JP2003160570A - Pyperazine derivative and pharmaceuticals containing the same for treating life-style related disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preventive or a curative medicine for life-style related diseases such as diabetes and obesity. <P>SOLUTION: A compound represented by formula (I) is provided [wherein, A<SP>1</SP>is a halogenated lower alkyl or a halogenated lower alkoxy, or a group represented by formula (a) (wherein, X<SP>1</SP>is O or SO<SB>2</SB>; R<SP>1</SP>is a halogenated lower alkyl or a halogenated lower alkoxy); X<SP>2</SP>is O or SO<SB>2</SB>; n is an integer of 2-6; Z is O or S; X<SP>3</SP>is a single bond, a lower alkylene or a lower alkenylene; X<SP>4</SP>is a single bond, NR<SP>2</SP>(wherein, R<SP>2</SP>is H, a lower alkyl or a lower alkoxy), CO, NHSO<SB>2</SB>, NHCO, NHCONH, or NHCSNH; B<SP>1</SP>is an aryl which may have substituents, an aryl lower alkyl which may have substituents, an aryl lower alkenyl which may have substituents or a heteroaryl which may have substituents]. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a piperazine derivative and a pharmaceutical composition containing the same, in particular, a medicament for lifestyle-related diseases.

[0002]

2. Description of the Related Art Nowadays, the number of obese patients is increasing as the diet becomes rich and the living environment becomes convenient. With the increase in obesity, various cardiovascular diseases such as diabetes, hypertension and hyperlipidemia are also increasing as lifestyle-related diseases. Diabetes mellitus is generally insulin-dependent (type I, IDDM) with decreased insulin-producing cells and non-insulin-dependent (II
Type. NIDDM) and classified. 90 people with diabetes today
% Or more is the latter. In non-insulin-dependent diabetes mellitus (hereinafter also referred to as type II diabetes mellitus), the blood insulin concentration is high, but the sensitivity of somatic cells to insulin is reduced (insulin resistance). Uptake is blocked. Currently, thiazolidine derivatives and the like have been developed as therapeutic agents for type II diabetes that improve insulin resistance. See also WO 01/24
No. 786 describes various heterocyclic derivatives including piperazine derivatives useful as therapeutic agents for diabetes and obesity. JP 59-80671 (EP 102213)
A) describes ethanolamine derivatives having activity against antiobesity and antihyperglycemia. FR 26
81319 A describes a piperidine derivative, and is disclosed in JP-A-5-194451 (EP 533579 A), W.
O99 / 67208, WO98 / 56771, WO90
/ 13539, DE 341070 A, JP-A-61-122286 (EP 182540 A) and the like describe piperazine derivatives, but these have nothing to do with the treatment of obesity and diabetes.

[0003]

There is a demand for the development of a novel preventive or therapeutic drug for diabetes, particularly type II diabetes.
Further, development of a preventive or therapeutic drug for obesity is also desired. Furthermore, the development of a drug having both effects as a lifestyle-related disease is desired. In particular, it is desired to provide a pharmaceutical product which has good oral absorbability and / or has no side effects on the central nervous system, digestive organs and the like.

[0004]

[Means for Solving the Problems] In view of the above situation, the present inventors have conducted diligent studies, and as a result, found that the piperazine derivative is useful as a prophylactic or therapeutic drug for lifestyle-related diseases such as diabetes and obesity, and shown below. The present invention has been completed. Formula (1):

[Chemical 3] (In the formula, A ¹ is halogenated lower alkyl, halogenated lower alkoxy, or the formula:

[Chemical 4] A group represented by (X ¹ is O or SO ₂ ; R ¹ is halogenated lower alkyl, or halogenated lower alkoxy);
X ² is O or SO ₂ ; n is an integer of 2 to 6; Z is O or S; X ³ is a single bond, lower alkylene, or lower alkenylene; X ⁴ is a single bond, NR ² (R ² is hydrogen, lower Alkyl or lower alkoxy), CO, NHSO ₂ , NHC
O, NHCONH, or NHCSNH; B ¹ is represented by optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryl lower alkenyl, or optionally substituted heteroaryl) Compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (2) The compound according to the above 1, a prodrug thereof, a pharmaceutically acceptable salt thereof, wherein A ¹ is a group represented by (a),
Or solvates thereof. (3) A group in which A ¹ is represented by (a); X ¹ is O, the compound according to 1 above, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (4) A group in which A ¹ is represented by (a); X ¹ is O; X ² is O, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. . (5) The compound according to the above 1, wherein B ¹ is an optionally substituted phenyl, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (6) The substituents on the optionally substituted phenyl are halogen, C3 to C4 lower alkylene, hydroxy, lower alkoxy, halogenated lower alkyl, lower alkyl, lower alkylthio, C1 to C2 lower alkylenedioxy, and substituted. The compound of the above 5, which is the same or different 1 to 3 groups selected from the group consisting of optionally substituted amino, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (7) The compound according to any one of 1 to 6 above, wherein X ³ is a single bond; X ⁴ is a single bond or NH, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (8) X ³ is CH ₂ ; X ⁴ is NHSO ₂ , NHCO, NHC
The compound according to any one of 1 to 6 above, which is ONH or NHCSNH, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (9) X ³ is CH═CH; X ⁴ is a single bond, and the above 1 to
7. The compound according to any of 6, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (10) The compound according to any one of 1 to 9 above, wherein Z is O, a prodrug thereof, a pharmaceutically acceptable salt thereof,
Or solvates thereof. (11) The compound according to any one of 1 to 9 above, wherein Z is S, a prodrug thereof, a pharmaceutically acceptable salt thereof,
Or solvates thereof. (12) A pharmaceutical composition comprising the compound according to any one of 1 to 11 above, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (13) A prophylactic or therapeutic drug for diabetes, which comprises the compound according to any one of 1 to 11 above, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. (14) A prophylactic or therapeutic drug for obesity, which comprises the compound according to any one of 1 to 11 above, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

The terms used in this specification are explained below.
It Unless otherwise specified, each term is used alone or in other terms.
When used in combination with either, it has the following meanings.
And Lower alkyl is a straight or branched C1 to C
6 alkyl, including methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, sec-butyl
Ru, t-butyl, n-pentyl, i-pentyl, neo
-Pentyl, tert-pentyl, n-hexyl etc. are examples.
Shown. Preferably, it is C1-C4 alkyl,
Is methyl. Lower alkoxy is the above lower alkyl
Include oxy linked to, for example, methoxy, etoxy
Ci, i-propoxy, tert-butoxy, pentyloxy
Ci, hexyloxy and the like are exemplified. Preferably meth
It is shi. Halogen means F, Cl, Br, I
It Preferred is F or Cl. Low halogenated
In alkyl, the number of halogens is not particularly limited
However, preferably 1 to 5, more preferably 1 to 3,
It is preferably three. Preferred halogenated lower alcohol
Kill is trifluoro lower alkyl (eg, —CF)₃,-
CH₂CF₃), More preferably a trihalogenated polymer.
Chill (Example: -CF₃). Halogenated lower alcohol
The number of halogens is not particularly limited in
1 to 5, more preferably 1 to 3, and particularly preferably
The number is 3. Preferred halogenated lower alkoxy
Is trifluoro lower alkoxy (eg, —OCF ₃,-
OCH₂CF₃), More preferably trihalogenated
Methoxy (Example: -OCF₃).

Lower alkylene is a straight or branched C1
To C6 alkylene, methylene, ethylene, n-
Propylene, i-propylene, n-butylene, i-butylene, sec-butylene, t-butylene, n-pentylene, i-pentylene, neo-pentylene, tert-
Pentylene, n-hexylene and the like are exemplified. It is preferably C1-C4 alkylene, more preferably methylene or ethylene. Lower alkenyl is straight-chain or branched C
Including 2 to C6 alkenyl, vinyl, allyl, 1-
Examples include propenyl, i-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-i-butenyl, 2-i-butenyl, pentenyl, hexenyl and the like. It is preferably C2-C4 alkenyl, more preferably vinyl. Lower alkenylene is linear or branched C2 to C
6 alkenylene is included, more preferably C2-C4 alkenylene, and particularly preferably vinylene or propenylene. Aryl means a monocyclic or condensed aromatic hydrocarbon group, and examples thereof include phenyl, α-naphthyl, β-naphthyl, anthryl, indenyl, phenanthryl and the like. Phenyl, α-naphthyl and β-naphthyl are preferable, and phenyl is particularly preferable. Heteroaryl means an aromatic monocyclic or polycyclic group containing the same or different heteroatoms selected from O, S and N. The monocyclic group contains 1 to 1 heteroatoms.
Including 4-containing 5- or 6-membered ring groups, the aromatic ring groups include pyridyl, furyl, thienyl, tetrazolyl,
Pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,
Examples thereof include thiazolyl, thiadiazolyl, oxazinyl, triazinyl and the like, with preference given to furyl (eg 2-furyl), thienyl (eg 2-thienyl) and thiazole (eg 2-thiazole).

The polycyclic group has 2 to 5 heteroatoms.
Or a tricyclic heterocyclic group, preferably an 8- to 14-membered ring, and examples thereof include quinolyl, isoquinolyl, indolyl, benzimidazolyl, indazolyl, indoridinyl, benzofuryl, benzothienyl, acridinyl, phenanthridinyl and the like. It When the aryl or heteroaryl has a substituent, the substituent is
Halogen (eg: F, Cl), C3-C4 lower alkylene (eg: trimethylene), hydroxy, lower alkoxy (eg: methoxy), halogenated lower alkyl (eg: CC)
F ₃ ), lower alkyl (eg, methyl, isopropyl),
Lower alkylthio (eg methylthio), C1-C2 lower alkylenedioxy (eg methylenedioxy), optionally substituted amino (eg amino, mono- or di-lower alkylamino (eg dimethylamino), lower alkoxy) Exemplified are the same or different 1 to 3 groups selected from the group consisting of carbonylamino (eg BocNH). More preferably, it is halogen or lower alkoxy. As the substitution position on phenyl, p-position and m-position are particularly preferable. Aryl lower alkyl is preferably
Phenyl C1-C4 alkyl. Aryl lower alkenyl is preferably 2-phenylvinyl.
A ¹ is preferably a group represented by (a). X ¹ is preferably O. R ¹ is preferably lower alkyl halide, especially trihalogenated methyl. X ² is preferably O. n is preferably 3-5. Z is preferably O. X ³ and X ⁴ preferably include the following cases. (1) X ³ is a single bond; X ⁴ is a single bond or NH. (2) X ³ is CH ₂ ; X ⁴ is NHSO ₂ , NHCO, NHC
When it is ONH or NHCSNH. (3) X ³ is CH = CH; X ⁴ is a single bond.

A method for producing the compound of the present invention is exemplified below.
Compound (I) can be preferably synthesized by a well-known amide bond forming reaction. As the raw material, A ¹ -ph-X ²
- a piperazine derivative having the (CH ₂₎ n-group, -C
Z-X ³ -X ⁴ -B ¹ part and the corresponding carboxylic acid or thiocarboxylic acid reactive derivative thereof, or isocyanates, thioisocyanate, etc. are used, they are either commercially available products or easily synthesized possible is there. (Production method 1)

[Chemical 5] (In the formula, R is a leaving group such as OH, halogen and acetyl, and other symbols have the same meanings as described above.) Compound (II) is reacted with compound (III) in the presence of a base to give compound (I ) Is obtained. The reaction temperature is preferably about 0 ° C to 70 ° C, more preferably about 10 ° C.
~ 35 ° C. As the solvent, methylene chloride, ethyl acetate, tetrahydrofuran, dimethylformamide or the like can be used. The reaction time is several hours to several tens hours. As the base, triethylamine, pyridine, an inorganic base (eg, alkali metal, hydroxide, carbonate, bicarbonate, etc.) can be used.

(Production Method 2) Compound (II) and Compound (III)
A known condensing agent: carbodiimide (eg, N, N′-diethylcarbodiimide, N, N′-dicyclocarbodiimide, etc.), carbonyl compound (eg, carbonyldiimidazole, etc.), acylamino compound (eg, 2-ethoxy) -1-ethoxycarbonyl-1,2-dihydroquinoline, etc.) and the like. The reaction temperature is preferably about 0 ° C to 70 ° C, more preferably about 10 ° C to 35 ° C. As the solvent, methylene chloride, ethyl acetate, tetrahydrofuran, dimethylformamide or the like can be used. The reaction time is several hours to several tens hours. If desired, triethylamine, pyridine, an inorganic base (eg, alkali metal, hydroxide, carbonate, bicarbonate, etc.) can be used as the base.

(Production method 3)

[Chemical 6] (Wherein each symbol has the same meaning as defined above) Compound (II) is reacted with isocyanate or thioisocyanate (IV) in the presence of a base, if desired, to give compound (I-1) (in compound (I), X ³ =
A single bond, X ⁴ = NH) is obtained. The reaction temperature is preferably about 0 ° C to 70 ° C, more preferably about 0 to 35 ° C. As the solvent, methylene chloride, ethyl acetate, tetrahydrofuran, dimethylformamide or the like can be used. The reaction time is several hours to several tens hours. As the base, triethylamine, pyridine or the like can be used. If desired, prior to each of the above reactions, an appropriate protection reaction may be performed on the functional group according to a method well known to those skilled in the art, and after the reaction, a deprotection reaction may be performed. Examples of the pharmaceutically acceptable salt of compound (I) include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions and the like, or inner salts. Examples of the inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Ca, Mg, etc.), and examples of the organic bases include trimethylamine, triethylamine, choline, procaine, ethanolamine and the like. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and hydrochloride is preferable. Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, oxalic acid and the like. Examples of the basic amino acid include lysine, algin, ornithine, histidine and the like. In addition, the compound (I) may be a solvate such as water or alcohol.

The prodrug is a derivative of the compound of the present invention having a group capable of being chemically or metabolically decomposed, and is a compound which becomes a compound of the present invention which is pharmaceutically active in vivo by solvolysis or under physiological conditions. is there. Methods for selecting and producing suitable prodrug derivatives are described in Design of Prodrugs, Elsevier, Amsterdam 1985. When this compound has a carboxyl group, it is produced by reacting the starting acidic compound with a suitable alcohol, or by reacting the starting acidic compound with a suitable amine. Prodrugs such as amide derivatives are exemplified, for example, methyl ester, ethyl ester,
Examples thereof include n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholino ethyl ester and the like.
When the compound has a hydroxyl group, for example, a prodrug such as an acyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide or a suitable acid anhydride is exemplified, and for example, -OCOC. ₂ H ₅ , -OCO (t-Bu), -OCOC
₁₅ H ₃₁ , -OCO (m-COONa-Ph), -OCO
_{CH 2 CH 2 COONa, -OCOCH (} NH 2) CH 3,
-OCOCH ₂ N (CH _{3) 2} and the like. When the compound has an amino group, a prodrug such as an amide derivative produced by reacting a compound having an amino group with a suitable acid halide or a suitable mixed acid anhydride is exemplified, and for example,- NHCO (CH ₂ ) _{20
CH 3, -NHCOCH (NH 2)} CH 3 and the like.

The present compound can be orally or parenterally administered to animals including humans, but is preferably orally administered as a drug, especially as a preventive or therapeutic drug for lifestyle-related diseases such as diabetes and obesity. Examples of dosage forms include granules, tablets, capsules, injections and the like. Upon formulation, various additives such as excipients, disintegrants, binders,
Lubricants, stabilizers, coloring agents and coating agents can be used. The dose varies depending on the age, body weight, symptoms, administration method, etc. of the subject and is not particularly limited, but is usually about 20 mg to about 1000 mg per day for an adult when orally administered,
For parenteral administration, it is about 2 mg to about 100 mg. Administration of compound (I) increases the utilization rate of glucose, resulting in a decrease in blood glucose. This mechanism of action includes (1) increased responsiveness to insulin in each organ (improved insulin resistance), (2) increased insulin secretion due to increased sensitivity to glucose in the pancreas, and (3) It is possible that insulin synthesis may be promoted. That is, the compound (I) is useful as a prophylactic or therapeutic drug for type I or type II diabetes, preferably type II diabetes. Particularly preferred compound (I) has good oral absorbability, excellent pharmacokinetics such as blood concentration and bioavailability (AUC), and /
No side effects are observed in the central nervous system or digestive organs. (Example) (Abbreviation) Me: Methyl, Et: Ethyl, Boc: t-Butoxycarbonyl In the following example compounds, the number "Ex" corresponds to each example number. The structural formulas of the compounds of Examples 1 to 35 are shown below.

[Chemical 7]

[Chemical 8] Example 1

[Chemical 9] Compound 1 (3.50 g, 7.72 mmol) and triethylamine (3.7
To a solution of 7 ml, 27 mmol) in methylene chloride (50 ml) was added dropwise a solution of 4-methoxyphenyl isocyanate (1.0 ml, 7.72 mmol) in methylene chloride (50 ml) over 10 minutes under ice cooling, and then at room temperature. The mixture was stirred under a nitrogen stream for 2 hours. Extract with ethyl acetate. The organic layer is washed with water and saturated brine, the organic layer is dried over MgSO ₄ , and the solvent is distilled off under reduced pressure. The oily substance obtained was purified by silica gel chromatography (ethyl acetate / 2-propanol = 2).
Purify at 0/1 to obtain 3.5 g of the desired product. Recrystallize with ethyl acetate / ethyl ether. NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.007 (2H, quint, J = 6.6 Hz), 2.531 (4H, t, J = 4.8)
Hz), 2.596 (2H, t, J = 7.3 Hz), 3.515 (4H, t, J = 4.
8 Hz), 3.780 (3H, s), 4.030 (2H, t, J = 6.3 Hz), 6.3
03 (1H, s), 6.838 (2H, dd, J = 6.7 Hz, 2.1 Hz), 6.90-
7.01 (6H, m), 7.249 (2H, d, J = 8.2 Hz), 7.536 (2H, d,
9.2 Hz) Elemental analysis (%): C28H30F3N3O4 Calculated value: C = 63.51, H = 5.71, N = 7.94, F = 10.76 Experimental value: C = 63.50, H = 5.80, N = 7.95, F = 10.68

According to the same manner as in Example 1, the compounds of Examples 2 to 35 (Ex2 to 35) or salts thereof (eg, hydrochloride) were obtained.
The physical properties are shown below. Example 2 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.007 (2H, quint, J = 6.6 Hz), 2.526 (4H, t, J = 4.8)
Hz), 2.590 (2H, t, J = 7.3 Hz), 3.516 (4H, t, J = 4.
9 Hz), 4.037 (2H, t, J = 6.2 Hz), 6.335 (1H, s), 6.90
-7.01 (8H, m), 7.27-7.32 (2H, m), 7.535 (2H, d, J =
8.6Hz) Elemental analysis (%): C27H27F4N3O3 Calculated value: C = 62.66, H = 5.26, N = 8.12, F = 14.68 Experimental value: C = 62.50, H = 5.19, N = 8.01, F = 14.80 Example 3 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.002 (2H, quint, J = 6.6 Hz), 2.524 (4H, t, J = 5.1
Hz), 2.590 (2H, t, J = 7.3 Hz), 3.518 (4H, t, J = 5.
1 Hz), 4.035 (2H, t, J = 6.3 Hz), 6.381 (1H, s), 6.90
-7.02 (6H, m), 7.238 (2H, d, J = 6.7 Hz), 7.315 (2H,
d, J = 6.7 Hz), 7.537 (2H, d, J = 8.5 Hz) Elemental analysis (%): C27H27ClF3N3O3 ・ 0.2H ₂ O Calculated value: C = 60.32, H = 5.14, N = 7.82, Cl = 6.60, F = 1
0.60 Experimental value: C = 60.42, H = 5.05, N = 7.76, Cl = 6.57, F = 1
0.59 Example 4 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.006 (2H, quint, J = 7.2 Hz), 2.543 (4H, t, J = 4.9)
Hz), 2.606 (2H, t, J = 7.3 Hz), 3.542 (4H, t, J = 4.
8 Hz), 4.022 (2H, t, J = 6.1Hz), 6.472 (1H, s), 6.911 (2
H, dd, J = 6.9 Hz, 2.6 Hz), 6.96-7.06 (6H, m), 7.26
-7.31 (1H, m), 7.362 (2H, dd, J = 8.7 Hz, 1.4 Hz), 7.
537 (2H, d, 8.5 Hz) Elemental analysis (%): C27H28F3N3O3 ・ 0.2EtOAc Calculated value: C = 64.57, H = 5.77, N = 8.13, F = 11.02 Experimental value: C = 64.71, H = 5.55, N = 8.25, F = 10.85

Example 5 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.235 (2H, s), 3.071 (2H, t), 3.314 (4H, s), 3.581 (2)
H, d, J = 10.7 Hz), 4.094 (2H, t, J = 5.7 Hz), 4.292
(2H, d, J = 13.7 Hz), 7.048 (4H, dd, J = 8.8 Hz, 5.
1 Hz), 7.126 (2H, d, J = 8.9 Hz), 7.29-7.38 (2H, m),
7.63-7.68 (1H, m), 7.712 (2H, d, J = 8.5 Hz), 9.166
(1H, s), 11.028 (1H, s) Elemental analysis (%): C27H26F5N3O3 ・ HCl Calculated value: C = 56.70, H = 4.76, N = 7.35, Cl = 6.20, F = 1
6.61 Experimental value: C = 56.55, H = 4.63, N = 7.32, Cl = 6.18, F = 1
6.81 Example 6 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 1.173 (6H, d, J = 7.0 Hz), 2.235 (2H, s), 2.818 (1H,
quint, J = 6.9 Hz), 3.054 (2H, s), 3.291 (4H, s), 3.5
73 (2H, d, J = 10.7 Hz), 4.094 (2H, t, J = 5.7 Hz),
4.260 (2H, d, J = 14.3 Hz), 7.048 (4H, dd, J = 8.8 H
z, 4.8 Hz), 7.123 (4H, d, J = 8.2 Hz), 7.370 (2H, d,
J = 8.5 Hz), 7.711 (2H, d, J = 8.5Hz), 8.774 (1H,
s), 11.050 (1H, s) Example 7 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.237 (2H, s), 3.084 (2H, t), 3.347 (4H, s), 3.594 (2
H, d, J = 10.0 Hz), 4.097 (2H, t, J = 5.9 Hz), 4.314
(2H, d, J = 13.5 Hz), 7.047 (4H, dd, J = 8.8 Hz, 4.
6 Hz), 7.124 (2H, d, J = 8.8 Hz), 7.617 (2H, d, J =
8.6 Hz), 7.716 (4H, dd, J = 8.4 Hz, 3.1 Hz), 9.282
(1H, s), 10.946 (1H, s) Elemental analysis (%): C28H27F6N3O3 ・ HCl Calculated value: C = 55.68, H = 4.67, N = 6.96, Cl = 5.87, F = 1
8.87 Experimental value: C = 55.58, H = 4.47, N = 7.00, Cl = 6.10, F = 1
9.15

Example 8 NMR (CDCl3) δ ppm (300 MHZ) (HCl salt) 2.493 (2H, s), 2.919 (2H, s), 3.277 (2H, s), 3.668 (2
H, d, J = 12.0 Hz), 4.112 (4H, t, J = 5.2 Hz), 4.77
4 (2H, d, J = 13.8 Hz), 6.544 (1H, dd, J = 3.3Hz, 1.
8 Hz), 6.882 (2H, d, J = 9.2 Hz), 6.990 (4H, t, J =
8.1 Hz), 7.156 (1H, d, J = 3.4 Hz), 7.53-7.56 (3H,
m), 13.476 (1H, s) Example 9 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 1.149 (3H, t, J = 7.6 Hz), 2.222 (2H, s), 2.545 (2H) ,
s), 3.057 (2H, t), 3.336 (4H, s), 3.577 (2H, d, J = 1
3.1 Hz), 4.089 (2H, t, J = 5.7 Hz), 4.257 (2H, d, J =
12.0 Hz), 7.02-7.17 (8H, m), 7.358 (2H, d, J = 8.1
Hz), 7.708 (2H, d, J = 8.6 Hz), 8.726 (1H, s), 10.636
(1H, s) Elemental analysis (%): C29H32F3N3O3 ・ HCl Calculated value: C = 61.75, H = 5.90, N = 7.45, Cl = 6.29, F = 1
0.10 experimental value: C = 61.59, H = 5.78, N = 7.51, Cl = 6.34, F =
9.84 Example 10 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.236 (2H, s), 3.063 (2H, s), 3.301 (4H, s), 3.575 (2
H, d, J = 11.0 Hz), 3.713 (3H, s), 4.096 (2H, t, J =
5.8 Hz), 4.272 (2H, d, J = 13.1 Hz), 6.549 (1H, dd,
J = 8.1 Hz, 2.3 Hz), 7.03-7.17 (9H, m), 7.711 (2H,
d, J = 8.9 Hz), 8.832 (1H, s), 11.005 (1H, s) Elemental analysis (%): C28H30F3N3O4 ・ HCl Calculated value: C = 59.42, H = 5.52, N = 7.42, Cl = 6.26, F = 1
0.07 Experimental value: C = 59.32, H = 5.42, N = 7.47, Cl = 6.43, F =
9.87

Example 11 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.221 (2H, s), 3.044 (2H, s), 3.288 (4H, s), 3.564 (2)
H, d, J = 10.1 Hz), 3.746 (3H, s), 3.775 (3H, s), 4.
093 (2H, t, J = 6.1 Hz), 4.184 (2H, d, J = 14.6Hz),
6.468 (1H, dd, J = 8.5 Hz, 2.7 Hz), 6.592 (1H, d, J
= 2.4 Hz), 7.03-7.14 (6H, m), 7.268 (1H, d, J = 8.5
Hz), 7.713 (2H, d, J = 8.9 Hz), 7.928 (1H, s), 10.68
8 (1H, s) Elemental analysis (%): C29H32F3N3O5 ・ HCl Calculated value: C = 58.44, H = 5.58, N = 7.05, Cl = 5.95, F =
9.56 Experimental value: C = 58.26, H = 5.44, N = 7.09, Cl = 6.05, F =
9.42 Example 12 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.229 (2H, s), 3.063 (2H, t, J = 10.2 Hz), 3.288 (4H,
s), 3.568 (2H, d, J = 12.0 Hz), 3.807 (3H, s), 4.094
(2H, t, J = 5.9 Hz), 4.196 (2H, d, J = 14.1Hz), 6.8
6-6.91 (1H, m), 7.046 (6H, dd, J = 9.0 Hz, 4.3 Hz),
7.124 (2H, dd, J = 6.9 Hz, 2.2 Hz), 7.547 (1H, d, J =
7.8 Hz), 7.709 (2H, d, J = 8.8 Hz), 8.021 (1H, s), 10.822 (1H, s) Elemental analysis (%): C28H30F3N3O4 ・ HCl Calculated value: C = 59.42, H = 5.52, N = 7.42, Cl = 6.26, F = 1
0.07 Experimental value: C = 59.26, H = 5.35, N = 7.49, Cl = 6.39, F =
9.93 Example 13 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.222 (2H, s), 3.060 (2H, t, J = 10.3 Hz), 3.296 (4H,
s), 3.580 (2H, d, J = 11.6 Hz), 3.700 (3H, s), 3.708
(3H, s), 4.091 (2H, t, J = 5.9 Hz), 4.251 (2H, d, J
= 13.3 Hz), 6.843 (1H, d, J = 8.8 Hz), 6.97-7.19 (8
H, m), 7.710 (2H, d, J = 8.8 Hz), 8.658 (1H, s), 10.6
91 (1H, s) Elemental analysis (%): C29H32F3N3O5 ・ HCl Calculated value: C = 58.44, H = 5.58, N = 7.05, Cl = 5.95, F =
9.56 Experimental value: C = 58.36, H = 5.37, N = 7.13, Cl = 5.96, F =
9.33 Example 14 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 1.075 (3H, t, J = 6.9 Hz), 2.001 (2H, s), 2.826 (2H,
s), 3.084 (4H, s), 3.339 (2H, d, J = 10.5 Hz), 3.736
(2H, q, J = 6.9 Hz), 3.864 (2H, t, J = 5.8 Hz), 4.0
20 (2H, d, J = 13.3 Hz), 6.600 (2H, d, J = 8.9 Hz),
6.819 (4H, dd, J = 8.9 Hz, 5.8 Hz), 6.895 (2H, d, J
= 9.1 Hz), 7.110 (2H, d, J = 9.0 Hz), 7.483 (2H, d,
J = 8.9 Hz), 8.440 (1H, s), 10.633 (1H, s) Elemental analysis (%): C29H32F3N3O4 ・ HCl Calculated value: C = 60.05, H = 5.73, N = 7.24, Cl = 6.11, F =
9.83 Experimental value: C = 59.95, H = 5.69, N = 7.26, Cl = 6.29, F =
9.67

Example 15 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.205 (2H, s), 2.429 (3H, s), 3.065 (2H, s), 3.302 (4)
H, s), 3.583 (2H, d, J = 12.4 Hz), 4.086 (2H, t, J =
5.6 Hz), 4.263 (2H, d, J = 12.7 Hz), 7.042 (4H, dd,
J = 8.7 Hz, 5.1 Hz), 7.123 (2H, d, J = 8.9 Hz), 7.1
92 (2H, d, J = 8.9 Hz), 7.436 (2H, d, J = 8.6 Hz),
7.710 (2H, d, J = 8.6 Hz), 8.822 (1H, s), 10.560 (1H,
s) Elemental analysis (%): C28H30F3N3O3S ・ HCl Calculated value: C = 57.78, H = 5.37, N = 7.22, Cl = 6.09, F =
9.79, S = 5.51 Experimental value: C = 57.73, H = 5.44, N = 7.20, Cl = 6.28, F =
9.67, S = 5.49 Example 16 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.218 (2H, s), 3.051 (2H, s), 3.311 (4H, s), 3.548 (2
H, s), 4.089 (2H, t, J = 6.0 Hz), 4.238 (2H, d, J = 1
3.9 Hz), 5.957 (2H, s), 6.79-6.86 (2H, m), 7.045 (4H,
dd, J = 8.2 Hz, 5.2 Hz), 7.107 (1H, s), 7.138 (2H,
s), 7.710 (2H, d, J = 8.9 Hz), 8.725 (1H, s), 10.668
(1H, s) Elemental analysis (%): C28H28F3N3O5 ・ HCl Calculated value: C = 57.98, H = 5.04, N = 7.24, Cl = 6.11, F =
9.83 Experimental value: C = 57.99, H = 5.12, N = 7.28, Cl = 6.14, F =
9.58 Example 17 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.222 (2H, s), 3.074 (2H, s), 3.338 (4H, s), 3.558 (2)
H, s), 4.091 (2H, t, J = 5.8 Hz), 4.283 (2H, d, J = 1
2.2 Hz), 7.045 (4H, dd, J = 8.4 Hz, 5.0 Hz), 7.121 (2
H, d, J = 8.8 Hz), 7.266 (2H, d, J = 8.9 Hz), 7.586
(2H, d, J = 8.9Hz), 7.709 (2H, d, J = 8.6Hz), 9.07
3 (1H, s), 10.768 (1H, s) Elemental analysis (%): C28H27F6N3O4 ・ HCl Calculated value: C = 54.24, H = 4.55, N = 6.78, Cl = 5.72, F = 1
8.39 Experimental value: C = 53.99, H = 4.51, N = 6.82, Cl = 5.96, F = 1
8.31

Example 18 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.242 (2H, s), 3.050 (2H, s), 3.284 (4H, s), 3.559 (2)
H, s), 3.806 (3H, s), 4.095 (2H, t, J = 5.8 Hz), 4.26
3 (2H, d, J = 12.0 Hz), 7.03-7.14 (7H, m), 7.380 (1H,
dd, J = 9.1 Hz, 2.5 Hz), 7.633 (1H, d, J = 2.7 Hz),
7.711 (2H, d, J = 8.8 Hz), 8.894 (1H, s), 10.940 (1
(H, s) Elemental analysis (%): C28H29ClF3N3O4 ・ HCl ・ 0.3H ₂ O Calculated value: C = 55.51, H = 5.09, N = 6.94, Cl = 11.70, F =
9.41 Experimental value: C = 55.56, H = 4.94, N = 6.97, Cl = 11.70, F =
9.40 Example 19 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.144 (3H, s), 2.249 (2H, s), 3.028 (2H, d, J = 11.3 H
z), 3.299 (4H, s), 3.565 (2H, d, J = 11.3 Hz), 3.719
(3H, s), 4.096 (2H, t, J = 6.0 Hz), 4.206 (2H, d, J =
13.5 Hz), 6.709 (1H, dd, J = 8.9 Hz, 2.8 Hz), 6.78
1 (1H, d, J = 2.8 Hz), 7.03-7.14 (7H, m), 7.709 (2H,
d, J = 8.6 Hz), 8.254 (1H, s), 11.082 (1H, s) Elemental analysis (%): C29H32F3N3O4 ・ HCl Calculated value: C = 60.05, H = 5.73, N = 7.24, Cl = 6.11, F =
9.83 Experimental value: C = 59.95, H = 5.72, N = 7.20, Cl = 6.16, F =
9.69 Example 20 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.219 (2H, s), 2.967 (2H, d, J = 8.5 Hz), 3.244 (4H,
s), 3.526 (2H, d, J = 11.3 Hz), 4.06-4.14 (4H, m),
4.235 (2H, d, J = 5.5 Hz), 7.02-7.17 (8H, m), 7.312 (2
H, dd, J = 8.4 Hz, 5.7 Hz), 7.427 (1H, s), 7.710 (2
H, d, J = 8.5 Hz), 10.981 (1H, s) Elemental analysis (%): C28H29F4N3O3 ・ HCl ・ 0.3H ₂ O Calculated value: C = 58.65, H = 5.38, N = 7.33, Cl = 6.18, F = 1
3.25 Experimental value: C = 58.64, H = 5.24, N = 7.30, Cl = 6.23, F = 1
3.20

Example 21 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.230 (2H, s), 3.041 (2H, d, J = 11.6 Hz), 3.294 (4H,
d, J = 12.0 Hz), 3.573 (2H, d, J = 10.5 Hz), 3.783
(3H, s), 4.090 (2H, d, J = 5.9 Hz), 4.257 (2H, d, J
= 14.5 Hz), 7.02-7.19 (8H, m), 7.442 (1H, dd, J = 1
4.0 Hz, 2.3 Hz), 7.709 (2H, d, J = 8.6 Hz), 8.867 (1
H, s), 10.838 (1H, s) Elemental analysis (%): C28H29F4N3O4 ・ HCl Calculated value: C = 57.59, H = 5.18, N = 7.20, Cl = 6.07, F = 1
3.01 Experimental value: C = 57.42, H = 5.04, N = 7.15, Cl = 6.10, F = 1
2.84 Example 22 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.214 (2H, s), 2.959 (2H, d, J = 11.7 Hz), 3.17-3.26
(4H, m), 3.519 (2H, d, J = 11.6 Hz), 3.724 (3H, s),
4.06-4.13 (4H, m), 4.184 (2H, d, J = 5.8 Hz), 6.869 (2
H, d, J = 8.6 Hz), 7.02-7.07 (4H, m), 7.118 (2H, d, J
= 9.1 Hz), 7.196 (2H, d, J = 8.6 Hz), 7.309 (1H,
s), 7.708 (2H, d, J = 8.4 Hz), 10.849 (1H, s) Elemental analysis (%): C29H32F3N3O4 ・ HCl Calculated value: C = 60.05, H = 5.73, N = 7.24, Cl = 6.11, F =
9.83 Experimental value: C = 59.77, H = 5.57, N = 7.19, Cl = 6.27, F =
9.64 Example 23 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 1.722 (2H, quint, J = 7.3 Hz), 2.202 (2H, s), 2.578
(2H, t, J = 7.8 Hz), 2.88-3.25 (8H, m), 3.512 (2H, d,
J = 11.1 Hz), 4.073 (4H, t, J = 6.3 Hz), 6.808 (1H,
s), 7.041 (4H, t, J = 7.9 Hz), 7.118 (2H, d, J = 9.2
Hz), 7.192 (3H, t, J = 6.6 Hz), 7.283 (2H, d, J = 7.
5 Hz), 7.708 (2H, d, J = 9.1Hz), 10.641 (1H, s) Elemental analysis (%): C30H34F3N3O3 ・ HCl Calculated value: C = 62.33, H = 6.10, N = 7.27, Cl = 6.13, F =
9.86 Experimental value: C = 62.10, H = 6.11, N = 7.20, Cl = 6.19, F =
9.75

Example 24 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.187 (2H, s), 2.705 (2H, t, J = 7.5 Hz), 2.897 (2H,
s), 3.12-3.26 (6H, m), 3.482 (2H, d, J = 11.3 Hz), 4.
012 (2H, s), 4.055 (2H, t, J = 5.7 Hz), 6.926 (1H,
s), 7.021 (4H, dd, J = 8.7 Hz, 6.3 Hz), 7.099 (2H,
d, J = 9.1 Hz), 7.17-7.19 (3H, m), 7.277 (2H, t, J =
7.3 Hz), 7.687 (2H, d, J = 8.9 Hz), 10.778 (1H, s) Elemental analysis (%): C29H32F3N3O3 ・ HCl Calculated value: C = 61.75, H = 5.90, N = 7.45, Cl = 6.29, F = 1
0.10 Experimental value: C = 61.51, H = 5.77, N = 7.41, Cl = 6.17, F = 1
0.02 Example 25 NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.218 (2H, s), 3.040 (2H, s), 3.281 (4H, s), 3.560 (2
H, d, J = 11.3 Hz), 4.085 (2H, t, J = 5.9 Hz), 4.227
(2H, d, J = 12.4 Hz), 6.659 (2H, d, J = 8.8 Hz), 7.
043 (4H, dd, J = 8.5 Hz, 5.4 Hz), 7.121 (2H, d, J =
9.1 Hz), 7.193 (2H, d, J = 8.9 Hz), 7.708 (2H, d, J
= 8.8 Hz), 8.537 (1H, s), 9.100 (1H, s), 10.738 (1H,
s) Elemental analysis (%): C27H28F3N3O4 ・ HCl ・ 1.3MeOH Calculated value: C = 57.26, H = 5.81, N = 7.08, Cl = 5.97, F =
9.60 Experimental value: C = 57.47, H = 5.51, N = 6.98, Cl = 5.67, F =
9.31 Example 26 NMR (CDCL3) δ ppm (300 MHZ) (Free) 2.007 (2H, quint, J = 6.6 Hz), 2.46-2.56 (4H, m), 2.
596 (2H, t, J = 7.5 Hz), 3.50-3.60 (4H, m), 4.035
(2H, t, J = 6.0Hz), 6.585 (1H, s), 6.85-7.30 (9H, m),
7.398 (1H, s), 7.536 (2H, d, J = 8.4 Hz) Elemental analysis (%): C28H27F6N3O4 ・ HCl Calculated value: C = 54.24, H = 4.55, N = 6.78, Cl = 5.72,
F = 18.39, experimental value: C = 54.17, H = 4.39, N = 6.81, Cl = 5.54,
F = 18.35, Example 27 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.736 (2H, quint, J = 7.2Hz), 1.843 (2H, quint, J =
6.9Hz), 2.40-2.55 (6H, m), 3.40-3.55 (4H, m), 3.778 (3
H, s), 3.990 (2H, t, J = 6.0Hz), 6.278 (1H, brs), 6.80-
7.04 (8H, m), 7.240 (2H, d, J = 9.0Hz), 7.488 (2H, d, J =
9.0Hz), Elemental analysis (%): C29H32F3N3O4 ・ HCl Calculated value: C = 60.05, H = 5.73, N = 7.24, Cl = 6.11, F =
9.66 Experimental value: C = 60.07, H = 5.78, N = 7.32, Cl = 6.73, F =
9.66

Example 28 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.45-1.80 (4H, m), 1.832 (2H, quint, J = 7.2Hz), 2.42
4 (2H, t, J = 7.8Hz), 2.45-2.60 (4H, m), 3.46-3.56 (4H,
m), 3.781 (3H, s), 3.966 (2H, t, J = 6.3Hz), 6.228 (1H,
brs), 6.839 (1H, d, J = 8.7Hz), 6.87-7.03 (7H, m), 7.24
4 (2H, d, J = 9.0Hz), 7.534 (2H, d, J = 9.0Hz), Elemental analysis (%): C30H34F3N3O4 ・ HCl Calculated value: C = 60.65, H = 5.94, N = 7.07, Cl = 5.97, F =
9.59 Experimental value: C = 60.58, H = 5.93, N = 7.12, Cl = 6.58, F =
9.45 Example 29 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.665 (2H, quint, J = 6.9 Hz), 1.812 (2H, quint, J =
6.3 Hz), 2.30-2.55 (6H, m), 3.44-3.56 (4H, m),
4.033 (2H, t, J = 6.3 Hz), 6.557 (1H, s), 6.971 (2H,
d, J = 9.0 Hz), 7.122 (2H, d, J = 9.0 Hz), 7.372 (2H,
d, J = 8.7 Hz), 7.746 (2H, d, J = 8.7Hz), 7.868 (2H,
d, J = 9.0 Hz), 8.031 (2H, d, J = 9.0Hz) Elemental analysis (%): C29H29N3F6O5S ・ HCl Calculated value: C = 51.07, H = 4.43, N = 6.16, Cl = 5.20,
F = 16.71, S = 4.70, experimental value: C = 50.75, H = 4.26, N = 6.16, Cl = 5.68,
F = 16.64, S = 4.78,

Example 30 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.697 (2H, quint, J = 6.9Hz), 1.841 (2H, quint, J =)
8.4Hz), 2.431 (2H, t, J = 7.5Hz), 2.44-2.60 (4H, m),
3.44-3.54 (4H, m), 3.779 (3H, s), 4.032 (2H, t, J = 6.3H
z), 6.283 (1H, brs), 6.834 (2H, d, J = 9.0Hz), 6.975 (2
H, d, J = 9.3Hz), 7.240 (2H, d, J = 9.0Hz), 7.749 (2H,
d, J = 8.4Hz), 7.875 (2H, d, J = 9.3Hz), 8.037 (2H, d, J
= 8.4Hz), Elemental analysis (%): C29H32F3N3O5S ・ HCl ・ 1 / 4H2O Calculated value: C = 55.15, H = 5.19, N = 6.65, Cl = 5.61, F =
9.02, S = 5.08 Experimental value: C = 55.09, H = 5.20, N = 6.63, Cl = 5.74, F =
8.91, S = 4.94 Example 31 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.602 (2H, quint, J = 7.2Hz), 1.792 (2H, quint, J =
8.4Hz), 2.349 (2H, t, J = 7.2Hz), 2.30-2.50 (4H, m),
3.164 (2H, t, J = 7.8Hz), 3.37-3.52 (4H, m), 3.775 (3H,
s), 6.311 (1H, brs), 6.826 (2H, d, J = 9.0Hz), 7.230 (2
H, d, J = 9.0Hz), 7.855 (2H, d, J = 8.4Hz), 8.055 (2H,
d, J = 8.4Hz), Elemental analysis (%): C23H28F3N3O4S ・ HCl Calculated value: C = 51.54, H = 5.45, N = 7.84, Cl = 6.61, F = 1
0.63, S = 5.98 Experimental value: C = 51.51, H = 5.42, N = 7.80, Cl = 6.70, F = 1
0.62, S = 5.92 Example 32 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.609 (2H, quint, J = 7.5 Hz), 1.804 (2H, quint, J =
8.1 Hz), 2.359 (2H, t, J = 6.9 Hz), 2.35-2.50 (4H,
m), 3.168 (2H, t, J = 7.8 Hz), 3.35-3.55 (4H, m),
6.479 (1H, s), 7.134 (2H, d, J = 8.7 Hz), 7.369 (2H,
d, J = 8.7 Hz), 7.863 (2H, d, J = 8.7Hz), 8.062 (2H,
d, J = 8.7 Hz) Elemental analysis (%): C23H25N3F6O4S ・ HCl Calculated value: C = 46.82, H = 4.44, N = 7.12, Cl = 6.01,
F = 19.32, S = 5.43, experimental value: C = 46.78, H = 4.27, N = 7.14, Cl = 6.28,
F = 19.42, S = 5.52,

Example 33 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.608 (2H, quint, J = 7.2 Hz), 1.796 (2H, quint, J =
8.4 Hz), 2.358 (2H, t, J = 7.2 Hz), 2.35-2.55 (4H,
m), 3.170 (2H, t, J = 8.1 Hz), 3.42-3.52 (4H, m),
3.779 (3H, s), 3.842 (3H, s), 6.42-6.50 (2H, m),
6.800 (1H, s), 7.855 (2H, d, J = 8.7 Hz), 7.93-7.9
9 (1H, m) 8.058 (2H, d, J = 8.7Hz), Elemental analysis (%): C24H30N3F3O5S ・ HCl Calculated value: C = 50.93, H = 5.52, N = 7.42, Cl = 6.26,
F = 10.07, S = 5.67, experimental value: C = 50.72, H = 5.30, N = 7.33, Cl = 5.89,
F = 10.18, S = 5.65, Example 34 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.601 (2H, quint, J = 6.9 Hz), 1.793 (2H, quint, J =
8.4 Hz), 2.352 (2H, t, J = 7.2 Hz), 2.30-2.50 (4H,
m), 3.145 (2H, t, J = 8.1 Hz), 3.38-3.50 (4H, m),
3.776 (3H, s), 6.320 (1H, s), 6.826 (2H, d, J = 9.0
Hz), 7.233 (2H, d, J = 9.0 Hz), 7.403 (2H, d, J = 8.
7 Hz), 7.968 (2H, d, J = 8.7 Hz) Elemental analysis (%): C23H28N3F3O5S ・ HCl Calculated value: C = 50.05, H = 5.30, N = 7.61, Cl = 6.42,
F = 10.32, S = 5.81, experimental value: C = 49.94, H = 5.17, N = 7.57, Cl = 6.31,
F = 10.46, S = 5.77, Example 35 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.678 (2H, quint, J = 6.9 Hz), 1.822 (2H, quint, J =
6.6 Hz), 2.30-2.52 (6H, m), 3.40-3.54 (4H, m),
3.767 (3H, s), 3.968 (2H, t, J = 6.3 Hz), 6.406 (1H,
), 6.821 (2H, d, J = 8.7 Hz), 6.866 (2H, d, J = 8.7
Hz), 7.130 (2H, d, J = 9.0Hz), 7.234 (2H, d, J = 9.0
Hz) Elemental analysis (%): C23H28N3F3O4 ・ HCl Calculated value: C = 54.82, H = 5.80, N = 8.34, Cl = 7.04,
F = 11.31, experimental value: C = 54.81, H = 5.75, N = 8.32, Cl = 6.95,
F = 11.18,

Compounds of Examples 36 to 57 (Ex 36 to 5
The structural formula of 7) is shown below.

[Chemical 10] Example 36

[Chemical 11] Compound 2 (3.15 g, 19.0 mmol), ethyl acetate (200 mL), thionyl chloride (2.00 mL, 27.4 mmol), and dimethylformamide (5 drops) were added to a 500 mL flask, and the mixture was stirred at room temperature for 1 hour, and then the reaction solution was added. A crystalline residue was obtained by concentration under reduced pressure. This residue was dissolved in tetrahydrofuran (300 mL), compound 1 (8.58 g, 18.9 mmol) and triethylamine (16.0 mL, 115 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated saline (200 mL), extracted with ethyl acetate (200 mL x 2), washed with saturated saline (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The extraction residue was purified by silica gel column chromatography to obtain the target compound (7.66 g, 77%). NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.006 (2H, quintet, J = 6.8Hz), 2.45-2.60 (4H, m),
2.586 (2H, t, J = 7.2Hz), 3.60-3.83 (4H, m), 4.040 (2
H, t, J = 6.3Hz), 6.809 (1H, d, J = 15.0Hz), 6.921
(2H, d, J = 8.7Hz), 6.976 (2H, d, J = 8.7Hz), 7.003
(2H, d, J = 9.0Hz), 7.067 (2H, dd, J = 8.7Hz, 8.7H
z), 7.512 (2H, dd, J = 9.0Hz, 5.1Hz), 7.539 (2H, d,
J = 9.0Hz), 7.646 (1H, d, J = 15.6Hz) Elemental analysis (%): C29H28F4N2O3 ・ HCl Calculated value: C = 61.65, H = 5.17, N = 4.96, Cl = 6.28, F = 1
3.45 Experimental value: C = 61.37, H = 4.98, N = 5.03, Cl = 6.21, F = 1
3.41

The compounds of Examples 37 to 57 (Ex 37 to 57) or salts thereof (eg, hydrochloride) were obtained according to Example 36. The physical properties are shown below. Example 37 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.006 (2H, quint, J = 6.6Hz), 2.46-2.60 (4H, m), 2.587
(2H, t, J = 7.2Hz), 3.60-3.85 (4H, m), 4.038 (2H, t, J
= 6.3Hz), 6.85-7.38 (11H, m), 7.531 (2H, d, J = 8.4H
z), 7.627 (1H, d, J = 15.6Hz) Elemental analysis (%): C29H28F4N2O3 ・ HCl Calculated value: C = 61.65, H = 5.17, N = 4.96, Cl = 6.27, F = 1
3.45 Experimental value: C = 61.52, H = 5.00, N = 4.98, Cl = 6.41, F = 1
3.52 Example 38 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.006 (2H, quint, J = 6.6Hz), 2.46-2.58 (4H, m), 2.586
(2H, t, J = 7.2Hz), 3.60-3.84 (4H, m), 4.039 (2H, t, J
= 6.3Hz), 6.90-7.58 (13H, m), 7.726 (2H, d, J = 15.6H
z), Elemental analysis (%): C29H28F4N2O3 ・ HCl Calculated value: C = 61.65, H = 5.17, N = 4.96, Cl = 6.27, F = 1
3.45 Experimental value: C = 61.31, H = 4.97, N = 5.00, Cl = 6.90, F = 1
3.12

Example 39 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.002 (2H, quint, J = 6.6Hz), 2.46-2.56 (4H, m), 2.580
(2H, t, J = 6.9Hz), 3.50-3.84 (4H, m), 4.036 (2H, t, J
= 6.3Hz), 6.55-7.04 (8H, m), 7.40-7.65 (5H, m), Elemental analysis (%): C27H27F3N2O4 ・ HCl Calculated value: C = 60.39, H = 5.26, N = 5.22, Cl = 6.60 , F = 1
0.61 experimental value: C = 60.13, H = 5.23, N = 5.17, Cl = 6.75, F = 1
0.38 Example 40 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.005 (2H, quint, J = 6.6Hz), 2.44-2.60 (4H, m), 2.584
(2H, t, J = 7.2Hz), 3.60-3.85 (4H, m), 4.038 (2H, t, J
= 6.3Hz), 6.680 (1H, d, J = 15.3Hz), 6.87-7.34 (9H,
m), 7.537 (2H, d, J = 8.4Hz), 7.816 (1H, d, J = 15.3H
z) Elemental analysis (%): C27H27F3N2O3S ・ HCl Calculated value: C = 57.10, H = 5.20, N = 4.98, Cl = 6.31, F = 1
0.14, S = 5.71 Experimental value: C = 57.00, H = 5.02, N = 4.90, Cl = 6.56, F = 1
0.00, S = 5.70

Example 41

[Chemical 12] In 25 mL of methylene chloride, the compound 1 (1.5
g) and Compound 3 (0.77 g) were added, and WSCD.HCl (water-soluble carbodiimide) 0.95 g and 1-hydroxybenzotriazole 0.58 g triethylamine 2.31 mL were further added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water, saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The extraction residue is purified by silica gel column chromatography (chloroform / methanol = 50/1) to obtain 1.9 g of the desired product. NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.010 (2H, quint, J = 6.6Hz), 2.46 ~ 2.60 (4H, m), 2.59
4 (2H, t, J = 7.2Hz), 3.60 ~ 3.84 (4H, m), 4.042 (2H, t,
J = 6.6Hz), 6.898 (1H, d, J = 15.3Hz), 6.90 ~ 7.46 (1
0H, m), 7.536 (2H, d, J = 8.4Hz), 7.641 (1H, d, J = 15.
3Hz) Elemental analysis (%): C30H28F6N2O4 ・ HCl Calculated value: C = 57.10, H = 4.63, N = 4.44, Cl = 5.62, F = 1
8.06, Experimental value: C = 57.00, H = 4.59, N = 4.44, Cl = 5.90, F = 1
8.21, Example 42 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.017 (2H, quint, J = 7.5Hz), 2.40-2.60 (4H, m), 2.598
(2H, t, J = 7.8Hz), 3.50-3.90 (4H, m), 3.936 (3H, s),
4.040 (2H, t, J = 6.0Hz), 5.80-5.95 (1H, brs), 6.728
(1H, d, J = 15.6Hz), 6.88-7.14 (9H, m), 7.536 (2H, d,
J = 8.7Hz), 7.614 (1H, d, J = 15.6Hz) Elemental analysis (%): C30H31F3N2O5 ・ HCl ・ 1 / 2H2O Calculated value: C = 59.85, H = 5.52, N = 4.65, Cl = 5.89, F =
9.47 Experimental value: C = 60.00, H = 5.38, N = 4.65, Cl = 6.01, F =
9.37

Example 43 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.011 (2H, quint, J = 6.9Hz), 2.40-2.65 (6H, m), 3.55-
3.90 (4H, m), 3.920 (3H, s), 4.037 (2H, t, J = 6.3Hz),
5.772 (1H, brs), 6.731 (1H, d, J = 15.6Hz), 6.832 (1H,
d, J = 8.1Hz), 6.90-7.18 (8H, m), 7.534 (2H, d, J =
8.4Hz), 7.594 (1H, d, J = 15.6Hz) Elemental analysis (%): C30H31F3N2O5 ・ 1.35 HCl ・ H2O Calculated value: C = 57.76, H = 5.55, N = 4.49, Cl = 7.67, F =
9.14 Experimental value: C = 57.52, H = 5.30, N = 4.37, Cl = 7.27, F =
8.69 Example 44 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.014 (2H, quint, J = 7.2 Hz), 2.40-2.65 (4H, m), 2.60
5 (2H, t, J = 6.9Hz), 3.60-3.90 (4H, m), 4.029 (2H, t,
J = 6.3Hz), 6.713 (1H, d, J = 15.3Hz), 6.82-7.04 (8H,
m), 7.381 (2H, d, J = 8.7Hz), 7.531 (2H, d, J = 8.7H
z), 7.623 (1H, d, J = 15.3Hz) Elemental analysis (%): C29H29F3N2O4 ・ HCl ・ 1 / 4H2O Calculated value: C = 61.38, H = 5.42, N = 4.94, Cl = 6.25, F =
10.04 Experimental value: C = 61.37, H = 5.33, N = 4.85, Cl = 6.12, F =
9.75 Example 45 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.014 (2H, quintet, J = 6.6Hz), 2.48-2.58 (4H, m),
2.598 (2H, t, J = 7.2Hz), 3.62-3.84 (4H, m), 4.044 (2
H, t, J = 6.2Hz), 6.813 (1H, d, J = 15.6Hz), 6.921
(2H, d, J = 9.3Hz), 6.975 (2H, d, J = 7.8Hz), 7.004
(2H, d, J = 9.3Hz), 7.162 (1H, ddd, J = 7.8Hz, J =
9.9Hz, 7.8Hz), 7.19-7.30 (1H, m), 7.353 (1H, ddd, J
= 2.1Hz, J = 11.0Hz, 7.8Hz), 7.538 (2H, d, J = 9.0H
z), 7.581 (1H, d, J = 16.5Hz) Elemental analysis (%): C29H27F5N2O3 ・ HCl Calculated value: C = 59.75, H = 4.84, N = 4.81, Cl = 6.08, F = 1
6.29 Experimental value: C = 59.45, H = 4.66, N = 4.90, Cl = 5.80, F = 1
6.06 Example 46 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.006 (2H, quintet, J = 6.6Hz), 2.47-2.57 (4H, m),
2.588 (2H, t, J = 7.4Hz), 3.61-3.82 (4H, m), 4.038 (2
H, t, J = 6.3Hz), 6.80-7.03 (9H, m), 7.44-7.54 (1H,
m), 7.530 (2H, d, J = 9.0Hz), 7.667 (1H, d, J = 15.6
Hz) Elemental analysis (%): C29H27F5N2O3 ・ HCl ・ H2O Calculated value: C = 59.38, H = 4.88, N = 4.78, Cl = 6.04, F = 1
6.19 Experimental value: C = 59.38, H = 4.68, N = 4.84, Cl = 6.03, F = 1
6.23

Example 47 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.009 (2H, quintet, J = 6.6Hz), 2.50-2.57 (4H, m),
2.595 (2H, t, J = 7.2Hz), 3.60-3.88 (4H, m), 4.042 (2
H, t, J = 6.3Hz), 6.795 (1H, tt, J = 2.3Hz, 9.0Hz),
6.890 (1H, d, J = 15.3Hz), 6.89-7.08 (8H, m), 7.532
(2H, d, J = 8.4Hz), 7.560 (1H, d, J = 15.6Hz) Example 48 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.000 (2H, quintet, J = 6.8Hz), 2.47-2.55 (4H, m),
2.577 (2H, t, J = 7.2Hz), 3.61-3.81 (4H, m), 4.036 (2
H, t, J = 6.3Hz), 5.988 (2H, s), 6.715 (1H, d, J = 1
5.3Hz), 6.798 (1H, d, J = 8.1Hz), 6.89-7.06 (8H, m),
7.531 (2H, d, J = 8.7Hz), 7.597 (1H, d, J = 15.6Hz) Elemental analysis (%): C30H29F3N2O5 ・ HCl Calculated value: C = 60.97, H = 5.12, N = 4.74, Cl = 6.00 , F =
9.64 Experimental value: C = 60.90, H = 5.05, N = 4.78, Cl = 6.17, F =
9.44 Example 49 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.004 (2H, quintet, J = 6.8Hz), 2.374 (3H, s), 2.48-
2.56 (4H, m), 2.582 (2H, t, J = 7.4Hz), 3.62-3.84 (4H,
m), 4.039 (2H, t, J = 6.2Hz), 6.865 (1H, d, J = 15.3
Hz), 6.918 (2H, d, J = 9.3Hz), 6.973 (2H, d, J = 7.8
Hz), 7.001 (2H, d, J = 8.7Hz), 7.14-7.37 (4H, m), 7.5
37 (2H, d, J = 8.7Hz), 7.649 (1H, d, J = 15.3Hz) Elemental analysis (%): C30H31F3N2O3 ・ HCl Calculated value: C = 64.23, H = 5.75, N = 4.99, Cl = 6.32 , F = 1
0.16 Experimental value: C = 64.04, H = 5.71, N = 5.03, Cl = 6.39, F = 1
0.05

Example 50 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.002 (2H, quintet, J = 6.8Hz), 2.368 (3H, s), 2.46-
2.56 (4H, m), 2.580 (2H, t, J = 7.4Hz), 3.62-3.82 (4H,
m), 4.037 (2H, t, J = 6.3Hz), 6.833 (1H, d, J = 15.6
Hz), 6.916 (2H, d, J = 9.3Hz), 6.973 (2H, d, J = 8.4
Hz), 6.998 (2H, d, J = 9.3Hz), 7.178 (2H, d, J = 7.8H
z), 7.422 (2H, d, J = 8.1Hz), 7.534 (2H, d, J = 8.4H
z), 7.653 (1H, d, J = 15.3Hz) Elemental analysis (%): C30H31F3N2O3 ・ HCl Calculated value: C = 64.23, H = 5.75, N = 4.99, Cl = 6.32, F = 1
0.16 Experimental value: C = 64.08, H = 5.73, N = 5.01, Cl = 6.33, F = 1
0.02 Example 51 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.004 (2H, quintet, J = 6.8Hz), 2.48-2.55 (4H, m),
2.583 (2H, t, J = 6.9Hz), 3.62-3.82 (4H, m), 4.038 (2
H, t, J = 6.3Hz), 6.880 (1H, d, J = 15.6Hz), 6.916
(2H, d, J = 9.3Hz), 6.974 (2H, d, J = 9.0Hz), 6.998
(2H, d, J = 9.0Hz), 7.33-7.42 (3H, m), 7.49-7.57 (2
H, m), 7.675 (1H, d, J = 15.3Hz) Elemental analysis (%): C29H29F3N2O3 ・ HCl ・ 0.6H2O Calculated value: C = 62.44, H = 5.64, N = 5.02, Cl = 6.36, F = 1
0.22 Experimental value: C = 62.32, H = 5.44, N = 5.05, Cl = 6.21, F = 1
0.08 Example 52 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.007 (2H, quintet, J = 6.6Hz), 2.48-2.56 (4H, m),
2.588 (2H, t, J = 7.2Hz), 3.64-3.81 (4H, m), 3.838 (3
H, s), 4.039 (2H, t, J = 6.2Hz), 6.863 (1H, d, J = 1
5.6Hz), 6.88-7.06 (6H, m), 7.126 (1H, d, J = 7.8Hz),
7.297 (1H, t, J = 7.8Hz), 7.538 (2H, d, J = 8.1Hz),
7.638 (1H, d, J = 15.6Hz) Elemental analysis (%): C30H31F3N2O4 ・ HCl Calculated value: C = 62.44, H = 5.59, N = 4.86, Cl = 6.14, F =
9.88 Experimental value: C = 62.18, H = 5.56, N = 4.83, Cl = 6.01, F =
9.68

Example 53 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.998 (2H, quintet, J = 6.9Hz), 2.46-2.56 (4H, m),
2.574 (2H, t, J = 7.2Hz), 3.61-3.81 (4H, m), 3.821 (3
H, s), 4.032 (2H, t, J = 6.3Hz), 6.759 (1H, d, J = 1
5.3Hz), 6.888 (2H, d, J = 8.7Hz), 6,917 (2H, d, J =
8.7Hz), 6.967 (2H, d, J = 8.7Hz), 6.994 (2H, d, J =
9.0Hz), 7.473 (2H, d, J = 9.0Hz), 7.527 (2H, d, J =
8.7Hz), 7.648 (1H, d, J = 15.3Hz) Elemental analysis (%): C30H31F3N2O4 ・ HCl Calculated value: C = 62.44, H = 5.59, N = 4.86, Cl = 6.14, F =
9.88 Experimental value: C = 62.30, H = 5.57, N = 4.84, Cl = 6.36, F =
9.79 Example 54 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.010 (2H, quintet, J = 6.9Hz), 2.46-2.56 (4H, m),
2.583 (2H, t, J = 7.2Hz), 3.008 (6H, s), 3.63-3.83 (4
H, m), 4.038 (2H, t, J = 6.3Hz), 6.669 (1H, d, J = 1
5.0Hz), 6.670 (2H, d, J = 9.0Hz), 6.919 (2H, d, J =
9.0Hz), 6.973 (2H, d, J = 7.2Hz), 7.000 (2H, d, J =
9.0Hz), 7.357 (2H, d, J = 8.1Hz), 7.428 (2H, d, J =
9.0Hz), 7.642 (1H, d, J = 15.3Hz), Example 55 NMR (CDCl3) δ ppm (300MHZ) (Free) 2.021 (2H, quintet, J = 7.2Hz), 2.50-2.59 (4H, m),
2.606 (2H, t, J = 7.4Hz), 3.64-3.85 (4H, m), 4.045 (2
H, t, J = 6.2Hz), 6.920 (2H, d, J = 9.0Hz), 6.962 (1
H, d, J = 16.2Hz), 6.978 (2H, d, J = 8.1Hz), 7.004
(2H, d, J = 9.0Hz), 7.539 (2H, d, J = 8.7Hz), 7.628
(4H, s), 7.687 (1H, d, J = 15.3Hz) Elemental analysis (%): C30H28F6N2O3 ・ HCl Calculated value: C = 58.59, H = 4.75, N = 4.55, Cl = 5.76, F = 1
8.53 Experimental value: C = 58.52, H = 4.69, N = 4.59, Cl = 6.06, F = 1
8.68

Example 56 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.021 (2H, quintet, J = 6.6Hz), 2.50-2.60 (4H, m),
2.608 (2H, t, J = 6.9Hz), 3.66-3.88 (4H, m), 4.044 (2
H, t, J = 6.3Hz), 6.89-7.03 (7H, m), 7.47-7.80 (7H.
m), 6.962 (1H, d, J = 16.2Hz), 6.978 (2H, d, J = 8.1
Hz), 7.004 (2H, d, J = 9.0Hz), 7.539 (2H, d, J = 8.7H
z), 7.628 (4H, s), 7.687 (1H, d, J = 15.3Hz) Elemental analysis (%): C30H28F6N2O3 ・ HCl Calculated value: C = 58.59, H = 4.75, N = 4.55, Cl = 5.76, F = 1
8.53 Experimental value: C = 58.52, H = 4.69, N = 4.59, Cl = 6.06, F = 1
8.68 Example 57 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.013 (2H, quint, J = 6.6 Hz), 2.46-2.60 (4H, m),
2.598 (2H, t, J = 6.9 Hz), 3.66-3.84 (4H, m), 4.04
2 (2H, t, J = 6.6 Hz), 6.86-7.46 (11H, m), 7.536 (2
H, d, J = 8.4 Hz), 7.643 (1H, d, J = 15.6 Hz), elemental analysis (%): C30H28N2F6O4 ・ HCl Calculated value: C = 57.10, H = 4.63, N = 4.44, Cl = 5.62,
F = 18.06, experimental value: C = 56.99, H = 4.51, N = 4.44, Cl = 5.59,
F = 18.15,

Compounds of Examples 58-72 (Ex 58-7
2) or a salt thereof (eg, hydrochloride) was synthesized. The structure and physical properties are shown below.

[Chemical 13] Example 58 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.62-1.89 (4H, m), 2.438 (2H, t, J = 7.5 Hz), 2.44-2.
52 (4H, m), 3.60-3.80 (4H, m), 3.031 (3H, s), 3.973 (2H,
t, J = 6.3 Hz), 6.745 (1H, d, J = 15.3Hz), 6.866 (2H,
d, J = 9.3Hz), 6.891 (2H, d, J = 9Hz), 7.133 (2H, d, J = 9
Hz) 7.471 (2H, d, J = 9 Hz), 7.638 (1H, d, J = 15.3Hz) Elemental analysis (%): C25H29F3N2O4 Calculated value: C = 62.75, H = 6.11, N = 5.85, F = 11.91 Experimental value: C = 62.67, H = 6.09, N = 5.95, F = 12.08 Example 59 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.62-1.80 (2H, m), 1.838 (2H, quint, J = 6.3 Hz),
2.450 (2H, t, J = 7.5Hz), 2.44-2.58 (4H, m), 3.58
-3.84 (4H, m), 3.977 (2H, t, J = 6.6 Hz), 6.84-7.4
8 (9H, m), 7.629 (1H, d, J = 15.3 Hz) Elemental analysis (%): C25H26N2F6O4 ・ HCl Calculated value: C = 52.78, H = 4.78, N = 4.92, Cl = 6.23,
F = 20.04, experimental value: C = 52.74, H = 4.78, N = 4.97, Cl = 6.28,
F = 20.60, Example 60 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.60 to 1.90 (4H, m), 2.40 to 2.54 (6H, m), 3.55 to 3.80 (4H,
m), 3.975 (2H, t, J = 6.0 Hz), 6.796 (1H, d, J = 15.3H
z) ,. 6.867 (2H, d, J = 9.3Hz) 7.02 ~ 7.17 (4H, m), 7.46 ~
7.55 (2H, m), 7.634 (1H, d, J = 15.3Hz), Elemental analysis (%): C24H26F4N2O3 ・ HCl Calculated value: C = 57.32, H = 5.41, N = 5.57, Cl = 7.05, F = 1
5.11, Experimental value: C = 57.32, H = 5.29, N = 5.59, Cl = 7.19, F = 1
5.29,

Example 61 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.54 to 1.95 (4H, m), 2.362 (2H, t, J = 7.5Hz), 2.38 to 2.50
(4H, m), 3.151 (2H, t, J = 7.5 Hz), 3.55 ~ 3.80 (4H, m),
6.786 (1H, d, J = 15.3Hz) ,. 7.00 ~ 7.60 (4H, m), 7.632 (1
H, d, J = 15.3Hz), 7.978 (2H, d, J = 8.7Hz) Elemental analysis (%): C24H26F4N2O4S ・ HCl Calculated value: C = 52.32, H = 4.94, N = 5.08, Cl = 6.43, F = 1
3.79, S = 5.82 Experimental value: C = 52.25, H = 4.79, N = 5.05, Cl = 6.65, F = 1
3.77, S = 5.81 Example 62 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.611 (2H, quint, J = 7.5Hz), 1.816 (2H, quint, J = 8.
1Hz), 2.358 (2H, t, J = 7.2Hz), 2.35 ~ 2.46 (4H, m), 3.1
71 (2H, t, J = 7.8 Hz), 3.50 to 3.80 (4H, m), 6.787 (1H,
d, J = 15.6Hz), .7.00 ~ 7.10 (2H, m), 7.46 ~ 7.54 (2H,
m), 7.631 (1H, d, J = 15.6Hz), 7.863 (2H, d, J = 8.4Hz),
8.068 (2H, d, J = 8.4Hz) Elemental analysis (%): C24H26F4N2O3S ・ HCl Calculated value: C = 53.88, H = 5.09, N = 5.24, Cl = 6.63, F = 1
4.20, S = 5.99 Experimental value: C = 53.76, H = 4.91, N = 5.19, Cl = 6.82, F = 1
4.13, S = 5.96 Example 63 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.50-1.90 (4H, m), 2.367 (2H, t, J = 7.5 Hz), 2.35
-2.50 (4H, m), 3.169 (2H, t, J = 7.5 Hz), 3.50-
3.80 (4H, m), 6.867 (1H, d, J = 15.3 Hz), 7.16- 7.50
(4H, m), 7.622 (1H, d, J = 15.3 Hz), 7.860 (2H, d, J
= 8.4 Hz), 8.063 (2H, d, J = 8.4Hz) Elemental analysis (%): C25H26N2F6O4S ・ HCl Calculated value: C = 49.96, H = 4.53, N = 4.66, Cl = 5.90,
F = 18.97, S = 5.34, experimental value: C = 49.88, H = 4.26, N = 4.63, Cl = 5.82,
F = 19.26, S = 5.28,

Example 64 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.618 (2H, quint, J = 7.2 Hz), 1.70-1.90 (4H, m),
2.369 (2H, t, J = 7.2Hz), 2.35-2.50 (4H, m), 3.172
(2H, t, J = 7.5 Hz) 3.50-3.80 (4H, m), 6.936 (1H,
d, J = 15.3 Hz), 7.169 (4H, brs), 7.705 (1H, d, J =
15.3 Hz), 7.861 (2H, d, J = 8.4 Hz), 8.065 (2H, d, J
= 8.4Hz) Elemental analysis (%): C25H26N2F6O3S ・ HCl Calculated value: C = 51.33, H = 4.65, N = 4.79, Cl = 6.06,
F = 19.49, S = 5.48, experimental value: C = 51.17, H = 4.54, N = 4.76, Cl = 6.07,
F = 19.42, S = 5.29, Example 65 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.627 (2H, quint, J = 6.9 Hz), 1.815 (2H, quint, J =
8.4 Hz), 2.380 (2H, t, J = 7.2 Hz), 2.34-2.52 (4H,
m), 3.170 (2H, t, J = 7.8 Hz) 3.55-3.80 (4H, m),
6.917 (1H, d, J = 15.3 Hz), 7.46-7.72 (3H, m), 7.6
75 (1H, d, J = 15.3 Hz), 7.760 (1H, brs), 7.861 (2H,
d, J = 8.7 Hz), 8.064 (2H, d, J = 8.7Hz) Elemental analysis (%): C25H26N2F6O3S ・ HCl Calculated value: C = 51.33, H = 4.65, N = 4.79, Cl = 6.06,
F = 19.49, S = 5.48, experimental value: C = 51.17, H = 4.49, N = 4.82, Cl = 5.75,
F = 20.51, S = 5.38, Example 66 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.60 to 1.90 (4H, m), 2.458 (2H, t, J = 7.2Hz), 2.46 to 2.56
(4H, m), 3.60 ~ 3.80 (4H, m), 3.994 (2H, t, J = 6.0 Hz),
6.806 (1H, d, J = 15.6Hz), .6.88 ~ 7.10 (8H, m), 7.47 ~
7.56 (4H, m), 7.642 (1H, d, J = 15.6Hz) Elemental analysis (%): C30H30F4N2O3 ・ HCl Calculated value: C = 62.23, H = 5.40, N = 4.84, Cl = 6.12, F = 1
3.12 Experimental value: C = 62.04, H = 5.23, N = 4.88, Cl = 6.45, F = 1
2.95

Example 67 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.44 to 1.66 (4H, m), 1.831 (2H, quint, J = 6.9Hz), 2.41
1 (2H, t, J = 7.5Hz), 2.44 ~ 2.54 (4H, m), 3.58 ~ 3.84 (4H,
m), 3.965 (2H, t, J = 6.3Hz), 6.803 (1H, d, J = 15.6H
z) ,. 6.86 ~ 7.10 (8H, m), 7.46 ~ 7.58 (4H, m), 7.638 (1H, d,
J = 15.6Hz) Elemental analysis (%): C31H32F4N2O3 ・ HCl Calculated value: C = 62.78, H = 5.61, N = 4.72, Cl = 5.98, F = 1
2.81 Experimental value: C = 62.76, H = 5.66, N = 4.80, Cl = 6.34, F = 1
2.78 Example 68 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.679 (2H, quint, J = 6.3Hz), 1.847 (2H, quint, J = 6.
0Hz), 2.30 ~ 2.60 (6H, m), 3.55 ~ 3.80 (4H, m), 4.034 (2
H, d, J = 6.3Hz), 6.794 (1H, d, J = 15.6Hz), 6.93 ~ 7.56
(6H, m), 7.637 (1H, d, J = 15.6Hz), 7.749 (2H, d, J = 8.
4Hz), 7.879 (2H, d, J = 8.7Hz), 8.040 (2H, d, J = 8.4Hz) Elemental analysis (%): C30H30F4N2O4S ・ HCl Calculated value: C = 57.46, H = 4.98, N = 4.47, Cl = 5.65, F = 1
2.12, S = 5.11 Experimental value: C = 57.23, H = 4.99, N = 4.44, Cl = 5.66, F = 1
1.95, S = 5.10 Example 69 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.679 (2H, quint, J = 7.8 Hz), 1.848 (2H, quint, J =
6.6 Hz), 2437 (2H, t, J = 7.5 Hz), 2.40-2.60 (4H,
m), 3.55-3.85 (4H, m), 4.036 (2H, t, J = 6.0 Hz),
6.891 (1H, d, J = 15.6 Hz), 6.94 7.50 (6H, m), 7.63
3 (1H, d, J = 15.3 Hz), 7.750 (2H, d, J = 8.4 Hz),
7.880 (2H, d, J = 9.0 Hz), 8.042 (2H, d, J = 8.4 Hz), Elemental analysis (%): C31H30N2F6O5S ・ HCl ・ 1 / 2H2O Calculated value: C = 53.03, H = 4.59, N = 3.99, Cl = 5.05,
F = 16.24, S = 4.57, experimental value: C = 53.12, H = 4.33, N = 3.98, Cl = 4.97,
F = 16.31, S = 4.57,

Example 70 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.684 (2H, quint, J = 6.9Hz), 1.826 (2H, quint, J = 6.)
6Hz), 2.30 ~ 2.60 (6H, m), 3.55 ~ 3.82 (4H, m), 3.968 (2
H, t, J = 6.3Hz), 6.56 to 6.76 (3H, m), 6.800 (1H, d, J =
15.3Hz), 7.00 to 7.60 (9H, m), 7.634 (1H, d, J = 15.3Hz) Elemental analysis (%): C30H30F4N2O3 ・ HCl Calculated value: C = 62.23, H = 5.40, N = 4.84, Cl = 6.12, F = 1
3.12 Experimental value: C = 62.17, H = 5.25, N = 4.87, Cl = 6.18, F = 1
3.00 Example 71 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.005 (2H, quintet, J = 6.9Hz), 2.43-2.58 (4H, m),
2.585 (2H, t, J = 7.2Hz), 2.794 (2H, t, J = 6.6Hz),
3.321 (2H, t, J = 6.5Hz), 3.57-3.70 (4H, m), 4.034 (2
H, t, J = 6.2Hz), 6.914 (2H, d, J = 9.3Hz), 6.975 (2
H, d, J = 9.0Hz), 6,999 (2H, d, J = 9.3Hz), 7.132 (2
H, dd, J = 8.7Hz, 8.7Hz), 7.535 (2H, d, J = 8.4Hz),
8.049 (2H, dd, J = 9.0Hz, 5.4Hz) Elemental analysis (%): C29H30F4N2O3 ・ HCl ・ 0.4H2O Calculated value: C = 60.66, H = 5.58, N = 4.88, Cl = 6.17, F = 1
3.23 Experimental value: C = 60.68, H = 5.39, N = 4.94, Cl = 6.41, F = 1
3.10 Example 72 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.928 (2H, quintet, J = 6.9Hz), 2.08-2.17 (2H, m),
2.40-2.52 (4H, m), 3.32-3.41 (2H, m), 3.65-3.74 (2H,
m), 3.982 (2H, t, J = 6.3Hz), 6.019 (1H, d, J = 12.6H
z), 6.641 (1H, d, J = 12.3Hz), 6.884 (2H, d, J = 9.0
Hz), 6.965 (2H, d, J = 8.4Hz), 6.983 (2H, d, J = 9.0
Hz), 7.017 (2H, dd, J = 8.7Hz, 8.7Hz), 7.357 (2H, dd,
J = 8.7Hz, 5.4Hz), 7.531 (2H, d, J = 8.4Hz), Elemental analysis (%): C29H28F4N2O3 ・ HCl Calculated value: C = 61.65, H = 5.18, N = 4.96, Cl = 6.28, F = 1
3.45 Experimental value: C = 61.47, H = 5.09, N = 4.92, Cl = 6.27, F = 1
3.33

The compounds of Examples 73 to 95 or salts thereof (eg, hydrochloride) were synthesized. The structure and physical properties are shown below.

[Chemical 14]

[Chemical 15] Example 73 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.991 (2H, quintet, J = 7.1Hz), 2.38-2.59 (4H, m),
2.583 (2H, t, J = 7.2Hz), 3.36-3.59 (2H, m), 3.66-3.
88 (2H, m), 4.030 (2H, t, J = 6.0Hz), 6.912 (2H, d, J
= 9.6Hz), 6.970 (2H, d, J = 9.3Hz), 6.998 (2H, d, J
= 9.6Hz), 7.101 (2H, dd, J = 8.9Hz, 8.9Hz), 7.425 (2
H, dd, J = 8.7Hz, 5.1Hz), 7.536 (2H, d, J = 9.0Hz) Elemental analysis (%): C27H26F4N2O3 ・ HCl ・ 0.3H2O Calculated value: C = 59.57, H = 5.11, N = 5.15 , Cl = 6.51, F = 1
3.96 Experimental value: C = 59.58, H = 5.03, N = 5.23, Cl = 6.26, F = 1
4.06 Example 74 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.986 (2H, quintet, J = 6.8Hz), 2.35-2.63 (4H, m),
2.578 (2H, t, J = 7.2Hz), 3.34-3.55 (2H, m), 3.64-3.
88 (2H, m), 4.025 (2H, t, J = 6.2Hz), 6.907 (2H, d, J
= 9.3Hz), 6.969 (2H, d, J = 9.0Hz), 6.993 (2H, d, J
= 9.0Hz), 7.362 (2H, d, J = 9.0Hz), 7.382 (2H, d, J =
8.7Hz), 7.530 (2H, d, J = 8.4Hz) Elemental analysis (%): C27H26Cl1F3N2O3 ・ HCl ・ 0.2H2O Calculated value: C = 58.01, H = 4.94, N = 5.01, Cl = 12.68, F =
10.20 Experimental value: C = 57.96, H = 4.73, N = 5.06, Cl = 12.39, F =
10.13 Example 75 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.990 (2H, quintet, J = 6.7Hz), 2.42-2.56 (4H, m),
2.576 (2H, t, J = 7.2Hz), 3.42-3.83 (4H, m), 3.832 (3
H, s), 4.027 (2H, t, J = 6.3Hz), 6.911 (4H, d, J = 8.
1Hz), 6.969 (2H, d, J = 8.7Hz), 6.992 (2H, d, J = 9.
0Hz), 7.389 (2H, d, J = 9.0Hz), 7.530 (2H, d, J = 9.0
Hz) Elemental analysis (%): C28H29F3N2O4 ・ HCl Calculated value: C = 61.04, H = 5.49, N = 5.08, Cl = 6.43, F = 1
0.34 experimental value: C = 61.08, H = 5.20, N = 5.16, Cl = 6.40, F = 1
0.19

Example 76 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.989 (2H, quintet, J = 6.8Hz), 2.34-2.54 (4H, m),
2.579 (2H, t, J = 7.2Hz), 3.34-3.57 (2H, m), 3.68-3.
91 (2H, m), 4.027 (2H, t, J = 6.2Hz), 6.909 (2H, d, J
= 8.7Hz), 6.970 (2H, d, J = 9.0Hz), 6.993 (2H, d, J
= 9.0Hz), 7.39-7.43 (5H, m), 7.531 (2H, d, J = 9.0H
z) Example 77 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.980 (2H, quint, J = 6.9Hz), 2.128 (2H, quint, J =
7.8Hz), 2.40 ~ 2.70 (6H, m), 2.90 ~ 3.06 (4H, m), 3.32 ~
3.45 (2H, m), 3.74 to 3.88 (2H, m), 4.022 (2H, t, J = 6.3H
z), 6.86 ~ 7.05 (6H, m), 7.349 (1H, d, J = 7.8Hz), 7.534
(1H, d, J = 8.4Hz), 7.746 (1H, d, J = 8.1Hz), 7.802 (1
(H, s) Elemental analysis (%): C31H31F3N2O4 ・ HCl Calculated value: C = 63.21, H = 5.48, N = 4.76, Cl = 6.02, F =
9.68 Experimental value: C = 62.83, H = 5.44, N = 4.79, Cl = 6.45, F =
9.48 Example 78 Elemental analysis (%): C30H33F3N4O6S.HCl.1 / 4H2O Calculated value: C = 53.33, H = 5.15, N = 8.29, Cl = 5.25, F =
8.44, S = 4.75 Experimental value: C = 53.25, H = 4.85, N = 8.23, Cl = 5.45, F =
8.35, S = 4.64 Example 79 Elemental analysis (%): C31H36F3N5O6S.HCl Calculated value: C = 53.18, H = 5.33, N = 10.00, Cl = 5.06, F =
8.14, S = 4.58 Experimental value: C = 53.07, H = 5.10, N = 9.87, Cl = 5.11, F =
7.84, S = 4.53

Example 80 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.990 (2H, quint, J = 7.2Hz), 2.42 to 2.70 (6H, m), 3.3
4 to 3.46 (2H, m), 3.74 to 3.86 (2H, m), 4.016 (2H, t, J =
6.0Hz), 6.815 (2H, d, J = 9.0Hz), 6.85 ~ 7.03 (6H, m),
7.530 (2H, d, J = 8.7Hz), 7.759 (2H, d, J = 8.7Hz), Elemental analysis (%): C28H27F3N2O5 ・ HCl Calculated value: C = 59.52, H = 5.00, N = 4.96, Cl = 6.27, F = 1
Experimental value: C = 59.45, H = 4.78, N = 5.02, Cl = 6.15, F =
9.84 Example 81 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.992 (2H, quint, J = 6.9Hz), 2.45 ~ 2.65 (6H, m), 3.4
6 ~ 3.58 (2H, m), 3.72 ~ 3.84 (2H, m), 4.024 (2H, t, J =
6.3Hz), 6.86 ~ 7.06 (7H, m), 7.534 (2H, d, J = 9.0Hz),
7.640 (2H, d, J = 4.5Hz), Elemental analysis (%): C28H26BrF3N2O4 ・ HCl ・ 1 / 5H2O Calculated value: C = 53.26, H = 4.37, N = 4.44, Br = 12.65, Cl
= 5.61, F = 9.03 Experimental value: C = 53.19, H = 4.24, N = 4.41, Br = 12.81, Cl
= 5.72, F = 8.85 Example 82 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.005 (2H, quintet, J = 6.9Hz), 2.43-2.58 (4H, m),
2.585 (2H, t, J = 7.2Hz), 2.794 (2H, t, J = 6.6Hz),
3.321 (2H, t, J = 6.5Hz), 3.57-3.70 (4H, m), 4.034 (2
H, t, J = 6.2Hz), 6.914 (2H, d, J = 9.3Hz), 6.975 (2
H, d, J = 9.0Hz), 6.999 (2H, d, J = 9.3Hz), 7.132 (2
H, dd, J = 8.7Hz, 8.7Hz), 7.535 (2H, d, J = 8.4Hz),
8.049 (2H, dd, J = 9.0Hz, 5.4Hz) Elemental analysis (%): C30H30F4N2O4 ・ HCl ・ 0.5H2O Calculated value: C = 59.65, H = 5.34, N = 4.64, Cl = 5.87, F = 1
2.58 Experimental value: C = 59.56, H = 5.27, N = 4.68, Cl = 5.89, F = 1
2.49 Example 83 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.004 (2H, quintet, J = 7.1Hz), 2.50-2.57 (4H, m),
2.595 (2H, t, J = 7.4Hz), 3.64-3.70 (2H, m), 3.75-3.
81 (2H, m), 4.037 (2H, t, J = 6.2Hz), 6.917 (2H, d, J
= 9.6Hz), 6.977 (2H, d, J = 9.0Hz), 7.003 (2H, d, J
= 9.0Hz), 7.188 (2H, dd, J = 8.7Hz, 8.7Hz), 7.154 (1
H, d, J = 14.7Hz), 7.539 (2H, d, J = 9.0Hz), 7.932
(1H, d, J = 15.0Hz), 8.085 (2H, dd, J = 8.9Hz, = 5.
6Hz)

Example 84 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.012 (2H, quin
tet, J = 6.6Hz), 2.44-2.60 (4H, m), 2.597 (2H, t, J
= 7.2Hz), 3.60-3.75 (4H, m), 4.041 (2H, t, J = 6.6H
z), 4.089 (2H, s), 6.89-7.04 (6H, m), 7.160 (2H, dd,
J = 8.4Hz, 8.4Hz), 7.537 (2H, d, J = 8.4Hz), 8.094
(2H, dd, J = 8.7Hz, 5.4Hz) Example 85 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.004 (2H, quint, J = 7.2Hz), 2.38 ~ 2.84 (8H, m), 3.30
~ 3.75 (7H, m), 4.019 (2H, t, J = 6.0Hz), 4.504 (1H, d,
J = 15.3Hz), 4.780 (1H, d, J = 15.3Hz), 6.85 ~ 7.25
(9H, m), 7.531 (2H, d, J = 8.4Hz), Elemental analysis (%): C30H32F3N3O4S ・ HCl Calculated value: C = 57.73, H = 5.33, N = 6.73, Cl = 5.68, F =
9.13, S = 5.14 Experimental value: C = 57.64, H = 5.23, N = 6.66, Cl = 5.87, F =
8.99, S = 5.18 Example 86 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.983 (2H, quint, J = 7.2Hz), 2.38 to 2.84 (8H, m), 3.30
~ 3.75 (7H, m), 4.024 (2H, t, J = 6.3Hz), 4.352 (1H, d,
J = 15.3Hz), 4.582 (1H, d, J = 15.3Hz), 6.25 ~ 6.40
(2H, m), 6.85 ~ 7.40 (7H, m), 7.534 (2H, d, J = 8.4Hz), Elemental analysis (%): C30H32F3N3O5 ・ HCl Calculated value: C = 59.26, H = 5.47, N = 6.91 , Cl = 5.83, F =
9.37 Experimental value: C = 59.27, H = 5.36, N = 6.92, Cl = 6.02, F =
9.26

Example 87 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.964 (2H, quint, J = 6.9Hz), 2.35 to 2.60 (6H, m), 3.2
4 to 3.36 (2H, m), 3.50 to 3.62 (2H, m), 3.72 to 3.80 (2H, m),
4.007 (2H, t, J = 6.3Hz), 5.78 ~ 5.90 (1H, m), 6.896 (2
H, d, J = 9.0Hz), 6.92 ~ 7.04 (4H, m), 7.485 (2H, d, J =
8.7Hz), 7.531 (2H, d, J = 8.4Hz), 7.814 (2H, d, J = 8.
7Hz), Elemental analysis (%): C28H29F3N3O5S ・ HCl Calculated value: C = 51.86, H = 4.66, N = 6.48, Cl = 10.93, F =
8.79, S = 4.94 Experimental value: C = 51.50, H = 4.47, N = 6.40, Cl = 10.87, F =
8.50, S = 4.83 Example 88 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.968 (2H, quint, J = 6.9Hz), 2.34 to 2.64 (6H, m), 3.2
4 to 3.36 (2H, m), 3.50 to 3.64 (2H, m), 3.734 (2H, d, J =
4.2Hz), 3.866 (3H, s), 4.006 (2H, t, J = 6.0Hz), 5.60 ~
5.70 (1H, m), 6.895 (2H, d, J = 9.0Hz), 6.93 ~ 7.04 (6H,
m), 7.531 (2H, d, J = 9.0Hz), 7.803 (2H, d, J = 9.0Hz),
7.814 (2H, d, J = 8.7Hz), Elemental analysis (%): C29H32F3N3O6S ・ HCl Calculated value: C = 54.08, H = 5.16, N = 6.52, Cl = 5.50, F =
8.85, S = 4.98 Experimental value: C = 53.96, H = 5.09, N = 6.51, Cl = 5.69, F =
8.70, S = 5.13 Example 89 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.961 (2H, quint, J = 6.6Hz), 2.30 ~ 2.50 (4H, m), 2.5
48 (2H, t, J = 6.9Hz), 3.26 ~ 3.38 (2H, m), 3.52 ~ 3.63 (2
H, m), 3.797 (2H, d, J = 4.5Hz), 4.005 (2H, t, J = 6.0H
z), 5.90 ~ 6.03 (1H, m), 6.94 ~ 7.04 (6H, m), 7.534 (2H,
d, J = 8.7Hz), 7.787 (2H, d, J = 8.4Hz), 8.016 (2H, d, J
= 8.4Hz), Elemental analysis (%): C29H29F6N3O5S ・ HCl Calculated value: C = 51.07, H = 4.43, N = 6.16, Cl = 5.20, F = 1
6.71, S = 4.70 Experimental value: C = 50.93, H = 4.38, N = 6.15, Cl = 5.56, F = 1
6.91, S = 4.59

Example 90 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.976 (2H, quint, J = 6.9Hz), 2.30 to 2.60 (4H, m), 2.5
63 (2H, t, J = 7.2Hz), 3.37 ~ 3.52 (2H, m), 3.58 ~ 3.68 (2
H, m), 3.770 (3H, s), 4.013 (2H, t, J = 6.0Hz), 4.127 (2
H, d, J = 4.2Hz), 6.06 ~ 6.18 (1H, m), 6.832 (2H, d, J =
9.0Hz), 6.86 ~ 7.02 (6H, m), 7.100 (1H, brs), 7.218 (2
H, d, J = 9.0Hz), 7.531 (2H, d, J = 9.0Hz), Elemental analysis (%): C30H33F3N4O5 ・ HCl Calculated value: C = 57.83, H = 5.50, N = 8.99, Cl = 5.69, F =
9.15 Experimental value: C = 57.73, H = 5.45, N = 9.02, Cl = 5.84, F =
9.03 Example 91 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.979 (2H, quint, J = 6.9 Hz), 2.40-2.60 (4H, m),
2.568 (2H, t, J = 7.2 Hz), 3.40-3.70 (4H, m), 3.76
6 (3H, s), 4.017 (2H, t, J = 6.0 Hz), 4.166 (2H, d, J
= 4.2 Hz), 6.30-6.60 (2H, m), 6.77-7.18 (10H,
m), 7.50-7.60 (2H, m), Elemental analysis (%): C30H33N4F3O5 Calculated value: C = 61.43, H = 5.67, N = 9.55, F = 9.72, Experimental value: C = 61.09, H = 5.68, N = 9.53, F = 9.35, Example 92 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.962 (2H, quint, J = 6.9Hz), 2.35 ~ 2.50 (4H, m), 2.5
48 (2H, t, J = 7.2Hz), 3.24 ~ 3.36 (2H, m), 3.50 ~ 3.63 (2
H, m), 3.764 (2H, d, J = 4.2Hz)), 4.005 (2H, t, J = 6.0H
z), 5.75 ~ 5.87 (1H, m), 6.84 ~ 7.24 (8H, m), 7.531 (2H, d,
J = 8.4Hz), 7.84 to 7.94 (2H, m), Elemental analysis (%): C28H29F4N3O5S ・ HCl Calculated value: C = 53.21, H = 4.78, N = 6.65, Cl = 5.61, F = 1
2.02, S = 5.07 Experimental value: C = 53.03, H = 4.62, N = 6.54, Cl = 5.80, F = 1
1.93, S = 5.23

Example 93 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.003 (2H, quint, J = 6.9Hz), 2.35 to 2.60 (4H, m), 2.5
96 (2H, t, J = 6.9Hz), 3.42-3.56 (2H, m), 3.62-3.76 (2
H, m), 4.033 (2H, t, J = 6.3Hz)), 4.194 (2H, d, J = 3.9H
z), 6.436 (1H, d, J = 15.9Hz), 6.75 ~ 7.14 (9H, m), 7.4
4k〜7.64 (5H, m), Elemental analysis (%): C31H31F4N3O4 ・ HCl Calculated value: C = 59.86, H = 5.19, N = 6.76, Cl = 5.70, F = 1
2.22 Experimental value: C = 59.70, H = 5.02, N = 6.77, Cl = 5.86, F = 1
2.28 Example 94 NMR (CDCl3) δ ppm (300 MHZ) (Free) 2.004 (2H, quint, J = 6.9 Hz), 2.40-2.66 (6H, m),
3.38-3.80 (4H, m), 4.035 (1H, t, J = 6.3 Hz), 4.203
(2H, d, J = 3.9 Hz), 6.589 (1H, d, J = 15.9Hz), 6.85
-7.04 (7H, m), 7.537 (2H, d, J = 9.0 Hz), 7.58-
7.70 (5H, m), Elemental analysis (%): C32H31N3F6O4 ・ HCl Calculated value: C = 57.19, H = 4.80, N = 6.25, Cl = 5.28, F
= 16.96, Experimental value: C = 57.03, H = 4.55, N = 6.26, Cl = 5.24, F
= 17.34, Example 95 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.989 (2H, quint, J = 6.9 Hz), 2.38-2.83 (8H, m),
3.132 (1H, quint, J = 8.7 Hz), 3.34-3.74 (4H, m),
3.534 (2H, quint, J = 9.9 Hz), 3.94-4.08 (4H, m),
4.523 (1H, d, J = 15.3 Hz), 4.751 (1H, d, J = 15.3 H
z), 6.70-6.78 (1H, m), 6.86-7.26 (9H, m), 7.536
(2H, d, J = 8.4 Hz), Elemental analysis (%): C32H35N4F3O5S ・ HCl Calculated value: C = 56.43, H = 5.33, N = 8.23, Cl = 5.21,
F = 8.37, S = 4.71, Experimental value: C = 56.25, H = 5.09, N = 8.20, Cl = 5.20,
F = 8.39, S = 4.65,

Compounds of Examples 96 to 97 (Ex96 to 9
The structural formula of 7) is shown below.

[Chemical 16] Example 96

[Chemical 17] Compound 1 (1.00 g, 2.21 mmol) and triethylamine (0.
92 ml, 6.60 mmol) in tetrahydrofuran (10 ml), 4-methoxyphenyl isothiocyanate (0.37 ml,
2.65 mmol) under ice-cooling, and then at room temperature under a nitrogen stream 3
Stir for hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 ml), 4N hydrogen chloride-containing ethyl acetate (1.10 ml, 4.40 mmol) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from methanol / diethyl ether to obtain the desired product (0.832 g, yield 64.8%). NMR (DMSO-d6) δ ppm (300 MHZ) (HCl salt) 2.234 (2H, s), 3.129 (2H, s), 3.311 (2H, s), 3.48-3.6
2 (4H, m), 3.750 (3H, s), 4.102 (2H, t, J = 5.5 Hz),
4.901 (2H, d, J = 13.4 Hz), 6.896 (2H, d, J = 8.2 H
z), 7.055 (4H, dd, J = 8.9 Hz, 4.6 Hz), 7.127 (2H,
d, J = 8.2 Hz), 7.199 (2H, d, J = 7.9 Hz), 7.714 (2
H, d, J = 8.5 Hz), 9.589 (1H, s), 11.023 (1H, s) Elemental analysis (%): C28H30F3N3O3S ・ HCl Calculated value: C = 57.78, H = 5.37, N = 7.22, Cl = 6.09 , F =
9.79, S = 5.51 Experimental value: C = 57.68, H = 5.30, N = 7.14, Cl = 6.17, F =
9.68, S = 5.65

According to Example 96, the compound of Example 97
(Ex97) or a salt thereof (eg, hydrochloride) was obtained. The physical properties are shown below. Example 97 NMR (CDCl3) δ ppm (300 MHZ) (Free) 1.999 (2H, quint, J = 6.6 Hz), 2.45-2.75 (6H, m),
3.83-3.94 (4H, m), 4.029 (2H, t, J = 6.0 Hz), 6.8
6-7.24 (6H, m), 7.535 (2H, d, 8.4 Hz) Elemental analysis (%): C28H27F6N3O3S Calculated value: C = 56.09, H = 4.54, N = 7.01, F = 19.01,
S = 5.35 Experimental value: C = 55.73, H = 4.40, N = 6.94, F = 18.77,
S = 5.43

Test Example 1 Male KK-Ay mice aged 7-8 weeks (CLEA Japan, Inc.) were orally administered with this compound for 7 days (dose: 80 mg / kg), and after oral fasting for 24 hours, oral glucose tolerance test (OGTT). I went. For OGTT, glucose (3 g / kg) was orally administered, and 15 minutes later, blood was collected from the abdominal aorta with a syringe containing 50 U heparin and centrifuged at 12,000 xg for 5 minutes to collect plasma. Blood glucose concentration (: Glucose) was measured using a new Bradger test (Beringer Mannheim).
lin) was measured using Insulin-EIA Test (Grazyme).
The body weight of the mouse immediately after the experiment was also examined. The average value of 6 mice is shown below as a relative value when the average value of each value in the control group to which the compound was not previously administered is 100.

[Table 1] This compound markedly lowered blood glucose concentration and improved insulin resistance by oral administration in obese model mice. Thus, the compound is
It is useful as a preventive or therapeutic drug for type 2 diabetes. Moreover, since the weight of the mouse was reduced, it is also useful as a preventive or therapeutic drug for obesity. Test Example 2 "Glucose clamp test" 11-week-old male Zucker fatty acid
This compound was orally repeatedly administered to rats for 7 days, and after a 24-hour fast, a tube was inserted and a glucose clamp test was conducted. From right crotch vein Insulin (18mU / kg / min) [Novoline R Note 40
(Novo Nordisk)]. In addition, 50% Glucose [Otsuka Pharmaceutical Co., Ltd.] will be infused continuously through the left hip vein.
Blood is collected from the right hip artery and the infusion rate is adjusted so that the blood glucose level is 120 to 130 mg / dl. Calculate the glucose infusion rate (GIR) at that time. (Insulin resistance index)

[Table 2]

[0048]

INDUSTRIAL APPLICABILITY The present compound is also useful as a preventive or therapeutic drug for lifestyle-related diseases such as diabetes and obesity. The preferred compounds are useful as oral agents because they are excellent in absorbability and pharmacokinetics even when orally administered.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 277/48 C07D 277/48 4C086 307/54 307/54 307/66 307/66 317/60 317/60 317/66 317/66 333/24 333/24 405/06 405/06 409/06 409/06 (72) Inventor Shuhei Koshida 5-12-4 Sagisu, Fukushima-ku, Osaka City, Osaka Prefecture Shionogi Pharmaceutical Co., Ltd. F Term (reference) 4C022 DA03 4C023 EA02 4C033 AD15 AD17 AD20 4C037 HA30 4C063 AA01 BB03 CC04 CC75 CC92 EE01 4C086 AA01 AA02 AA03 BC50 BC82 GA02 GA03 GA10 GA12 MA01 MA04 NA14 ZA70 ZC35

Claims (14)

[Claims] 1. The formula: (In the formula, A ¹ is halogenated lower alkyl, halogenated lower alkoxy, or the formula: A group represented by (X ¹ is O or SO ₂ ; R ¹ is halogenated lower alkyl, or halogenated lower alkoxy);
X ² is O or SO ₂ ; n is an integer of 2 to 6; Z is O or S; X ³ is a single bond, lower alkylene, or lower alkenylene; X ⁴ is a single bond, NR ² (R ² is hydrogen, lower Alkyl or lower alkoxy), CO, NHSO ₂ , NHC
O, NHCONH, or NHCSNH; B ¹ is represented by optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryl lower alkenyl, or optionally substituted heteroaryl) Compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 2. The compound according to claim 1, wherein A ¹ is a group represented by (a), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 3. The compound according to claim 1, wherein A ¹ is a group represented by (a); X ¹ is O, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 4. A group in which A ¹ is represented by (a); X ¹ is O; X ²
The compound of claim 1, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein O is O. 5. The compound according to claim 1, wherein B ¹ is an optionally substituted phenyl, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 6. A substituent in the optionally substituted phenyl is halogen, C3 to C4 lower alkylene, hydroxy, lower alkoxy, halogenated lower alkyl, lower alkyl, lower alkylthio, C1 to C2 lower alkylenedioxy, and The compound of claim 5, which is the same or different 1 to 3 groups selected from the group consisting of optionally substituted amino, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. object. 7. The compound according to any one of claims 1 to 6, wherein X ³ is a single bond; X ⁴ is a single bond or NH, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvent thereof. Japanese food. 8. X ³ is CH ₂ ; X ⁴ is NHSO ₂ , NHCO,
NHCONH or NHCSNH, Claim 1-
7. The compound according to any of 6, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 9. A compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, wherein X ³ is CH═CH; X ⁴ is a single bond. object. 10. The compound according to any one of claims 1 to 9, wherein Z is O, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 11. The compound according to any one of claims 1 to 9, wherein Z is S, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 13. A prophylactic or therapeutic drug for diabetes, which comprises the compound according to any one of claims 1 to 11, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. 14. An agent for preventing or treating obesity, which comprises the compound according to any one of claims 1 to 11, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.