1H), 1.20-1.40 (m, 4H), 1.50-1.65 (m, 1H), 1.93-2.05 (m, 1H), 2.10-2.56 (m, 10H), 2.56-2.70 (m, 1H), 2.73 (t, J = 5.8 Hz, 1H), 2.90-3.00 (m, 1H), 4.01 (t, J = 5.8 Hz, 2H), 6.78-6.83 (m, 2H), 6.91-6.97 (m, 2H), 7.40-7.50 (m, 3H), 7.78-7.92 (m, 3H), 8.22-8.31 (brd-s , 1H)

ESI-MS: 474 (M + H) ⁺

Example 27; 1- [4-cyano-5-methyl-4- (2-pyridyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] piperazine

The crude aldehyde obtained by oxidizing 4-cyano-5-methyl-4- (2-pyridyl) hexanol synthesized according to the method of Example 25 with SO ₃ -pyridine, which is a conventional method, was used in Example 42 The title compound (yield 69.1%) of colorless oil was synthesized by reductive amination according to the method.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.74 (d, J = 6.8 Hz, 3H), 0.90-1.10 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.24-1.30 (m, 1H), 1.53-1.66 (m, 1H), 2.03-2.23 (m, 2H), 2.24-2.74 (m, 10H), 2.81 (t, J = 5.4 Hz, 2H), 4.06t, J = 5.4 Hz, 2H), 6.79-6.85 (m, 2H), 6.92-6.98 (m, 2H), 7.21 (ddd, J = 1.2 Hz, 4.8 Hz, 8.0 Hz, 1H), 7.57 (dt, J = 1.2 Hz, 8.0 Hz , 1H), 7.69 (dt, J = 2.0 Hz, 8.0 Hz, 1H), 8.58-8.62 (m, 1H)

ESI-MS: 425 (M + H) ⁺

Example 28; 1- [4-cyano-5-methyl-4- (4-pyridyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] piperazine

According to the method of Example 25, the title compound was obtained as a yellow oil (yield 70%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.79 (d, J = 6.8 Hz, 3H), 1.00-1.20 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.50-1.64 (m, 1H), 1.85-2.00 (m, 1H), 2.08-2.25 (m, 2H), 2.26-2.75 (m, 10H), 2.82 (t, J = 5.4 Hz, 2H), 4.07 (t, J = 5.4 Hz , 2H), 6.79-6.85 (m, 2H), 6.92-6.98 (m, 2H), 7.31 (dd, J = 1.6 Hz, 4.4 Hz, 2H), 8.63 (dd, J = 1.6 Hz, 4.4 Hz, 2H )

ESI-MS: 425 (M + H) ⁺

Example 29; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-phenylpiperazine

100 mg (0.30 mmol) of 4-cyano-5-methyl-5-phenylhexyl iodide was dissolved in 2 ml of acetonitrile, and 55 mg (0.36 mmol) of potassium carbonate and 60 mg (0.36 mmol) of phenylpiperazine were added at 60 ° C. Heated to. After the reaction was completed, the mixture was partitioned with ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. This crude product was treated with 20 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/5) to give 137 mg (quantitative) of the title compound as a colorless syrup. Physical and chemical data of the title compound are as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.4 Hz, 3H), 1.08-1.26 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.52-1.66 (m, 1H), 1.88-1.98 (m, 1H), 2.08-2.23 (m, 2H), 2.28-2.37 (m, 2H), 2.42-2.52 (m, 4H), 3.10-3.20 (m, 4H), 6.82- 6.86 (m, 1H), 6.88-6.92 (m, 2H), 7.22-7.32 (m, 4H), 7.34-7.40 (m, 3H)

ESI-MS: 362 (M + H) ⁺

Example 30; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-phenylethyl) piperazine

Using 1- (2-phenylethyl) piperazine, the title compound was synthesized according to the method of Example 29 (yield 100%; colorless oil).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.4 Hz, 3H), 1.08-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.63 (m, 1H), 1.84-1.93 (m, 1H), 2.07-2.19 (m, 2H), 2.24-2.60 (m, 12H), 2.74-2.82 (m, 2H), 7.16-7.21 (m, 3H), 7.24- 7.31 (m, 3H), 7.35-7.38 (m, 4H)

ESI-MS: 390 (M + H) ⁺

Example 31; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (3-phenylpropyl) piperazine

The title compound was synthesized according to the method of Example 29 using 1- (3-phenylpropyl) piperazine (yield 100%; colorless oil).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.04-1.20 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.50-1.62 (m, 1H), 1.74-1.92 (m, 3H), 2.06-2.18 (m, 2H), 2.20-2.50 (m, 12H), 2.61 (t, J = 7.6 Hz, 2H), 7.14-7.19 (m, 3H) , 7.23-7.31 (m, 3H), 7.34-7.37 (m, 4H)

ESI-MS: 404 (M + H) ⁺

Example 32; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) -N- {2- (3-fluorophenoxy) ethyl} amino] Pyrrolidine

Dissolve 250 mg (0.74 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) amino] pyrrolidine in 7 ml of dichloromethane and separate 171 mg (1.11 mmol) of synthesized 3-fluorophenoxyacetaldehyde, 0.08 ml (1.48 mmol) of acetic acid, and 235 mg (1.11 mmol) of sodium triacetoxyborohydride were added in this order. After completion of the reaction, the mixture was adjusted to alkaline with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 25 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/3) to give 290 mg (0.61 mmol, 82.2%) of the title compound as a colorless syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.25 (m, H), 1.20 (d, J = 6.8 Hz, 3H), 1.47-1.80 (m, 2H), 1.85-2.28 (m, 4H), 2.29-2.70 (m, 6H), 2.48 (t, J = 6.8 Hz, 2H), 2.90-3.25 (m, 4H), 3.40-3.55 (m, 1H) , 3.98 (t, J = 5.6 Hz, 2H), 6.56-6.62 (m, 1H), 6.63-6.90 (m, 3H), 7.18-7.25 (m, 1H), 7.26-7.40 (m, 5H)

ESI-MS: 477 (M + H) ⁺

Example 33; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) -N- {2- (3-cyanophenoxy) ethyl} amino] Pyrrolidine

250 mg (0.74 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) amino] pyrrolidine was dissolved in 7 ml of dichloromethane, Separately, 179 mg (1.11 mmol) of 3-cyanophenoxyacetaldehyde, 0.08 ml (1.48 mmol), and sodium triacetoxyborohydride 235 mg (1.11 mmol) synthesized in the same manner as in the preparation of 3-fluorophenoxyacetaldehyde In turn. After completion of the reaction, the mixture was adjusted to alkaline with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 25 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/3) to give 318 mg (0.66 mmol, 88.9%) of the title compound as a colorless syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.25 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.47-1.80 (m, 2H), 1.85-2.28 (m, 4H), 2.29-2.72 (m, 6H), 2.48 (t, J = 6.8 Hz, 2H), 2.90-3.05 (m, 4H), 3.42-3.55 (m, 1H) , 4.01 (t, J = 5.6 Hz, 2H), 7.11-7.15 (m, 2H), 7.23-7.40 (m, 7H)

ESI-MS: 484 (M + H) ⁺

Example 34; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) -N- {2- (2-cyanophenoxy) ethyl} amino] Pyrrolidine

Dissolve 263 mg (0.78 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) amino] pyrrolidine in 7 ml of dichloromethane and separate 251 mg (1.56 mmol) of synthesized 3-cyanophenoxyacetaldehyde, 0.09 ml (1.56 mmol) of acetic acid, and 247 mg (1.17 mmol) of sodium triacetoxyborohydride were added in this order. After the completion of the reaction, the mixture was adjusted to alkaline with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 25 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/3) to give 311 mg (0.64 mmol, 82.4%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.25 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 1.45-1.80 (m, 2H), 1.85-2.16 (m, 3H), 2.16-2.70 (m, 7H), 2.54 (t, J = 6.8 Hz, 2H), 2.90-3.12 (m, 4H), 3.45-3.60 (m, 1H) , 4.11 (t, J = 6.8 Hz, 2H), 6.40-7.04 (m, 2H), 7.26-7.40 (m, 5H), 7.50-7.58 (m, 2H)

ESI-MS: 484 (M + H) ⁺

Example 35; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -3- [N- (2-cyanoethyl) -N- {2- (4-cyanophenoxy) ethyl} amino] Pyrrolidine

217 mg (1.00 mmol) of 4-cyano-5-methyl-5-phenylhexylhexanol was dissolved in 5.00 ml of acetonitrile and cooled to 0 ° C. After adding 320 µl (2.30 eq) of triethylamine and 85 µl (1.10 eq) of mesyl chloride to the solution, the temperature was raised to room temperature. After 15 minutes, 450 mg (3.00 eq) of sodium iodide, 370 mg (1.30 mmol) of 3- [N- (2-cyanoethyl) -N- {2- (4-cyanophenoxy) ethyl} amino] pyrrolidine Was added, and it heated at 60 degreeC. After the reaction was completed, saturated brine was added, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This crude product was treated with 37 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/1) to give 316 mg (0.65 mmol, 65%) of the title compound as a pale yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.10-1.25 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 1.48-1.63 (m, 1H), 1.65-1.77 (m, 1H), 1.78-1.97 (m, 1H), 1.98-2.17 (m, 2H), 2.19-2.30 (m, 1H), 2.30-2.73 (m, 6H), 2.48 ( t, J = 6.8 Hz, 2H), 2.90-3.07 (m, 4H), 3.43-3.56 (m, 1H), 4.04 (t, J = 5.8 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H ), 7.27-7.34 (m, 1H), 7.34-7.40 (m, 4H), 7.59 (d, J = 9.2 Hz, 2H)

ESI-MS: 484 (M + H) ⁺

Example 36; 1-[(4-cyano-5-methyl-4- (2-thienyl) hexyl) -3- [N- (2-cyanoethyl) -N- {2- (4-cyanophenoxy) Ethyl} amino] pyrrolidine

The title compound was synthesized according to the method of Example 35 using 4-cyano-5-methyl-5- (2-thienyl) hexanol (yield 38%; light yellow syrup).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.25-1.40 (m, 1H), 1.55-1.85 (m, 2H), 1.98-2.12 (m, 3H), 2.18-2.78 (m, 7H), 2.48 (t, J = 6.8 Hz, 2H), 2.90-3.10 (m, 4H), 3.44-3.58 (m, 1H) , 4.05 (t, J = 5.6 Hz, 2H), 6.92-6.98 (m, 3H), 7.10-7.13 (m, 1H), 7.25-7.29 (m, 1H), 7.59 (d, J = 8.8 Hz, 2H )

ESI-MS: 490 (M + H) ⁺

Example 37; 1-[(4-cyano-5-methyl-4- (2-thienyl) hexyl) -3- [N- (2-cyanoethyl) -N- {2- (3-cyanophenoxy) Ethyl} amino] pyrrolidine

The title compound was synthesized according to the method of Example 35 using 4-cyano-5-methyl-5- (2-thienyl) hexanol and 3-cyanophenoxyacetaldehyde (yield 98%; light yellow) syrup).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.28-1.45 (m, 1H), 1.58-1.90 (m, 2H), 2.00-2.15 (m, 3H), 2.20-2.31 (m, 1H), 2.32-2.80 (m, 6H), 2.49 (t, J = 6.8 Hz, 2H), 2.90-3.08 (m, 4H) , 3.47-3.62 (m, 1H), 4.02 (t, J = 5.6 Hz, 2H), 6.96 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 7.11-7.16 (m, 3H), 7.24-7.29 ( m, 2H), 7.38 (dd, J = 7.8 Hz, 9.0 Hz, 1H)

ESI-MS: 490 (M + H) ⁺

Example 38; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(6-phenylpyridin-3-yl) methyl] piperazine

(6-phenylpyridin-3-yl) methanol (185 mg, 1.00 mmol) and 0.29 ml of triethylamine were dissolved in 5 ml of acetonitrile, and 85.1 µl (1.10 mmol) of methanesulfonyl chloride was added dropwise. After confirming the disappearance of the raw material by thin layer chromatography, 340 mg (1.19 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine at room temperature was added to the reaction solution. 899 mg sodium iodide, 5 ml of dimethylformamide, and 1 ml of water were added. Then, it heated at 80 degreeC. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/2) to give 300 mg (0.66 mmol, 66.3%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06-1.26 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.48-1.64 (m, 1H), 1.84-1.97 (m, 1H), 2.06-2.22 (m, 2H), 2.23-2.60 (m, 10H), 3.54 (s, 2H), 7.24-7.32 (m, 1H), 7.32-7.43 ( m, 5H), 7.43-7.50 (m, 2H), 7.66-7.74 (m, 2H), 7.95-7.99 (m, 2H), 8.58 (brd-s, 1H)

ESI-MS: 453 (M + H) ⁺

Example 39; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(5-phenylisoxazo-3-yl) methyl ] piperazine

0.15-ml (5-phenylisoxazol-3-yl) methanol (61.3 mg, 0.35 mmol) and triethylamine were dissolved in 3 ml of acetonitrile, and 27.1 µl (0.35 mmol) of methanesulfonyl chloride was added dropwise. After confirming the disappearance of the raw material by thin layer chromatography, 100 mg (0.35 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine at room temperature was added to the reaction solution, followed by 262 mg of sodium iodide. And 2 ml of dimethylformamide were added. Then, it heated at 70 degreeC. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 15 g of Cromatorex NH silica gel (ethyl acetate / hexane = 2/3) to give 45 mg (0.10 mmol, 29.0%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06-1.26 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.48-1.64 (m, 1H), 1.86-1.98 (m, 1H), 2.06-2.20 (m, 2H), 2.25-2.70 (m, 10H), 3.63 (s, 2H), 6.54 (s, 1H), 7.24-7.32 (m, 1H), 7.32-7.39 (m, 4H), 7.39-7.49 (m, 3H), 7.74-7.79 (m, 2H)

ESI-MS: 443 (M + H) ⁺

Example 40; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-phenylthiazo-4-yl) methyl] piperazine

0.10 ml of (2-phenylthiazol-4-yl) methanol (66.9 mg, 0.35 mmol) and triethylamine were dissolved in 3 ml of acetonitrile, and 27.1 µl (0.35 mmol) of methanesulfonyl chloride was added dropwise. After confirming the disappearance of the raw material by thin layer chromatography, 100 mg (0.35 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine at room temperature was added to the reaction solution, followed by 262 mg of sodium iodide. , 2 ml of dimethylformamide and 2 ml of acetonitrile were added. Then, it heated at 70 degreeC. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 15 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/2) to give 63 mg (0.14 mmol, 40.0%) of the title compound as a colorless syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.25 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.48-1.64 (m, 1H), 1.82-1.98 (m, 1H), 2.05-2.22 (m, 2H), 2.23-2.80 (m, 10H), 3.74 (s, 2H), 7.13 (s, 1H), 7.25-7.32 (m, 1H), 7.32-7.39 (m, 4H), 7.39-7.45 (m, 3H), 7.91-7.95 (m, 2H)

ESI-MS: 459 (M + H) ⁺

Example 41; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(2-phenyloxazo4-yl) methyl] piperazine

(2-phenyloxazol-4-yl) methanol (61.3 mg, 0.35 mmol) and 0.10 ml of triethylamine were dissolved in 3 ml of acetonitrile, and 27.1 µl (0.35 mmol) of methanesulfonyl chloride was added dropwise. After confirming the disappearance of the raw material by thin layer chromatography, 100 mg (0.35 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine at room temperature was added to the reaction solution, followed by 262 mg of sodium iodide. And 2 ml of dimethylformamide were added. Then, it heated at 70 degreeC. Saturated brine was added after completion | finish of reaction, and it extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 15 g of Cromatorex NH silica gel (ethyl acetate / hexane = 2/3) to give 41 mg (0.09 mmol, 26.5%) of the title compound as a colorless syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.07-1.24 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.49-1.64 (m, 1H), 1.84-1.96 (m, 1H), 2.06-2.20 (m, 2H), 2.26-2.74 (m, 10H), 3.54 (s, 2H), 7.24-7.32 (m, 1H), 7.32-7.39 ( m, 4H), 7.41-7.46 (m, 3H), 7.58 (s, 1H), 8.01-8.06 (m, 2H)

ESI-MS: 443 (M + H) ⁺

Further, in the above examples, (6-phenylpyridin-3-yl) methanol and (5-phenylisoxazol-3-yl) methanol are Med. Chem. Synthesis was carried out according to the method described in 1998 , 41, 2390-2410, and (2-phenyloxazol-4-yl) methanol was obtained from Org. Chem. It synthesize | combined according to the method of 1996 , 61, 6496-6497, and (2-phenylthiazol-4-yl) methanol was Bull. Chem. Soc. It synthesize | combined according to the method described in Jpn, 71 , 1391-1396 (1998).

Example 42; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (4-phenyl-2-oxo-3-oxa zolidinyl) ethyl] piperazine

2- (4-phenyl-2-oxo-3-oxazolidinyl) acetaldehyde dimethyl acetal was dissolved in 5 ml of acetone and 6 ml of 2.5N hydrochloric acid and heated. After completion of the reaction, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure to give 300 mg of a crude product of 2- (4-phenyl-2-oxo-3-oxazolidinyl) acetaldehyde. Got. This crude product was used for the following reactions without purification. That is, 2- (4-phenyl-2-oxo-3-oxazolidinyl) acetaldehyde is dissolved in 5 ml of dichloroethane, and the above 2- (4-phenyl-2-oxo-3-oxazolidinyl) acetaldehyde 300 mg (1.46 mmol), 0.11 ml (2.00 mmol) of acetic acid and 318 mg (1.50 mmol) of sodium triacetoxyborohydride were added sequentially. After completion of the reaction, the mixture was adjusted to alkaline with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/1) to give 447 mg (0.94 mmol, 94.2%) of the title compound as a colorless syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.08-1.22 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.48-1.63 (m, 1H), 1.85-1.96 (m, 1H), 2.06-2.18 (m, 2H), 2.20-2.52 (m, 12H), 2.84 (dt, J = 6.4 Hz, 14.4 Hz, 1H), 3.57 (dt, J = 6.4 Hz, 14.4 Hz, 1H), 4.05 (dd, J = 7.6 Hz, 8.8 Hz, 1H), 4.61 (t, J = 8.8 Hz, 1H), 4.90-4.98 (m, 1H), 7.25-7.32 ( m, 2H), 7.34-7.43 (m, 8H)

ESI-MS: 475 (M + H) ⁺

Example 43; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(3-phenyl-2-oxo-5-oxazole ridinyl) methyl] piperazine

J. Med. Chem. 5- (hydroxymethyl) -3-phenyl-2-oxooxazolidine was synthesized according to the method described in 989 , 2, 673-1681. This 5- (hydroxymethyl) -3-phenyl-2-oxooxazolidine (193 mg, 1.00 mmol) and 0.29 ml of triethylamine were dissolved in 5 ml of acetonitrile, and 85.1 µl (1.10 mmol) of methanesulfonyl chloride was dissolved. Dropped. After disappearance of the raw material was confirmed by thin layer chromatography, 340 mg (1.19 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine at room temperature was added to the reaction solution, followed by 899 mg of sodium iodide. , 5 ml of dimethylformamide and 1 ml of water were added. Then, it heated at 60 degreeC. Saturated brine was added after completion | finish of reaction, and it extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 50 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/1) to give 110 mg (0.24 mmol, 23.9%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.10-1.25 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.65 (m, 1H), 1.86-2.03 (m, 1H), 2.05-2.22 (m, 2H), 2.22-2.80 (m, 12H), 3.75-3.82 (m, 1H), 4.06 (t, J = 8.8 Hz, 1H) , 4.70-4.80 (m, 1H), 7.11-7.16 (m, 1H), 7.27-7.33 (m, 1H), 7.33-7.40 (m, 6H), 7.51-7.56 (m, 2H)

ESI-MS; 461 (M + H) ⁺

Example 44; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(5-phenyl1,2,4-oxadiazol- 3 yl) methyl] piperazine

Benzamide oxime 95.3 mg (0.70 mmol) and molecular sieve 4A (400 mg) were dissolved in 3 ml of tetrahydrofuran, 32 mg (0.8 mmol) of sodium hydride were further added, and 20 mg was heated to 60 ° C. After 10 minutes, 3 ml of a tetrahydrofuran solution of 500 mg (1.40 mmol) of 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(methoxycarbonyl) methyl] piperazine was added It was heated to reflux. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was treated with preparative (preparation) chromatography (100% ethyl acetate) and again with 25 g of Cromatorex NH silica gel (ethyl acetate / hexane = 3/5) to give 127 mg (0.29 mmol, 40.9%) of the title compound as colorless. Obtained as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.4 Hz, 3H), 1.04-1.20 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 1.45-1.60 (m, 1H), 1.80-1.92 (m, 1H), 2.05-2.18 (m, 2H), 2.22-2.31 (m, 2H), 2.31-2.50 (m, 4H), 2.55-2.70 (m, 4H), 3.90 ( s, 2H), 4.06 (t, J = 8.8 Hz, 1H), 4.70-4.80 (m, 1H), 7.25-7.32 (m, 1H), 7.33-7.37 (m, 4H), 7.45-7.51 (m, 3H), 8.06-8.10 (m, 2H)

ESI-MS: 444 (M + H) ⁺

Example 45; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(5- (3-fluorophenyl) -1,2,4-oxadiazol-3-yl) methyl] Piperazine

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(5-phenyl1,2,4-oxa in Example 44 using 3-fluorobenzamide oxime The title compound was synthesized according to the preparation method of diazol-3-yl) methyl] piperazine (yield 26%; light yellow syrup).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06-1.22 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.83-1.96 (m, 1H), 2.05-2.20 (m, 2H), 2.20-2.54 (m, 6H), 2.55-2.76 (m, 4H), 3.90 (s, 2H), 4.06 (t, J = 8.8 Hz, 1H), 4.70-4.80 (m, 1H), 7.17-7.25 (m, 1H), 7.25-7.32 (m, 1H), 7.32-7.38 (m, 4H), 7.42-7.48 (m, 1H), 7.77-7.82 (m, 1H), 7.86-7.90 (m, 1H)

ESI-MS: 462 (M + H) ⁺

Example 46; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] piperidine

100 mg (0.30 mmol) of 4-cyano-5-methyl-5-phenylhexyl iodide was dissolved in 2 ml of acetonitrile, and 55 mg (0.36 mmol) of potassium carbonate and 4- [2- (4-fluorophenoxy) 80 mg (0.36 mmol) of ethyl] piperidine were added and heated to 60 ° C. After the reaction was completed, the mixture was partitioned with ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. This crude product was treated with 40 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/5) to give 120 mg (0.28 mmol, 94.7%) of the title compound as a colorless syrup. Physical and chemical data of the title compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.24 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.22-1.32 (m, 2H), 1.42-1.80 (m, 7H), 1.81-1.92 (m, 2H), 2.07-2.18 (m, 2H), 2.20-2.28 (m, 2H), 2.70-2.80 (m, 2H), 3.93 ( t, J = 6.8 Hz, 2H), 6.78-6.83 (m, 2H), 6.92-6.98 (m, 2H), 7.25-7.38 (m, 5H)

ESI-MS: 423 (M + H) ⁺

Example 47; 1-benzyl-4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidine

2.39 g (15.0 mmol) of 3-methyl-2-phenylpentanenitrile was dissolved in 70 ml of DMF, and 600 mg (60% wt, 15 mmol) of sodium hydride were added and heated to 60 ° C. After 30 minutes, to the room temperature, 2.90 g (9.31 mmol) of 1-benzyl-4-methanesulfonyloxypropylpiperidine dissolved in 10 ml of DMF was added and heated again. After the reaction was completed, the mixture was partitioned with ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. This crude product was treated with 100 g of silica gel (ethyl acetate / hexane = 1/100 to 1/0) to give 2.57 g (6.86 mmol, 73.7%) of the title compound as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 0.85-0.98 (m, 1H), 1.06-1.26 (m, 6H), 1.18 (d, J = 6.4 Hz, 3H), 1.30-1.44 (m, 1H), 1.44-1.56 (m, 2H), 1.74-1.90 (m, 3H), 2.03-2.15 (m, 2H), 2.76-2.86 (m, 2H), 3.44 ( s, 2H), 7.20-7.38 (m, 10H)

Example 48; 1- [2- (4-fluorophenoxy) ethyl] -4-[(4-cyano-5-methyl-4-phenyl) hexyl ] piperidine

200 mg (0.70 mmol) of 4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidine is dissolved in 5 ml of acetonitrile, 69 mg (0.50 mmol) of potassium carbonate and 4-fluorophenoxyethyl 110 mg (0.50 mmol) of bromide was added, and it heated at 60 degreeC. After the reaction was completed, the mixture was partitioned with ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain a crude product. This crude product was treated with 40 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1/7) to give 160 mg (0.38 mmol, 76.0%) of the title compound as a colorless syrup. Physical and chemical data of the title compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 0.85-0.98 (m, 1H), 1.10-1.30 (m, 5H), 1.19 (d, J = 6.8 Hz, 3H), 1.30-1.43 (m, 1H), 1.50-1.66 (m, 2H), 1.74-1.85 (m, 1H), 1.92-2.03 (m, 2H), 2.05-2.14 (m, 2H), 2.72 ( t, J = 6.0 Hz, 2H), 2.88-2.95 (m, 2H), 4.03 (t, J = 6.0 Hz, 2H), 6.79-6.84 (m, 2H), 6.92-6.98 (m, 2H), 7.26 -7.38 (m, 5 H)

ESI-MS: 423 (M + H) ⁺

Example 49; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [3-cyano-3- (2-thienyl) propyl] piperazine

3-cyano-3- (2-thienyl) propanol (114 mg) and 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (90 mg) (Japanese Patent Application No. 10-280103) Gazette, see Formula 86), to obtain the vitreous of the title compound as a yellow oil (63 mg, 22%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.73 (m, 2H), 1.82-1.95 (m, 2H), 1.95-2.08 (m, 2H), 2.08-2.18 (m, 2H), 2.20-2.45 (m, 10H), 4.10-4.15 (m, 1H), 6.90- 6.99 (m, 1 H), 7.04-7.06 (m, 1 H), 7.26-7.30 (m, 1 H), 7.35-7.40 (m, 5H).

In addition, 63 mg of the vitreous (title compound) was treated by a conventional method to obtain 60 mg of hydrochloride.

Hydrochloride;

ESI-Mass; 449 (MH ⁺ ).

Example 50; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(4-cyano-4- (4'-fluoro phenyl) butyl) piperazine

2-[(3-cyano-3-phenyl) propyl] -1,3-dioxolane (1.77 g) was dissolved in a solution of 2N HCl (15 mL) and tetrahydrofuran (15 mL). After stirring at room temperature for 13 hours, 2N NaOH (15 mL) and ethyl acetate were added, and the organic layer was distributed. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered and concentrated under reduced pressure. In the obtained residue (5-oxo-2-phenylpropanenitrile), 99 mg, 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (99 mg), and acetic acid (0.1 mL) were diluted with dichloromethane ( 3.5 mL), and sodium triacetoxy borohydride (147 mg) was added thereto. After stirring for 18 hours and 30 minutes at room temperature, saturated aqueous sodium hydrogen carbonate solution was added and neutralized, followed by extraction with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and the drying agent was filtered off and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate system) to give the title compound (136 mg, 88%; yield 1-[(4-cyano-5-methyl-4-phenyl) hexyl] Based on piperazine).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.04-1.19 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.50-1.70 (m, 3H), 1.80-2.00 (m, 3H), 2.08-2.20 (m, 2H), 2.20-2.45 (m, 12H), 3.80-3.88 (m, 1H), 7.25-7.40 (m, 9H).

Furthermore, 141 mg of hydrochloride were obtained by treating 136 mg of the vitreous (title compound) by a conventional method.

Hydrochloride;

ESI-Mass; 461 (MH ⁺ ).

Example 51; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [4-hydroxy4- (4'-fluorophenyl ) butyl] piperazine

1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (100 mg), 4-chloro-4'-fluorobutyrophenone (91 mg), triethylamine (0.1 mL) dissolved Acetonitrile solution (10 mL) was stirred under reflux conditions. After 6 hours, the mixture was returned to room temperature, water and ethyl acetate were added, and the organic layer was distributed. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate system) to obtain precursor 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [4- (4-fluorophenyl ) Butan-1-one] piperazine (56 mg). 27 mg of this was dissolved in ethanol (2 mL), hydroxyammonium chloride (8.3 mg) and sodium acetate (9.8 mg) were added, and the mixture was stirred under reflux conditions. After 2 hours, the mixture was returned to room temperature, water and ethyl acetate were added, and the organic layer was distributed. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate system) to give a title compound as a colorless oil (17 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 1.06-1.20 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.50-1.62 (m, 1H), 1.75-1.82 (m, 2H), 1.82-1.92 (m, 1H), 2.05-2.20 (m, 2H), 2.22-2.55 (m, 12H), 2.72-2.78 (m, 2H), 6.99- 7.05 (m, 2H), 7.25-7.30 (m, 1H), 7.31-7.36 (m, 4H), 7.58-7.62 (m, 2H).

Also, 14 mg of hydrochloride was obtained by treating 17 mg of the vitreous (title compound) by a conventional method.

Hydrochloride;

ESI-Mass; 465 (MH ⁺ ).

Example 52; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [4-methyl-3-phenylpentane] piperazin

According to the method of Example 49, the title compound was obtained (85 mg, 60%) in light yellow oil.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.71 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 1.03-1.16 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H), 1.46-1.60 (m, 3H), 1.70-2.16 (m, 6H), 2.18-2.42 (m, 10H), 7.07-7.13 (m , 2H), 7.14-7.18 (m, 1H), 7.20-7.32 (m, 4H), 7.33-7.36 (m, 4H).

This vitreous body was also treated in the same manner as in Example 1 to obtain hydrochloride (80 mg) of the title compound.

Hydrochloride;

ESI-Mass; 446 (MH ⁺ ).

Example 53; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [4-methyl-3-phenylhexane] piperazin

The title compound (150 mg, yield 94%) was obtained in accordance with the method of Example 1 described in Japanese Patent Application Laid-Open No. 11-206862.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.69 (d, J = 6.86 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 1.03-1.16 (m, 2H), 1.19 (d, J = 6.6 Hz, 3H), 1.18-1.28 (m, 2H), 1.65-1.90 (m, 4H), 2.05-2.14 (m, 3H), 2.14-2.44 (m , 10H), 7.07-7.13 (m, 2H), 7.14-7.18 (m, 1H), 7.20-7.32 (m, 3H), 7.33-7.36 (m, 4H).

In addition, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 460 (MH ⁺ ).

Example 54; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (4-fluorophenoxy) buty-3-yl] piperazine

According to the method of Example 104 described in Japanese Patent Application Laid-Open No. 11-206862, a pale yellow oily title compound was obtained (183 mg, 38%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.04-1.19 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H), 1.50-1.64 (m, 1H), 1.82-1.92 (m, 1H), 2.06-2.18 (m, 2H), 2.22-2.28 (m, 2H), 2.28-2.40 (m, 4H), 2.48-2.64 (m, 5H), 2.75 ( dd, J = 7.7 Hz, 13.4 Hz, 1H), 4.65-4.73 (m, 1H), 5.20 (d, J = 10.6 Hz, 1H), 5.25 (d, J = 17.4 Hz, 1H), 5.85 (ddd, J = 5.8 Hz, 10.6 Hz, 17.4 Hz, 1H), 6.81-6.88 (m, 2H), 6.88-6.97 (m, 2H), 7.25-7.31 (m, 1H), 7.32-7.40 (m, 4H).

In addition, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 450 (MH ⁺ ).

Example 55; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [3-aryloxy-2- (4-fluoro phenoxy) propyl] piperazine

According to the method of Example 104 described in JP-A 11-206862, a colorless oily title compound was obtained (67 mg, 62%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.18 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 1.48-1.66 (m, 1H), 1.87 (dt, J = 4.4 Hz, 12.4 Hz, 1H), 2.06-2.18 (m, 2H), 2.22-2.40 (m, 6H), 2.44-2.54 (m, 1H), 2.68-2.74 (m , 2H), 2.93-3.00 (m, 1H), 3.95-3.98 (m, 2H), 4.06 (d, J = 5.2 Hz, 2H), 5.16 (brd, J = 10.4 Hz, 1H), 5.24 (dd, J = 1.6 Hz, 17.2 Hz, 1H), 5.81-5.92 (m, 1H), 6.80-6.97 (m, 4H), 7.24-7.33 (m, 1H), 7.34-7.39 (m, 4H).

In addition, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 494 (MH ⁺ ).

Example 56; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [3- (n-propanoxy) -2- (4-fluorophenoxy ) propyl] piperazine

At room temperature under hydrogen atmosphere, 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [3-aryloxy-2- (4-fluorophenoxy) propyl] piperazine (85 mg ) Was dissolved in ethanol (3.5 mL), and 10% palladium carbon (10 mg) was added thereto, followed by stirring. After 3 hours and 20 minutes, palladium carbon was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (34 mg, 40%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.6 Hz, 3H), 0.88 (dt, J = 2.7 Hz, 7.2 Hz, 3H), 1.05-1.20 (m, 1H), 1.19 (d , J = 6.6 Hz, 3H), 1.50-1.60 (m, 4H), 1.82-1.92 (m, 1H), 2.05-2.20 (m, 3H), 2.20-2.60 (m, 9H), 2.66-2.78 (m , 2H), 3.31-3.41 (m, 2H), 3.61 (d, J = 5.5 Hz, 1H), 4.06 (d, J = 5.1 Hz, 1H), 6.81-6.98 (m, 4H), 7.25-7.32 ( m, 1H), 7.32-7.40 (m, 4H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 496 (MH ⁺ ).

Example 57; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [3-hydroxy-2- (4-fluorophenoxy ) propyl] piperazine

1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [3-aryloxy-2- (4-fluorophenoxy) propyl] piperazine (125 mg) was converted to tetrahydrofuran ( 5 mL) and sodium borohydride (14.4 mg) followed by iodine (64 mg) / tetrahydrofuran (2 mL). After stirring for 1 hour, ethyl acetate and water were added to distribute the organic layer, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography ( Hexane / ethyl acetate) to give the title compound (70 mg, 61%) as light yellow oil. This vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 436 (MH ⁺ ).

Example 58; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (1,2,3,4-tetrahydroquinolyl ) ethyl] piperazine

According to the method of Example 89 described in Japanese Patent Application Laid-Open No. 11-206862, the title compound was obtained from 1,2,3,4-tetrahydroquinoline (34%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.66 (m, 1H), 1.85-1.98 (m, 2H), 2.05-2.20 (m, 2H), 2.24-2.56 (m, 11H), 2.73 (brt, J = 6.4 Hz, 2H), 3.29 (brt, J = 5.6 Hz , 3H), 3.36-3.41 (m, 2H), 3.39 (brt, J = 7.8 Hz, 2H), 3.45-3.52 (m, 2H), 6.52-6.59 (m, 2H), 6.90-6.94 (m, 1H ), 7.00-7.15 (m, 1H), 7.26-7.32 (m, 1H), 7.34-7.38 (m, 4H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 445 (MH ⁺ ).

Example 59; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -N- (4-fluorophenyl) -N '-(2-methylpropyl ) -1 (2H) -pyrazinecarboxyimida mid

To a dichloromethane (10 mL) solution in which 1- (fluorophenyl) -3-isobutylurea (300 mg), triphenylphosphine (561 mg) and triethylamine (0.3 mL) were added in an ice bath under a nitrogen atmosphere, 4 Dichloromethane (4 mL) solution in which carbon bromide (948 mg) was dissolved was added. After 45 minutes, the mixture was returned to room temperature, water and dichloromethane were added, and the organic layer was partitioned. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off, concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography ( Hexane / ethyl acetate type) to obtain a colorless oily intermediate carbodiimide. This carbodiimide and 1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (100 mg) were dissolved in 2-propanol (10 mL) and stirred under reflux conditions. After 2 hours, the solvent was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (174 mg, 25%; 2 steps) as a colorless individual.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 0.88-0.91 (m, 6H), 1.05-1.18 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.50-1.65 (m, 2H), 1.67-1.80 (m, 2H), 1.88-1.98 (m, 1H), 2.06-2.20 (m, 2H), 2.22-2.36 (m, 4H), 2.79 ( brd, J = 6.8 Hz, 1H), 3.05 (dd, J = 6.0 Hz, 6.8 Hz, 1H), 3.14-3.20 (m, 1H), 4.82-4.91 (m, 1H), 6.52- 6.58 (m, 1H ), 6.72-6.78 (m, 1H), 6.91-7.04 (m, 3H), 7.22-7.31 (m, 4H), 7.35-7.38 (m, 3H).

In addition, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 478 (MH ⁺ ).

Example 60; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -N- (4-fluorobenzyl) -N '-(2-methylpropyl ) -1 (2H) -pyrazinecarboxyimida mid

According to the method of Example 59, the title compound was obtained as colorless oil (62%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 0.80-0.88 (m, 6H), 1.05-1.18 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 1.43-1.60 (m, 1H), 1.84-1.95 (m, 1H), 2.05-2.20 (m, 2H), 2.25-2.40 (m, 6H), 2.87-2.95 (m, 2H), 3.22- 3.38 (m, 4H), 3.49 (s, 2H), 4.35-4.45 (m, 2H), 7.02-7.09 (m, 2H), 7.27-7.34 (m, 3H), 7.34-7.41 (m, 4H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 492 (MH ⁺ ).

Example 61; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -N, N'-dicyclohexylpyrazinecarboximidamide

According to the method of Example 59, the title compound was obtained as colorless oil (yield 62%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.04-1.46 (m, 9H), 1.21 (d, J = 6.8 Hz, 3H), 1.46-1.74 (m, 6H), 1.74-1.86 (m, 6H), 1.86-1.18 (m, 2H), 2.07-2.22 (m, 2H), 2.24-2.40 (m, 6H), 3.05-3.16 (m, 2H), 3.23- 3.32 (m, 4H), 3.41-3.52 (m, 1H), 7.28-7.34 (m, 1H), 7.35-7.42 (m, 4H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 492 (MH ⁺ ).

Example 62; N-cyano-4-[(4-cyano-5-methyl-4-phenyl) hexyl] -N '-[(4-fluorophenoxy ) ethyl] pyrazinecarboxyimidamid

N-cyano-N'-ethyl (4-fluorophenoxy) -O-phenylisourea (168 mg) and 1-[(4-cyano-5-methyl-4-phenyl) hexyl] pipe under nitrogen atmosphere Razine (80 mg) was dissolved in 2-propanol (5 mL) and stirred under reflux. After 24 hours, the residue was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (98 mg, 71%) as a colorless object.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.20-1.34 (m, 1H), 1.50-1.70 (m, 1H), 1.92 (ddd, J = 4.9Hz, 11.6Hz, 13.6Hz, 1H), 2.05-2.23 (m, 2H), 2.24-2.38 (m, 6H), 3.43-3.50 (m, 2H), 3.78- 3.82 (m, 2H), 4.04-4.09 (m, 2H), 5.00-5.05 (m, 1H), 6.80-6.85 (m, 2H), 6.92-7.01 (m, 2H), 7.27-7.32 (m, 1H ), 7.34-7.39 (m, 4 H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 491 (MH ⁺ ).

Example 63; (2-thienyl)-[(4-cyano-5-methyl-4-phenyl) hexylpiperazino] methaneimine

According to the method of Example 62, the title compound was obtained as colorless oil (yield 62%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.20 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.50-1.64 (m, 1H), 1.88-2.08 (m, 1H), 2.08-2.22 (m, 2H), 2.28-2.38 (m, 6H), 3.32-3.44 (m, 4H), 7.00 (dd, J = 3.6 Hz, 5.2 Hz , 1H), 7.14 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.26-7.32 (m, 1H), 7.34 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.35-7.39 (m, 4H ).

This vitreous body was treated in the same manner as in Example 1 to obtain hydrochloride of the title compound.

Hydrochloride;

ESI-Mass; 345 (MH ⁺ ).

Example 64; 1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1-phenylbutyl cyanide

2-chloro-1-isobutyl-1H-benzo [d] imidazole (4 g) and 1- (4-cyano-5-methyl-4-hexyl) piperazine (5 g) were added to tetrahydrofuran (10 ml). It melt | dissolved and stirred for 6 hours in the 150 degreeC oil bath in open system. The reaction was purified by NH silica gel (ethyl acetate / hexane system) to give the title compound as a brown oil (6.8 g, 85%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H), 1.20-1.35 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.52-1.67 (m, 1H), 1.95-2.07 (m, 1H), 2.08-2.23 (m, 1H), 2.23-2.43 (m , 4H), 2.43-2.50 (m, 4H), 3.21-3.25 (m, 4H), 3.80 (d, J = 7.6 Hz, 2H), 7.08-7.64 (m, 9H)

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 458 (MH ⁺ ).

Example 65; Bis-1,4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine

Thionyl chloride (4 mL) was added to (4-cyano-5-methyl-4-phenyl) hexanol (2.33 g) under ice-cooling in a nitrogen atmosphere, followed by stirring under heating under reflux. After 2 hours, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to give (4-cyano-5-methyl-4-phenyl) hexyl chloride as yellow oil (2.35 g, 93). %) Was obtained. The obtained chloride (454 mg), [(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (166 mg), and sodium iodide (289 mg) were dissolved in acetonitrile (5 mL) and stirred under reflux conditions. After returning to room temperature after 2 hours, ethyl acetate and water were added to distribute the organic layer, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, and the residue was NH silica gel. Purification by column chromatography (hexane / ethyl acetate system) afforded the title compound (213 mg, 23%) as a pale yellow oil.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 6H), 1.02-1.16 (m, 2H), 1.19 (d, J = 6.8 Hz, 6H), 1.46-1.60 (m, 2H), 1.80-1.92 (m, 2H), 2.40-2.17 (m, 4H), 2.17-2.36 (m, 12H), 7.23-7.31 (m, 2H), 7.33-7.37 (m, 8H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 485 (MH ⁺ ).

Example 66; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-[(3-cyano-4-methyl-3-phenyl) pentyl] piperazine

According to the method of Example 65, the title compound was obtained in pale yellow oil (yield 52%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 0.765 (d, J = 6.4 Hz, 3H), 1.00-1.18 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.44-1.60 (m, 1H), 1.80-2.00 (m, 4H), 2.00-2.18 (m, 4H), 2.18-2.44 (m , 10H), 7.26-7.32 (m, 2H), 7.33-7.40 (m, 8H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 471 (MH ⁺ ).

Example 67; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (1 ', 2'-methylenedioxyphenyl ) ethyl] piperidine

The title compound was obtained in the same manner as in Example 49 (yield 51%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.48-1.76 (m, 7H), 1.80-1.94 (m, 2H), 2.06-2.18 (m, 2H), 2.18-2.28 (m, 2H), 2.53-2.60 (m, 2H), 2.70-2.80 (m, 2H), 5.92 ( s, 2H), 6.82-6.70 (m, 2H), 6.70-6.78 (m, 1H), 7.26-7.40 (m, 5H).

Further, this vitreous (title compound) was treated in the same manner as in Example 1 to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 433 (MH ⁺ ).

Example 68; 1- [4-cyano-4- (3-cyano-5-thienyl) -5-methylhexyl] -4- [2- (4-cyano phenoxy) ethyl] piperazine

4-Cyano-4- (3-cyano-5-thienyl) -5-methylhexanol (0.13 g) was dissolved in acetonitrile (5 ml), triethylamine (0.21 ml) and mesyl chloride (0.048). ml) was added, and it stirred at room temperature for 1 hour. Water was added, extraction was performed with ethyl acetate, and the mixture was washed with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain a pale yellow oily substance. The oily substance was dissolved in DMF (2 ml), a solution of DMF (4 ml) of 1- [2- (4-cyanophenoxy) ethyl] piperazine (0.14 g), triethylamine (0.21 ml), sodium iodide (0.15 g) was added. After stirring overnight at 60 ° C, ethyl acetate was added and washed with water and brine. After drying over anhydrous magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by (NH) silica gel column chromatography (hexane / ethyl acetate system) to obtain the title compound (0.09 g, 33%) as a pale yellow oil.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92d, J = 6.8 Hz, 3H, 1.20 (d, J = 6.8 Hz, 3H), 1.21-1.31 (m, 1H), 1.60-1.73 (m, 1H ), 1.77 (dt, J = 4 Hz, J = 13.2 Hz, 1H), 2.06 (qui, J = 6.8 Hz, 1H), 2.20 (dt, J = 4 Hz, J = 13.2 Hz, 1H), 2.33 (t, J = 7.6 Hz, 2H), 2.42 (bs, 4H), 2.58 (bs, 4H), 2.82 (t, J = 5.6 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 1.2 Hz, 1H).

In addition, the vitreous (title compound) was treated by a conventional method to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 462 (MH ⁺ ).

Example 69; 1- [4-cyano-4- (3-cyano-5-thienyl) -5-methylhexyl] -4- [2- (3-cyano phenoxy) ethyl] piperazine

As in Example 68, from 4-cyano-4- (3-cyano-5-thienyl) -5-methylhexanol and 1- [2- (3-cyanophenoxy) ethyl] piperazine The pale yellow oily title compound (0.15 g, 58%) was obtained.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.22-1.32 (m, 1H), 1.60-1.73 (m, 1H), 1.79 (dt, J = 4 Hz, J = 12.4 Hz, 1H), 2.07 (qui, J = 6.8 Hz, 1H), 2.21 (dt, J = 4 Hz, J = 12.4 Hz, 1H), 2.34 (t , J = 7.2 Hz, 2H), 2.43 (bs, 4H), 2.59 (bs, 4H), 2.82 (t, J = 5.6 Hz, 2H), 4.11 (t, J = 5.6 Hz, 2H), 7.12-7.40 (m, 5 H), 7.91 (s, 1 H).

In addition, the vitreous (title compound) was treated by a conventional method to obtain a hydrochloride salt.

Hydrochloride;

ESI-Mass; 462 (MH ⁺ ).

Example 70; 1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [2- (3-cyano phenoxy) ethyl] piperazine

400 mg (1.61 mmol) of 4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexanol was dissolved in 10.0 ml of acetonitrile and cooled to 0 ° C. 0.26 ml (1.85 mmol) of triethylamine and 0.14 ml (1.77 mmol) of mesyl chloride were added to this solution, and the temperature was raised to room temperature. After 20 minutes, ether and saturated brine were added. The ether layer was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. One-half (about 0.1 mmol) of this crude mesyl product was dissolved in 8.00 ml of dimethylformamide, 724 mg (4.83 mmol) of sodium iodide, 111 mg (0.81 mmol) of potassium carbonate, and 1- [2- (3- 243 mg (1.05 mmol) of cyanophenoxy) ethyl] piperazine were added and heated to 60 ° C. After the reaction was completed, saturated brine was added, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to afford the crude product. This crude product was treated with Cromatorex NH silica gel (eluted with ethyl acetate / hexane = 1/1) to give 289 mg (0.63 mmol, 77.3%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.80 Hz, 3H), 1.21 (d, J = 6.40 Hz, 3H), 1.20-1.38 (m, 1H), 1.60-1.86 (m, 2H), 2.01-2.12 (m, 1H), 2.18-2.30 (m, 1H), 2.30-2.75 (m, 10H), 2.80-2.90 (m, 2H), 4.08-4.18 (m, 2H), 7.11- 7.18 (m, 3H), 7.23-7.28 (m, 1H), 7.34-7.40 (m, 1H), 7.52 (d, J = 3.60 Hz, 1H)

ESI-MS: 462 (M + H) ⁺

Example 71; 1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [2- {N- (2- cyanoethyl) anilino} ethyl] piperazine

1- [4-cyano-5-methyl-4- (5-cyano-2 in Example 70) using [2- {N- (2-cyanoethyl) anilino} ethyl] piperazine The title compound was synthesized according to the procedure for preparing -thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine (yield 90.1%; light yellow oil).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.4 Hz, 3H), 1.20-1.33 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H), 1.58-1.73 (m, 1H), 1.73-1.84 (m, 1H), 2.02-2.11 (m, 1H), 2.23 (dt, J = 4.0 Hz, 12.8 Hz, 1H), 2.31-2.64 (m, 12H), 2.68t, J = 7.2 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.69 (t, J = 7.2 Hz, 2H), 6.67 (d, J = 8.0 Hz, 3H), 6.76 (t, J = 7.4 Hz , 1H), 7.15 (d, J = 4.00 Hz, 1H), 7.23-7.30 (m, 2H), 7.52 (d, J = 4.0 Hz, 1H)

ESI-MS: 489 (M + H) ⁺

Example 72; 1- [4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexyl] -4- [2- (3-cyano phenoxy) ethyl] piperazine

111 mg (0.31 mmol) of 4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexyl iodide was dissolved in 1.5 ml of acetonitrile, 56.2 µl (0.40 mmol) of triethylamine and 109 mg (0.47 mmol) of 1- (3-cyanophenoxyethyl) piperazine were added and stirred for 3 days. The organic layer was partitioned between ethyl acetate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 12.5 g of Cromatorex NH silica gel (ethyl acetate / hexane = 1: 2) to give 144 mg (quantitative) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.4 Hz, 3H), 1.15-1.28 (m, 1H), 1.26 (d, J = 6.4 Hz, 3H), 1.60-1.75 (m, 1H), 2.17-2.27 (m, 1H), 2.27-2.70 (m, 12H), 2.81 (t, J = 6.0 Hz, 2H), 4.10 (t, J = 6.Hz, 2H), 7.11-7.16 ( m, 2H), 7.22-7.26 (m, 1H), 7.26-7.28 (m, 2H), 7.33-39 (m, 1H)

ESI-MS: 462 (M + H) ⁺

Example 73; 1- [4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexyl] -4- [2- (3-fluorophenoxy ) ethyl] piperazine

The title compound was synthesized according to the method of Example 72 (yield 82.3%).

* ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92d, J = 6.4 Hz, 3H, 1.15-1.29 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 1.60-1.74 (m, 1H), 2.17-2.27 (m, 1H), 2.27-2.70 (m, 12H), 2.80 (t, J = 6.0 Hz, 2H), 4.08 (t, J = 6.0 Hz, 2H), 6.59-6.70 (m , 3H), 7.16-7.24 (m, 1H), 7.26-7.28 (m, 2H)

ESI-MS: 455 (M + H) ⁺

Example 74; 1- [4-cyano-5-methyl-4- (3-cyano-2-thienyl) hexyl] -4- [2- (4-fluorophenoxy ) ethyl] piperazine

The title compound was synthesized according to the method of Example 72 (yield 70.2%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.14-1.29 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 1.60-1.74 (m, 1H), 2.17-2.27 (m, 1H), 2.27-2.70 (m, 12H), 2.78 (t, J = 6.0 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 6.81-6.85 (m , 2H), 6.93? 6.98 (m, 1 H), 7.26-7.28 (m, 2 H)

ESI-MS: 455 (M + H) ⁺

Example 75; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine

The title compound was synthesized according to the method of Example 72 using 4-cyano-5-methyl-4- (2-thienyl) hexyl iodide (yield 94.7%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.20-1.38 (m, 1H), 1.55-1.72 (m, 1H), 1.73-1.83 (m, 1H), 2.02-2.12 (m, 1H), 2.12-2.22 (m, 1H), 2.28-2.35 (m, 2H), 2.35-2.65 (m, 8H), 2.81 ( t, J = 5.9 Hz, 2H), 4.10 (t, J = 5.9 Hz, 2H), 6.93-6.97 (m, 1H), 7.10-7.17 (m, 3H), 7.22-7.30 (m, 2H), 7.33 -7.39 (m, 1 H).

ESI-MS: 437 (M + H) ⁺

Example 76; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (4-cyanophenoxy) ethyl] piperazine

The title compound was synthesized according to the method of Example 72 using 4-cyano-5-methyl-4- (2-thienyl) hexyl iodide (yield 40.9%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.56-1.70 (m, 1H), 1.72-1.81 (m, 1H), 2.01-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.27-2.34 (m, 2H), 2.34-2.62 (m, 8H), 2.81 ( t, J = 6.0 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 6.92-6.96 (m, 3H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.24- 7.27 ( m, 2H), 7.57 (d, J = 8.8 Hz, 2H).

ESI-MS: 437 (M + H) ⁺

Example 77; 1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [3- (5-cyano -2-thienyl) propyl] piperazine

200 mg (0.56 mmol) of 4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl iodide was dissolved in 3 ml of acetonitrile, 78.0 µl (0.56 mmol) of triethylamine and 1 178 mg (0.76 mmol) of-[3- (5-cyano-2-thienyl) propyl] piperazine were added and stirred at 55 ° C. After 5 hours, the reaction solution was concentrated and treated with Cromatorex NH silica gel (ethyl acetate / hexane = 1/2) to give 243 mg (0.52 mmol, 92.8%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.18-1.31 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.60-1.72 (m, 1H), 1.73-1.91 (m, 3H), 2.00-2.10 (m, 1H), 2.17-2.27 (m, 1H), 2.28-2.50 (m, 12H), 2.88 (t, J = 7.6 Hz, 2H) , 6.80 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.45 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 4.0 Hz, 1H)

ESI-MS: 466 (M + H) ⁺

Example 78; 1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [3- (2-thienyl ) propyl] piperazine

The title compound was synthesized according to the preparation method described in Example 77 (yield 96.4%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.19-1.31 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.60-1.72 (m, 1H), 1.72-1.81 (m, 1H), 1.82-1.91 (m, 2H), 2.00-2.10 (m, 1H), 2.17-2.24 (m, 1H), 2.27-2.54 (m, 12H), 2.85 ( t, J = 7.6 Hz, 2H), 6.78 (dd, J = 0.8 Hz, 3.6 Hz, 1H), 6.91 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.10 (dd, J = 0.8 Hz, 5.2 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 4.0 Hz, 1H)

ESI-MS: 441 (M + H) ⁺

Example 79; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [3- (5-cyano-2-thienyl ) propyl] piperazine

Using the 4-cyano-5-methyl-4- (2-thienyl) hexyl iodide, the title compound was synthesized according to the preparation described in Example 77 (yield 96.4%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.23-1.37 (m, 1H), 1.60-1.70 (m, 1H), 1.72-1.90 (m, 3H), 2.02-2.09 (m, 1H), 2.11-2.20 (m, 1H), 2.26-2.52 (m, 12H), 2.88 (t, J = 7.6 Hz, 2H) , 6.80 (d, J = 3.6 Hz, 1H), 6.94 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.26 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.45 (d, J = 3.6 Hz, 1H)

ESI-MS: 441 (M + H) ⁺

Example 80; 1- [4-cyano-5-methyl-4- (4-cyano-2-thienyl) hexyl] -4- [3- (2-thienyl ) propyl] piperazine

4-cyano-5-methyl-4- (4-cyano-2-thienyl) hexanol and 1- [3- (2-thienyl) propyl] piperazine synthesized according to the method of Example 69 It was prepared under the conditions of synthesis of tert-butyl4- [3- (2-thienyl) propyl] -1-piperazinecarboxylate described below (yield 23.6%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.22-1.32 (m, 1H), 1.59-1.72 (m, 1H), 1.72-1.91 (m, 3H), 2.02-2.12 (m, 1H), 2.15-2.24 (m, 1H), 2.28-2.56 (m, 12H), 2.85 (t, J = 7.6 Hz, 2H) , 6.77-6.80 (m, 1H), 6.91 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H ), 7.89 (d, J = 1.2 Hz, 1H)

ESI-MS: 441 (M + H) ⁺

Example 81; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4-[(2-benzooxazoyl) methyl ] piperazine

1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] piper synthesized in the same manner as 1- [3- (5-cyano-2-thienyl) propyl] piperazine described above 230 mg (0.82 mmol) of razin was dissolved in 5 ml of acetonitrile, 120 mg (0.72 mmol) of 2- (chloromethyl) benzoxazole and 0.10 ml (0.72 mmol) of triethylamine were added and heated to 50 ° C. After 5 hours, the reaction solution was concentrated and treated with Cromatorex NH silica gel (ethyl acetate / hexane = 1/2) to give 244 mg (0.58 mmol, 80.5%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.20-1.38 (m, 1H), 1.55-1.69 (m, 1H), 1.71-1.81 (m, 1H), 2.00-2.09 (m, 1H), 2.10-2.19 (m, 1H), 2.28-2.53 (m, 6H), 2.55-2.73 (m, 4H), 3.86 ( s, 2H), 6.93 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.10 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.24 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.30-7.36 (m, 2H), 7.50-7.55 (m, 1H), 7.68-7.73 (m, 1H)

ESI-MS: 423 (M + H) ⁺

Example 82; 1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4-[(2-benzooxazoyl ) methyl] piperazine

200 mg (0.56 mmol) of 4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl iodide was dissolved in 3 ml of acetonitrile, 78.0 µl (0.56 mmol) of triethylamine and 1 146 mg (0.67 mmol) of-[(2-benzooxazoyl) methyl] piperazine were added and stirred at 55 ° C. After 14 hours, the reaction solution was concentrated and treated with Cromatorex NH silica gel (ethyl acetate / hexane = 1/2) to give 237 mg (0.53 mmol, 94.6%) of the title compound as a yellow syrup.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.20-1.30 (m, 1H), 1.59-1.70 (m, 1H), 1.70-1.80 (m, 1H), 2.00-2.09 (m, 1H), 2.15-2.25 (m, 1H), 2.33 (t, J = 7.2 Hz, 2H), 2.37-2.52 (m, 4H) , 2.57-2.72 (m, 4H), 3.87 (s, 2H), 7.14 (d, J = 4.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.50 (d, J = 4.0 Hz, 1H), 7.51-7.55 (m, 1H), 7.68-7.73 (m, 1H)

ESI-MS: 448 (M + H) +

Example 83; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4-[{2- (5-cyanobenzooxazoyl )} methyl] piperazine

The title compound was synthesized according to the preparation method described in Example 82 (yield 89.3%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.22-1.36 (m, 1H), 1.56-1.70 (m, 1H), 1.71-1.80 (m, 1H), 2.00-2.09 (m, 1H), 2.10-2.19 (m, 1H), 2.29-2.36 (m, 2H), 2.36-2.52 (m, 4H), 2.56- 2.71 (m, 4H), 3.89 (s, 2H), 6.93 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.10 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.25 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.60-7.66 (m, 2H), 8.02-8.04 (m, 1H)

ESI-MS: 448 (M + H) ⁺

Example 84; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (3-fluorophenoxy) ethyl] piperazine

In acetonitrile solution (3 ml) of 1-iodine-4-cyano-5-methyl-4- (3-thienyl) hexane (50 mg) and triethylamine (0.06 ml) at room temperature under nitrogen atmosphere, 1- [2- (4-fluorophenoxy) ethyl] piperazine (50 mg) synthesized according to the method of Preparation Example 1 described in 11-206862 was added. After stirring at 50 ° C. for 4 hours, the solvent was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane / ethyl acetate system) to obtain a yellow oily title compound (62 mg, 96%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 1.55-1.65 (m, 1H), 1.74-1.84 (m, 1H), 2.02-2.12 (m, 2H), 2.29 (t, J = 7.2 Hz, 2H), 2.30-2.47 (m, 4H), 2.47-2.65 (m, 4H), 2.79 (t, J = 6.0 Hz , 2H), 4.07 (t, J = 6.0 Hz, 2H), 6.58-6.70 (m, 3H), 6.92 (dd, J = 1.5 Hz, 5.0 Hz, 1H), 7.17-7.24 (m, 1H), 7.26 -7.28 (m, 1 H), 7.33 (dd, J = 3.0 Hz, 5.0 Hz, 1 H).

Further, 62 mg of the vitreous (title compound) was dissolved in methanol, and an excess of 4N hydrochloric acid and ethyl acetate solution was added. After stirring, the mixture was concentrated under reduced pressure. After water was added to the obtained residue, it was immersed in a dry ice methanol cooling bath to freeze the aqueous solution. The solvent was removed by day and night lyophilization to obtain the hydrochloride (white amorphous, 62 mg) of the title compound.

Hydrochloride;

ESI-Mass; 430 (MH ⁺ ).

Example 85; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (85%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 1.15-1.30 (m, 1H), 1.54-1.66 (m, 1H), 1.75-1.85 (m, 1H), 2.02-2.15 (m, 2H), 2.25-2.33 (m, 2H), 2.33-2.48 (m, 4H), 2.48-2.65 (m, 4H), 2.80 ( t, J = 5.7 Hz, 2H), 4.10 (t, J = 5.7 Hz, 2H), 6.93 (dd, J = 1.3 Hz, 5.1 Hz, 1H), 7.10-7.30 (m, 2H), 7.20-7.26 ( m, 1H), 7.26-7.28 (m, 1H), 7.32-7.39 (m, 2H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 437 (MH ⁺ ).

Example 86; 1- {4-cyano-5-methyl-4- [4- (2-cyano) thienyl] hexyl} -4- [2- (3-fluorophenoxy ) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (76%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.84 (d, J = 6.8 Hz, 3H), 1.01-1.02 (m, 1H), 1.17 (d, J = 6.6 Hz, 3H), 1.50-1.70 (m, 1H), 1.75-1.85 (m, 1H), 2.00-2.08 (m, 1H), 2.08-2.18 (m, 1H), 2.27-2.33 (m, 2H), 2.33-2.48 (m, 4H), 2.48- 2.66 (m, 4H), 2.80 (t, J = 5.8 Hz, 2H), 4.07 (t, J = 5.8 Hz, 2H), 6.59-6.70 (m, 3H), 7.17-7.25 (m, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 455 (MH ⁺ ).

Example 87; 1- {4-cyano-5-methyl-4- [4- (2-cyano) -thienyl] hexyl} -4- [2- (3-cyanophenoxy ) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (78%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.84 (d, J = 6.8 Hz, 3H), 1.01-1.02 (m, 1H), 1.17 (d, J = 6.6 Hz, 3H), 1.50-1.65 (m, 1H), 1.75-1.85 (m, 1H), 2.00-2.09 (m, 1H), 2.09-2.18 (m, 1H), 2.27-2.33 (m, 2H), 2.33-2.48 (m, 4H), 2.48- 2.66 (m, 4H), 2.81 (t, J = 5.8 Hz, 2H), 4.10 (t, J = 5.8 Hz, 2H), 7.12-7.16 (m, 2H), 7.23-7.28 (m, 1H), 7.36 (dt, J = 0.8 Hz, 7.8 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 462 (MH ⁺ ).

Example 88; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (2-cyano-4-fluorophenoxy ) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (72%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H), 1.73-1.83 (m, 1H), 2.00-2.11 (m, 1H), 2.11-2.20 (m, 1H), 2.27-2.33 (m, 2H), 2.33-2.51 (m, 4H), 2.51- 2.70 (m, 4H), 2.86 (t, J = 5.8 Hz, 2H), 4.17 (t, J = 5.8 Hz, 2H), 6.89-6.97 (m, 2H), 7.09-7.12 (m, 1H), 7.20 7.30 (m, 2 H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 455 (MH ⁺ ).

Example 89; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (2-cyano-4-fluorophenoxy ) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (72%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 1.16-1.20 (m, 1H), 1.50-1.66 (m, 1H), 1.76-1.86 (m, 1H), 2.01-2.13 (m, 2H), 2.24-2.33 (m, H), 2.33-2.51 (m, 4H), 2.51-2.70 (m, 4H), 2.87 ( t, J = 5.8 Hz, 2H), 4.17 (t, J = 5.8 Hz, 2H), 6.89-6.97 (m, 2H), 7.20-7.30 (m, 3H), 7.33-7.38 (m, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 455 (MH ⁺ ).

Example 90; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (4-cyano-2-fluorophenoxy ) ethyl] piperazine

A colorless oily title compound was obtained in the same manner as in Example 84 using 2- (4-cyano-2-fluorophenoxy) ethylpiperazine synthesized in the same manner as in Reference Example 69 (64%) .

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H), 1.72-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.11-2.20 (m, 1H), 2.27-2.33 (m, 2H), 2.33-2.51 (m, 4H), 2.51- 2.70 (m, 4H), 2.85 (t, J = 5.8 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 6.94 (dd, J = 3.7 Hz, 5.2 Hz, 1H), 7.00 (t, J = 8.2 Hz, 1H), 7.10 (dd, J = 1.3 Hz, 3.7 Hz, 1H), 7.24-7.27 (m, 1H), 7.35 (dd, J = 1.9 Hz, 10.4 Hz, 1H), 7.38-7.42 (m, 1 H).

This vitreous body was treated in the same manner as in Example 84 to obtain the hydrochloride salt of the title compound.

ESI-Mass; 455 (MH ⁺ ).

Example 91; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (4-cyano-2-fluorophenoxy ) ethyl] piperazine

Based on the preparation of 2- (4-cyano-2-fluorophenoxy) ethylpiperazine, synthesized in the manner according to Reference Example 69, the title compound was obtained as a colorless oily compound (64%) according to the preparation method of Example 84. .

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H), 1.74-1.84 (m, 1H), 2.00-2.13 (m, 2H), 2.25-2.33 (m, 2H), 2.33-2.49 (m, 4H), 2.49-2.68 (m, 4H), 2.85 ( t, J = 5.8 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 6.92 (dd, J = 1.5 Hz, 5.1 Hz, 1H), 7.00 (t, J = 8.4 Hz, 1H), 7.25 -7.28 (m, 1H), 7.32-7.37 (m, 2H), 7.40 (ddd, J = 1.3 Hz, 1.8 Hz, 8.4 Hz, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 455 (MH ⁺ ).

Example 92; 1- {4-cyano-5-methyl-4-[(2,5-dibromo) -3-thienyl] hexyl} -4- [2- (3- cyanophenoxy) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (78%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.52-1.70 (m, 1H), 1.82-2.02 (m, 1H), 2.30-2.53 (m, 8H), 2.53-2.68 (m, 4H), 2.81t, J = 5.8 Hz, 2H), 4.10 (t, J = 5.8 Hz, 2H), 7.04 (s, 1H), 7.11-7.20 (m, 2H), 7.22-7.29 (m, 1H), 7.34-7.39 (m, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 593, 595, 597 (MH ⁺ ).

Example 93; 1- {4-cyano-5-methyl-4- (2-bromo-5-cyano-3-thienyl) hexyl} -4- [2- (3-cyanophenoxy) ethyl] piperazine

1- {4-cyano-5-methyl-4-[(2,5-dibromo) -3-thienyl] hexyl} -4- [2- (3-cyanophenoxy) ethyl] piperazine (145 mg) was dissolved zinc cyanide (57.3 mg) and 1,1'-bis (diphenylphosphino) ferrocene (13.5 mg) in a mixed solvent of dimethylformamide (10 mL) / water (0.1 mL) under a nitrogen atmosphere. . Palladium-dibenzylidene acetone complex (8.9 mg) was added, and after nitrogen-exchanging 3 times, it stirred at 120 degreeC for 4 hours. Water, diethyl ether and ammonia water were added, and the organic layer was partitioned, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the drying agent was filtered off and concentrated under reduced pressure, and then LC-MS (ODS column; acetonitrile / water system). ) To give the title compound (8 mg, 6.7%) as a yellow oil.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.19-1.25 (m, 1H), 1.53-1.68 (m, 1H), 2.00-2.10 (m, 1H), 2.30-2.70 (m, 12H), 2.83 (t, J = 5.7 Hz, 2H), 4.11 (t, J = 5.7 Hz, 2H), 7.11-7.17 (m , 2H), 7.22-7.27 (m, 1H), 7.34-7.39 (m, 1H), 7.55 (s, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 540, 542 (MH ⁺ ).

Example 94; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (4-methylthiophenoxy) ethyl] piperazine

According to Example 45 described in Japanese Patent Application Laid-Open No. 11-206862, a colorless oily title compound was obtained (64%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.55-1.70 (m, 1H), 1.71-1.82 (m, 1H), 2.02-2.10 (m, 1H), 2.11-2.21 (m, 1H), 2.27-2.35 (m, 2H), 2.35-2.50 (m, 4H), 2.44 ( s, 3H), 2.50-2.65 (m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 4.07 (t, J = 5.9 Hz, 2H), 6.84 (brd, J = 8.8 Hz, 2H), 6.94 (dd, J = 3.7 Hz, 4.9 Hz, 1H), 7.11 (brd, J = 3.7 Hz, 1H), 7.22-7.29 (m, 3H).

Furthermore, the hydrochloride of this free body (title compound) was obtained according to the method of Example 84.

* ESI-Mass; 456 (MH ⁺ ).

Example 95; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (4-methylsulfonylphenoxy ) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (85%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.22-1.38 (m, 1H), 1.55-1.71 (m, 1H), 1.71-1.82 (m, 1H), 2.02-2.10 (m, 1H), 2.11-2.21 (m, 1H), 2.27-2.35 (m, 2H), 2.35-2.50 (m, 4H), 2.50- 2.65 (m, 4H), 2.83 (t, J = 5.8 Hz, 2H), 3.03 (s, 3H), 4.16 (t, J = 5.8 Hz, 2H), 6.84 (brd, J = 8.8 Hz, 2H), 6.94 (dd, J = 3.7 Hz, 4.9 Hz, 1H), 7.11 (brd, J = 3.7 Hz, 1H), 7.22-7.29 (m, 3H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 490 (MH ⁺ ).

Example 96; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-acetylphenoxy) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (72%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.22-1.38 (m, 1H), 1.55-1.71 (m, 1H), 1.71-1.82 (m, 1H), 2.02-2.10 (m, 1H), 2.11-2.21 (m, 1H), 2.28-2.35 (m, 2H), 2.35-2.50 (m, 4H), 2.50- 2.65 (m, 4H), 2.59 (s, 3H), 2.82 (t, J = 5.8 Hz, 2H), 4.14 (t, J = 5.8 Hz, 2H), 6.94 (dd, J = 3.5 Hz, 4.9 Hz, 1H), 7.09-7.13 (m, 2H), 7.24-7.28 (m, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.47-7.50 (m, 1H), 7.54 (brd, J = 7.9 Hz , 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 454 (MH ⁺ ).

Example 97; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (3-acetylphenoxy) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (60%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H), 1.75-1.84 (m, 1H), 2.02-2.13 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.47 (m, 4H), 2.47-2.68 (m, 4H), 2.59 ( s, 3H), 2.81 (t, J = 5.9 Hz, 2H), 4.14 (t, J = 5.9 Hz, 2H), 6.92 (dd, J = 1.4 Hz, 4.9 Hz, 1H), 7.09-7.13 (m, 1H), 7.25-7.28 (m, 1H), 7.32-7.38 (m, 2H), 7.47-7.50 (m, 1H), 7.51-7.56 (m, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 454 (MH ⁺ ).

Example 98; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (4-cyanophenoxy) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (55%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H), 1.72-1.84 (m, 1H), 2.02-2.12 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.45 (m, 4H), 2.45-2.65 (m, 4H), 2.81 ( t, J = 5.8 Hz, 2H), 4.12 (t, J = 5.8 Hz, 2H), 6.90-6.97 (m, 3H), 7.23-7.32 (m, 1H), 7.32-7.36 (m, 1H), 7.57 (d, J = 8.6 Hz, 2H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 437 (MH ⁺ ).

Example 99; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (4-methylthiophenoxy) ethyl] piperazine

In accordance with Example 45 described in Japanese Patent Application Laid-Open No. 11-206862, a title compound was obtained as a colorless oil (59%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H), 1.72-1.84 (m, 1H), 2.02-2.12 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.48 (m, 4H), 2.44 (s, 3H), 2.48-2.65 ( m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 4.06 (t, J = 5.9 Hz, 2H), 6.84 (brd, J = 6.6 Hz, 2H), 6.92 (dd, J = 1.5 Hz, 5.1 Hz, 1H), 7.22-7.28 (m, 3H), 7.33 (dd, J = 3.0 Hz, 5.1 Hz, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 456 (MH ⁺ ).

Example 100; 1- [4-cyano-5-methyl-4- (3-thienyl) hexyl] -4- [2- (4-methylsulfonylphenoxy ) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (56%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.50-1.68 (m, 1H), 1.74-1.84 (m, 1H), 2.02-2.12 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.48 (m, 4H), 2.48-2.65 (m, 4H), 2.82 ( t, J = 5.9 Hz, 2H), 3.03 (s, 3H), 4.16 (t, J = 5.9 Hz, 2H), 6.92 (dd, J = 1.5 Hz, 5.1 Hz, 1H), 7.02 (brd, J = 8.8 Hz, 2H), 7.24-7.29 (m, 1H), 7.33 (dd, J = 3.0 Hz, 5.1 Hz, 1H), 7.86 (brd, J = 8.8 Hz, 2H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 490 (MH ⁺ ).

Example 101; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- [2- (3-bromophenoxy) ethyl] piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (87%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.20-1.40 (m, 1H), 1.55-1.70 (m, 1H), 1.72-1.82 (m, 1H), 2.00-2.10 (m, 2H), 2.10-2.22 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.50 (m, 4H), 2.50- 2.65 (m, 4H), 2.78 (t, J = 5.8 Hz, 2H), 4.06 (t, J = 5.8 Hz, 2H), 6.80-6.85 (m, 1H), 6.94 (brdd, J = 3.5 Hz, 5.0 Hz, 1H), 7.04-7.15 (m, 4H), 7.24-7.28 (m, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 490, 492 (MH ⁺ ).

Example 102; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- (2-phenoxyethyl) piperazine

According to the preparation described in Example 84, the title compound was obtained as colorless oil (97%).

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.20-1.40 (m, 1H), 1.55-1.70 (m, 1H), 1.72-1.82 (m, 1H), 2.00-2.10 (m, 2H), 2.10-2.22 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.50 (m, 4H), 2.50- 2.65 (m, 4H), 2.80 (t, J = 5.8 Hz, 2H), 4.09 (t, J = 5.8 Hz, 2H), 6.87-6.97 (m, 4H), 7.08-7.12 (m, 1H), 7.23 -7.30 (m, 2 H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 412 (MH ⁺ ).

Example 103; 1- [4-cyano-5-methyl-4- (2-bromo-5-thienyl) hexyl] -4- [2- (3-cyanophenoxy ) ethyl] piperazine

[4-cyano-5-methyl-4- (2-bromo-5-thienyl) hexyloxy] -tert-butyldimethyl obtained in Example 114-5) of Japanese Patent Application Laid-Open No. 11-206862 Using silane (700 mg), yellow cyano 4-cyano-5-methyl-4- (2-bromo-5-thier) according to Example 114-8) described in Japanese Patent Application Laid-Open No. 11-206862. Nil) hexanol (371 mg, 80%) was synthesized. From 105 mg of the compound and 96 mg of 2- (3-cyanophenoxy) ethylpiperazine, a colorless oily title compound (138 mg, 62%) was synthesized according to the preparation method described in Example 84.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.20-1.40 (m, 1H), 1.55-1.70 (m, 1H), 1.90-2.05 (m, 1H), 2.05-2.20 (m, 2H), 2.30-2.38 (m, 2H), 2.38-2.50 (m, 4H), 2.50-2.65 (m, 4H), 2.81 ( t, J = 5.8 Hz, 2H), 4.10 (t, J = 5.8 Hz, 2H), 6.90 (dd, J = 3.8 Hz, 8.6 Hz, 2H), 7.10-7.17 (m, 2H), 7.22-7.30 ( m, 1H), 7.33-7.40 (m, 1H).

In addition, the hydrochloride of this vitreous (title compound) was obtained in accordance with the method described in Example 84.

ESI-Mass; 515, 517 (MH ⁺ ).

Example 104; 1- [4-cyano-4- (3-cyano-5-thienyl) -5-methylhexyl] -4- [2- (4-methyl sulfonylphenoxy) ethyl] piperazine

According to the method of Example 68, 4-cyano-4- (3-cyano-5-thienyl) -5-methylhexanol and 1- [2- (4-methylsulfonylphenoxy) ethyl] pipe The title compound (39%) of light yellow oily product was synthesized from razine. Moreover, this vitreous (title compound) was processed by the conventional method, and the hydrochloride salt was obtained.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.21-1.31 (m, 1H), 1.60-1.72 (m, 1H), 1.78 (dt, J = 4 Hz, J = 13.2 Hz, 1H), 2.07 (qui, J = 6.8 Hz, 1H), 2.20 (dt, J = 4 Hz, J = 13.2 Hz, 1H), 2.33 (t , J = 7.2 Hz, 2H), 2.42 (bs, 4H), 2.59 (bs, 4H), 2.83 (t, J = 5.6 Hz, 2H), 3.03 (s, 3H), 4.16 (t, J = 5.6 Hz , 2H), 7.02 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 1.2 Hz, 1H ).

Hydrochloride;

ESI-Mass; 515 (MH ⁺ ).

Example 105; 1- [4-cyano-4- (3-cyano-5-thienyl) -5-methylhexyl] -4- [2- (3-acetylphenoxy ) ethyl] piperazine

According to the method of Example 68, 4-cyano-4- (3-cyano-5-thienyl) -5-methylhexanol and 1- [2- (3-acetylphenoxy) ethyl] piperazine ( From pale yellow oil to give the title compound (yield 38%). Moreover, this vitreous (title compound) was processed by the conventional method, and the hydrochloride salt was obtained.

Vitreous;

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.21-1.32 (m, 1H), 1.60-1.74 (m, 1H), 1.78 (dt, J = 4 Hz, J = 13.2 Hz, 1H), 2.07 (qui, J = 6.8 Hz, 1H), 2.20 (dt, J = 4 Hz, J = 13.2 Hz, 1H), 2.29-2.37 (m, 2H), 2.43 (bs, 4H), 2.59 (bs, 4H), 2.60 (s, 3H), 2.83 (t, J = 5.6 Hz, 2H), 4.15 (t, J = 5.6 Hz, 2H) , 7.10-7.13 (m, 1H), 7.29 (d, J = 1.2 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.49 (dd, J = 1.6 Hz, J = 2.8 Hz, 1H), 7.52-7.55 (m, 1H), 7.90 (d, J = 1.2 Hz, 1H).

Hydrochloride;

ESI-Mass; 479 (MH ⁺ ).

Example 106; 1- [4-cyano5-methyl-4- (2-thienyl) hexyl] -4-[{2- (5-cyanobenzofuranyl )} methyl] piperazine

The title compound was synthesized according to the method of Example 75 using 1-[{2- (5-cyanobenzofuranyl)} methyl] piperazine (yield 100%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.22-1.37 (m, 1H), 1.56-1.70 (m, 1H), 1.70-1.80 (m, 1H), 2.00-2.09 (m, 1H), 2.10-2.19 (m, 1H), 2.32 (t, J = 7.2 Hz, 2H), 2.35-2.65 (m, 8H) , 3.70 (s, 2H), 6.65 (brd-s, 1H), 6.93 (dd, J = 3.2 Hz, 5.2 Hz, 1H), 7.10 (dd, J = 1.2 Hz, 3.2 Hz, 1H), 7.24 (dd , J = 1.2 Hz, 5.2 Hz, 1H), 7.52-7.54 (m, 2H), 7.85-7.87 (m, 1H)

ESI-MS: 447 (M + H) ⁺

Example 107; 1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- (2-phenoxytyl ) piperazine

Using 1- [2-phenoxyethyl] piperazine, the title compound was synthesized according to the method of Example 77 (yield 96.5%). Physical and chemical data of the title compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.20-1.32 (m, 1H), 1.60-1.72 (m, 1H), 1.72-1.82 (m, 1H), 2.00-2.12 (m, 1H), 2.17-2.27 (m, 1H), 2.33 (t, J = 7.2 Hz, 2H), 2.32-2.48 (m, 4H) , 2.50-2.70 (m, 4H), 2.81 (t, J = 6.0 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 6.88-6.97 (m, 3H), 7.15 (d, J = 4.0 Hz, 1H), 7.25-7.30 (m, 2H), 7.51 (d, J = 4.0 Hz, 1H)

ESI-MS: 437 (M + H) ⁺

Example 108; 1- [4-cyano-5-methyl-4- (5-cyano-2-thienyl) hexyl] -4- [2- (3 -bromorphenoxy) ethyl] piperazine

Using 1- [2- (3-bromophenoxy) ethyl] piperazine, the title compound was synthesized according to the method of Example 77 (yield 83.5%). Physical and chemical data of the title compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.20-1.32 (m, 1H), 1.60-1.72 (m, 1H), 1.72-1.83 (m, 1H), 2.02-2.12 (m, 1H), 2.17-2.28 (m, 1H), 2.28-2.50 (m, 6H), 2.50-2.67 (m, 4H), 2.80 ( t, J = 6.0 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 6.81-6.86 (m, 1H), 7.05-7.10 (m, 2H), 7.10-7.14 (m, 1H), 7.16 (d, J = 3.6 Hz, 1H), 7.52 (d, J = 3.6 Hz, 1H)

MS (ESI) m / z 515, 517 (M + H) ⁺

Examples 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, according to the methods of Examples 1, 89 or 99 described in Japanese Patent Application Laid-Open No. 11-206862 or according to these methods 120 compounds were synthesized.

Example 109; 1- [4-cyano-5-methyl-4- (2-bromo-5-thienyl) hexyl] -4- [2- (3-cyanophenoxy ) ethyl] piperazine

The title compound was obtained as light brown oil according to Example 1 described in Japanese Patent Application Laid-Open No. 11-206862.

Hydrochloride:

ESI-MS (m / e): 515, 517 (M + H).

Example 110; 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (3-chlorophenoxy ) ethyl] piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.21-1.32 (m, 1H), 1.55-1.73 (m, 2H ), 2.00-2.12 (m, 1H), 2.15-2.30 (m, 1H), 2.30-2.38 (m, 2H), 2.38-2.45 (m, 4H), 2.50-2.65 (m, 4H), 2.80 (t , J = 5.8 Hz, 2H), 4.07 (t, J = 5.8 Hz, 2H), 6.76-6.82 (m, 1H), 6.88-6.95 (m, 1H), 7.13-7.21 (m, 3H), 7.51 ( d, J = 3.8 Hz, 1H).

Hydrochloride:

ESI-MS (m / e): 471 (M + H).

Example 111; 1- [4-cyano-5-methyl-4- (2-cyano-5-thienyl) hexyl] -4- [2- (3-iodephenoxy ) ethyl] piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.21-1.32 (m, 1H), 1.55-1.73 (m, 2H ), 2.00-2.12 (m, 1H), 2.15-2.30 (m, 1H), 2.30- 2.38 (m, 2H), 2.38-2.45 (m, 4H), 2.50-2.65 (m, 4H), 2.79 (t , J = 5.8 Hz, 2H), 4.06 (t, J = 5.8 Hz, 2H), 6.86-6.99 (m, 1H), 6.96-7.01 (m, 1H), 7.15 (d, J = 3.8 Hz, 1H) , 7.25-7.30 (m, 2H), 7.51 (d, J = 3.8 Hz, 1H).

Hydrochloride:

ESI-MS (m / e): 563 (M + H).

Example 112; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- {N- [3-cyanophenyl) -N -isopropylamino] ethyl} piperazine

Hydrochloride:

ESI-MS (m / e): 478 (M + H).

Example 113; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- {N- [3-cyanophenyl) -N -methylamino] ethyl} piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.20-1.40 (m, 1H), 1.45-1.70 (m, 1H ), 1.70-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.20 (m, 1H), 2.24-2.60 (m, 12H), 3.00 (s, 3H), 3.46 (t, J = 7.4 Hz, 2H), 6.84-6.98 (m, 4H), 7.11 (dd, J = 3.5 Hz, 1.1 Hz, 1H), 7.23-7.33 (m, 2H).

Hydrochloride:

ESI-MS (m / e): 450 (M + H).

Example 114; Synthesis of 1- [3-cyano-4-methyl-5- (2-thienyl) pentyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.85-1.98 (m, 1H), 2.00-2.20 (m, 2H ), 2.30-2.70 (m, 10H), 2.80 (t, J = 5.9 Hz, 2H), 4.09 (t, J = 5.9 Hz, 2H), 6.95 (dd, J = 5.1 Hz, 3.7 Hz, 1H), 7.10-7.15 (m, 3H), 7.22-7.29 (m, 2H), 7.33-7.39 (m, 1H).

Hydrochloride;

ESI-MS (m / e): 423 (M + H).

Example 115; 1- [3-cyano-4-methyl-5- (2-thienyl) pentyl] -4- [2- (4-fluorophenoxy ) ethyl] piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.85-1.98 (m, 1H), 2.00-2.20 (m, 2H ), 2.30-2.70 (m, 10H), 2.78 (t, J = 5.9 Hz, 2H), 4.04 (t, J = 5.9 Hz, 2H), 6.80-6.85 (m, 2H), 6.92-6.99 (m, 3H), 7.10-7.13 (m, 1H), 7.26-7.30 (m, 1H).

Hydrochloride;

ESI-MS (m / e): 416 (M + H).

Example 116; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- (cyclohexylmethyl) piperazine

Trifluoroacetate;

ESI-MS (m / e): 388 (M + H)

Example 117; 4- [4- (4-phenylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide

Vitreous;

Rf = 0.5 (developing solvent, ethyl acetate: hexane = 2: 1, Fuji Silysia Chemical Ltd., NH TLC)

Hydrochloride;

ESI-MS (m / e): 444 (M + H).

Example 118; 4- [4- (4-cyano-4-phenylpiperidinyl) -piperidinyl] -1-isopropyl- 1-phenylbutyl cyanide

Vitreous;

Rf = 0.4 (developing solvent, ethyl acetate: hexane = 2: 1, Fuji Silysia Chemical Ltd., NH TLC)

Hydrochloride;

ESI-MS (m / e): 469 (M + H).

Example 119; 4- [4- (4-benzylpiperidinyl) -piperidinyl] -1-isopropyl-1-phenylbutyl cyanide

Vitreous;

Rf = 0.5 (developing solvent, ethyl acetate: hexane = 2: 1, Fuji Silysia Chemical Ltd., NH TLC)

Hydrochloride;

ESI-MS (m / e): 458 (M + H).

Example 120; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- {2- [N- (1,2,3,4 -tetrahydro-1-quinolinyl) Sulfamoyl] ethyl} piperazine

The title compound was synthesize | combined according to the method of Example 63 or 67 described in Unexamined-Japanese-Patent No. 11-206862, or according to these methods.

Trifluoroacetate;

ESI-MS (m / e): 515 (M + H)

Example 121; 1- [3-cyano-4-methyl-5- (2-thienyl) pentyl] -4- {2- [N- (1,2,3,4 -tetrahydro-1-quinolinyl) Sulfamoyl] ethyl} piperazine

The title compound was synthesize | combined according to the method of Example 63 or 67 described in Unexamined-Japanese-Patent No. 11-206862, or according to these methods.

Trifluoroacetate;

ESI-MS (m / e): 501 (M + H).

Example 122; 1- [4-cyano-5-methyl-4- (2-thienyl) hexyl] -4- {2- [N- (piperidinyl) sulfamoyl] ethyl} piperazine

The title compound was synthesize | combined according to the method of Example 63 or 67 described in Unexamined-Japanese-Patent No. 11-206862, or according to these methods.

Hydrochloride;

ESI-MS (m / e): 467 (M + H).

Example 123; Bis-1,4-[(3-cyano-4-methyl-3-phenyl) pentyl] piperazine

3-methyl-2- (2-oxoethyl) -2-phenylbutanenitrile (100 mg) and anhydrous piperazine (22 mg) are dissolved in methylene chloride solution (5 ml), acetic acid (0.085 ml) and triacetoxyborohydride Sodium (158 mg) was added and stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added, the organic layer was distributed, washed with water, and dried over anhydrous sodium sulfate. The residue which was concentrated under reduced pressure was purified by Chromatorex NH silica gel column chromatography (hexane: ethyl acetate system) to give a colorless oily title compound (81 mg, 71%). This vitreous was treated by a conventional method to obtain hydrochloride (89 mg) of the title compound.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 6H), 1.10-1.20 (m, 2H), 1.19 (d, J = 6.8 Hz, 6H), 1.50-1.60 (m, 2H ), 1.90-2.15 (m, 6H), 2.00-2.45 (m, 8H), 7.25-7.42 (m, 10H).

Hydrochloride;

ESI-MS (m / e): 457 (M + H).

According to the method of Example 123, the title compounds of Examples 124 to 126 were synthesized.

Example 124; Bis-1,4-[(3-cyano-4-methyl-3-phenyl) pentyl] homopiperazine

Hydrochloride;

ESI-MS (m / e): 471 (M + H).

Example 125; Bis-1,4-[(3-cyano-4-methyl-3-phenyl) hexyl] homopiperazine

Hydrochloride;

ESI-MS (m / e): 499 (M + H).

Example 126; Bis-1,4- [3-cyano-4-methyl-3- (2-thienyl) pentyl] piperazine

Hydrochloride;

ESI-MS (m / e): 469 (M + H).

Example 127; (S) -3-phenyl-2-amino-propanoic acid {1-[(4-cyano-5-methyl-4-phenyl) hexyl ] piperazinyl} amide

1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperazine (10 mg) and N- (tert-butoxycarbonyl) -L-phenylalanine (14 mg) were added to methylene chloride (0.5 ml). After dissolving, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10 mg) and triethylamine (0.015 ml) were added, and the mixture was stirred at room temperature overnight. After purification by silica gel chromatography (diethyl ether), the solvent was removed by nitrogen blowing. After the obtained residue was dissolved in methylene chloride (0.4 ml), trifluoroacetic acid (0.2 ml) was added and stirred at room temperature for 9 hours. The reaction solvent was removed overnight by blowing nitrogen at 35 ° C. to obtain the hydrochloride of the title compound (21 mg, 91%).

Hydrochloride;

ESI-MS (m / e): 433 (M + H).

According to the method of Example 127, the title compounds of Examples 128 and 129 were synthesized.

Example 128; (S) -3-phenyl-2-amino-propanoic acid {1- [4-cyano-5-methyl-5- (2-thionyl ) hexyl] piperazinyl} amide

Hydrochloride;

ESI-MS (m / e): 439 (M + H).

Example 129; (S) -3-phenyl-2-amino-propanoic acid {1- [3-cyano-4-methyl-4- (2-thionyl ) hexyl] piperazinyl} amide

Hydrochloride;

ESI-MS (m / e): 425 (M + H).

Example 130; 5- [3- (benzylamino) -4-hydroxytetrahydro-1H-1-pyrrolyl] -2-isopropyl-5-oxo-2- (2-thienyl) pentanenitrile

At room temperature under a nitrogen atmosphere, 5- (2,5-dihydro-1H-1-pyrrolyl) -2-isopropyl-5-oxo-2- (2-thienyl) pentanenitrile (260 mg) was diluted with dimethyl sulfoxide. (2 ml) and dissolved in a mixed solvent of water (0.1 ml), N-bromosuccinimide (177 mg) was added and stirred overnight. The reaction solution was separated with ethyl acetate / water, and the obtained organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane system) to give a colorless oily intermediate (140 mg). This intermediate (20 mg) was dissolved in tetrahydrofuran (0.05 ml), 1N aqueous sodium hydroxide solution (0.06 ml) was added, and the mixture was stirred at room temperature. After stirring for 45 minutes, benzylamine (11 mg) / tetrahydrofuran (0.05 ml) solution was added, and it stirred at 70 degreeC overnight. After returning to room temperature, the reaction liquid was separated by ethyl acetate / water, and the obtained organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by Chromatorex NH silica gel column chromatography (ethyl acetate / hexane system) to give a colorless oily title compound (20 mg).

Hydrochloride;

ESI-MS (m / e): 412 (M + H).

According to the method of Example 130, the title compounds of Examples 131 to 136 were synthesized.

Example 131; 5- [3- (N-methylbenzylamino) -4-hydroxytetrahydro-1H-1- pyrrolyl] -2-isopropyl-5-oxo-2- (2-thienyl) pentanenitrile

Hydrochloride;

ESI-MS (m / e): 426 (M + H).

Example 132; 5- [3- (2-thienylethylamino) -4-hydroxytetrahydro-1H-1 -pyrrolyl] -2-isopropyl-5-oxo-2- (2-thienyl) pentanenitrile

Hydrochloride;

ESI-MS (m / e): 432 (M + H).

Example 133; 5- [3- (N-phenylpiperazino) -4-hydroxytetrahydro-1H-1- pyrrolyl] -2-isopropyl-5-oxo-2- (2-thienyl) pentanenitrile

Trifluoroacetate;

ESI-MS (m / e): 467 (M + H).

Example 134; 5- {3- [4- (2,3-dihydro-1H-1-indolyl) piperidino] -4-hydroxy citetrahydro-1H-pyrrolyl} -2-isopropyl-5-oxo 2- (2-thienyl) pentanenitrile

Trifluoroacetate;

ESI-MS (m / e): 507 (M + H).

Example 135; 5- [3- (3-pyridylethylamino) -4-hydroxytetrahydro-1H-1 -pyrrolyl] -2-isopropyl-5-oxo-2- (2-thienyl) pentanenitrile

Trifluoroacetate;

ESI-MS (m / e): 427 (M + H).

Example 136; 5- {3- [4- (1H-1-Indolyl) piperidino] -4-hydroxytetrahydro- 1H-pyrrolyl} -2-isopropyl-5-oxo-2- (2-thi Nil) pentanenitrile

Trifluoroacetate;

ESI-MS (m / e): 505 (M + H).

According to the method of Example 64, the title compounds of Examples 137 to 172 were synthesized.

Example 137; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (benzothiazolyl) piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H), 1.50-1.70 (m, 1H ), 1.87-1.20 (m, 1H), 2.08-2.24 (m, 2H), 2.30-2.38 (m, 1H), 2.40-2.48 (m, 4H), 3.52-3.64 (m, 4H), 7.04-7.10 (m, 1H), 7.24-7.34 (m, 2H), 7.35-7.40 (m, 4H), 7.50-7.61 (m, 2H).

Hydrochloride;

ESI-MS (m / e): 449 (M + H).

Example 138; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [2- (6-methoxy) benzothiazolyl ] piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H), 1.50-1.70 (m, 1H ), 1.87-1.20 (m, 1H), 2.08-2.24 (m, 2H), 2.30-2.38 (m, 1H), 2.38-2.48 (m, 4H), 3.50-3.62 (m, 4H), 3.82 (s , 3H), 6.86-6.92 (m, 1H), 7.12-7.15 (m, 1H), 7.22-7.35 (m, 3H), 7.35-7.40 (m, 3H), 7.43-7.48 (m, 1H).

Hydrochloride;

ESI-MS (m / e): 419 (M + H).

Example 139; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-benzoxazolyl) piperazine

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H), 1.50-1.70 (m, 1H ), 1.77-1.20 (m, 1H), 2.08-2.25 (m, 2H), 2.28-2.38 (m, 1H), 2.38-2.48 (m, 4H), 3.60-3.72 (m, 4H), 6.98-7.04 (m, 1H), 7.12-7.18 (m, 1H), 7.22-7.28 (m, 1H), 7.28-7.43 (m, 5H).

Hydrochloride;

ESI-MS (m / e): 403 (M + H).

Example 140; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-quinolinyl) piperazine

Vitreous;

Rf = 0.6 (developing solvent, diethyl ether, Merck silica gel 60F 254TLC)

Hydrochloride;

ESI-MS (m / e): 413 (M + H).

Example 141; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (1-isoquinolinyl) piperazine

Vitreous;

Rf = 0.45 (developing solvent, diethyl ether, Merck silica gel 60F 254TLC)

Hydrochloride;

ESI-MS (m / e): 413 (M + H).

Example 142; 4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepane-1-yl ] -1-isopropyl-1-phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 8.1 Hz, 6H), 1.08-1.30 (m, 1H), 1.20 (d, J = 7.0 Hz, 3H), 1.50-1.70 (m, 1H), 1.77-1.20 (m, 2H), 2.00-2.32 (m, 4H), 2.40-2.52 (m, 2H), 2.60-2.67 (m, 2H), 2.67-2.73 (m, 2H), 3.48-3.60 (m, 4H), 3.81 (d, J = 7.3 Hz, 2H), 7.07-7.18 (m, 3H), 7.25-7.42 (m, 5H), 7.51- 7.56 (m, 1 H).

Hydrochloride;

ESI-MS (m / e): 472 (M + H).

Example 143; 4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepane-1-yl ] -1-isopropyl-1- (2-crophenyl) Butyl Cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 8.1 Hz, 6H), 1.08-1.30 (m, 1H), 1.20 (d, J = 7.0 Hz, 3H), 1.50-1.70 (m, 1H), 1.77-1.20 (m, 2H), 2.00-2.32 (m, 4H), 2.40-2.52 (m, 2H), 2.60-2.67 (m, 2H), 2.67-2.73 (m, 2H), 3.48-3.60 (m, 4H), 3.81 (d, J = 7.3 Hz, 2H), 7.05-7.35 (m, 5H), 7.3035-7.40 (m, 1H), 7.51- 7.56 (m, 1 H), 7.72-7.79 (m, 1 H).

Hydrochloride;

ESI-MS (m / e): 506 (M [ ³⁴ Cl] + H), 508 (M [ ³⁶ Cl] + H).

Example 144; 1-isopropyl-4- [4- (1H-benzo [d] imidazol-2-yl) piperazino] -1- phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.04-1.25 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.50-1.70 (m, 1H ), 1.87-1.99 (m, 1H), 2.05-2.23 (m, 2H), 2.25-2.40 (m, 2H), 2.40-2.47 (m, 4H), 3.42-3.58 (m, 4H), 7.00-7.40 (m, 9 H).

Hydrochloride;

ESI-MS (m / e): 402 (M + H).

Example 145; 1-isopropyl-4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1-phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.50-1.70 (m, 1H ), 1.92-2.03 (m, 1H), 2.08-2.25 (m, 2H), 2.28-2.45 (m, 2H), 2.45-2.56 (m, 4H), 3.25-3.35 (m, 4H), 3.59 (s , 3H), 7.02-7.62 (m, 9H).

Hydrochloride;

ESI-MS (m / e): 416 (M + H).

Example 146; 1-isopropyl-4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1-phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 7.3 Hz, 3H), 1.50-1.70 (m, 1H), 1.92-2.03 (m, 1H), 2.08-2.25 (m, 2H), 2.28-2.45 (m, 2H), 2.45-2.56 (m, 4H), 3.20-3.35 (m, 4H), 4.03 (q, J = 7.3 Hz, 2H), 7.14-7.64 (m, 9H).

Hydrochloride;

ESI-MS (m / e): 430 (M + H).

Example 147; 4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino] -1-isopropyl -1- (2-thienyl) butyl cyanide

Vitreous;

Rf = 0.35 (developing solvent, ethyl acetate: hexane = 1: 1, Fuji Silysia Chemical Ltd., NH TLC)

Hydrochloride;

ESI-MS (m / e): 436 (M + H).

Example 148; 4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino] -1- isopropyl-1- (2-thienyl) butyl cyanide

Vitreous;

Rf = 0.4 (developing solvent, ethyl acetate: hexane = 1: 1, Fuji Silysia Chemical Ltd., NH TLC)

Hydrochloride;

ESI-MS (m / e): 464 (M + H).

Example 149; 1-isopropyl-4- [4- (1-isopropyl-1H-benzo [d] imidazol-2-yl) piperazino] -1-phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.6 Hz, 3H), 1.10-1.25 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H), 1.50-1.68 (m, 7H ), 1.90-2.04 (m, 1H), 2.05-2.24 (m, 2H), 2.25-2.45 (m, 2H), 2.45-2.53 (m, 4H), 3.15-3.25 (m, 4H), 4.56-4.68 (m, 1H), 7.09-7.19 (m, 2H), 7.25-7.33 (m, 1H), 7.34-7.42 (m, 5H), 7.60-7.64 (m, 1H).

Hydrochloride;

ESI-MS (m / e): 444 (M + H).

Example 150; 4- [4- (1H-benzo [d] imidazol-2-yl) -1,4-diazepan-1-yl] -1- isopropyl-1-phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.74 (d, J = 6.6 Hz, 3H), 1.00-1.15 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H), 1.40-1.50 (m, 1H ), 1.78-1.93 (m, 3H), 2.00-2.17 (m, 2H), 2.30-2.40 (m, 2H), 2.45-2.55 (m, 2H), 2.57-2.64 (m, 2H), 3.57-3.63 (m, 4 H), 6.96-7.52 (m, 9 H).

Hydrochloride;

ESI-MS (m / e): 416 (M + H).

Example 151; 4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepan-1-yl] -1- isopropyl-1-phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 1.07-1.17 (m, 1H), 1.18 (d, J = 6.6 Hz, 3H), 1.45-1.60 (m, 1H ), 1.76-2.25 (m, 5H), 2.40-2.50 (m, 2H), 2.60-2.67 (m, 2H), 2.68-2.76 (m, 2H), 3.53-3.63 (m, 4H), 3.57 (s , 3H), 7.08-7.54 (m, 9H).

Hydrochloride;

ESI-MS (m / e): 430 (M + H).

Example 152; 4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) -1,4-diazepan-1-yl] -1- isopropyl-1-phenylbutyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.05-1.17 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H), 1.40 (t, J = 7.2 Hz, 3H), 1.47-1.62 (m, 1H), 1.76-2.23 (m, 5H), 2.40-2.50 (m, 2H), 2.60-2.67 (m, 2H), 2.68-2.76 (m, 2H), 3.51-3.63 (m, 4H), 4.02 (d, J = 7.2 Hz, 3H), 7.06-7.54 (m, 9H).

Hydrochloride;

ESI-MS (m / e): 444 (M + H).

Example 153; 1-isopropyl-4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (4-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 1.13-1.23 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.56-1.66 (m, 1H), 1.89-1.97 (m, 1H), 2.04-2.22 (m, 2H), 2.34-2.41 (m, 2H), 2.50-2.51 (m, 4H), 3.26-3.29 (m, 4H), 4.01-4.07 (m, 2H), 7.05-7.10 (m, 2H), 7.14-7.25 (m, 3H), 7.34-7.38 (m, 2H), 7.60-7.62 (m , 1H).

Example 154; 1-isopropyl-4- [4- (1-benzyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (4-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.6 Hz, 3H), 1.08-1.15 (m, 1H), 1.18 (d, J = 6.6 Hz, 3H), 1.53-1.57 (m, 1H ), 1.85-1.93 (m, 1H), 2.02-2.19 (m, 2H), 2.29-2.38 (m, 2H), 2.42 (m, 4H), 3.21-3.24 (m, 4H), 5.20 (s, 2H) ), 6.99-7.11 (m, 4H), 7.15-7.21 (m, 3H), 7.26-7.35 (m, 5H), 7.62-7.65 (m, 1H).

Example 155; 1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (4-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.8 Hz, 3H), 0.82-0.85 (m, 6H), 1.12-1.25 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H ), 1.57-1.63 (m, 1H), 1.90-1.98 (m, 1H), 2.04-2.12 (m, 1H), 2.14-2.42 (m, 4H), 2.48 (m, 4H), 3.23-3.25 (m) , 4H), 3.81 (d, J = 7.3 Hz, 2H), 7.05-7.20 (m, 2H), 7.21-7.23 (m, 3H), 7.33-7.38 (m, 2H), 7.60-7.63 (m, 1H ).

Example 156; 1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (3-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77-0.89 (m, 9H), 1.13-1.26 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H), 1.58-1.65 (m, 1H), 1.90 -1.98 (m, 1H), 2.04-2.41 (m, 5H), 2.41-2.50 (m, 4H), 3.23-3.25 (m, 4H), 3.80 (d, J = 7.5 Hz, 2H), 6.98-7.03 (m, 1H), 7.08-7.23 (m, 5H), 7.33-7.39 (m, 1H), 7.60-7.63 (m, 1H).

Example 157; 1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.80-0.88 (m, 9H), 1.15-1.25 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.58-1.64 (m, 1H), 2.04 -2.16 (m, 1H), 2.25-2.51 (m, 9H), 3.22-3.25 (m, 4H), 3.80 (d, J = 7.5 Hz, 2H), 7.02-7.08 (m, 1H), 7.13-7.21 (m, 4H), 7.29-7.33 (m, 1H), 7.58-7.62 (m, 2H).

Example 158; 1-isopropyl-4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (3-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.80 (d, J = 6.8 Hz, 3H), 1.15-1.27 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.58-1.66 (m, 1H ), 1.89-1.97 (m, 1H), 2.01-2.24 (m, 2H), 2.34-2.41 (m, 2H), 2.51-2.53 (m, 4H), 3.29-3.32 (m, 4H), 3.59 (s , 3H), 6.98-7.04 (m, 1H), 7.08-7.21 (m, 5H), 7.33-7.39 (m, 1H), 7.58-7.61 (m, 1H).

Example 159; 1-isopropyl-4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (3-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.80 (d, J = 6.8 Hz, 3H), 1.13-1.28 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.58-1.66 (m, 1H), 1.89-1.97 (m, 1H), 2.04-2.24 (m, 2H), 2.33-2.41 (m, 2H), 2.51-2.52 (m, 4H), 3.27-3.30 (m, 4H), 4.01-4.07 (m, 2H), 6.98-7.04 (m, 1H), 7.08-7.27 (m, 5H), 7.33-7.39 (m, 1H), 7.59-7.62 (m , 1H).

Example 160; 1-isopropyl-4- [4- (1-benzyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (3-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78 (d, J = 6.6 Hz, 3H), 1.08-1.18 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.54-1.65 (m, 1H ), 1.84-1.92 (m, 1H), 2.04-2.20 (m, 2H), 2.28-2.36 (m, 2H), 2.38-2.43 (m, 4H), 3.22-3.25 (m, 4H), 5.20 (s , 2H), 6.96-7.01 (m, 2H), 7.05-7.10 (m, 2H), 7.14-7.21 (m, 4H), 7.26-7.36 (m, 4H), 7.63-7.64 (m, 1H).

Example 161; 1-isopropyl-4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-fluorophenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.81 (d, J = 6.8 Hz, 3H), 1.15-1.28 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.59-1.68 (m, 1H), 2.04-2.16 (m, 1H), 2.25-2.54 (m, 8H), 3.27-3.30 (m, 4H), 4.00-4.06 (m, 2H), 7.02-7.08 (m, 1H), 7.13-7.24 (m, 4H), 7.29-7.34 (m, 1H), 7.58-7.63 (m, 2H).

Example 162; Synthesis of 1-isopropyl-4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-tril) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.25-1.40 (m, 1H), 1.53-1.70 (m , 1H), 1.97-2.10 (m, 1H), 2.20-2.35 (m, 1H), 2.40-2.50 (m, 1H), 2.47 (s, 3H), 3.05-3.20 (m, 2H), 3.10-3.30 (m, 4H), 3.33-3.50 (m, 4H), 3.59 (s, 3H), 7.07-7.15 (m, 2H), 7.20-7.29 (m, 3H), 7.34-7.46 (m, 3H).

Example 163; 1-isopropyl-4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (4-fluorophenyl) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.66 (d, J = 6.4 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H), 1.10-1.30 (m, 1H), 1.50-1.67 (m , 1H), 1.95-2.30 (m, 2H), 2.15-2.27 (m, 1H), 2.95-3.20 (m, 2H), 3.10-3.30 (m, 4H), 3.35-3.50 (m, 4H), 3.59 (s, 3H), 7.07-7.15 (m, 2H), 7.28 (t, J = 8.8 Hz, 2H), 7.34-7.46 (m, 2H), 7.43-7.50 (m, 2H).

Example 164; 1-isopropyl-4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-chlorophenyl) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.73 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.10-1.35 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.50-1.68 (m, 1H), 2.00-2.15 (m, 1H), 2.50-2.70 (m, 1H), 2.78-2.90 (m, 1H), 3.00-3.20 (m, 2H ), 3.05-3.30 (m, 4H), 3.25-3.45 (m, 4H), 4.06 (q, J = 7.2 Hz, 2H), 7.06-7.15 (m, 2H), 7.38-7.49 (m, 4H), 7.54 (dd, J = 7.6 Hz, 2.0 Hz, 1 H), 7.65 (dd, J = 7.6 Hz, 2.0 Hz, 1 H).

Example 165; 1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-chlorophenyl) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.75 (d, J = 6.8 Hz, 9H), 1.12 (d, J = 6.4 Hz, 3H), 1.15-1.45 (m, 1H), 1.50-1.70 (m , 1H), 2.00-2.25 (m, 2H), 2.50-2.65 (m, 1H), 2.75-2.90 (m, 1H), 3.00-3.30 (m, 2H), 3.00-3.30 (m, 4H), 3.20 -3.45 (m, 4H), 3.87 (d, J = 7.2 Hz, 2H), 7.00-7.18 (m, 2H), 7.38-7.48 (m, 4H), 7.54 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1 H).

Example 166; 1-isopropyl-4- [4- (1-methyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-methoxyphenyl) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.68 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.50-1.65 (m , 1H), 1.90-2.05 (m, 1H), 2.35-2.50 (m, 1H), 2.57-2.70 (m, 1H), 2.95-3.20 (m, 2H), 3.05-3.25 (m, 4H), 3.30 -3.50 (m, 4H), 3.59 (s, 3H), 3.81 (s, 3H), 6.98-7.04 (m, 1H), 7.07-7.15 (m, 3H), 7.33-7.43 (m, 4H).

Example 167; 1-isopropyl-4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-methoxyphenyl) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.67 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.10-1.30 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.45-1.60 (m, 1H), 1.90-2.05 (m, 1H), 2.35-2.50 (m, 1H), 2.58-2.70 (m, 1H), 2.90-3.10 (m, 2H ), 3.00-3.20 (m, 4H), 3.25-3.45 (m, 4H), 3.81 (s, 3H), 4.06 (q, J = 7.2 Hz, 2H), 7.01 (t, J = 7.6 Hz, 1H) , 7.06-7.14 (m, 3H), 7.36 (t, J = 7.6 Hz, 1H), 7.35-7.45 (m, 3H).

Example 168; 1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-methoxyphenyl) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.67 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.4 Hz, 6H), 1.09 (d, J = 6.4 Hz, 3H), 1.05- 1.30 (m, 1H), 1.45-1.65 (m, 1H), 1.90-2.03 (m, 1H), 2.10-2.20 (m, 1H), 2.35-2.50 (m, 1H), 2.57-2.70 (m, 1H ), 3.00-3.20 (m, 2H), 3.10-3.25 (m, 4H), 3.25-3.45 (m, 4H), 3.81 (s, 3H), 3.86 (d, J = 7.6 Hz, 2H), 7.01 ( td, J = 7.6 Hz, 2.0 Hz, 1H), 7.06-7.14 (m, 3H), 7.33-7.46 (m, 4H).

Example 169; 1-isopropyl-4- [4- (1-benzyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-methoxyphenyl) butyl cyanide

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.67 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.10-1.25 (m, 1H), 1.45-1.65 (m , 1H), 1.90-2.00 (m, 1H), 2.33-2.45 (m, 1H), 2.55-2.70 (m, 1H), 2.90-3.20 (m, 2H), 3.10-3.25 (m, 4H), 3.25 -3.45 (m, 4H), 3.79 (s, 3H), 5.30 (s, 2H), 6.97-7.20 (m, 7H), 7.21-7.47 (m, 6H).

Example 170; 1-isopropyl-4- [4- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-methylphenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.87 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.20-1.28 (m, 1H), 1.44 (t, J = 7.3 Hz, 3H), 1.55-1.70 (m, 1H), 2.06-2.20 (m, 1H), 2.25-2.45 (m, 4H), 2.45-2.58 (m, 7H), 3.25-3.35 (m, 4H), 4.04 (q, J = 7.3 Hz, 2H), 7.15-7.23 (m, 6H), 7.57-7.68 (m, 1H), 7.59-7.60 (m, 1H).

Hydrochloride;

ESI-MS (m / e): 444 (M + H).

Example 171; 1-isopropyl-4- [4- (1-benzyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-methylphenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.86 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H), 1.17-1.25 (m, 1H), 1.50-1.65 (m, 1H ), 2.00-2.10 (m, 1H), 2.20-2.48 (m, 8H), 2.49 (s, 3H), 3.19-3.24 (m, 4H), 5.19 (s, 2H), 6.99-7.01 (m, 1H) ), 7.08-7.21 (m, 8H), 7.27-7.38 (m, 2H), 7.43-7.55 (m, 1H), 7.63-7.65 (m, 1H).

Hydrochloride;

ESI-MS (m / e): 506 (M + H).

Example 172; 1-isopropyl-4- [4- (1-isobutyl-1H-benzo [d] imidazol-2-yl) piperazino ] -1- (2-methylphenyl) butyl cyanide

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.83 (d, J = 4.0 Hz, 3H), 0.85 (d, J = 4.0 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.20-1.29 (m, 1H), 1.54-1.65 (m, 1H), 2.05-2.16 (m, 1H), 2.24-2.51 (m, 9H), 2.52 (s, 3H) , 3.20-3.25 (m, 4H), 3.80 (d, J = 7.5 Hz, 2H), 7.12-7.22 (m, 6H), 7.48-7.56 (m, 1H), 7.59-7.60 (m, 1H).

Hydrochloride;

ESI-MS (m / e): 472 (M + H).

Example 173; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2- cyanoethyl) -N-benzylamino] Pyrrolidine

1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2-cyanoethyl) amino obtained in Reference Example 81 ] Pyrrolidine 300 mg (0.81 mmol) was dissolved in 8 ml of dichloromethane, 98.9 mg (0.93 mmol) of benzaldehyde, 0.09 ml (1.62 mmol) of acetic acid, and 258 mg (1.22 mmol) of sodium triacetoxyborohydride were added sequentially. After the completion of the reaction, the mixture was adjusted to alkaline with 5N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was treated with 25 g of Cromatorex NH silica gel (ethyl acetate: hexane = ethyl acetate 25%) to give 220 mg (0.48 mmol, 59.1%) of the title compound as a colorless syrup. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.16-1.29 (m, 1H), 1.54-1.66 (m, 1H), 1.70-1.84 (m, 2H), 1.91-2.08 (m, 2H), 2.17-2.37 (m, 5H), 2.38-2.51 (m, 2H), 2.51-2.58 (m, 1H), 2.61- 2.68 (m, 1H), 2.78-2.94 (m, 2H), 3.40-3.50 (m, 1H), 3.60 (d, J = 14 Hz, 1H), 3.71 (d, J = 14 Hz, 1H), 7.13 (d , J = 3.6 Hz, 1H), 7.32-7.39 (m, 5H), 7.50 (d, J = 3.6 Hz, 1H)

In addition, 4-cyano-4- (5-cyano-2) synthesized according to Reference Examples 104 and 105 from 4-cyano-4- (2-thienyl) -5-methylhexanoic acid obtained in Reference Example 103. Example 173 titled according to the preparation of Example 173 from -thienyl) -5-methylhexanol (hereinafter referred to as "alcohol b") and (3R) -3-tert-butoxycarbonylaminopyrrolidine Diastereomers of the compounds are synthesized. Likewise, the enantiomer of Example 173 title compound is synthesized from alcohol b and (3S) -3-tert-butoxycarbonylaminopyrrolidine according to the preparation of Example 173 above.

Example 174; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2- cyanoethyl) -N- (2- Thienylmethyl) amino] pyrrolidine

*

1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N-, obtained in Reference Example 81 according to the preparation of Example 173. The title compound was synthesized from (2-cyanoethyl) amino] pyrrolidine and 2-thiophenecarboxyaldehyde. Physical and chemical data of the compound were as follows.

Yield 46.7%

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.16-1.29 (m, 1H), 1.54-1.67 (m, 1H), 1.67-1.84 (m, 2H), 1.95-2.09 (m, 2H), 2.17-2.35 (m, 3H), 2.35-2.56 (m, 5H), 2.61-2.70 (m, 1H), 2.80- 2.96 (m, 2H), 3.44- 3.54 (m, 1H), 3.84 (d, J = 15.0 Hz, 1H), 3.92 (d, J = 15.0 Hz, 1H), 6.92-7.04 (m, 2H), 7.13 (d, J = 4.0 Hz, 1H), 7.23-7.31 (m, 1H), 7.51 (d, J = 4.0 Hz, 1H)

Example 175; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2- cyanoethyl) -N-benzylamino] Pyrrolidine

The title compound could be prepared according to the following two methods (Synthesis Methods A and B).

Synthesis Method A

(1) (3S) -3- [N- (2-cyanoethyl) -N-benzylamino] pyrrolidine

(3S) -3- [N- (2-cyanoethyl) from (3S) -3-amino-1- (tert-butoxycarbonyl) pyrrolidine according to the preparation of Reference Example 81 and Example 173. -N-benzylamino] -1- (tert-butoxycarbonyl) pyrrolidine was synthesized. This was subjected to deprotection of the Boc group in accordance with Reference Example 80 to obtain the title compound (yield 78.2%; 3 steps). Physical and chemical data of the compound were as follows.

Physical and chemical data of (3S) -3- [N- (2-cyanoethyl) -N-benzylamino] -1- (tert-butoxycarbonyl) pyrrolidine :

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 1.77-1.95 (m, 1H), 1.98-2.12 (m, 1H), 2.32 (t, J = 6.8 Hz, 2H), 2.87 ( t, J = 6.8 Hz, 2H), 3.10-3.78 (m, 7H), 7.27-7.39 (m, 5H)

Physical and chemical data of (3S) -3- [N- (2-cyanoethyl) -N-benzylamino] pyrrolidine :

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.66-1.78 (m, 1H), 1.88-2.02 (m, 1H), 2.31 (t, J = 6.8 Hz, 2H), 2.78-2.95 (m, 4H), 3.02-3.12 (m, 2H), 3.32-3.41 (m, 1H), 2.87 (t, J = 6.8 Hz, 2H), 3.64 (d, J = 14 Hz, 1H), 3.71 (d, J = 14 Hz, 1H ), 7.27-7.38 (m, 5H)

(2) 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl ) -N -Benzylamino] pyrrolidine

Optical activator 4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl iodide [iodide C (optical activator)] is obtained from alcohol B Example 77 (1) It was synthesized according to. The title compound was synthesized in accordance with Example 77 (2), from (3S) -3- [N- (2-cyanoethyl) -N-benzylamino] pyrrolidine obtained from iodide C and (1). . Physical and chemical data of the compound were as follows.

Yield 90.6%

ESI-MS: 460 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.16-1.30 (m, 1H), 1.56-1.68 (m, 1H), 1.70-1.81 (m, 2H), 1.93-2.10 (m, 2H), 2.21-2.44 (m, 7H), 2.57-2.67 (m, 2H), 2.80-2.95 (m, 2H), 3.39- 3.48 (m, 1H), 3.62 (d, J = 14 Hz, 1H), 3.69 (d, J = 14 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.23-7.37 (m, 5H), 7.52 (d, J = 4.0 Hz, 1H)

Synthesis Method B

According to the preparation of Example 173, the title compound was synthesized from the above iodide C (or alcohol B) and (3S) -3-tert-butoxycarbonylaminopyrrolidine.

Example 176; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl ) -N-benzylamino] pyrrolidine

The optically active 4-cyano-4- (2-thienyl) -5-methylhexyl iodide [iodide D (optical activator)] was synthesized from alcohol A in accordance with Example 77 (1). According to Example 75, this iodide D and (3S) -3- [N- (2-cyanoethyl) -N-benzylamino] pyrroli of Example 175 [Synthesis Method A] (1) (1) The title compound was synthesized from Dean. Physical and chemical data of the compound were as follows.

Yield 97%

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.20-1.35 (m, 1H), 1.55-1.68 (m, 1H), 1.69-1.82 (m, 2H), 1.92-2.10 (m, 2H), 2.17-2.43 (m, 7H), 2.54-2.66 (m, 2H), 2.87 (t, J = 6.8 Hz, 2H) , 3.37-3.46 (m, 1H), 3.62 (d, J = 14 Hz, 1H), 3.68 (d, J = 14 Hz, 1H), 6.95 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.15 (dd , J = 1.2 Hz, 3.6 Hz, 1H), 7.23-7.39 (m, 6H),

Example 177; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl ) -N- (3-cyanobenzyl) Amino] pyrrolidine

(3S) -3- [N- (2-cyanoethyl) -N- (3-cyanobenzyl) amino] pi synthesized according to Iodide D and the preparation of Example 175 [Synthesis A] (1) The title compound was synthesized from lollidine according to Example 75. Physical and chemical data of the compound were as follows.

Yield 82%

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.22-1.34 (m, 1H), 1.54-1.67 (m, 1H), 1.67-1.80 (m, 2H), 1.93-2.09 (m, 2H), 2.16-2.27 (m, 2H), 2.27-2.43 (m, 5H), 2.59-2.72 (m, 2H), 2.88 ( t, J = 6.8 Hz, 2H), 3.34-3.43 (m, 1H), 3.68 (d, J = 15 Hz, 1H), 3.74 (d, J = 15 Hz, 1H), 6.96 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.27 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.41-7.48 (m, 1H), 7.54-7.58 (m , 1H), 7.62-7.66 (m, 2H)

Example 178; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4-[{3-methoxy- (2R) -2- (2-pyridyloxy)} propyl] piperazine

According to Example 75, the title compound was synthesized from iodide D and 1-[{3-methoxy- (2R) -2- (2-pyridyloxy)} propyl] piperazine. Physical and chemical data of the compound were as follows. The physical properties of the title compound obtained are shown below.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.21-1.35 (m, 1H), 1.55-1.69 (m, 1H), 1.70-1.80 (m, 1H), 2.00-2.18 (m, 2H), 2.20-2.62 (m, 10H), 2.62-2.72 (m, 2H), 3.38 (s, 3H), 3.60-3.70 ( m, 2H), 5.47-5.55 (m, 1H), 6.71-6.78 (m, 1H), 6.81-6.87 (m, 1H), 6.94 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.10 (dd) , J = 1.6 Hz, 3.6 Hz, 1H), 7.25 (dd, J = 1.6 Hz, 5.2 Hz, 1H), 7.50-7.58 (m, 1H), 8.09-8.13 (m, 1H)

Example 179; 1- (6-bromo-2-pyridyl)-(3R) -3- {N- [4-cyano-4- (2-thienyl) -5- methylhexyl] amino} pyrrolidine

According to Example 75, iodide C (optical activator) and (3R) -3- {N- [4-cyano-4- (2-thienyl) -5-methylhexyl] amino} pyrrolidine From the title compound were synthesized. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.23-1.36 (m, 1H), 1.57-1.70 (m, 1H), 1.73-1.83 (m, 2H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.56-2.71 (m, 2H), 3.14-3.22 (m, 1H), 3.34- 3.44 (m, 2H), 3.49-3.58 (m, 1H, 3.59-3.66 (m, 1H, 6.21 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.94 (dd) , J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.22 (dd, J = 7.2 Hz, 8.0 Hz, 1H), 7.26 (dd, J = 1.2 Hz , 5.2Hz, 1H)

Example 180; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] -4- [2- (5 -chlorobenzoxazoyl) methyl] piperazine

From 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] piperazine and 2-chloromethyl-5-chlorobenzoxazole synthesized according to Example 83 The title compound was synthesized in accordance with Example 77. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.58-1.71 (m, 1H), 1.71-1.81 (m, 1H), 2.00-2.10 (m, 1H), 2.16-2.26 (m, 1H), 2.34 (t, J = 6.8 Hz, 2H), 2.37-2.54 (m, 4H) , 2.54-2.73 (m, 4H), 3.86 (s, 2H), 7.14 (d, J = 4.0 Hz, 1H), 7.31 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 4.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H)

Example 181; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] -4- [2- (5-methyl benzoxazoyl) methyl] piperazine

2-Chloromethyl-5- synthesized according to Example 180 with 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] piperazine according to Example 83 The title compound was synthesized from methylbenzoxazole in the same manner as in Example 77. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.58-1.70 (m, 1H), 1.70-1.81 (m, 1H), 2.00-2.10 (m, 1H), 2.16-2.26 (m, 1H), 2.33 (t, J = 6.8 Hz, 2H), 2.46 (s, 3H), 2.37 -2.54 (m, 4H), 2.55-2.73 (m, 4H), 3.85 (s, 2H), 7.12-7.16 (m, 1H), 7.14 (d, J = 4.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.47-7.49 (m, 1H), 7.51 (d, J = 4.0 Hz, 1H)

Example 182; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] -4- [2-benzothiazoylmethyl ] piperazine

2-chloromethylbenzothiazole synthesized according to Example 180 with 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] piperazine and according to Example 83 From Example 77, the title compound was synthesized. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.20-1.32 (m, 1H), 1.59-1.72 (m, 1H), 1.72-1.83 (m, 1H), 2.01-2.10 (m, 1H), 2.18-2.28 (m, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.35-2.52 (m, 4H) , 2.54-2.74 (m, 4H), 3.95 (s, 2H), 7.14 (d, J = 3.6 Hz, 1H), 7.33-7.39 (m, 1H), 7.42-7.48 (m, 1H), 7.51 (d , J = 3.6 Hz, 1H), 7.84-7.88 (m, 1H), 7.94-7.99 (m, 1H)

Example 183; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (5-trifluoro methyl-2-pyridyloxy) ethyl] piperazine

According to Example 75, 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (5-trifluoromethyl-2-pyridyloxy) ethyl] pipe The title compound was synthesized from lazine. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.20-1.38 (m, 1H), 1.55-1.70 (m, 1H), 1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.20 (m, 1H), 2.31 (t, J = 7.4 Hz, 2H), 2.30-2.48 (m, 4H) , 2.48-2.65 (m, 4H), 2.78 (t, J = 6.0 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.94 (dd, J = 3.6Hz, 5.2Hz, 1H), 7.11 (dd, J = 1.2Hz, 3.6Hz, 1H), 7.75 (dd, J = 2.4Hz, 8.8Hz, 1H), 8.39-8.44 (m, 1H)

Example 184; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] -4- [2- (5- trifluoromethyl-2-pyridyloxy) ethyl] pipe Razin

According to Example 77, 4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl iodide and 1- [2- (5-trifluoromethyl-2-pyridyl The title compound was synthesized from oxy) ethyl] piperazine. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.20-1.31 (m, 1H), 1.60-1.82 (m, 2H), 2.00-2.10 (m, 1H), 2.17-2.28 (m, 1H), 2.28-2.48 (m, 6H), 2.48-2.65 (m, 4H), 2.79 (t, J = 6.0 Hz, 2H) , 4.49 (t, J = 6.0 Hz, 2H), 6.83 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 4.0 Hz, 1H), 7.76 (dd, J = 2.4Hz, 8.8Hz, 1H), 8.40-8.44 (m, 1H)

Example 185; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (5-chloro-3- pyridyloxy) ethyl] piperazine

According to Example 75, titled from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (5-chloro-3-pyridyloxy) ethyl] piperazine The compound was synthesized. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.20-1.37 (m, 1H), 1.55-1.71 (m, 1H), 1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.25-2.49 (m, 6H), 2.49-2.65 (m, 4H), 2.80 ( t, J = 5.6 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 6.94 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H ), 7.22 (t, J = 2.0 Hz, 1H), 7.24-7.28 (m, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H)

Example 186; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] -4- [2- (5- chloro-3-pyridyloxy) ethyl] piperazine

According to Example 77, 4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl iodide and 1- [2- (5-chloro-3-pyridyloxy) ethyl ] The title compound was synthesized from piperazine. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.92 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.20-1.30 (m, 1H), 1.60-1.72 (m, 1H), 1.72-1.82 (m, 1H), 2.00-2.11 (m, 1H), 2.17-2.28 (m, 1H), 2.28-2.48 (m, 6H), 2.49-2.65 (m, 4H), 2.81 ( t, J = 5.6 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 7.15 (d, J = 4.0 Hz, 1H), 7.21-7.23 (m, 1H), 7.51 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H)

Example 187; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (5-chloro-3- pyridyloxy) ethyl] piperidine

According to Example 75, from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 4- [2- (5-chloro-3-pyridyloxy) ethyl] piperidine The title compound was synthesized. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.20-1.38 (m, 2H), 1.40-1.56 (m, 1H), 1.60-1.93 (m, 9H), 2.00-2.20 (m, 2H), 2.25-2.35 (m, 2H), 2.77-2.87 (m, 2H), 4.02 (t, J = 6.4 Hz, 2H) , 6.95 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.17-7.20 (m, 1H), 7.24-7.28 (m, 1H), 8.16 -8.20 (m, 2H)

Example 188; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- (3-pyridylamino) piperidine

According to Example 75, the title compound was synthesized from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 4- (3-pyridylamino) piperidine. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.24-1.38 (m, 1H), 1.38-1.50 (m, 2H), 1.58-1.71 (m, 1H), 1.73-1.83 (m, 1H), 1.95-2.21 (m, 5H), 2.29-2.36 (m, 2H), 2.72-2.81 (m, 2H), 3.20- 3.31 (m, 1H), 3.48-3.56 (m, 1H), 6.81-6.86 (m, 2H), 6.94 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.05 (dd, J = 4.8 Hz, 12.8 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.26 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.92 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H)

Example 189; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- {N-isopropyl-N- (2-pyridyl) amino} ethyl] piperazine

According to Example 75, 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- {N-isopropyl-N- (2-pyridyl) amino} ethyl ] The title compound was synthesized from piperazine. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.14-1.21 (m, 9H), 1.24-1.38 (m, 1H), 1.58-1.70 (m, 1H), 1.72-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.28-2.66 (m, 12H), 3.41 (t, J = 8.0 Hz, 2H), 4.74- 4.84 (m, 1H), 6.47-6.53 (m, 2H), 6.94 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.2 Hz, 3.6 Hz, 1H), 7.24-7.29 ( m, 1H), 7.37-7.44 (m, 1H), 8.12-8.16 (m, 1H)

Example 190; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (6-methoxymethyl-2 -pyridyloxy) ethyl] piperazine

According to Example 75, 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (6-methoxymethyl-2-pyridyloxy) ethyl] piperazine From the title compound were synthesized. Physical and chemical data of the compound were as follows.

ESI-MS: 457 (M + H) ⁺

Example 191; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (6-fluoromethyl- 2-pyridyloxy) ethyl] piperazine

According to Example 75, 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (6-fluoromethyl-2-pyridyloxy) ethyl] piperazine From the title compound were synthesized. Physical and chemical data of the compound were as follows.

The physical properties of the title compound obtained are shown below.

ESI-MS: 445 (M + H) ⁺

Example 192; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (6-bromo-2- pyridyloxy) ethyl] piperazine

According to Example 75, from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (6-bromo-2-pyridyloxy) ethyl] piperazine The title compound was synthesized. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.22-1.38 (m, 1H), 1.58-1.70 (m, 1H), 1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.20 (m, 1H), 2.25-2.65 (m, 10H), 2.76 (t, J = 6.0 Hz, 2H) , 4.42 (t, J = 6.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 6.94 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H ), 7.11 (dd, J = 1.6 Hz, 3.6 Hz, 1H), 7.24-7.28 (m, 1H), 7.40 (t, J = 8.0 Hz, 1H)

Example 193; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (6-fluoro-2- pyridyloxy) ethyl] piperazine

According to Example 75, from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (6-fluoro-2-pyridyloxy) ethyl] piperazine The title compound was synthesized. Physical and chemical data of the compound were as follows.

ESI-MS: 431 (M + H) ⁺

Example 194; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (2-pyridyloxy) ethyl] piperazine

According to Example 75, the title compound was synthesized from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (2-pyridyloxy) ethyl] piperazine. . Physical and chemical data of the compound were as follows.

ESI-MS: 413 (M + H) ⁺

Example 195; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (6-methyl-2-pyridyl oxy) ethyl] piperazine

According to Example 75, titled from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (6-methyl-2-pyridyloxy) ethyl] piperazine The compound was synthesized. Physical and chemical data of the compound were as follows.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.22-1.38 (m, 1H), 1.58-1.70 (m, 1H), 1.71-1.82 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.27-2.70 (m, 10H), 2.42 (s, 3H), 2.77 (t, J = 6.0 Hz, 2H), 4.41 (t, J = 6.0 Hz, 2H), 6.51-6.55 (m, 1H), 6.67-6.72 (m, 1H), 6.94 (dd, J = 3.6 Hz, 5.2 Hz, 1H), 7.11 (dd, J = 1.6 Hz, 3.6 Hz, 1H), 7.25 (dd, J = 1.6 Hz, 5.2 Hz, 1H), 7.43 (dd, J = 7.2 Hz, 8.4 Hz, 1H)

Example 196; 1- [4-cyano-4- (2-thienyl) -5-methylhexyl] -4- [2- (6-cyano-2- pyridyloxy) ethyl] piperazine

According to Example 75, from 4-cyano-4- (2-thienyl) -5-methylhexyl iodide and 1- [2- (6-cyano-2-pyridyloxy) ethyl] piperazine The title compound was synthesized. Physical and chemical data of the compound were as follows.

ESI-MS: 438 (M + H) ⁺

Example 197; 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl] -4- [2- (6-cyano -2-pyridyloxy) ethyl] piperazine

According to Example 77, 4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl iodide and 1- [2- (6-cyano-2-pyridyloxy) The title compound was synthesized from ethyl] piperazine. Physical and chemical data of the compound were as follows.

ESI-MS: 463 (M + H) ⁺

Example 198; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [N- [2- (4-fluorophenoxy) ethyl] -N-2-cyanoethyl] aminopiperi Dean

The title compound was obtained in the same manner as in Example 35.

Hydrochloride; ESI-Mass; 491 (MH ⁺ ).

Example 199; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (2-hydroxybenzyl) piperazine

The title compound was obtained according to the preparation method of Example 3.

Hydrochloride; ESI-Mass; 406 (MH ⁺ ).

Example 200; 1-[[(4-cyano-5-methyl-4- (2-thienyl)] hexyl] -4- [3- [1- (4-fluorophenyl ) cyclohexyl] propyl] piperazine

The title compound was obtained in the same manner as in Example 70 using the 4- [3- [1- (4-fluorophenyl) cyclohexyl] propyl] piperazine.

Hydrochloride; ESI-Mass; 510 (MH ⁺ ).

Example 201; 1-[[4-cyano-5-methyl-4- (3-benzothienyl)] hexyl] -4- [2- (3-cyanophenoxy ) ethyl] piperazine

The title compound was obtained in the same manner as in Example 70.

Hydrochloride; ESI-Mass; 487 (MH ⁺ ).

Example 202; 1-[[4-cyano-5-methyl-4- (3-benzothienyl)] hexyl] -4-benzylpiperazine

The title compound was obtained in the same manner as in Example 70.

Hydrochloride; ESI-Mass; 432 (MH ⁺ ).

Example 203; 1-[[4-cyano-5-methyl-4- (3-benzothienyl)] hexyl] -4- (3-cyanobenzyl) piperazine

The title compound was obtained according to the preparation method of Example 3.

Hydrochloride; ESI-Mass; 457 (MH ⁺ ).

Example 204; 1-[[4-cyano-5-methyl-4- (3-benzothienyl)] hexyl] -4-[(2-thienyl) methyl ] piperazine

The title compound was obtained according to the preparation method of Example 3.

Hydrochloride; ESI-Mass; 438 (MH ⁺ ).

Example 205; 1-[[4-cyano-5-methyl-4- (3-benzothienyl)] hexyl] -4-[(4-cyano-2- thienyl) methyl] piperazine

The title compound was obtained according to the preparation method of Example 3.

Hydrochloride; ESI-Mass; 463 (MH ⁺ ).

Example 206; 1-[[4-cyano-5-methyl-4- (3-benzothienyl)] hexyl] -4- (6-methyl-2-picolinyl ) piperazine

The title compound was obtained according to the preparation method of Example 3.

Hydrochloride; ESI-Mass; 447 (MH ⁺ ).

Example 207; 1-[[4-cyano-5-methyl-4- (1-methyl-2-pyrrolyl)] hexyl] -4- [2- (3-cyanophenoxy ) ethyl] piperazine

The title compound was obtained in the same manner as in Example 70.

Oxalate; ESI-Mass; 434 (MH ⁺ ).

Example 208; 1-[[4-cyano-5-methyl-4- (5-cyano-2-thienyl)] hexyl] -4- [N- [2- (4- fluorophenoxy) ethyl] -N 2-cyanoethyl] aminopiperidine

The title compound was obtained in the same manner as in Example 35.

Hydrochloride; ESI-Mass; 522 (MH ⁺ ).

Example 209; 1-[[4-cyano-5-methyl-4- (2-thienyl)] hexyl] -4- [N- [2- (4-fluoro phenoxy) ethyl] -N-2-cyano Ethyl] aminopiperidine

The title compound was obtained in the same manner as in Example 35.

Hydrochloride; ESI-Mass; 497 (MH ⁺ ).

Example 210; 1-[[4-cyano-5-methyl-4- (2-thienyl)] hexyl] -4-[(2-benzoxazolyl) amino] piperidine

The title compound was obtained in the same manner as in Example 17.

Hydrochloride; ESI-Mass; 423 (MH ⁺ ).

Example 211; 1-[[4-cyano-5-methyl-4- (5-cyano-2-thienyl)] hexyl-4-[(2-benzoxazolyl ) amino] piperidine

The title compound was obtained in the same manner as in Example 17.

Hydrochloride; ESI-Mass; 448 (MH ⁺ ).

Example 212; 1-[[4-cyano-5-methyl-4- (2-furyl)] hexyl] -4- [2- (3-cyanophenoxy) ethyl] piperazine

The title compound was obtained in the same manner as in Example 70.

Oxalate; ESI-Mass; 421 (MH ⁺ ).

Example 213; 1-[[4-cyano-5-methyl-4- (2-furyl)] hexyl] -4-[(2-benzoxazolyl) amino] piperidine

The title compound was obtained in the same manner as in Example 17.

Oxalate; ESI-Mass; 407 (MH ⁺ ).

Example 214; 1-[[4-cyano-5-methyl-4- (2-thienyl)] hexyl] -4- [N- (2-benzoxazolyl ) -N- (2-cyanoethyl) amino] Piperidine

The title compound was obtained in the same manner as in Example 35.

Hydrochloride; ESI-Mass; 476 (MH ⁺ ).

Example 215; 1-[[4-cyano-5-methyl-4- (2-furyl)] hexyl] -4- [N- (2-benzoxazolyl) -N- (2-cyanoethyl) amino] piperi Dean

The title compound was obtained in the same manner as in Example 35.

Oxalate; ESI-Mass; 460 (MH ⁺ ).

Example 216; 1-[[(4-cyano-5-methyl-4-phenyl)] hexyl] -4- (2-pyridyl) piperazine

The title compound was obtained in the same manner as in Example 70.

Hydrochloride; ESI-Mass; 363 (MH ⁺ ).

Example 217; 1-[[(4-cyano-5-methyl-4- (2-thienyl)] hexyl] -4- (2-pyridyl) piperazin

The title compound was obtained in the same manner as in Example 70.

Hydrochloride; ESI-Mass; 369 (MH ⁺ ).

Example 218; 1-[(2-oxo-1,2-dihydro-3-quinolyl) methyl] -4-[(4-cyano-5-methyl- 4-phenyl) hexyl] piperazine

According to Example 3, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.64 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H), 1.00-1.20 (m, 1H), 1.40-1.60 (m , 1H), 1.95-2.15 (m, 1H), 2.10-2.25 (m, 1H), 2.60-3.05 (m, 11H), 3.59 (s, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.30-7.38 (m, 1H), 7.35-7.50 (m, 5H), 7.62 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.89 (s, 1H ), 11.88 (s, 1 H).

Example 219; 1-[(2-oxo-1,2-dihydro-3-quinolyl) methyl] -4-[(4-cyano-5-methyl- 4-phenyl) hexyl] piperidine

According to Example 3, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.63 (d, J = 6.8 Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.45 (m, 6H), 1.09 (d, J = 6.8 Hz , 3H), 1.60 (br d, J = 12.8 Hz, 2H), 1.87-2.08 (m, 2H), 2.10-2.23 (m, 1H), 2.75-2.95 (m, 2H), 3.20-3.35 (m, 2H), 4.08 (s, 2H), 7.19-7.25 (m, 1H), 7.28-7.44 (m, 6H), 7.53-7.58 (m, 1H), 7.65-7.70 (m, 1H), 8.13 (s, 1H), 12.13 (s, 1H).

Example 220; 1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(4-cyano-5- methyl-4-phenyl) hexyl] piperidine

According to Example 3, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.63 (d, J = 6.8 Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.45 (m, 6H), 1.09 (d, J = 6.8 Hz , 3H), 1.59 (br d, J = 13.2 Hz, 2H), 1.87-2.08 (m, 2H), 2.10-2.23 (m, 1H), 2.73-2.95 (m, 2H), 3.15-3.33 (m, 2H), 3.98 (s, 2H), 2.26 (d, J = 6.8 Hz, 1H), 7.28-7.35 (m, 1H), 7.36-7.44 (m, 4H), 7.50 (dd, J = 6.4 Hz, 2.0 Hz, 1H), 7.62-7.68 (m, 1H).

Example 221; 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(4- cyano-5-methyl-4-phenyl) hexyl] piperidine

According to Example 3, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.63 (d, J = 6.8 Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.40 (m, 6H), 1.09 (d, J = 6.4 Hz , 3H), 1.53 (br d, J = 13.2 Hz, 2H), 1.87-2.08 (m, 2H), 2.10-2.23 (m, 1H), 2.40-2.60 (m, 2H), 3.04 (br d, J = 11.6 Hz, 2H), 3.68 (s, 2H), 7.25-7.35 (m, 1H), 7.36-7.44 (m, 4H), 7.59 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H).

Example 222; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (methanesulfonylamino) phenyl] methyl} piperazine

According to Example 3, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.64 (d, J = 6.4 Hz, 3H), 0.80-1.20 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H), 1.40-1.60 (m , 1H), 1.90-2.15 (m, 1H), 2.10-2.25 (m, 1H), 2.60-3.10 (m, 11H), 3.03 (s, 3H), 3.65 (s, 2H), 7.13 (t, J = 7.2 Hz, 1H), 7.26-7.47 (m, 8H).

Example 223; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (p-toluenesulfonylamino ) phenyl] methyl} piperazine

According to Example 3, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.65 (d, J = 6.4 Hz, 3H), 0.80-1.20 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H), 1.45-1.60 (m , 1H), 1.95-2.15 (m, 1H), 2.10-2.25 (m, 1H), 2.33 (s, 3H), 2.60-3.05 (m, 11H), 3.34 (s, 2H), 7.05-7.12 (m , 2H), 7.16-7.24 (m, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.29-7.37 (m, 1H), 7.37-7.46 (m, 4H), 7.58 (d, J = 8.0 Hz, 2H).

Example 224; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (methanesulfonylamino) phenyl] methyl} piperidine

According to Example 3, the title compound was obtained as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.80 (d, J = 6.8 Hz, 3H), 0.85-1.05 (m, 1H), 1.05-1.45 (m, 6H), 1.22 (d, J = 6.4 Hz, 3H ), 1.50-1.68 (m, 2H), 1.73-1.88 (m, 1H), 1.90-2.05 (m, 2H), 2.00-2.20 (m, 2H), 2.75-2.90 (m, 2H), 3.04 (s , 3H), 3.60 (s, 2H), 6.96-7.11 (m, 2H), 7.24-7.36 (m, 2H), 7.34-7.44 (m, 4H), 7.46-7.52 (m, 1H).

Example 225; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1-{[2- (p-toluenesulfonylamino ) phenyl] methyl} piperidine

According to Example 3, the title compound was obtained as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 0.85-1.02 (m, 1H), 1.08-1.30 (m, 5H), 1.25-1.44 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 1.57 (br t, J = 13.6 Hz, 2H), 1.76-1.90 (m, 3H), 2.06-2.16 (m, 2H), 2.37 (s, 3H), 2.68 (br d, J = 11.2 Hz, 2H), 3.13 (s, 2H), 6.91 (d, J = 7.2 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.16-7.22 (m, 1H), 7.26-7.41 (m, 5H), 7.46 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H).

Example 226; 1- [4-cyano-5-methyl-4- (2-chlorophenyl) hexyl] -4- [2- (4-fluorophenoxy ) ethyl] piperazine

According to Example 48, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.72 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.00-1.25 (m, 1H), 1.42-1.60 (m , 1H), 1.95-2.10 (m, 1H), 2.45-2.65 (m, 1H), 2.60-3.10 (m, 13H), 4.09 (t, J = 5.2 Hz, 2H), 6.89-6.99 (m, 2H ), 7.10 (t, J = 8.8 Hz, 2H), 7.37-7.46 (m, 2H), 7.51 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.62 (dd, J = 7.6 Hz, 1.6 Hz, 1H).

Example 227; 1- [4-cyano-5-methyl-4- (0-tolyl) hexyl] -4- [2- (4-fluorophenoxy) ethyl] piperazine

According to Example 48, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.76 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 1.10-1.30 (m, 1H), 1.43-1.60 (m , 1H), 1.93-2.07 (m, 1H), 2.15-2.30 (m, 1H), 2.38-2.53 (m, 1H), 2.45 (s, 3H), 2.65-3.05 (m, 12H), 4.07 (t , J = 5.2 Hz, 2H), 6.89-6.96 (m, 2H), 7.10 (t, J = 8.0 Hz, 2H), 7.18-7.27 (m, 3H), 7.38-7.44 (m, 1H).

Example 228; 1- [4-cyano-5-methyl-4- (2-methoxyphenyl) hexyl] -4- [2- (4-fluorophenoxy ) ethyl] piperazine

According to Example 48, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.66 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.00-1.20 (m, 1H), 1.40-1.55 (m , 1H), 1.85-2.00 (m, 1H), 2.30-2.43 (m, 1H), 2.55-2.70 (m, 1H), 2.60-3.05 (m, 12H), 3.79 (s, 3H), 4.07 (t , J = 5.2 Hz, 2H), 6.88-6.96 (m, 2H), 6.99 (t, J = 7.6 Hz, 1H), 7.05-7.14 (m, 3H), 7.32-7.42 (m, 2H).

Example 229; N- {1-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidin-4-yl} p-toluene sulfonamide

According to Example 15, the title compound was obtained as a light brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.8 Hz, 3H), 0.95-1.15 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.30-1.45 (m, 2H ), 1.35-1.55 (m, 1H), 1.63-1.75 (m, 2H), 1.75-1.95 (m, 5H), 2.00-2.15 (m, 2H), 2.15-2.25 (m, 2H), 2.45-2.65 (m, 2H), 3.00-3.15 (m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.31-7.40 (m, 5H), 7.75 (d, J = 7.6 Hz, 2H).

Example 230; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- [3-hydroxy-1- (4-fluorophenoxy ) propan-2-yl] piperazine

According to Example 15, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.64 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.00-1.40 (m, 1H), 1.43-1.60 (m , 1H), 1.93-2.15 (m, 2H), 2.10-2.25 (m, 1H), 2.60-3.20 (m, 11H), 3.45-3.60 (m, 2H), 4.04 (d, J = 5.6 Hz, 2H ), 6.88-6.96 (m, 3H), 7.26 (t, J = 7.6 Hz, 1H), 7.30-7.38 (m, 1H), 7.36-7.46 (m, 4H).

Example 231; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4- (3-cyanobenzyloxy) piperidine

According to Example 15, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.64 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H), 1.63-1.80 (m, 2H), 1.85-2.00 (m , 2H), 2.13-2.27 (m, 1H), 2.30-2.45 (m, 1H), 2.35-2.55 (m, 1H), 2.75-3.00 (m, 4H), 3.00-3.20 (m, 2H), 3.50 -3.60 (m, 1H), 4.52 (s, 2H), 7.33-7.40 (m, 1H), 7.40-7.48 (m, 4H), 7.54 (t, J = 8.0 Hz, 1H), 7.66 (d, J) = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.77 (m, 1H).

Example 232; 4-[(3-cyano-4-methyl-3-phenyl) pentyl] -1- {2- [3- (p-toluenesulfonylamino ) phenoxy] ethyl} piperazine

According to Example 3, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.64 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H), 2.13-2.50 (m, 1H), 2.20-2.50 (m , 2H), 2.37 (s, 3H), 2.45-2.50 (m, 2H), 2.50-2.60 (m, 2H), 2.60-2.80 (m, 4H), 2.70-3.00 (m, 4H), 3.63 (t , J = 6.4 Hz, 2H), 6.41 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.0 Hz, 2.4 Hz, 1H) , 7.09 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.32-7.40 (m, 1H), 7.38-7.48 (m, 4H), 7.46 (d, J = 8.0 Hz, 2H).

Example 233; 4-[(4-cyano-5-methyl-4-phenyl) hexyl] -1- {2- [3- (p-toluenesulfonylamino ) phenoxy] ethyl} piperazine

According to Example 15, the title compound oxalate was obtained as a light brown solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.64 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H), 1.00-1.20 (m, 1H), 1.43-1.60 (m , 1H), 1.90-2.13 (m, 2H), 2.15-2.25 (m, 1H), 2.37 (s, 3H), 2.25-2.50 (m, 4H), 2.80-3.00 (m, 8H), 3.57 (t , J = 6.8 Hz, 2H), 6.38-6.43 (m, 1H), 6.46 (s, 1H), 6.68 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H ), 7.36 (d, J = 8.4 Hz, 2H), 7.30-7.40 (m, 1H), 7.36-7.48 (m, 4H), 7.45 (d, J = 8.4 Hz, 2H).

Example 234; 1-[(4-cyano-5-methyl-4-phenyl) hexyl] -4-{[3- (p-toluenesulfonylamino ) phenoxy] methyl} piperidine

According to Example 15, the title compound was obtained as a yellow amorphous.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.75 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 1.05-1.30 (m, 3H), 1.30-1.45 (m, 1H ), 1.45-1.65 (m, 1H), 1.65 (br d, J = 12.4 Hz, 2H), 1.65-1.80 (m, 1H), 1.75-1.95 (m, 2H), 2.00-2.18 (m, 2H) , 2.26 (t, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.67-2.80 (m, 2H), 3.31 (d, J = 7.6 Hz, 2H), 6.43 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.67-6.76 (m, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 6.8 Hz, 2H), 7.20- 7.40 (m, 5H), 7.45 (d, J = 8.0 Hz, 2H).

Example 235; 1-[(3-cyano-4-methyl-3-phenyl) pentyl] -4-{[3- (p-toluenesulfonylamino ) phenoxy] methyl} piperidine

According to Example 3, the title compound was obtained as a light brown amorphous form.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.73 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H), 1.15-1.30 (m, 2H), 1.35-1.52 (m, 1H ), 1.68 (br d, J = 12.4 Hz, 2H), 1.73-2.05 (m, 3H), 2.00-2.18 (m, 2H), 2.30-2.43 (m, 2H), 2.40 (s, 3H), 2.70 -2.90 (m, 2H), 3.20-3.38 (m, 2H), 6.38 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.58 (d, J = 1.6 Hz, 1H), 7.00 (dd, J = 8.0Hz, 2.0Hz, 1H), 7.07 (t, J = 8.0Hz, 1H), 7.22 (d, J = 7.6Hz, 2H), 7.25-7.40 (m, 5H), 7.43 (d, J = 8.4Hz , 2H).

Example 236; 1- (3-cyanobenzyl) -4-[(4-cyano-5-methyl-4-phenyl) hexyl] piperidine

According to Example 48, the title compound oxalate was obtained as a colorless solid.

Oxalate;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.63 (d, J = 6.8 Hz, 3H), 0.70-0.85 (m, 1H), 1.00-1.30 (m, 5H), 1.08 (d, J = 6.4 Hz , 3H), 1.20-1.35 (m, 1H), 1.58 (br d, J = 12.8 Hz, 2H), 1.87-2.08 (m, 2H), 2.10-2.23 (m, 1H), 2.61 (br t, J = 11.2 Hz, 2H), 3.11 (br d, J = 10.8 Hz, 2H), 4.10 (s, 2H), 7.28-7.33 (m, 1H), 7.34-7.44 (m, 4H), 7.61 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.84-7.90 (m, 2H).

Example 237; 1-[(5-phenyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(4- cyano-5-methyl-4-phenyl) hexyl] piperidine

According to Example 3, the title compound was obtained as a light brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 0.85-1.00 (m, 1H), 1.10-1.45 (m, 4H), 1.19 (d, J = 6.8 Hz, 3H ), 1.50-1.65 (m, 2H), 1.60-2.20 (m, 5H), 2.80-3.00 (m, 2H), 3.54 (s, 2H), 7.24-7.48 (m, 10H), 7.64-7.70 (m) , 1H), 7.78-7.84 (m, 1H).

Example 238; Ethyl 1-benzyl-4- (4-cyano-5-methyl-4-phenylhexyl) -2-piperazinecarboxylate

It synthesize | combined according to Example 15 using 1-benzyl-2- (ethoxycarbonyl) piperazine (Synthesis 318, 1991).

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.76 (d, J = 6.6 Hz, 3H), 1.05-1.10 (m, 1H), 1.18-1.31 (m, 6H), 1.50-1.63 (m, 1H), 1.86 -1.94 (m, 1H), 2.04-2.15 (m, 2H), 2.21-2.54 (m, 7H), 2.96 (m, 1H), 3.22-3.27 (m, 1H), 3.51 (m, 1H), 3.86 -3.90 (m, 1H), 4.12-4.23 (m, 2H), 7.21-7.37 (m, 10H).

Example 239; Ethyl 4- (4-cyano-5-methyl-4-phenylhexyl) -1- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate

It synthesize | combined according to Example 48 using ethyl 4- (4-cyano-5-methyl-4-phenylhexyl) -2- piperazinecarboxylate.

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06-1.11 (m, 1H), 1.17-1.29 (m, 6H), 1.51-1.62 (m, 1H), 1.86 -1.91 (m, 1H), 2.05-2.11 (m, 2H), 2.22-2.36 (m, 4H), 2.52-2.55 (m, 3H), 2.94-3.01 (m, 2H), 3.13-3.16 (m, 1H), 3.38-3.39 (m, 1H), 4.01-4.03 (m, 2H), 4.14-4.22 (m, 2H), 6.78-6.82 (m, 2H), 6.92-6.97 (m, 2H), 7.26- 7.31 (m, 1 H), 7.36-7.37 (m, 4 H).

Example 240; 1- (4-cyano-5-methyl-4-phenylhexyl) -3-hydroxymethyl-4- [2- (4-fluorophenoxy ) ethyl] piperazine

To a diethyl ether solution (5.0 ml) of lithium aluminum hydride (20 mg), under ice cooling, ethyl 4- (4-cyano-5-methyl-4-phenylhexyl) -1- [2- (4-fluorophenoxy ) Ethyl] -2-piperazinecarboxylate 213 mg of diethyl ether solution (3.0 ml) was dripped slowly. After stirring for 1 hour under ice-cooling, water (0.1 ml), a prescribed sodium hydroxide aqueous solution (0.1 ml), and water (0.2 ml) were sequentially added to the reaction solution. Anhydrous magnesium sulfate was added to the reaction solution, and unnecessary substances were filtered out. The solvent was removed under reduced pressure to obtain the title compound (194 mg).

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.6 Hz, 3H), 1.09-1.16 (m, 1H), 1.20 (dd, J = 6.8 Hz, 1.8 Hz, 3H), 1.53-1.60 ( m, 1H), 1.86-1.91 (m, 1H), 2.04-2.27 (m, 5H), 2.35-2.61 (m, 5H), 2.74-2.78 (m, 1H), 3.02-3.06 (m, 1H), 3.12-3.18 (m, 1H), 3.51-3.54 (m, 1H), 3.97-4.02 (m, 3H), 6.80-6.85 (m, 2H), 6.94-6.98 (m, 2H), 7.26-7.33 (m , 1H), 7.35-7.39 (m, 4H).

Example 241; Ethyl 1-benzyl-4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate

It synthesize | combined according to Example 48 using 1-benzyl-2- (ethoxycarbonyl) piperazine (Synthesis 318, 1991).

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24-1.28 (m, 3H), 2.36-2.12 (m, 1H), 2.54-2.61 (m, 2H), 2.71-2.83 (m, 4H), 3.02 (m, 1H), 3.31-3.34 (m, 1H), 3.53-3.56 (m, 1H), 3.89-3.92 (d, J = 16.6 Hz, 1H), 3.99-4.05 (m, 2H), 4.11-4.24 (m, 2H), 6.79-6.83 (m, 2H), 6.93-6.98 (m, 2H), 7.23-7.34 (m, 5H).

Example 242; Ethyl 1- (4-cyano-5-methyl-4-phenylhexyl) -4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate

It synthesize | combined according to Example 15 using ethyl 4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate.

Vitreous;

ESI-MS (m / e): 496 (M + H).

In addition, ethyl 4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate

Was dissolved ethyl 1-benzyl-4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate (977 mg) synthesized according to the preparation method of Example 241 in ethanol (15 ml). 210 mg of 10% Pd-C was added, hydrogen-substituted, stirred, and concentrated under reduced pressure after completion of the reaction to give a crude product (752 mg; 100%).

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24-1.28 (m, 3H), 2.33-2.34 (m, 1H), 2.48-2.50 (m, 1H), 2.72-2.91 (m, 4H), 3.04-3.10 ( m, 2H), 3.56-3.59 (m, 1H), 4.04-4.08 (m, 2H), 4.16-4.22 (m, 2H), 6.82-6.86 (m, 2H), 6.94-6.99 (m, 2H).

Example 243; 1- (4-cyano-5-methyl-4-phenylhexyl) -2-hydroxymethyl-4- [2- (4-fluorophenoxy ) ethyl] piperazine

Example 240, using ethyl 1- (4-cyano-5-methyl-4-phenylhexyl) -4- [2- (4-fluorophenoxy) ethyl] -2-piperazinecarboxylate Synthesized according to

Vitreous;

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77 (d, J = 6.8 Hz, 3H), 1.07-1.14 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H), 1.43-1.56 (m, 1H ), 1.79-1.90 (m, 1H), 2.04-2.83 (m, 13H), 3.47-3.51 (m, 1H), 3.83-3.91 (m, 1H), 4.01-4.10 (m, 2H), 6.80-6.84 (m, 2H), 6.94-6.98 (m, 2H), 7.26-7.40 (m, 5H).

Test Example

The compound according to the present invention, while evaluating the calcium channel inhibitory effect (in vitro) in vitro (Test Example 1), and at the same time the reduction effect in the rat middle cerebral artery occlusion model (Test Example 2) ) And analgesic action (Test Example 3) in formalin test using mice. Each test method and the result are as follows.

Test Example 1; Measurement of Potential Dependent Calcium Channel Activity Using Fluorescent Pigment (fura2)

At present, the most important mechanism of cerebral infarction (ischemic neuronal death) is the "glutamic acid-Ca hypothesis". In other words, when cerebral blood flow decreases, anaerobic glycolysis is solved and ATP of brain tissue is depleted. Due to this energy depletion, the ion concentration gradient inside and outside the cell cannot be maintained, and depolarization occurs. In pre-synapse, depolarization activates the potential-dependent calcium channel, causing excessive release of glutamic acid. At post-synapse, dispolarization activates the potential-dependent calcium channel to raise intracellular Ca ²⁺ concentration, and excessively released glutamic acid stimulates glutamic acid receptors to raise intracellular Ca ²⁺ concentration. As a result, various enzymes depending on the Ca ²⁺ concentration such as culpine and phospholipase are activated to induce neuronal death. The experimental system can evaluate Ca ²⁺ influx at presynapses among these flowcharts.

In this system, 10 μM L-type inhibitor, 1 μM N-type inhibitor w-conotoxin GVIA, and 1 μM P-Q type inhibitor w-Agatoxin-IVA were 16%, 18%, and 64% for Ca ²⁺ influx, respectively. It is known to show inhibition (see literature below). Therefore, this system is considered to be suitable for evaluating the inhibition of N type and P / Q type.

References: D. Bowman, S. Alexander and D. Lodge, Pharmacological characterization of the calcium channels coupled to the plateau phase of KCl-induced intracellular free Ca ²⁺ elevation in chicken and rat synaptosomes, Neuropharmacology, 32 (11) 1195- 1202 (1993)

(1) Preparation of cerebral cortical synaptosomes: According to the method described in Neuropharmacology, 32 (11), 1195-1202, 1993, cerebral cortical synaptosomes were prepared as follows. In other words, the cerebral cortex was taken out of the rat cranial brain and roughly crushed with scissors. The mixture was placed in a homogenizer, homogenized in 0.3 M sucrose, and then centrifuged (1,500 g × 10 minutes) at 4 ° C. The obtained supernatant was further centrifuged at 10,000C x 20 min. 0.3 M sucrose was added to the obtained precipitate and suspended. The suspension was combined with 0.8 M sucrose and centrifuged (10,000 g x 30 minutes). The resulting precipitate was referred to as "Solution A" (118mM-NaCl, 4.6mM-KCl, 1mM-CaCl ₂ , 1mM-MgCl ₂ , 1.2mM-Na ₂ HPO ₄ , 10mM-D-glucose, 20mM-HEPES-NaOH pH 7.4, 0.1 % -BSA) to prepare a cerebral cortical synaptosome.

(2) Calcium channel inhibitory effect: 4mM-fura2 / AM (同仁) was suspended in the solution A to obtain a load solution. Equivalent load solution was added to the synaptosome solution prepared by the method shown above, and it incubated for 40 minutes at room temperature. After completion of the incubation, the load solution was removed by centrifugal treatment, and washed twice with Solution A again. Solution A containing the compound of the present invention was added thereto and incubated at room temperature for 10 minutes. 1/10 volume of "Solution B" (122.6 mM-KCl, 1 mM-CaCl ₂ , 1 mM-MgCl ₂ , 1.2 mM-Na ₂ HPO ₄ , 10 mM-D-glucose, 20 mM-HEPES-NaOH pH 7.4, 0.1 % -BSA) was added to stimulate the calcium channel. The intracellular calcium ion concentration was measured by ARUGUS-FDSS (Hamamatsu Photonics Co., Ltd.) by two wavelengths of 340 nm and 380 nm, and the IC ₅₀ value of each test compound was determined. In addition, verapamil hydrochloride was used as a comparative control compound.

result

TABLE 1

Test Example 2; Reduction Effect in Rat Middle Cerebral Artery Occlusion Model (I)

Calcium ions in cells play an important role in the expression of various cellular functions. However, excessively high calcium ion concentration in a cell causes a cell disorder (see Documents 1 and 2 below). For example, neuronal disorders caused by excitatory amino acids in cerebral ischemia result in excessive elevation of calcium ion concentration in cells [3, 4]. In focal cerebral ischemia, elevated excitatory amino acids disrupt the mechanism of membrane potential maintenance [3] and induce membrane depolarization [5], increasing the influx of calcium ions into cells through translocation-dependent calcium channels [6, 7]. . From the above facts, the hypothesis that neuronal cell death is based on excitatory toxicity by excitatory amino acids is related to the hypothesis that an increase in intracellular calcium ion concentration is associated, and that activation of dislocation-dependent calcium channels contributes to the induction of neuronal death. It is suggested that [8]. From electrophysiological and pharmacological studies, dislocation-dependent calcium channels present in neurons are classified into six subtypes (T, L, N, P, Q, R types) [9]. Among them, N, P, and Q types play an important role in the release of glutamic acid from rat cortical synaptosomes [10, 11]. Thus, in the rat middle cerebral artery occlusion model, the protective effect against a neuronal cell disorder induced after focal cerebral ischemia of the representative compound of the present invention was evaluated.

(1) Preparation of Specimen: The compound represented by the formula (I) according to the present invention was dissolved in physiological saline, and prepared in a timely manner so as to have a capacity of 1.5, 5, or 15 mg / kg / h. Sample concentrations were calculated based on the average body weight of the animals. In addition, the average body weight was calculated by measuring the weights of all the animals to be used in the experiment. For example 5 mg / kg / h

Sample concentration = 5 mg × average body weight (kg) / dose per hour (0.616 ml)

Calculated as

(2) Preparation of nylon embolization: Embolization of 4-0 monofilament nylon (Ethicon, Inc., Somerville, NJ) was used for occlusion of the middle cerebral artery. Nylon embolization was used to round the tip with a flame, fragment it to a length of 25 mm, and label it with an oily felt pen at a position of 17 mm from the tip.

(3) Implantation of Intravenous Catheter: An intravenous catheter (Atom Intravenous Catheter 3Fr, Atom Medikaru, Tokyo) was implanted under 70% bovine-2% halotane anesthesia. A catheter filled with saline was inserted from the femoral vein in the left foot.

(4) Obstruction of the middle cerebral artery: The obstruction of the middle cerebral artery was performed according to the method of Longa et al. [12]. Surgery was performed under 70% scavenging-2% halotane anesthesia immediately after catheter implantation. The rat was inclined to face up under a stereoscopic microscope for surgery, and the area of the right common carotid artery was branched into the external and internal carotid arteries. The outer carotid artery was cut off at the peripheral side, and a nylon embolus was inserted into the inner carotid artery from the distal end of the cut outer carotid artery. The embolus was inserted and fixed from the tip of the embolus to the position where the position of 17 mm overlaps the branching points of the external and internal carotid arteries. In order to resume blood flow, the nylon embolism was withdrawn again 2 hours after middle cerebral artery occlusion.

(5) Screening of animals showing ischemic symptoms: 30 minutes after the middle cerebral artery occlusion, the rats are held by the tail, and the rats are lifted and the hemiplegia of the anterior leg (paralysis of the forelimb on the opposite side loaded with infarction) is clearly expressed in the middle cerebral artery. This blockage was used in the experiment as an example of the ischemic state.

(6) Administration of Media and Specimens: Rats with hemiplegia expressed in the cerebral hemiplegia were inserted into the cage of the thermoregulator 30 minutes after the middle cerebral artery occlusion, and the temperature monitor probe was fixed in the rectum. Next, the syringe containing the medium or sample was placed in an intravenous catheter, and half the dose (0.34 ml) injected during 1 hour was intravenously administered for 1 minute. Thereafter, an infusion syringe pump (Razel Scientific Instruments, Inc., Stamford, Connecticut, USA) was continuously administered at a rate of 0.682 ml / h for 24 hours. During dosing and two hours after the end of dosing, the rectal temperature was adjusted within the range of 37.0 ° C. to 38.5 ° C. under a body temperature control system.

(7) Measurement of infarct size: (TTC staining of brain slices) After 24 hours from the middle cerebral artery occlusion, the rats were brainwashed, and the attached blood was washed in ice-cold physiological saline. The posterior brains were used to slice at intervals of 2 mm from the tip (6 slices in total) and soaked in 2% -TTC solution so that the back side of the brain was top. TTC was timely dissolved in physiological saline. After standing at room temperature for 1 hour or more in a TTC solution, it used for the measurement of the area of a hard dye.

(8) Calculation of infarct volume: The upper surface (back side of the brain) of each slice was used for the area calculation. The brain slice was inputted into a computer (PM7500 / 100, Apple Japan, Tokyo) using an image input device (CCD color camera, Sankyo, Tokyo). The area of cerebral cortex in the image was measured using image analysis software (NIH image ver. 1.60, National Institutes of Health, USA). The volume of the infarct of one individual was multiplied by the area (unit = mm 2) of the measured infarction of each slice (2 = unit = mm), which is the thickness of the slice, and calculated as the total of six slices (unit = mm).

(9) Data interpretation method

The volume of cerebral cortex (unit = ㎣) was expressed as mean ± standard error. Statistical significance between the media control group and each sample group was analyzed by Dunnett's multiple comparison test, and the significance level was 5% on both sides. The dose reactivity was analyzed by regression analysis, and the significance level was 5% on one side.

(10) Results: After 2 hours occlusion of the middle cerebral artery by nylon embolization, blood flow was resumed by removing the nylon embolization, and the volume of infarct was measured 24 hours after the middle cerebral artery occlusion. As a result, the compound according to the present invention significantly inhibited the volume of cerebral cortex infarct, and as a result of the regression analysis, dose-dependentness was confirmed in the action of reduction of the infarction by the compound according to the present invention. For example, the compound of Example 70 was administered intravenously at doses of 1.5, 5 and 15 mg / kg / h from 30 minutes after middle cerebral artery occlusion for a volume 134.3 ± 12.3 mm 3 (n = 19) of cerebral cortical infarction in the control group. By administration, the volume of cerebral cortex was 4% (128.9 ± 12.5 μs, n = 16), 20% (108.0 ± 14.9 μs, n = 15) and 44% (75.7 ± 11.2 μs, n = 12; p, respectively). <0.01) was reduced. In addition, the compound of Example 75 was administered intravenously at doses of 1.5, 5, and 15 mg / kg / h from 30 minutes after middle cerebral artery occlusion for a volume of 162.9 ± 8.4 mm 3 (n = 15) of cerebral cortex infarction in the control group. The volume of cerebral cortex is 26% (119.9 ± 12.6 ms, n = 16), 37% (102.0 ± 14.1 ms, n = 14; p <0.01) and 49 percent (83.7 ± 21.3 ms, n = 11; p <0.001).

That is, the compound according to the present invention inhibits calcium ion influx into the rat cerebral cortex synaptosomes induced by high concentrations of KCl, thereby inhibiting glutamic acid release from the rat cerebral cortex slice. In addition, in the present experiment, the compound of the present invention had a protective action against neuronal cell disorders caused by focal cerebral ischemia, and showed a significant reduction effect by administration 30 minutes after ischemia. Therefore, the compound according to the present invention can be shown to be effective by post administration even in human stroke.

These results also indicate that SNX-111 [CAS Registry No .: 107452-89-1], an N-type calcium channel inhibitory peptide, protected glutamic acid release from the cerebral cortex and subsequent neuronal disorders in the rat regional cerebral ischemia model. Reports [13, 14], and ω-agatoxin IVA, which are P / Q type channel inhibitory peptides, are also supported by the report showing neuroprotective effects in rat ischemic models of rats [15].

references:

[1] Schanne, F. A. X., Kane, A. B., Young, E. E., Farber, J. L. Calcium dependence of toxic cell death: a final common pathway. Science 206: 700-702 (1979).

[2] Kristian, T., Siesjo, B.K. Calcium in ischemic cell death. Stroke 29: 705-718 (1998).

[3] Graham, S.H., Shiraisi, K., Panter, S.S., Simon, R.P., Faden, A.I. Changes in extracellular amino acid neurotransmitters produced by focal cerebral ischemia. Neurosci. Lett. 110: 124-130 (1990).

[4] Rothman, S.M., Olney, J.W. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19: 105-111 (1986).

[5] Siesjo, B.K., Bengtsson, F. Calcium influxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: A unifying hypothesis. J. Cereb. Blood Flow Metab. 9: 127-140 (1989).

[6] Mayer, M.L., Miller, R.J. Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2 + in mammalian neurons. Trends Pharmacol. Sci. 11: 254-260 (1990).

[7] Osuga, H., Hakim, A.M. Relationship between extracellular glutamate concentration and voltage-sensitive calcium channel function in focal cerebral ischemia in the rat. J. Cereb. Blood Flow Metab. 16: 629-636 (1996).

[8] Choi, D.W. Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage. Trends Neurosci. 11: 465-469 (1988).

[9] Randall, A.D., Tsien, R.W. Pharmacological dessection of multiple types of Ca2 + channel currents in rat cerebellar granule neurons. J. Neurosci. 15: 2995-3012 (1995).

[10] Turner, T. J., Dunlap, K. Pharmacological characterization of presynaptic calcium channels using subsecond biochemical measurements of synaptosomal neurosecretion. Neuropharmacology 34: 1469-1478 (1995).

[11] Maubecin, V.A., Sanchez, V.N., Rosato Siri, M.D., Cherksey, B.D., Sugimori, K., Llinas, R., Uchitel, O.D. Pharmacological characterization of the voltage-dependent Ca2 + channels present in synaptosomes from rat and chicken central nervous system. J. Neurochem. 64: 2544-2551 (1995).

[12] Longa, E.Z., Weinstein, P.R., Carlson, S., Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20: 84-91 (1989).

[13] Bowersox, S.S., Singh, T., Luther, R.R. Selective blockade of N-type voltage-sensitive calcium channels protects against brain injury after transient focal ischemia in rats, Brain Res. 747: 343-347 (1997).

[14] Takizawa, S., Matsushima, K., Fujita, H., Nanri, K., Ogawa, S., Shinohara, Y. A selective N-type calcium channel antagonist reduces extracellular glutamate release and infarct volume in focal cerebral ischemia. J. Cereb. Blood flow Metab. 15: 611-618 (1995).

[15] Asakura, K., Matsuo, Y., Kanemasa, T., Ninomiya, M. P / Q-type Ca2 + channel blocker ω-agatoxin IVA protect against brain injury after focal ischemia in rats. Brain Res. 7760: 140-145 (1997).

Test Example 3; Analgesic Effect in Formalin Test in Mice (I)

N-type calcium channel, which is one of nerve specific calcium channels, is selectively inhibited by SNX-111, which is a low molecular peptide. In the formalin test, which is one of analgesic assays, it has been reported that SNX-111 exhibits analgesic action by intra spinal administration [1, 2]. Therefore, the analgesic action when intravenous administration of the compound of the present invention was examined by a formalin test [3] using a mouse.

(1) Experimental Animals: ddy mice (males, 4-7 weeks old) purchased from SLC Co., Ltd. were used for the experiments. Mice were subjected to preliminary breeding (breeding conditions: room temperature 23 ± 1 ° C., humidity 55 ± 5%, light and dark cycles every 12 hours) for 4 days or more. About 20 groups were housed in a polycarbonate cage for 20 mice covered with a floor cloth (White Flake, Charles River, Tokyo). Transferred to the laboratory on the morning of the experiment. MF (Oriental Co., Ltd., Tokyo) was taken freely as a feed. The water also consumed tap water freely.

(2) Test compound: Examples 7, 20, 47, 49, 58, 63, 64, 198, 199, 209, 189, 123, 124, 219 and 221 were used as test compounds. As an existing analgesic drug, morphine, a narcotic potent analgesic drug, and indomethacin, an anti-inflammatory analgesic drug, were used as reference drugs.

(3) Preparation of test compound: The compound according to the present invention was dissolved in 5.28% Mannitol so as to be 1 mg / ml (10 mg / kg). The test compound was prepared by weighing on the day of the experiment. On the other hand, morphine was dissolved in physiological saline to 3mg / ml (30mg / kg) and indomethacin was suspended in 0.5% methyl cellulose to 1mg / ml (10mg / kg). The test compound was prepared by weighing on the day of the experiment.

(4) Preparation of Reagent: 30 µl of a commercially available 35.0 to 38.0% formaldehyde solution was taken, and added to 970 µl of saline solution. This was used as 3% formalin. In addition, formalin is a 37% formaldehyde liquid, and since the purity of the used formaldehyde liquid is represented by 35.0 to 38.0%, the 3% formalin used and prepared this time is exactly 2.84 to 3.08% formalin.

(5) Dose, route of administration, number of experimental examples: The compound of the present invention was administered intravenously at 10 mg / kg (0.1 ml of 10 mg body weight per 1 mg / ml of solution). Morphine was orally administered 30 mg / kg (0.1 mg / g body weight of 3 mg / ml solution). Indomethacin was orally administered 10 mg / kg (1 mg / ml suspension of 0.1 ml per 10 g of body weight). The control was administered 0.1 ml intravenously or orally per 10 g body weight. Each group performed five cases.

(6) Test method: 10 mg / kg of the compound of the present invention was intratracheally administered, 30 mg / kg of morphine was administered orally, and 10 mg / kg of indomethacin. After 5, 30, and 90 minutes of each administration, 20 µl of 3% formalin was subcutaneously administered to the sole of the left hind leg of the mouse, and placed in a transparent plastic observation cage. Immediately after formalin administration, the licking time of the mouse licking left hind limb was measured for 5 minutes as an index of pain. The control received the same amount of each solvent. The licking time in the control was 100%, and the inhibition rate (%) of the compound of the present invention was calculated by the following formula.

Expression:% inhibition = (control licking time-test compound licking time) / control licking time) × 100

(7) Results: The compounds according to the present invention significantly inhibited the licking time with respect to the control group, and the inhibition rate was in the range of 33% to 88%. In particular, Example 189 exhibited analgesic activity with a 59% inhibition rate. On the other hand, morphine exhibited analgesic action at a suppression rate of 54%, and analgesic action was not confirmed at an inhibition rate of indomethacin at -38%.

That is, the compound according to the present invention is a neuron specific calcium channel inhibitor, exhibits analgesic action like the N-type calcium channel inhibitor SNX-111, even when compared to the existing analgesic drugs, the same analgesic action as morphine, a narcotic potent analgesic drug Moreover, it shows the analgesic effect superior to indomethacin which is an anti-inflammatory analgesic drug. Therefore, the compound according to the present invention is very useful for the treatment and improvement of pain.

references:

[1] Annika B. Malmberg, and Tony L. Yaksh (1994) Voltage-Sensitive Calcium Channels in Spinal Nociceptive Processing: Blockade of N- and P- Type Channels Inhibits Formalin-Induced Nociception. The Journal of Neuroscience 14 (8): 4882-4890.

[2] S. Scott Bowersox, Theresa Gadbois, Tejinder Singh, Mark Pettus, Yong-Xiang Wang and Robert R. Luther (1996) Selective N-type Neuronal Voltage-Sensitive Calcium Channel Blocker, SNX-111, Produces Spinal Antinociception in Rat Models of Acute, Persistent and Neuropathic Pain. The Journal of pharmacology and Experimental Therapeutics 279 (3): 1243-1249.

[3] Hunskaar S, Fasmer OB and Hole K (1985) Formalin test in mice, a useful technique for evaluating mild analgesics. Journal of Neuroscience Methods 14 (1): 69-76.

Claims (4)

A compound represented by the following general formula (I-b) or a salt thereof:

In which R13 represents a hydrogen atom or a nitrile group; Ring B represents (1) a substituted or unsubstituted phenyl ring or a (2) thienyl group. The method of claim 1, Compounds characterized in that the compound is selected from the following group: 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl) -N-benzylamino] Pyrrolidine:

, 1- [4-cyano-4- (2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl) -N-benzylamino] pyrrolidine:

, 1- [4-cyano-4- (2-thienyl) -5-methylhexyl]-(3S) -3- [N- (2-cyanoethyl) -N- (3-cyanobenzyl) amino ] Pyrrolidine:

, 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2-cyanoethyl) -N-benzylamino] Pyrrolidine:

, And 1- [4-cyano-4- (5-cyano-2-thienyl) -5-methylhexyl]-(3R) -3- [N- (2-thienylmethyl) amino] pyrrolidine:

. Cerebral vascular disorders Acute phase, Stroke, Cerebral infarction, Head trauma, Cerebral neuronal cell death, Alzheimer's disease, Parkinson's disease, Brain comprising a compound represented by formula (I) according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier Atrophic lateral sclerosis, Huntington's disease, circulatory metabolic disorders, brain dysfunction, pain, convulsions, schizophrenia, migraine, epilepsy, manic-depressive disorder, neurodegenerative diseases, cerebral ischemia, AIDS dementia, edema, anxiety disorders, diabetic neuropathy, A pharmaceutical composition for treating or preventing a disease selected from cerebrovascular dementia and multiple sclerosis. An analgesic drug comprising a compound represented by formula (I) according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.

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