Compound having agonistic activity on somatostatin receptor, and use thereof for medical purposes

Abstract

Provision of orally-available and low-toxic somatostatin receptor subtype 2 agonist. Since the compound represented by the general formula (I): ##STR00001##
[wherein all symbols represent the same meanings as those described in the description] a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is non-peptidic low-molecular compound which has strong somatostatin receptor subtype 2 agonist activity, the compound is orally-available. Additionally, since the compound is low-toxic, the compound is useful for the prevention and/or treatment of the somatostatin related diseases such as acromegaly or gastrointestinal obstruction.

Claims

1. A compound of general formula (I): ##STR00148## wherein R.sup.1 is (1) halogen, (2) hydroxyl, (3) C1-4 alkyl which may be substituted with substituents selected from the group consisting of (a) OR.sup.7 and (b) halogen, (4) C1-4 alkoxy, or (5) C3-8 cycloalkyl; p is an integer of 0 to 3; when p is 2 or more, each R.sup.1 may be the same or different; R.sup.2 is (1) halogen, (2) oxo, (3) OR.sup.3, (4) COR.sup.4, (5) COOR.sup.5, (6) SO.sub.2R.sup.6, (7) C1-4 alkyl which may be substituted with substituents selected from the group consisting of (a) OR.sup.7, (b) COR.sup.8, (c) COOR.sup.9, (d) SO.sub.2R.sup.10, (e) halogen, and (f) cyano, (8) C3-6 monocyclic carbon ring which may be substituted with substituents selected from the group consisting of (a) C1-4 alkyl, (b) phenyl, and (c) hydroxymethyl, (9) 5 to 6 membered monocyclic hetero ring which may be substituted with substituents selected from the group consisting of (a) C1-4 alkyl, (b) phenyl, and (c) hydroxymethyl, (10) NR.sup.76R.sup.77, (11) CONR.sup.78R.sup.79, (12) NR.sup.80COR.sup.81 or (13) cyano; R.sup.3 and R.sup.7 are independently (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4) COR.sup.4; R.sup.4 and R.sup.8 are independently C1-4 alkyl or amino; R.sup.5, R.sup.6, R.sup.9 and R.sup.10 are independently hydrogen or C1-4 alkyl; R.sup.76 to R.sup.81 are independently hydrogen or C1-4 alkyl; q is an integer of 0 to 3; when q is 2 or more, more than one R.sup.2 may be same or different; Ring A is benzene, benzimidazole, indazole, indole, imidazole, triazole, pyrazole, pyridine, pyrimidine, thiophene, oxazole, thiazole, or oxadiazole; Ring G is benzene; L is (1) bond, (2) CR.sup.21CR.sup.22.fwdarw., (3) X.fwdarw., (4) XCR.sup.23R.sup.24.fwdarw., (5) CR.sup.25R.sup.26X.fwdarw., (6) XCR.sup.27R.sup.28O.fwdarw., (7) XOCR.sup.29R.sup.30.fwdarw., (8) OCR.sup.31R.sup.32X.fwdarw., or (9) CR.sup.33R.sup.34OX.fwdarw.(wherein the arrow is a binding position in each group); R.sup.21 to R.sup.34 are independently hydrogen or C1-4 alkyl; X is (1) O, (2) C(O), (3) NR.sup.41, (4) C(O)NR.sup.42, or (5) NR.sup.43C(O); R.sup.41 to R.sup.43 are independently hydrogen or C1-4 alkyl; M is a bond; Z is piperidine which may be substituted with a substituent selected from the group consisting of (a) halogen, (b) NR.sup.53R.sup.54, (c) OR.sup.55, (d) C1-4 alkyl which may be substituted with NR.sup.56R.sup.57 and/or OR.sup.58, and (e) oxo; R.sup.53 to R.sup.58 represent independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, C(O)O(C1-4 alkyl), C(O)OCH.sub.2R.sup.68, oxetanyl, or oxolanyl; a salt thereof, an N-oxide thereof, or a solvate thereof.

2. The compound according to claim 1, wherein the compound is (1) 1-{3-(3,5-dimethylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine, (2) 1-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine, (3) 3-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]vinyl}benzonitrile, (4) 4-(4-amino-1-piperidinyl)-N,5-bis(3,5-dimethyphenyl)pyridine-3-carboxamide, (5) 1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethyphenyl)-4-pyridyl]piperidin-4-amine, (6) 1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethyphenyl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine, (7) 1-[3-(3,5-dimethoxyphenyl)-5-(5,7-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-N-(2-fluoroethyl)-4-piperidinamine, (8) 1-[3-(3-fluoro-5-methoxyphenyl)-5-(1H-indazol-6-yl)-4-pyridinyl]-4-piperidinamine, (9) 5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-2-methylphenol, (10) 1-[3-(5-chloro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine, (11) (3-{4-(4-amino-1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-3-pyridinyl}-5-fluorophenyl)methanol, or (12) {4-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]phenyl} acetonitrile.

3. The compound according to claim 1, wherein the compound is (1) rac-(3R,4S)-4-amino-1-[3-(3,5-dimethoxyphenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-3-piperidinol, or (2) rac-(3R,4S)-4-amino-1-[3-(6-fluoro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)-4-pyridinyl]-3-piperidinol.

4. A pharmaceutical composition which comprises the compound of the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, or a solvate thereof and a pharmaceutically acceptable excipient.

5. A medicine comprising the compound according to claim 1, a salt thereof, an N-oxide thereof, or a solvate thereof and at least one drug selected from the group consisting of pegvisomant, bromocriptine, and cabergoline.

6. A medicine comprising the compound according to claim 1, a salt thereof, an N-oxide thereof, or a solvate thereof and at least one drug selected from the group consisting of prochlorperazine, levomepromazine, risperidone, metoclopramide, domperidone, diphenhydramine, chlorpheniramine, dimenhydrinate, promethazine, diprophylline, famotidine, cimetidine, scopolamine, tropisetron, granisetron, ondansetron, azasetron, ramosetron, indisetron, palonosetron, cisapride, mosapride, dexamethasone, betamethasone, prednisolone, aprepitant, olanzapine, quetiapine, perospirone, methylnaltrexone and morphine.

7. A method for treating a somatostatin related disease, comprising administering to a mammal in need thereof an effective amount of the compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, or a solvate thereof, wherein the somatostatin related disease is acromegaly.

Description

EXAMPLE

(1) The present invention is described in following Example and Biological example, but the present invention is not limited only to them. Name of the present invention compounds and compounds shown in Example are named by ACD/Name (Ver.6.00, Advanced Chemistry Development Inc.), or Chemdraw Ultra (Ver.12.0, Cambridge Soft).

(2) The solvents in a parenthesis described at chromatography separation or TLC mean used eluting solvent or developing solvent, and the ratio means volume ratio. NH silica means that CHROMATOREX NH TLC PLATE (catalog no.; 3800003, (FUJI SILYSIA CHEMICAL LTD.)) are used.

(3) Hi-flash SI or Hi-flash NH in a parenthesis at medium pressure liquid chromatography means used column type. (Hi-flash SI: silica gel (YAMAZEN CO.), Hi-flash NH: Aminopropyl-supported silica gel (YAMAZEN CO.))

(4) LC-MS/ELSD condition:

(5) Condition (1) {Column: Waters Xterra MS C.sub.18 (particle size: 510.sup.6 m; column length:504.6 mm I.D.); flow rate: 1.5 mL/min; column temperature: 40 C.; mobile phase (A): aqueous solution of 0.1% trifluoroacetic acid; mobile phase (B):0.1% trifluoroacetic acid-methanol solution; gradient (rate of mobile phase (A): mobile phase (B)): [0 min] 95:5; [1 min] 95:5; [4 min] 0:100; [4.5 min] 0:100; [4.51 min] 95:5; [6 min] 95:5; detector: UV(PDA), ELSD, MS} UPLC-MS/ELSD condition:
Condition (2) {Column: Waters ACQUITY C.sub.18 (particle size: 1.710.sup.6 m; column length: 302.1 mm I.D.); flow rate: 1.0 mL/min; column temperature: 40 C.; mobile phase (A): aqueous solution of 0.1% trifluoroacetic acid; mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; gradient (rate of mobile phase (A): mobile phase (B)): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95:5; [1.5 min] 95:5; detector: UV(PDA), ELSD, MS}

(6) The numerical value shown at the NMR data is measurements of the .sup.1H-NMR when the measurement solvent described there is used.

(7) In addition, specific functional groups in the formula are shown by symbols and abbreviations. The symbols, the abbreviations and the meanings are described below.

(8) Boc: tert-butoxycarbonyl group

(9) Cbz: benzyloxicarbonyl group

(10) Ns: 2-nitrobenzenesulfonyl group

(11) The following Biological Example 2 is exemplified as an example of test which shows usefulness of the present invention compounds against acromegary, and Biological Example 3 is exemplified as an example of test which shows usefulness of the present invention compounds against digestive symptom with a gastrointestinal obstruction. However, target diseases of the present invention compounds are not limited to them. According to the above, it is obvious that the present invention compounds are useful for the prevention and/or treatment for all of diseases which may be related with somatostatin itself or hormones regulated by somatostatin.

Reference Example 1

methyl 5-bromo-4-[4-(tert-butoxycarbonylamino)-1-piperidyl]pyridine-3-carboxylate

(12) To a dimethylformamide (20 mL) solution of methyl 5-bromo-4-iodopyridine-3-carboxylate (3.0 g), which was produced by the reaction of 5-bromo-4-iodopyridine-3-carboxylic acid (CAS#491588-98-8) and trimethylsilyldiazomethane, was added triethylamine (1.84 mL) and 4-tert-butoxycarbonylaminopiperidine (CAS#73874-95-0) (2.63 g), the mixture was stirred at 70 degrees C. for 5 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate followed by washing with water and saturated brine sequentially. After drying, the organic layer was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (2.47 g) having the following physical property values.

(13) Description: pale yellowish white powder;

(14) TLC: Rf 0.26 (n-hexane:ethyl acetate=1:2);

(15) NMR (300 MHz, CHLOROFORM-d): 8.65 (s, 1H), 8.57 (s, 1H), 4.54 (br. s, 1H), 3.95 (s, 3H), 3.76-3.63 (m, 1H), 3.36-3.25 (m, 2H), 3.16-3.03 (m, 2H), 2.09-1.98 (m, 2H), 1.71-1.59 (m, 2H), 1.47 (s, 9H).

Reference Example 2

methyl 4-[4-(tert-butoxycarbonylamino)-1-piperidyl]-5-phenylpyridine-3-carboxylate

(16) Tripotassium phosphate (425 mg), phenylboronic acid (CAS#98-80-6) (122 mg) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.1 mg) was added to a 1,4-dioxane solution (8 mL) of the compound (207 mg) produced in the Reference example 1, and the mixture was stirred at 90 degrees C. for 2 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and sequentially washed with water and saturated brine. After drying, the organic layer was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (206 mg) having the following physical property values.

(17) Description: pale yellowish white oil;

(18) TLC: Rf 0.31 (n-hexane:ethyl acetate=1:2);

(19) MASS (APCI, Pos.): 412 (M+H)+.

Reference Example 3

tert-butyl N-[1-[3-[(3,5-dimethylphenyl)carbamoyl]-5-phenyl-4-pyridyl]-4-piperidyl]carbamate

(20) Under argon atmosphere, a solution of 3,5-dimethylaniline (CAS#108-69-0) (194 mg) in anhydrous tetrahydrofuran (10 mL) was cooled to 0 degrees C. After N-butyllithium in hexane (1.6 mol, 2.0 mL) was added to it, and the mixture was stirred at room temperature for 10 min. The reaction solution was cooled to 78 degrees C., the solution of the compound (206 mg) produced in the reference example 2 in tetrahydrofuran (10 mL) was added to it. The reaction solution was warmed to room temperature over 3 hours or more, and quenched with aqueous solution of saturated ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=3:1) to obtain the title compound (52 mg) having the following physical property values.

(21) Description: pale yellowish white powder;

(22) TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

(23) MASS (APCI, Pos.): 501 (M+H)+.

Example 1

4-(4-amino-1-piperidyl)-N-(3,5-dimethylphenyl)-5-phenyl-pyridine-3-carboxamide

(24) ##STR00079##

(25) To a solution of the compound (52 mg) produced in the Reference example 3 in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred for 30 min and concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5) to obtain the present invention compound (26 mg) having the following physical property values.

(26) Description: beige amorphous;

(27) Purity (LC-MS/ELSD): 100% (retention time: 3.45 min);

(28) TLC: Rf 0.24 (ethyl acetate:methanol=9:1, NH silica gel);

(29) NMR (300 MHz, CHLOROFORM-d): 8.94 (br. s, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 7.53-7.28 (m, 7H), 6.81 (s, 1H), 3.21-3.05 (m, 2H), 2.83-2.56 (m, 3H), 2.34 (s, 6H), 1.74-1.59 (m, 2H), 1.48 (br. s, 2H), 1.35-1.18 (m, 2H);

(30) MASS (ESI, Pos.): 401 (M+H)+.

Example 2(1)-Example 2(30)

(31) Using methyl 5-bromo-4-iodopyridine-3-carboxylate or a corresponding reagent in place of it, using 4-tert-butoxycarbonylaminopiperidine or a corresponding reagent in place of it, using 3,5-dimethylaniline or a corresponding reagent in place of it, using a corresponding reagent in place of phenylboronic acid, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 1.fwdarw.Reference example 3.fwdarw.Reference example 2.fwdarw.Example 1.

Example 2(1)

4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-6-fluoro-3,3-bipyridine-5-carboxamide

(32) ##STR00080##

(33) Description: colorless oil;

(34) Purity (LC-MS/ELSD): 100% (retention time: 3.41 min);

(35) MASS (ESI, Pos.): 420 (M+H)+.

Example 2(2)

4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide

(36) Description: colorless oil;

(37) Purity (LC-MS/ELSD): 95% (retention time: 3.41 min);

(38) MASS (ESI, Pos.): 405 (M+H)+.

Example 2(3)

4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-5-(2-methylphenyl)pyridine-3-carboxamide

(39) Description: ivory powder;

(40) Purity (LC-MS/ELSD): 100% (retention time: 3.53 min);

(41) MASS (ESI, Pos.): 415 (M+H)+.

Example 2(4)

4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-5-(3-methylphenyl)pyridine-3-carboxamide

(42) Description: ivory powder;

(43) Purity (LC-MS/ELSD): 100% (retention time: 3.56 min);

(44) MASS (ESI, Pos.): 415 (M+H)+.

Example 2(5)

4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-5-(4-methylphenyl)pyridine-3-carboxamide

(45) Description: ivory powder;

(46) Purity (LC-MS/ELSD): 100% (retention time: 3.56 min);

(47) MASS (ESI, Pos.): 415 (M+H)+.

Example 2(6)

4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-5-(5-pyrimidinyl)pyridine-3-carboxamide

(48) Description: colorless oil;

(49) Purity (LC-MS/ELSD): 99% (retention time: 3.39 min);

(50) MASS (ESI, Pos.): 403 (M+H)+.

Example 2(7)

4-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-5-(2,4-dimethyl-1,3-thiazol-5-yl)pyridine-3-carboxamide

(51) Description: colorless oil;

(52) Purity (LC-MS/ELSD): 100% (retention time: 3.50 min);

(53) MASS (ESI, Pos.): 436 (M+H)+.

Example 2(8)

4-(4-amino-1-piperidinyl)-5-(3,5-difluorophenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(54) Description: white powder;

(55) Purity (LC-MS/ELSD): 100% (retention time: 3.42 min);

(56) TLC: Rf 0.55 (ethyl acetate:methanol=9:1, NH silica gel);

(57) NMR (300 MHz, CHLOROFORM-d): 8.75 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.29 (s, 2H), 6.96-6.81 (m, 4H), 3.24-3.09 (m, 2H), 2.92-2.62 (m, 3H), 2.35 (s, 6H), 1.77-1.61 (m, 2H), 1.52 (br. s, 2H), 1.35-1.19 (m, 2H);

(58) MASS (ESI, Pos.): 437 (M+H)+.

Example 2(9)

4-(4-amino-1-piperidinyl)-5-(3,4-difluorophenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(59) Description: white powder;

(60) Purity (LC-MS/ELSD): 100% (retention time: 3.44 min);

(61) TLC: Rf 0.53 (ethyl acetate:methanol=9:1, NH silica gel);

(62) MASS (ESI, Pos.): 437 (M+H)+.

Example 2(10)

4-(4-amino-1-piperidinyl)-5-(2,5-difluorophenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(63) Description: white powder;

(64) Purity (LC-MS/ELSD): 100% (retention time: 3.49 min);

(65) TLC: Rf 0.49 (ethyl acetate:methanol=9:1, NH silica gel);

(66) MASS (ESI, Pos.): 437 (M+H)+.

Example 2(11)

4-(4-amino-1-piperidinyl)-5-(2,3-difluorophenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(67) Description: white powder;

(68) Purity (LC-MS/ELSD): 100% (retention time: 3.52 min);

(69) TLC: Rf 0.48 (ethyl acetate:methanol=9:1, NH silica gel);

(70) MASS (ESI, Pos.): 437 (M+H)+.

Example 2(12)

4-(4-amino-1-piperidinyl)-5-(2,5-dimethylphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(71) Description: white powder;

(72) TLC: Rf 0.45 (ethyl acetate:methanol=9:1, NH silica gel);

(73) NMR (300 MHz, CHLOROFORM-d): 9.09 (s, 1H), 8.85 (s, 1H), 8.24 (s, 1H), 7.32 (s, 2H), 7.21-7.10 (m, 2H), 6.94 (s, 1H), 6.81 (s, 1H), 3.24-3.14 (m, 1H), 3.10-3.00 (m, 1H), 2.89-2.78 (m, 1H), 2.66-2.52 (m, 2H), 2.35 (s, 3H), 2.34 (s, 6H), 2.14 (s, 3H), 1.72-1.55 (m, 2H), 1.51 (br. s, 2H), 1.31-1.05 (m, 2H);

(74) Mass(APCI, Pos.): 429 (M+H)+.

Example 2(13)

4-(4-amino-1-piperidinyl)-5-(2-fluoro-5-methoxyphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(75) Description: white powder;

(76) Purity (UPLC-MS/ELSD): 100% (retention time: 0.6 min);

(77) TLC: Rf 0.42 (ethyl acetate:methanol=9:1, NH silica gel);

(78) MASS (ESI, Pos.): 449 (M+H)+.

Example 2(14)

4-(4-amino-1-piperidinyl)-5-(2-fluoro-5-methylphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(79) Description: white powder;

(80) Purity (UPLC-MS/ELSD): 100% (retention time: 0.6 min);

(81) TLC: Rf 0.47 (ethyl acetate:methanol=9:1, NH silica gel);

(82) MASS (ESI, Pos.): 433 (M+H)+.

Example 2(15)

4-(4-amino-1-piperidinyl)-5-(2-methoxy-5-methylphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(83) Description: white powder;

(84) Purity (UPLC-MS/ELSD): 100% (retention time: 0.6 min);

(85) TLC: Rf 0.42 (ethyl acetate:methanol=9:1, NH silica gel);

(86) MASS (ESI, Pos.): 445 (M+H)+.

Example 2(16)

4-(4-amino-1-piperidinyl)-5-(3,5-dimethoxyphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(87) Description: white powder;

(88) Purity (UPLC-MS/ELSD): 100% (retention time: 0.59 min);

(89) TLC: Rf 0.39 (ethyl acetate:methanol=9:1, NH silica gel);

(90) MASS (ESI, Pos.): 461 (M+H)+.

Example 2(17)

4-(4-amino-1-piperidinyl)-5-(2,5-difluorophenyl)-N-(3-chloro-4-fluorophenyl)pyridine-3-carboxamide

(91) Description: white powder;

(92) Purity (UPLC-MS/ELSD): 100% (retention time: 0.57 min);

(93) TLC: Rf 0.51 (ethyl acetate:methanol=9:1, NH silica gel);

(94) NMR (300 MHz, CHLOROFORM-d): 9.11 (s, 1H), 8.85 (s, 1H), 8.32 (s, 1H), 7.96 (dd, J=6.50, 2.65 Hz, 1H), 7.48-7.38 (m, 1H), 7.21-7.09 (m, 3H), 7.05-6.97 (m, 1H), 3.20-3.10 (m, 2H), 2.87-2.64 (m, 3H), 1.80-1.64 (m, 2H), 1.54 (br. s, 2H), 1.30-1.12 (m, 2H);

(95) MASS (ESI, Pos.): 461 (M+H)+.

Example 2(18)

4-(4-amino-1-piperidinyl)-5-(3,5-dimethoxyphenyl)-N-(3-chloro-4-fluorophenyl)pyridine-3-carboxamide

(96) Description: beige powder;

(97) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.51 min);

(98) TLC: Rf 0.56 (ethyl acetate:methanol=9:1, NH silica gel);

(99) NMR (300 MHz, CHLOROFORM-d): 9.76 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H), 7.98 (dd, J=6.50, 2.65 Hz, 1H), 7.43 (ddd, J=9.00, 4.00, 2.70 Hz, 1H), 7.15 (dd, J=9.00, 8.50 Hz, 1H), 6.51 (t, J=2.40 Hz, 1H), 6.45 (d, J=2.38 Hz, 2H), 3.83 (s, 6H), 3.22-3.11 (m, 2H), 2.80 (s, 3H), 1.82-1.69 (m, 2H), 1.53 (br. s, 2H), 1.38-1.22 (m, 2H);

(100) MASS (ESI, Pos.): 485 (M+H)+.

Example 2(19)

4-(4-amino-1-piperidinyl)-5-(4-hydroxy-3,5-dimethylphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(101) Description: beige powder;

(102) Purity (UPLC-MS/ELSD): 100% (retention time: 0.51 min);

(103) TLC: Rf 0.54 (ethyl acetate:methanol=9:1, NH silica gel);

(104) MASS (ESI, Pos.): 445 (M+H)+.

Example 2(20)

4-[4-(aminomethyl)-1-piperidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(105) ##STR00081##

(106) Description: white powder;

(107) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.56 min);

(108) TLC: Rf 0.40 (ethyl acetate:methanol=9:1, NH silica gel);

(109) NMR (300 MHz, CHLOROFORM-d): 9.56 (br. s, 1H), 8.93 (s, 1H), 8.34 (s, 1H), 7.33 (s, 2H), 7.04 (s, 1H), 6.92 (s, 2H), 6.79 (s, 1H), 3.21-3.08 (m, 2H), 2.76-2.62 (m, 2H), 2.52 (d, J=5.49 Hz, 2H), 2.37 (s, 6H), 2.33 (s, 6H), 1.68-1.56 (m, 5H), 1.31-1.20 (m, 2H);

(110) MASS (ESI, Pos.): 443 (M+H)+.

Example 2(21)

4-(4-amino-4-methyl-1-piperidinyl)-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(111) Description: white powder;

(112) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.56 min);

(113) TLC: Rf 0.62 (ethyl acetate:methanol=9:1, NH silica gel);

(114) NMR (300 MHz, CHLOROFORM-d): 9.61 (s, 1H), 8.93 (s, 1H), 8.36 (s, 1H), 7.32 (s, 2H), 7.05 (s, 1H), 6.96 (s, 2H), 6.80 (s, 1H), 3.06-2.94 (m, 2H), 2.95-2.82 (m, 2H), 2.38 (s, 6H), 2.33 (s, 6H), 1.62-1.30 (m, 6H), 1.03 (s, 3H);

(115) MASS (ESI, Pos.): 443 (M+H)+.

Example 2(22)

4-(4-amino-1-piperidinyl)-5-(3-hydroxy-5-methylphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(116) Description: white powder;

(117) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.50 min);

(118) TLC: Rf 0.37 (ethyl acetate:methanol=9:1, NH silica gel);

(119) MASS (ESI, Pos.): 431 (M+H)+.

Example 2(23)

4-[3-(aminomethyl)-1-pyrrolidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(120) Description: beige powder;

(121) Purity (UPLC-MS/ELSD): 99.5% (retention time: 0.58 min);

(122) TLC: Rf 0.44 (ethyl acetate:methanol=9:1, NH silica gel);

(123) NMR (300 MHz, CHLOROFORM-d): 8.48 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.27 (s, 2H), 6.99 (s, 1H), 6.92 (s, 2H), 6.82 (s, 1H), 3.27 (dd, J=10.1, 7.1 Hz, 1H), 3.20-3.08 (m, 2H), 2.89 (dd, J=10.1, 6.8 Hz, 1H), 2.55 (d, J=7.0 Hz, 2H), 2.35 (s, 6H), 2.34 (s, 6H), 2.16-2.03 (m, 1H), 1.93-1.81 (m, 1H), 1.57-1.40 (m, 3H);

(124) MASS (ESI, Pos.): 429 (M+H)+.

Example 2(24)

N,5-bis(3,5-dimethylphenyl)-4-{[3-(2-piperidinyl)propyl]amino}pyridine-3-carboxamide

(125) Description: white powder;

(126) Purity (UPLC-MS/ELSD): 99.5% (retention time: 0.62 min);

(127) TLC: Rf 0.58 (ethyl acetate:methanol=9:1, NH silica gel);

(128) NMR (300 MHz, CHLOROFORM-d): 8.55 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.25 (s, 2H), 7.01 (s, 1H), 6.96 (s, 2H), 6.89 (br. s., 1H), 6.82 (s, 1H), 3.05-2.935 (m, 1H), 2.81-2.69 (m, 2H), 2.59-2.46 (m, 1H), 2.35 (s, 6H), 2.34 (s, 6H), 2.32-2.22 (m, 1H), 1.84-0.86 (m, 11H);

(129) MASS (ESI, Pos.): 471 (M+H)+.

Example 2(25)

4-(2,7-diazaspiro[3.5]non-7-yl)-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(130) Description: white powder;

(131) Purity (UPLC-MS/ELSD): 93.3% (retention time: 0.58 min);

(132) TLC: Rf 0.25 (ethyl acetate:methanol=9:1, NH silica gel);

(133) NMR (300 MHz, CHLOROFORM-d): 8.76 (s, 1H), 8.67 (s, 1H), 8.35 (s, 1H), 7.25 (s, 2H), 7.04 (s, 1H), 6.92 (s, 2H), 6.83 (s, 1H), 3.55 (s, 4H), 2.89-2.82 (m, 4H), 2.36 (s, 6H), 2.33 (s, 6H), 2.07-1.47 (m, 5H);

(134) MASS (ESI, Pos.): 455 (M+H)+.

Example 2(26)

4-[(4-aminobutyl)amino]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(135) Description: white powder;

(136) Purity (UPLC-MS/ELSD): 99.6% (retention time: 0.60 min);

(137) TLC: Rf 0.56 (ethyl acetate:methanol=9:1, NH silica gel);

(138) NMR (300 MHz, CHLOROFORM-d): 8.55 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.22 (s, 2H), 7.02 (s, 1H), 6.98 (s, 2H), 6.94 (br. s, 1H), 6.83 (s, 1H), 2.81-2.72 (m, 2H), 2.53 (t, J=7.0 Hz, 2H), 2.36 (s, 6H), 2.34 (s, 6H), 1.44-1.18 (m, 6H);

(139) MASS (ESI, Pos.): 417 (M+H)+.

Example 2(27)

2-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-3,5-dimethyl-3-biphenylcarboxamide

(140) Description: white powder;

(141) TLC: Rf 0.36 (n-hexane:ethyl acetate=1:2, NH silica gel);

(142) NMR (300 MHz, CHLOROFORM-d): 10.80 (br. s., 1H), 8.04 (t, J=4.8 Hz, 1H), 7.37 (s, 2H), 7.22 (d, J=4.8 Hz, 2H), 7.01 (s, 1H), 6.92 (s, 2H), 6.77 (s, 1H), 3.06 (d, J=12.6 Hz, 2H), 2.60-2.76 (m, 2H), 2.52 (m, 1H), 2.37 (s, 6H), 2.33 (s, 6H), 1.73 (d, J=9.3 Hz, 2H), 1.48-1.21 (m, 4H);

(143) MASS (APCI, Pos.): 428 (M+H)+.

Example 2(28)

2-[4-(aminomethyl)-1-piperidinyl]-N-(3,5-dimethylphenyl)-3,5-dimethyl-3-biphenylcarboxamide

(144) Description: white powder;

(145) TLC: Rf 0.35 (n-hexane:ethyl acetate=1:4, NH silica gel);

(146) NMR (300 MHz, CHLOROFORM-d): 11.35 (br. s., 1H), 8.12 (br. s., 1H), 7.39 (s, 2H), 7.25-7.19 (m, 2H), 7.01 (s, 1H), 6.91 (s, 2H), 6.76 (s, 1H), 3.10 (d, J=11.9 Hz, 2H), 2.64 (t, J=11.9 Hz, 2H), 2.53 (d, J=6.0 Hz, 2H), 2.36 (s, 6H), 2.32 (s, 6H), 1.64 (d, J=11.9 Hz, 2H), 1.50-1.12 (m, 5H);

(147) MASS (APCI, Pos.): 442 (M+H)+.

Example 2(29)

4-[4-(2-aminoethyl)-1-piperidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(148) Description: white powder;

(149) Purity (UPLC-MS/ELSD): 100% (retention time: 0.60 min);

(150) TLC: Rf 0.56 (ethyl acetate:methanol=9:1, NH silica gel);

(151) NMR (300 MHz, CHLOROFORM-d): 9.56 (s, 1H), 8.92 (s, 1H), 8.33 (s, 1H), 7.34 (s, 2H), 7.05 (s, 1H), 6.93 (s, 2H), 6.80 (s, 1H), 3.19-3.07 (m, 2H), 2.75-2.61 (m, 4H), 2.38 (s, 6H), 2.34 (s, 6H), 1.63-1.12 (m, 9H);

(152) MASS (ESI, Pos.): 457 (M+H)+.

Example 2(30)

4-[4-(aminoethyl)-4-hydroxy-1-piperidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(153) Description: beige powder;

(154) Purity (UPLC-MS/ELSD): 99.7% (retention time: 0.55 min);

(155) TLC: Rf 0.47 (ethyl acetate:methanol=9:1, NH silica gel);

(156) NMR (300 MHz, CHLOROFORM-d): 9.43 (s, 1H), 8.89 (s, 1H), 8.35 (s, 1H), 7.31 (s, 2H), 7.04 (s, 1H), 6.95 (s, 2H), 6.80 (s, 1H), 3.20-3.03 (m, 2H), 3.01-2.88 (m, 2H), 2.51 (s, 2H), 2.38 (s, 6H), 2.33 (s, 6H), 1.75-1.40 (m, 7H);

(157) MASS (ESI, Pos.): 459 (M+H)+.

Example 3

4-(4-hydroxy-1-piperidinyl)-5-(3,5-dimethylphenyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide

(158) ##STR00082##

(159) Using 4-hydroxypiperidine (CAS#5382-16-1) in place of 4-tert-butoxycarbonylaminopiperidine, using 3,5-dimethylphenylboronic acid (CAS#172975-69-8) in place of phenylboronic acid, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 1.fwdarw.Reference example 3.fwdarw.Reference example 2.

(160) Description: white powder;

(161) Purity (UPLC-MS/ELSD): 99.4% (retention time: 0.73 min);

(162) TLC: Rf 0.32 (n-hexane:ethyl acetate=1:1);

(163) NMR (300 MHz, CHLOROFORM-d): 8.95 (s, 1H), 8.80 (s, 1H), 8.33 (s, 1H), 7.31 (s, 2H), 7.03 (s, 1H), 6.95 (s, 2H), 6.81 (s, 1H), 3.75-3.59 (m, 1H), 3.21-3.07 (m, 2H), 2.87-2.73 (m, 2H), 2.37 (s, 6H), 2.33 (s, 6H), 1.84-1.70 (m, 2H), 1.53-1.38 (m, 3H);

(164) MASS (ESI, Pos.): 430 (M+H)+.

Reference Example 4

benzyl ((1-(3-(3,5-dimethylphenyl)-5-((3,5-dimethylphenyl)carbamoyl)pyridin-4-yl)-4-fluoropiperidin-4-yl)methyl)carbamate

(165) Using benzyl N-[(4-fluoro-4-piperidyl)methyl]carbamate (purchased from WUXIAPPTEC, catalog number: WXFS0319) in place of 4-tert-butoxycarbonylaminopiperidine, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 1.fwdarw.Reference example 3.fwdarw.Reference example 2.

(166) Description: white powder;

(167) TLC: Rf 0.40 (n-hexane:ethyl acetate=1:1);

(168) MASS (ESI, Pos.): 595 (M+H)+.

Example 4

4-[4-(aminomethyl)-4-fluoro-1-piperidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(169) ##STR00083##

(170) Under argon atmosphere, 10% palladium on carbon (ca.50% wet) (200 mg) was added to a ethanol (10 mL)/tetrahydrofuran (10 mL) solution of the compound produced in Reference example 4 at room temperature, the mixture was stirred for 3 hours under the hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5) to obtain the present invention compound (290 mg) having the following physical property values.

(171) Description: white powder;

(172) Purity (UPLC-MS/ELSD): 100% (retention time: 0.56 min);

(173) TLC: Rf 0.71 (ethyl acetate:methanol=9:1, NH silica gel);

(174) NMR (300 MHz, CHLOROFORM-d) 9.08 (s, 1H), 8.83 (s, 1H), 8.36 (s, 1H), 7.28 (s, 2H), 7.04 (s, 1H), 6.94 (s, 2H), 6.81 (s, 1H), 3.12-2.96 (m, 4H), 2.69 (d, J=19.39 Hz, 2H), 2.37 (s, 6H), 2.33 (s, 6H), 1.83-1.43 (m, 6H);

(175) MASS (ESI, Pos.): 461 (M+H)+.

Reference Example 5

methyl 4-[4-(tert-butoxycarbonylamino)-1-piperidyl]-5-(3,5-dimethylphenyl)pyridine-3-carboxylate

(176) Using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 2.

(177) Description: pale yellow powder;

(178) Purity (LC-MS/ELSD): 100% (retention time: 4.23 min);

(179) TLC: Rf 0.14 (n-hexane:ethyl acetate=1:2);

(180) MASS (ESI, Pos.): 440 (M+H)+.

Reference Example 6

4-[4-(tert-butoxycarbonylamino)-1-piperidyl]-5-(3,5-dimethylphenyl)pyridine-3-carboxylic acid

(181) To a methanol (10 mL) solution of the compound (220 mg) produced in Reference example 5 was added 2M aqueous solution of sodium hydroxide (2.00 mL), and the mixture was stirred at 45 degrees C. overnight. The reaction solution was neutralized by 2M hydrochloric acid (2.00 mL), and then the solvent was removed under reduced pressure. The obtained residue was diluted with saturated brine and extracted with ethyl acetate. The title compound obtained by concentrating the organic layer was used for next reaction without further purification.

Reference Example 7

tert-butyl N-[1-[3-(3,5-dimethylphenyl)-5-[(3,5-dimethylphenyl)carbamoyl]-4-pyridyl]-4-piperidyl]carbamate

(182) To a dichloromethane (5 mL) solution of the compound (<0.50 mmol) produced in Reference example 6 was added benzotriazol-1-yloxy-tri(pyrrolidino)phosphonium hexafluorophosphate (pyBOP) (390 mg), triethylamine (105 microL) and 3,5-dimethylaniline (91 mg) at room temperature, and the mixture was stirred for 15 hours. The reaction solution was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (239 mg) having the following characteristics.

(183) Description: pale yellowish white powder.

Example 5(1)-Example 5(14)

(184) Using 4-tert-butoxycarbonylaminopiperidine, or a corresponding reagent in place of it, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, using 3,5-dimethylaniline, or a corresponding reagent in place of it, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 1.fwdarw.Reference example 2.fwdarw.Reference example 6.fwdarw.Reference example 7.fwdarw.Example 1.

Example 5(1)

4-(4-amino-1-piperidinyl)-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(185) ##STR00084##

(186) Description: pale yellow powder;

(187) Purity (LC-MS/ELSD): 100% (retention time: 3.63 min);

(188) TLC: Rf 0.42 (ethyl acetate:methanol=9:1, NH silica gel);

(189) NMR (300 MHz, CHLOROFORM-d): 9.11 (s, 1H), 8.83 (s, 1H), 8.33 (s, 1H), 7.31 (s, 2H), 7.04 (s, 1H), 6.94 (s, 2H), 6.81 (s, 1H), 3.20-3.06 (m, 2H), 2.75 (s, 2H), 2.70-2.54 (m, 1H), 2.38 (s, 6H), 2.34 (s, 6H), 1.79-1.64 (m, 2H), 1.55 (br. s, 2H), 1.38-1.18 (m, 2H);

(190) MASS (ESI, Pos.): 429 (M+H)+.

Example 5(2)

4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-N-(4,6-dimethyl-2-pyridyl)pyridine-3-carboxamide

(191) Description: white powder;

(192) Purity (LC-MS/ELSD): 100% (retention time: 3.35 min);

(193) TLC: Rf 0.65 (ethyl acetate:methanol=9:1, NH silica gel);

(194) NMR (300 MHz, CHLOROFORM-d): 10.37 (br. s, 1H), 8.96 (s, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.04 (s, 1H), 6.92 (s, 2H), 6.77 (s, 1H), 3.16-3.05 (m, 2H), 2.77-2.49 (m, 3H), 2.40 (s, 3H), 2.38 (s, 6H), 2.37 (s, 3H), 1.76-1.54 (m, 4H), 1.51 (br. s, 2H);

(195) MASS (ESI, Pos.): 430 (M+H)+.

Example 5(3)

4-[(3-aminopropyl)amino]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(196) Description: white powder;

(197) Purity (LC-MS/ELSD): 100% (retention time: 3.77 min);

(198) TLC: Rf 0.47 (ethyl acetate:methanol=9:1, NH silica gel);

(199) NMR (300 MHz, CHLOROFORM-d): 8.54 (s, 1H), 8.15 (s, 1H), 8.12-8.07 (m, 1H), 7.24-7.20 (m, 2H), 7.05-6.95 (m, 4H), 6.85-6.80 (m, 1H), 2.90-2.79 (m, 2H), 2.56 (t, J=6.80 Hz, 2H), 2.36 (s, 6H), 2.34 (s, 6H), 1.53-1.27 (m, 4H);

(200) MASS (ESI, Pos.): 403 (M+H)+.

Example 5(4)

4-(4-amino-1-piperidinyl)-N-(3,4-difluorophenyl)-5-(3,5-dimethylphenyl)pyridine-3-carboxamide

(201) Description: white powder;

(202) TLC: Rf 0.53 (ethyl acetate:methanol=9:1, NH silica gel);

(203) NMR (300 MHz, CHLOROFORM-d): 9.84 (s, 1H), 8.94 (s, 1H), 8.36 (s, 1H), 7.94-7.84 (m, 1H), 7.24-7.10 (m, 2H), 7.05 (s, 1H), 6.91 (s, 2H), 3.16-3.05 (m, 2H), 2.79-2.59 (m, 3H), 2.38 (s, 6H), 1.80-1.68 (m, 2H), 1.54 (br. s, 2H), 1.36-1.20 (m, 2H);

(204) MASS (APCI, Pos.): 437 (M+H)+.

Example 5(5)

4-(4-amino-1-piperidinyl)-N-(3-chloro-4-fluorophenyl)-5-(3,5-dimethylphenyl)pyridine-3-carboxamide

(205) Description: white powder;

(206) TLC: Rf 0.55 (ethyl acetate:methanol=9:1, NH silica gel);

(207) NMR (300 MHz, CHLOROFORM-d): 9.80 (br. s, 1H), 8.93 (s, 1H), 8.36 (s, 1H), 8.02-7.95 (m, 1H), 7.46-7.38 (m, 1H), 7.19-7.10 (m, 1H), 7.05 (s, 1H), 6.91 (s, 2H), 3.16-3.06 (m, 2H), 2.80-2.58 (m, 3H), 2.38 (s, 6H), 1.79-1.20 (m, 6H);

(208) MASS (APCI, Pos.): 453 (M+H)+.

Example 5(6)

N,5-bis(3,5-dimethylphenyl)-4-(4-piperidinylamino)pyridine-3-carboxamide

(209) Description: white powder;

(210) Purity (UPLC-MS/ELSD): 99.6% (retention time: 0.67 min);

(211) TLC: Rf 0.63 (ethyl acetate:methanol=9:1, NH silica gel);

(212) NMR (300 MHz, CHLOROFORM-d): 8.61 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.24-7.21 (m, 2H), 7.05-7.02 (m, 1H), 6.99-6.95 (m, 2H), 6.83-6.81 (m, 1H), 6.53 (d, J=9.89 Hz, 1H), 3.01-2.82 (m, 3H), 2.36 (s, 6H), 2.34 (s, 6H), 2.24-2.13 (m, 2H), 1.70-1.61 (m, 2H), 1.54 (br. s, 1H), 1.19-1.05 (m, 2H);

(213) MASS (ESI, Pos.): 429 (M+H)+.

Example 5(7)

N,5-bis(3,5-dimethylphenyl)-4-[4-(methylamino)-1-piperidyl]pyridine-3-carboxamide

(214) Description: white powder;

(215) Purity (UPLC-MS/ELSD): 100% (retention time: 0.64 min);

(216) TLC: Rf 0.63 (ethyl acetate:methanol=9:1, NH silica gel);

(217) MASS (ESI, Pos.): 443 (M+H)+.

Example 5(8)

N,5-bis(3,5-dimethylphenyl)-4-(1-piperazinyl)pyridine-3-carboxamide

(218) Description: pale yellow powder;

(219) Purity (UPLC-MS/ELSD): 100% (retention time: 0.62 min);

(220) TLC: Rf 0.72 (ethyl acetate:methanol=9:1, NH silica gel);

(221) NMR (300 MHz, CHLOROFORM-d): 8.68 (s, 1H), 8.35 (s, 1H), 8.27 (br. s, 1H), 7.28 (s, 2H), 7.04 (s, 1H), 6.92 (s, 2H), 6.83 (s, 1H), 3.16-3.08 (m, 4H), 2.94-2.84 (m, 4H), 2.36 (s, 6H), 2.33 (s, 6H);

(222) MASS (ESI, Pos.): 415 (M+H)+.

Example 5(9)

4-[3-(aminomethyl)-1-azetidinyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(223) Description: ivory powder;

(224) Purity (UPLC-MS/ELSD): 99.6% (retention time: 0.55 min);

(225) TLC: Rf 0.40 (ethyl acetate:methanol=9:1, NH silica gel);

(226) NMR (300 MHz, CHLOROFORM-d): 8.40 (s, 1H), 8.12 (s, 1H), 7.51 (br. s, 1H), 7.28 (br. s, 2H), 7.02-6.96 (m, 3H), 6.82 (br. s, 1H), 3.84-3.76 (m, 2H), 3.42-3.35 (m, 2H), 2.72 (d, J=7.0 Hz, 2H), 2.47-2.38 (m, 1H), 2.36 (s, 6H), 2.34 (s, 6H), 1.60-1.43 (m, 2H);

(227) MASS (ESI, Pos.): 415 (M+H)+.

Example 5(10)

N,5-bis(3,5-dimethylphenyl)-4-[(3-piperidinylmethyl)amino]pyridine-3-carboxamide

(228) Description: white powder;

(229) Purity (UPLC-MS/ELSD): 99.6% (retention time: 0.61 min);

(230) TLC: Rf 0.60 (ethyl acetate:methanol=9:1, NH silica gel);

(231) NMR (300 MHz, CHLOROFORM-d): 8.54 (s, 1H), 8.09 (s, 1H), 7.88 (br. s, 1H), 7.21 (s, 2H), 7.14-7.06 (m, 1H), 7.03-6.99 (m, 1H), 6.97 (s, 2H), 6.84-6.81 (m, 1H), 2.93-2.78 (m, 2H), 2.64-2.55 (m, 2H), 2.46-2.38 (m, 2H), 2.36 (s, 6H), 2.34 (s, 6H), 2.11-2.00 (m, 1H), 1.58 (br. s, 1H), 1.53-1.21 (m, 3H), 0.90-0.77 (m, 1H);

(232) MASS (ESI, Pos.): 443 (M+H)+.

Example 5(11)

N,5-bis(3,5-dimethylphenyl)-4-{[2-(2-piperidinyl)ethyl]amino}pyridine-3-carboxamide Description: ivory powder

(233) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.61 min);

(234) TLC: Rf 0.59 (ethyl acetate:methanol=9:1, NH silica gel);

(235) NMR (300 MHz, CHLOROFORM-d): 8.55 (s, 1H), 8.11 (s, 1H), 7.99 (br. s, 1H), 7.23 (s, 2H), 7.02 (s, 1H), 6.98 (s, 2H), 6.82 (s, 1H), 6.78-6.71 (m, 1H), 2.97-2.88 (m, 2H), 2.86-2.77 (m, 1H), 2.36 (s, 6H), 2.34 (s, 6H), 2.45-2.23 (m, 2H), 1.75-1.17 (m, 8H), 0.97-0.81 (m, 1H);

(236) MASS (ESI, Pos.): 457 (M+H)+.

Example 5(12)

4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-N-[3-(hydroxymethyl)-5-methylphenyl]pyridine-3-carboxamide

(237) Description: pale yellow powder;

(238) Purity (UPLC-MS/ELSD): 99.1% (retention time: 0.49 min);

(239) TLC: Rf 0.42 (ethyl acetate:methanol=9:1, NH silica gel);

(240) NMR (300 MHz, CHLOROFORM-d): 9.81 (br. s, 1H), 8.96 (s, 1H), 8.37 (s, 1H), 7.83-7.79 (m, 1H), 7.30-7.28 (m, 1H), 7.06-7.04 (m, 1H), 6.91-6.89 (m, 3H), 4.67 (s, 2H), 3.19-3.00 (m, 2H), 2.81-2.58 (m, 3H), 2.39 (s, 3H), 2.37 (s, 6H), 1.73-1.39 (m, 7H);

(241) MASS (ESI, Pos.): 445 (M+H)+.

Example 5(13)

4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-N-[3-(1-methyl-1H-pyrazol-3-yl)phenyl]pyridine-3-carboxamide

(242) Description: white powder;

(243) Purity (UPLC-MS/ELSD): 97.5% (retention time: 0.56 min);

(244) TLC: Rf 0.46 (ethyl acetate:methanol=9:1, NH silica gel);

(245) NMR (300 MHz, CHLOROFORM-d): 9.92 (br. s, 1H), 8.99 (s, 1H), 8.36 (s, 1H), 8.00-7.89 (m, 2H), 7.56-7.51 (m, 1H), 7.46-7.39 (m, 1H), 7.37 (d, J=2.30 Hz, 1H), 7.06 (s, 1H), 6.93 (s, 2H), 6.59 (d, J=2.20 Hz, 1H), 3.93 (s, 3H), 3.08-3.21 (m, 2H), 2.65-2.82 (m, 2H), 2.52-2.67 (m, 1H), 2.39 (s, 6H), 1.82-1.33 (m, 6H);

(246) MASS (ESI, Pos.): 481 (M+H)+.

Example 5(14)

4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-N-[3-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-carboxamide

(247) Description: white powder;

(248) Purity (UPLC-MS/ELSD): 99.6% (retention time: 0.50 min);

(249) TLC: Rf 0.45 (ethyl acetate:methanol=9:1, NH silica gel);

(250) NMR (300 MHz, CHLOROFORM-d): 10.21 (br. s, 1H), 9.01 (s, 1H), 8.48 (s, 1H), 8.40-8.36 (m, 2H), 8.09-8.02 (m, 1H), 7.90-7.84 (m, 1H), 7.60-7.53 (m, 1H), 7.06 (s, 1H), 6.93 (s, 2H), 3.19-3.10 (m, 2H), 2.81-2.69 (m, 2H), 2.69-2.58 (m, 1H), 2.39 (s, 6H), 1.83-1.25 (m, 6H);

(251) MASS (ESI, Pos.): 469 (M+H)+.

Reference Example 8

tert-butyl N-[1-[3-(3,5-dimethylphenyl)-5-(hydroxymethyl)-4-pyridyl]-4-piperidyl]carbamate

(252) To a suspension of lithium aluminum hydride (326 mg) in tetrahydrofuran (6 mL) was added the tetrahydrofuran (15 mL) solution of the compound (945 mg) produced in Reference example 5 at 0 degrees C., and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous solution of sodium sulfate (5 mL) and tetrahydrofuran (30 mL), and stirred for 30 min. To the reaction solution was added sodium sulfate anhydrous, and filtered. After that the filtrate was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:4) to obtain the title compound (460 mg) having the following physical property values.

(253) Description: colorless oil;

(254) TLC: Rf 0.30 (ethyl acetate);

(255) MASS (ESI, Pos.): 412 (M+H)+.

Reference Example 9

tert-butyl N-[1-[3-[(3,5-dimethylphenoxy)methyl]-5-(3,5-dimethylphenyl)-4-pyridyl]-4-piperidyl]carbamate

(256) Under argon atmosphere, diisopropylazodicarboxylate (40 microL) was added to an anhydrous tetrahydrofuran (4 mL) solution of the compound (41 mg) produced in Reference example 8, 3,5-dimethylphenol (CAS#108-68-9) (24 mg) and triphenylphosphine (52 mg) at 0 degrees C., and the mixture was stirred at room temperature for 1 hour followed by concentration. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (51 mg) having the following physical property values.

(257) Description: colorless oil;

(258) TLC: Rf 0.58 (n-hexane:ethyl acetate=1:1);

(259) MASS (ESI, Pos.): 516 (M+H)+.

Example 6

1-[3-[(3,5-dimethylphenoxy)methyl]-5-(3,5-dimethylphenyl)-4-pyridyl]piperidin-4-amine

(260) ##STR00085##

(261) Using the compound produced in Reference example 9 in place of the compound produced in Reference example 3, the present invention compound (23 mg) having the following physical property values was obtained by following the same procedure as in Example 1.

(262) Description: colorless oil;

(263) Purity (LC-MS/ELSD): 100% (retention time: 3.81 min);

(264) TLC: Rf 0.50 (ethyl acetate:methanol=9:1, NH silica gel);

(265) NMR (300 MHz, CHLOROFORM-d): 8.55 (s, 1H), 8.29 (s, 1H), 6.99 (s, 1H), 6.91 (s, 2H), 6.63 (s, 1H), 6.61 (s, 2H), 5.06 (s, 2H), 3.09-3.01 (m, 2H), 2.66-2.55 (m, 3H), 2.37 (s, 6H), 2.30 (s, 6H), 1.69-1.60 (m, 2H), 1.51 (br. s, 2H), 1.33-1.23 (m, 2H);

(266) MASS (ESI, Pos.): 416 (M+H)+.

Reference Example 10

tert-butyl N-[1-[3-(3,5-dimethylphenyl)-5-formyl-4-pyridyl]-4-piperidyl]carbamate

(267) To a dichloromethane (10 mL) solution of the compound (395 mg) produced in Reference example 8 was added Dess-Martin periodinate (814 mg) at room temperature, and the mixture was stirred for 2 hours. The reaction solution was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (400 mg) having the following physical property values.

(268) Description: beige powder;

(269) TLC: Rf 0.55 (n-hexane:ethyl acetate=1:1);

(270) MASS (ESI, Pos.): 410 (M+H)+.

Reference Example 11

tert-butyl N-[1-[3-(3,5-dimethylphenyl)-5-[2-(3,5-dimethylphenyl)-1-hydroxyethyl]-4-pyridyl]-4-piperidyl]carbamate

(271) Under argon atmosphere, [(3,5-dimethylphenyl)methyl]magnesium bromide (CAS#111823-36-0) (10.6 mL, 0.25 mol/L in tetrahydrofuran) was added to an anhydrous tetrahydrofuran (10 mL) solution of the compound (360 mg) produced in Reference example 10 at 0 degrees C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed, dried and concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (466 mg) having the following physical property values.

(272) Description: yellow oil;

(273) TLC: Rf 0.31 (n-hexane:ethyl acetate=1:1).

Example 7

1-[4-(4-amino-1-piperidyl)-5-(3,5-dimethylphenyl)-3-pyridyl]-2-(3,5-dimethylphenyl)ethanone

(274) ##STR00086##

(275) Using the compound produced in Reference example 11 in place of the compound produced in Reference example 8, the present invention compound (36 mg) having the following physical property values was obtained by following the same procedure as in Reference Example 10.fwdarw.Example 1.

(276) Description: pale yellow oil;

(277) Purity (LC-MS/ELSD): 100% (retention time: 3.80 min);

(278) TLC: Rf 0.65 (ethyl acetate:methanol=9:1, NH silica gel);

(279) NMR (300 MHz, CHLOROFORM-d): 8.46 (s, 1H), 8.25 (s, 1H), 7.00 (s, 1H), 6.97 (s, 2H), 6.90 (s, 1H), 6.86 (s, 2H), 4.12 (s, 2H), 2.9-2.83 (m, 2H), 2.71-2.57 (m, 3H), 2.36 (s, 6H), 2.29 (s, 6H), 1.57-1.48 (m, 4H), 1.19-1.04 (m, 2H); MASS (ESI, Pos.): 428 (M+H)+.

Reference Example 12

tert-butyl N-[1-[3-amino-5-(3,5-dimethylphenyl)-4-pyridyl]-4-piperidyl]carbamate

(280) Under argon atmosphere, diphenylphosphoryl azide (2.16 mL) was added to a 1,4-dioxane (30 mL) solution of the compound (2.20 g) produced in Reference example 6 and triethylamine (2.79 mL) at room temperature, and the mixture was stirred at 70 degrees C. for 1 hour. Water (3 mL) was added to the reaction solution and stirred at 70 degrees C. for 3 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and sequentially washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5) to obtain the title compound (1.12 g) having the following physical property values.

(281) Description; pale yellow amorphous;

(282) TLC: Rf 0.41 (ethyl acetate, NH silica gel);

(283) NMR (300 MHz, CHLOROFORM-d): 8.05 (s, 1H), 7.78 (s, 1H), 7.00 (s, 1H), 6.85 (s, 2H), 4.45-4.33 (m, 1H), 3.88 (s, 2H), 3.47-3.31 (m, 1H), 2.95-2.81 (m, 2H), 2.54-2.41 (m, 2H), 2.35 (s, 6H), 1.94-1.83 (m, 2H), 1.42 (s, 9H), 1.41-1.28 (m, 2H);

(284) MASS (ESI, Pos.): 397 (M+H)+.

Reference Example 13

tert-butyl N-[1-[3-(3,5-dimethylphenyl)-5-[(3,5-dimethylphenyl)methylamino]-4-pyridyl]-4-piperidyl]carbamate

(285) To an anhydrous 1,2-dichloroethane (10 mL) solution of the compound (40 mg) produced in Reference example 12 and 3,5-dimethylbenzaldehyde (CAS#5779-95-3) (67 mg) was added sodium borohydride (76 mg) and methanol (10 mL) at room temperature, and the mixture was stirred at 80 degrees C. for 5 hours. The reaction solution was diluted with ethyl acetate and sequentially washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (22 mg) having the following physical property values.

(286) Description: pale yellow oil;

(287) TLC: Rf 0.62 (n-hexane:ethyl acetate=1:1).

Example 8(1)-Example 8(3)

(288) Using a corresponding phenylboronic acid in place of phenylboronic acid, using 3,5-dimethylbenzaldehyde, or a corresponding reagent in place of it, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 1.fwdarw.Reference example 2.fwdarw.Reference example 6.fwdarw.Reference example 12.fwdarw.Reference example 13.fwdarw.Example 1.

Example 8(1)

4-(4-amino-1-piperidyl)-5-(3,5-dimethylphenyl)-N-[(3,5-dimethylphenyl)methyl]pyridin-3-amine

(289) ##STR00087##

(290) Description: pale yellow oil;

(291) TLC: Rf 0.64 (ethyl acetate:methanol=9:1, NH silica gel);

(292) NMR (300 MHz, CHLOROFORM-d): 7.93 (s, 1H), 7.76 (s, 1H), 7.03-6.97 (m, 3H), 6.92 (s, 1H), 6.90-6.84 (m, 2H), 4.79 (t, J=5.50 Hz, 1H), 4.33 (d, J=5.49 Hz, 2H), 2.97-2.84 (m, 2H), 2.65-2.39 (m, 3H), 2.36 (s, 6H), 2.32 (s, 6H), 1.80-1.65 (m, 2H), 1.54 (br. s, 2H), 1.33-1.16 (m, 2H),

(293) MASS (ESI, Pos.): 415 (M+H)+.

Example 8(2)

4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-3-pyridinamine

(294) Description: colorless oil;

(295) Purity (UPLC-MS/ELSD): 100% (retention time: 0.57 min);

(296) TLC: Rf 0.43 (ethyl acetate:methanol=9:1, NH silica gel);

(297) NMR (300 MHz, CHLOROFORM-d): 7.98 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.00 (s, 1H), 6.86 (s, 2H), 4.58 (t, J=5.50 Hz, 1H), 4.26 (d, J=5.49 Hz, 2H), 3.90 (s, 3H), 2.91-2.80 (m, 2H), 2.65-2.51 (m, 1H), 2.46-2.38 (m, 2H), 2.35 (s, 6H), 1.72 (d, J=11.90 Hz, 2H), 1.57 (br. s, 2H), 1.31-1.15 (m, 2H);

(298) MASS (ESI, Pos.): 391 (M+H)+.

Example 8(3)

4-(4-amino-1-piperidinyl)-N-(3-chlorobenzyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinamine

(299) Description: yellow amorphous powder;

(300) Purity (UPLC-MS/ELSD): 100% (retention time: 0.55 min);

(301) TLC: Rf 0.64 (ethyl acetate:methanol=10:1, NH silica gel);

(302) NMR (300 MHz, CHLOROFORM-d): 7.88 (s, 1H), 7.77 (s, 1H), 7.41-7.23 (m, 4H), 6.96-6.74 (m, 3H), 4.88 (t, J=5.7 Hz, 1H), 4.41 (d, J=5.7 Hz, 2H), 2.99-2.86 (m, 2H), 2.74-2.56 (m, 1H), 2.53-2.37 (m, 5H), 1.83-1.71 (m, 2H), 1.36-1.19 (m, 2H);

(303) MASS (ESI, Pos.): 425 (M+H)+.

Example 9

N,5-bis(3,5-dimethylphenyl)-4-(4-oxo-1-piperidyl)pyridine-3-carboxamide

(304) ##STR00088##

(305) Using the compound produced in Example 3 in place of the compound produced in Reference example 8, the present invention compound (150 mg) having the following physical property values was obtained by following the same procedure as in Reference example 10.

(306) Description: pale yellow powder;

(307) Purity (UPLC-MS/ELSD): 99.4% (retention time: 0.80 min);

(308) TLC: Rf 0.53 (n-hexane:ethyl acetate=1:1);

(309) NMR (300 MHz, CHLOROFORM-d): 8.69 (s, 1H), 8.39 (s, 1H), 8.13 (s, 1H), 7.25 (s, 2H), 7.04 (s, 1H), 6.99 (s, 2H), 6.83 (s, 1H), 3.28 (t, J=6.04 Hz, 4H), 2.36 (s, 6H), 2.33 (s, 6H), 2.29 (t, J=6.00 Hz, 4H);

(310) MASS (ESI, Pos.): 428 (M+H)+.

Example 10

4-[4-(dimethylamino)-1-piperidyl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-carboxamide

(311) ##STR00089##

(312) To an anhydrous 1,2-dichloroethane (10 mL) solution of the compound (115 mg) produced in Example 9 and dimethylamine (CAS#124-40-3) (1.35 mL, 2 mol/L in methanol) was added sodium triacetoxyborohydride (286 mg) at room temperature, and the mixture was stirred for 5 hours. The reaction solution was diluted with ethyl acetate and sequentially washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5) to obtain the present invention compound (111 mg) having the following physical property values.

(313) Description: white powder;

(314) Purity (UPLC-MS/ELSD): 98.9% (retention time: 0.59 min);

(315) TLC: Rf 0.65 (ethyl acetate:methanol=9:1, NH silica gel);

(316) NMR (300 MHz, CHLOROFORM-d): 9.19 (br. s, 1H), 8.86 (s, 1H), 8.32 (s, 1H), 7.33 (s, 2H), 7.05 (s, 1H), 6.93 (s, 2H), 6.79 (s, 1H), 3.25-3.15 (m, 3H), 2.77-2.65 (m, 2H), 2.38 (s, 6H), 2.32 (s, 6H), 2.19 (s, 6H), 1.69-1.42 (m, 4H);

(317) MASS (ESI, Pos.): 457 (M+H)+.

Reference Example 14

tert-butyl N-[[1-(3-bromo-5-nitro-4-pyridyl)-4-piperidyl]methyl]carbamate

(318) To a tetrahydrofuran (20 mL) solution of 3-bromo-4-chloro-5-nitropyridine (CAS#31872-63-6) (1.12 g) was added triethylamine (987 microL) and tert-butyl N-(4-piperidylmethyl)carbamate (CAS#135632-53-0) (2.63 g), and stirred at 70 degrees C. for 5 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and sequentially washed with water and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane: ethyl acetate=1:1) to obtain the title compound (1.80 g) having the following physical property values.

(319) Description: pale yellow powder;

(320) TLC: Rf 0.50 (n-hexane:ethyl acetate=1:1).

Reference Example 15

tert-butyl N-[[1-[3-(3,5-dimethylphenyl)-5-nitro-4-pyridyl]-4-piperidyl]methyl]carbamate

(321) Using the compound produced in Reference example 14 in place of the compound produced in Reference example 1, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 2.

(322) Description: orange powder;

(323) TLC: Rf 0.50 (n-hexane:ethyl acetate=1:1);

(324) MASS (ESI, Pos.): 441 (M+H)+.

Reference Example 16

tert-butyl N-[[1-[3-amino-5-(3,5-dimethylphenyl)-4-pyridyl]-4-piperidyl]methyl]carbamate

(325) Under argon atmosphere, 20% palladium hydroxide on carbon (Pd(OH).sub.2C) (500 mg, 50 wt % wet) was added to the ethanol (40 mL) solution of the compound (1.90 g) produced in Reference example 15, and the mixture was stirred for 8 hours under hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate) to obtain the title compound (1.77 g) having the following physical property values.

(326) Description: colorless oil;

(327) TLC: Rf 0.50 (ethyl acetate, NH silica gel);

(328) MASS (ESI, Pos.): 411 (M+H)+.

Reference Example 17

tert-butyl N-[[1-[3-[(3,5-dimethylbenzoyl)amino]-5-(3,5-dimethylphenyl)-4-pyridyl]-4-piperidyl]methyl]carbamate

(329) To an anhydrous pyridine (3 mL) solution of the compound produced in Reference example 16 was added 3,5-dimethylbenzoylchloride (CAS#6613-44-1) (222 microL) at room temperature, and stirred for 1 hour. After adding water, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (128 mg) having the following physical property values.

(330) Description: colorless amorphous powder;

(331) TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

(332) MASS (ESI, Pos.): 543 (M+H)+.

Example 11(1)-Example 11(68)

(333) Using 3-bromo-4-chloro-5-nitropyridine, or a corresponding reagent in place of it, using tert-butyl N-(4-piperidylmethyl)carbamate, or a corresponding reagent in place of it, using a corresponding reagent in place of phenylboronic acid, using 3,5-dimethylbenzoyl chloride, or a corresponding reagent in place of it, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 14.fwdarw.Reference example 2.fwdarw.Reference example 16.fwdarw.Reference example 17.fwdarw.Example 1.

Example 11(1)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3-fluorobenzamide

(334) ##STR00090##

(335) Purity (LC-MS/ELSD): 100% (retention time: 0.51 min);

(336) MASS (ESI, Pos.): 419 (M+H)+.

Example 11(2)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3-chlorobenzamide

(337) Purity (LC-MS/ELSD): 100% (retention time: 0.54 min);

(338) MASS (ESI, Pos.): 435 (M+H)+.

Example 11(3)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-difluorobenzamide

(339) Purity (LC-MS/ELSD): 100% (retention time: 0.52 min);

(340) MASS (ESI, Pos.): 437 (M+H)+.

Example 11(4)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3-chloro-4-fluorobenzamide

(341) Purity (LC-MS/ELSD): 100% (retention time: 0.55 min);

(342) MASS (ESI, Pos.): 453 (M+H)+.

Example 11(5)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide

(343) Purity (LC-MS/ELSD): 73% (retention time: 0.55 min);

(344) MASS (ESI, Pos.): 483 (M+H)+.

Example 11(6)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-pyridinecarboxamide

(345) Purity (LC-MS/ELSD): 99% (retention time: 0.53 min);

(346) MASS (ESI, Pos.): 402 (M+H)+.

Example 11(7)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]pyridine-4-carboxamide

(347) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(348) MASS (ESI, Pos.): 402 (M+H)+.

Example 11(8)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-thiazole-4-carboxamide

(349) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(350) MASS (ESI, Pos.): 408 (M+H)+.

Example 11(9)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4-methoxybenzamide

(351) Purity (LC-MS/ELSD): 100% (retention time: 0.51 min);

(352) MASS (ESI, Pos.): 431 (M+H)+.

Example 11(10)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3-methoxybenzamide

(353) Purity (LC-MS/ELSD): 100% (retention time: 0.52 min);

(354) MASS (ESI, Pos.): 431 (M+H)+.

Example 11(11)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-fluorobenzamide

(355) Purity (LC-MS/ELSD): 100% (retention time: 0.52 min);

(356) MASS (ESI, Pos.): 419 (M+H)+.

Example 11(12)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-dimethoxybenzamide

(357) Purity (LC-MS/ELSD): 100% (retention time: 0.55 min);

(358) MASS (ESI, Pos.): 461 (M+H)+.

Example 11(13)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1-methyl-1H-imidazole-5-carboxamide

(359) Purity (LC-MS/ELSD): 100% (retention time: 0.44 min);

(360) MASS (ESI, Pos.): 405 (M+H)+.

Example 11(14)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-5-methyl-1,2-oxazole-3-carboxamide

(361) Purity (LC-MS/ELSD): 100% (retention time: 0.52 min);

(362) MASS (ESI, Pos.): 406 (M+H)+.

Example 11(15)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-thiazole-2-carboxamide

(363) Purity (LC-MS/ELSD): 100% (retention time: 0.54 min);

(364) MASS (ESI, Pos.): 408 (M+H)+.

Example 11(16)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]pyridine-3-carboxamide

(365) Purity (LC-MS/ELSD): 100% (retention time: 0.47 min);

(366) MASS (ESI, Pos.): 402 (M+H)+.

Example 11(17)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1-methyl-1H-imidazole-4-carboxamide

(367) Purity (LC-MS/ELSD): 100% (retention time: 0.49 min);

(368) MASS (ESI, Pos.): 405 (M+H)+.

Example 11(18)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-5-methyl-1,2-oxazole-4-carboxamide

(369) Purity (LC-MS/ELSD): 99% (retention time: 0.56 min);

(370) MASS (ESI, Pos.): 406 (M+H)+.

Example 11(19)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,5-dimethyl-1H-pyrazole-3-carboxamide

(371) Purity (LC-MS/ELSD): 100% (retention time: 0.51 min);

(372) MASS (ESI, Pos.): 419 (M+H)+.

Example 11(20)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-5-(methylsulfonyl)-2-thiophenecarboxamide

(373) Purity (LC-MS/ELSD): 95% (retention time: 0.53 min);

(374) MASS (ESI, Pos.): 485 (M+H)+.

Example 11(21)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1-methyl-1H-pyrazole-4-carboxamide

(375) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(376) MASS (ESI, Pos.): 405 (M+H)+.

Example 11(22)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide

(377) Purity (LC-MS/ELSD): 100% (retention time: 0.48 min);

(378) MASS (ESI, Pos.): 419 (M+H)+.

Example 11(23)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-thiazole-5-carboxamide

(379) Purity (LC-MS/ELSD): 100% (retention time: 0.48 min);

(380) MASS (ESI, Pos.): 408 (M+H)+.

Example 11(24)

5-acetyl-N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-thiophenecarboxamide

(381) Purity (LC-MS/ELSD): 99% (retention time: 0.53 min);

(382) MASS (ESI, Pos.): 449 (M+H)+.

Example 11(25)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4,6-dimethoxy-2-pyrimidinecarboxamide

(383) Purity (LC-MS/ELSD): 100% (retention time: 0.52 min);

(384) MASS (ESI, Pos.): 463 (M+H)+.

Example 11(26)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-oxazole-2-carboxamide

(385) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(386) MASS (ESI, Pos.): 392 (M+H)+.

Example 11(27)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-5-methyl-1,3-thiazole-2-carboxamide

(387) Purity (LC-MS/ELSD): 100% (retention time: 0.56 min);

(388) MASS (ESI, Pos.): 422 (M+H)+.

Example 11(28)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,3-oxazole-4-carboxamide

(389) Purity (LC-MS/ELSD): 100% (retention time: 0.49 min);

(390) MASS (ESI, Pos.): 392 (M+H)+.

Example 11(29)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4-methyl-1,3-oxazole-5-carboxamide

(391) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(392) MASS (ESI, Pos.): 406 (M+H)+.

Example 11(30)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1-methyl-1H-pyrazole-5-carboxamide

(393) Purity (LC-MS/ELSD): 97% (retention time: 0.49 min);

(394) MASS (ESI, Pos.): 405 (M+H)+.

Example 11(31)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1-methyl-1H-pyrazole-3-carboxamide

(395) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(396) MASS (ESI, Pos.): 405 (M+H)+.

Example 11(32)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-1,5-dimethyl-1H-1,2,3-triazole-4-carboxamide

(397) Purity (LC-MS/ELSD): 100% (retention time: 0.53 min);

(398) MASS (ESI, Pos.): 420 (M+H)+.

Example 11(33)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4-methyl-1,3-thiazole-2-carboxamide

(399) Purity (LC-MS/ELSD): 100% (retention time: 0.55 min);

(400) MASS (ESI, Pos.): 422 (M+H)+.

Example 11(34)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2,5-dimethyl-1,3-thiazole-4-carboxamide

(401) Purity (LC-MS/ELSD): 100% (retention time: 0.57 min);

(402) MASS (ESI, Pos.): 436 (M+H)+.

Example 11(35)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-methyl-1,3-oxazole-4-carboxamide

(403) Purity (LC-MS/ELSD): 99% (retention time: 0.50 min);

(404) MASS (ESI, Pos.): 406 (M+H)+.

Example 11(36)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl][1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide

(405) Purity (LC-MS/ELSD): 99% (retention time: 0.51 min);

(406) MASS (ESI, Pos.): 443 (M+H)+.

Example 11(37)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-methyl-1,3-thiazole-4-carboxamide

(407) Purity (LC-MS/ELSD): 96% (retention time: 0.53 min);

(408) MASS (ESI, Pos.): 422 (M+H)+.

Example 11(38)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]benzamide

(409) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(410) MASS (ESI, Pos.): 401 (M+H)+.

Example 11(39)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-dimethylbenzamide

(411) Description: white powder;

(412) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.50 min);

(413) TLC: Rf 0.64 (ethyl acetate:methanol=9:1, NH silica gel);

(414) NMR (300 MHz, CHLOROFORM-d): 9.70 (s, 1H), 9.04 (s, 1H), 8.13 (s, 1H), 7.56 (s, 2H), 7.21 (s, 1H), 7.05 (s, 1H), 6.89 (s, 2H), 2.94-2.83 (m, 2H), 2.67-2.49 (m, 3H), 2.41 (s, 6H), 2.38 (s, 6H), 1.81 (d, J=9.52 Hz, 2H), 1.70-1.23 (m, 4H);

(415) MASS (ESI, Pos.): 429 (M+H)+.

Example 11(40)

benzyl [4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]carbamate Description: white powder

(416) Purity (UPLC-MS/ELSD): 100% (retention time: 0.56 min);

(417) TLC: Rf 0.61 (ethyl acetate:methanol=9:1, NH silica gel);

(418) NMR (300 MHz, CHLOROFORM-d): 9.21 (br. s, 1H), 8.06 (s, 1H), 7.48-7.30 (m, 6H), 7.02 (s, 1H), 6.85 (s, 2H), 5.26 (s, 2H), 2.86-2.75 (m, 2H), 2.66-2.40 (m, 3H), 2.36 (s, 6H), 1.82-1.24 (m, 6H);

(419) MASS (ESI, Pos.): 431 (M+H)+.

Example 11(41)

N-[4-[4-(aminoethyl)-1-piperidyl]-5-(3,5-dimethylphenyl)-3-pyridyl]-3,5-dimethylbenzamide

(420) Description: white powder;

(421) Purity (UPLC-MS/ELSD): 100% (retention time: 0.56 min);

(422) TLC: Rf 0.52 (ethyl acetate:methanol=9:1, NH silica gel);

(423) NMR (300 MHz, CHLOROFORM-d): 9.73 (s, 1H), 9.17 (s, 1H), 8.14 (s, 1H), 7.57 (s, 2H), 7.21 (s, 1H), 7.05 (s, 1H), 6.90 (s, 2H), 2.95-2.85 (m, 2H), 2.61-2.48 (m, 4H), 2.40 (s, 6H), 2.38 (s, 6H), 1.81-1.67 (m, 2H), 1.46 (br. s, 2H), 1.30-1.10 (m, 3H); MASS (ESI, Pos.): 443 (M+H)+.

Example 11(42)

N-{4-[4-(2-aminoethyl)-1-piperidinyl]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide

(424) Description: white powder;

(425) Purity (UPLC-MS/ELSD): 100% (retention time: 0.59 min);

(426) TLC: Rf 0.48 (ethyl acetate:methanol=9:1, NH silica gel);

(427) NMR (300 MHz, CHLOROFORM-d): 9.73 (s, 1H), 9.16 (s, 1H), 8.12 (s, 1H), 7.58 (s, 2H), 7.21 (s, 1H), 7.05 (s, 1H), 6.89 (s, 2H), 2.93-2.83 (m, 2H), 2.74-2.65 (m, 2H), 2.58-2.46 (m, 2H), 2.41 (s, 6H), 2.38 (s, 6H), 1.74-1.15 (m, 9H);

(428) MASS (ESI, Pos.): 457 (M+H)+.

Example 11(43)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3-hydroxybenzamide

(429) Description: white powder;

(430) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.47 min);

(431) TLC: Rf 0.42 (ethyl acetate:methanol=4:1, NH silica gel);

(432) NMR (300 MHz, CHLOROFORM-d): 9.67 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.46-7.31 (m, 3H), 7.05-6.94 (m, 4H), 2.99-2.89 (m, 2H), 2.75-2.56 (m, 2H), 2.47-2.37 (m, 1H), 2.33 (s, 6H), 1.49-1.37 (m, 2H), 1.13-0.98 (m, 2H);

(433) MASS (ESI, Pos.): 417 (M+H)+.

Example 11(44)

N-{4-[(3-amino-2,2-dimethylpropyl)amino]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide

(434) Description: beige powder;

(435) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.54 min);

(436) TLC: Rf 0.60 (ethyl acetate:methanol=9:1, NH silica gel);

(437) NMR (300 MHz, CHLOROFORM-d): 9.36 (s, 1H), 8.67 (s, 1H), 8.06 (s, 1H), 7.51 (s, 2H), 7.17 (s, 1H), 7.03 (s, 1H), 6.99 (s, 2H), 4.76 (br. s, 1H), 2.95 (s, 2H), 2.46 (s, 2H), 2.38 (s, 6H), 2.36 (s, 6H), 1.60 (br. s, 2H), 0.69 (s, 6H);

(438) MASS (ESI, Pos.): 431 (M+H)+.

Example 11(45)

N-{4-[(3-aminopentyl)amino]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide

(439) Description: brown viscous oil;

(440) Purity (UPLC-MS/ELSD): 99.7% (retention time: 0.54 min);

(441) TLC: Rf 0.63 (ethyl acetate:methanol=9:1, NH silica gel);

(442) NMR (300 MHz, CHLOROFORM-d): 8.77 (br. s., 1H), 8.64 (s, 1H), 8.07 (s, 1H), 7.53 (s, 2H), 7.19 (s, 1H), 7.02 (s, 1H), 6.99 (s, 2H), 6.96 (s, 1H), 3.25-3.13 (m, 1H), 3.05-2.92 (m, 1H), 2.54-2.43 (m, 1H), 2.39 (s, 6H), 2.36 (s, 6H), 1.80-1.03 (m, 6H), 0.77 (t, J=7.40 Hz, 3H);

(443) MASS (ESI, Pos.): 431 (M+H)+.

Example 11(46)

methyl 3-{[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]carbamoyl}benzoate

(444) Description: white powder;

(445) Purity (UPLC-MS/ELSD): 100% (retention time: 0.51 min);

(446) TLC: Rf 0.50 (ethyl acetate:methanol=9:1, NH silica gel);

(447) NMR (300 MHz, CHLOROFORM-d): 9.76 (s, 1H), 9.49 (s, 1H), 8.65-8.60 (m, 1H), 8.35-8.31 (m, 1H), 8.26-8.22 (m, 1H), 8.16 (s, 1H), 7.69-7.63 (m, 1H), 7.07 (s, 1H), 6.90 (s, 2H), 3.97 (s, 3H), 2.96-2.84 (m, 2H), 2.65-2.52 (m, 3H), 2.38 (s, 6H), 1.92-1.78 (m, 2H), 1.70-1.39 (m, 4H);

(448) MASS (ESI, Pos.): 459 (M+H)+.

Example 11(47)

3-{[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]carbamoyl}benzoic acid dihydrochloride

(449) Description: beige powder;

(450) Purity: (UPLC-MS/ELSD): 100% (retention time: 0.51 min);

(451) TLC: Rf 0.68 (methanol:28% NH.sub.3(aq)=19:1)

(452) NMR (300 MHz, CHLOROFORM-d): 8.73 (d, J=1.46 Hz, 1H), 8.59 (d, J=1.28 Hz, 1H), 8.37-8.29 (m, 2H), 8.23 (d, J=1.28 Hz, 1H), 7.73 (t, J=7.78 Hz, 1H), 7.18 (s, 1H), 7.10 (s, 2H), 3.66-3.56 (m, 2H), 3.23-3.11 (m, 1H), 3.06-2.91 (m, 2H), 2.42 (s, 6H), 1.87-1.74 (m, 2H), 1.60-1.39 (m, 2H);

(453) MASS (ESI, Pos.): 445 (M+H)+.

Example 11(48)

N-{4-[(3-aminopropyl)(methyl)amino]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide

(454) Description: white powder;

(455) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.56 min);

(456) TLC: Rf 0.50 (ethyl acetate:methanol=9:1, NH silica gel);

(457) NMR (300 MHz, CHLOROFORM-d): 9.63 (s, 1H), 9.30 (s, 1H), 8.14 (s, 1H), 7.52 (s, 2H), 7.20 (s, 1H), 7.05 (s, 1H), 6.90 (s, 2H), 2.71 (s, 3H), 2.62-2.55 (m, 4H), 2.40 (s, 6H), 2.37 (s, 6H), 1.55-1.40 (m, 2H), 1.19 (br. s., 2H);

(458) MASS (ESI, Pos.): 417 (M+H)+.

Example 11(49)

N-{4-[4-(aminomethyl)-1-piperidinyl]-5-(3,5-dimethylphenyl)-3-pyridinyl}benzamide

(459) Description: white powder;

(460) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.51 min);

(461) TLC: Rf 0.55 (ethyl acetate:methanol=9:1, NH silica gel);

(462) NMR (300 MHz, CHLOROFORM-d): 9.70 (s, 1H), 9.12 (s, 1H), 8.15 (s, 1H), 7.99-7.90 (m, 2H), 7.62-7.47 (m, 3H), 7.05 (s, 1H), 6.90 (s, 2H), 2.96-2.84 (m, 2H), 2.61-2.47 (m, 4H), 2.37 (s, 6H), 1.78-1.09 (m, 7H);

(463) MASS (ESI, Pos.): 415 (M+H)+.

Example 11(50)

N-{4-[4-(aminomethyl)-4-hydroxy-1-piperidinyl]-5-(2,5-difluorophenyl)-3-pyridinyl}-3-chloro-4-fluorobenzamide

(464) Description: white powder;

(465) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.48 min);

(466) TLC: Rf 0.37 (ethyl acetate:methanol=9:1, NH silica gel);

(467) NMR (300 MHz, CHLOROFORM-d): 9.65 (s, 1H), 8.96 (s, 1H), 8.15 (s, 1H), 7.98 (dd, J=6.77, 2.20 Hz, 1H), 7.86 (ddd, J=8.51, 4.39, 2.10 Hz, 1H), 7.37-7.25 (m, 1H), 7.23-7.10 (m, 2H), 7.07-6.91 (m, 1H), 3.08-2.91 (m, 2H), 2.85-2.68 (m, 2H), 2.58 (s, 2H), 1.95-1.35 (m, 7H);

(468) MASS (ESI, Pos.): 491 (M+H)+.

Example 11(51)

N-{4-[4-(aminomethyl)-1-piperidinyl]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethoxybenzamide

(469) Description: white powder;

(470) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.54 min);

(471) TLC: Rf 0.48 (ethyl acetate:methanol=9:1, NH silica gel);

(472) NMR (300 MHz, CHLOROFORM-d): 9.70 (s, 1H), 9.15 (s, 1H), 8.14 (s, 1H), 7.08 (d, J=2.20 Hz, 2H), 7.05 (s, 1H), 6.89 (s, 2H), 6.65 (t, J=2.20 Hz, 1H), 3.85 (s, 6H), 2.95-2.84 (m, 2H), 2.61-2.47 (m, 4H), 2.37 (s, 6H), 1.77-1.14 (m, 7H);

(473) MASS (ESI, Pos.): 475 (M+H)+.

Example 11(52)

N-[4-{[(3-aminopropyl)[2-(benzyloxy)ethyl]amino}-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-dimethylbenzamide

(474) Description: yellow oil;

(475) TLC: Rf 0.60 (ethyl acetate:methanol=9:1, NH silica gel);

(476) NMR (300 MHz, CHLOROFORM-d): 9.79 (s, 1H), 9.69 (s, 1H), 8.12 (s, 1H), 7.51 (s, 2H), 7.24-7.17 (m, 3H), 7.09 (s, 2H), 7.06-6.98 (m, 3H), 6.88 (s, 2H), 4.09 (s, 2H), 3.32 (t, J=4.9 Hz, 2H), 2.98 (t, J=4.9 Hz, 2H), 2.68 (t, J=7.1 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H), 2.34 (s, 6H), 2.31 (s, 6H), 1.56-1.19 (m, 4H);

(477) MASS (APCI, Pos.): 537 (M+H)+.

Example 11(53)

N-{4-[(3-aminopropyl)(2-hydroxyethyl)amino]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide

(478) Description: white powder;

(479) TLC: Rf 0.12 (ethyl acetate:methanol:28% ammonia water=9:1:0.1);

(480) NMR (300 MHz, CHLOROFORM-d): 10.00 (br. s., 1H), 9.75 (d, J=0.7 Hz, 1H), 8.10 (d, J=0.7 Hz, 1H), 7.63 (s, 2H), 7.16 (s, 1H), 7.04 (s, 1H), 6.90 (s, 2H), 3.72 (br. s., 2H), 3.11 (br. s., 2H), 2.79-2.50 (m, 4H), 2.38 (s, 6H), 2.37 (s, 6H), 2.01-1.36 (m, 2H), 1.37-1.16 (m, 2H);

(481) MASS (APCI, Pos.): 447 (M+H)+.

Example 11(54)

N-{4-[(4-amino-2-butanyl)amino]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide

(482) Description: white powder;

(483) TLC: Rf 0.43 (ethyl acetate:methanol=9:1, NH silica gel);

(484) NMR (300 MHz, CHLOROFORM-d): 9.42 (br. s., 1H), 8.69 (s, 1H), 8.05 (s, 1H), 7.51 (s, 2H), 7.33-7.23 (m, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 6.97 (s, 2H), 3.59-3.80 (m, 1H), 2.79-2.55 (m, 2H), 2.39 (s, 6H), 2.38-2.27 (m, 6H), 1.65-1.13 (m, 4H), 0.93 (d, J=6.2 Hz, 3H);

(485) MASS (APCI, Pos.): 417 (M+H)+.

Example 11(55)

N-{4-[3-(aminomethyl)-1-pyrrolidiny]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3-chloro-4-fluorobenzamide

(486) Description: orange powder;

(487) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.59 min);

(488) TLC: Rf 0.47 (ethyl acetate:methanol=9:1, NH silica gel);

(489) NMR (300 MHz, CHLOROFORM-d): 9.40 (s, 1H), 9.07 (br. s, 1H), 8.16 (s, 1H), 8.04-7.98 (m, 1H), 7.86-7.78 (m, 1H), 7.32-7.28 (m, 1H), 7.04 (s, 1H), 6.88 (s, 2H), 3.08-2.83 (m, 4H), 2.64 (d, J=6.04 Hz, 2H), 2.37 (s, 6H), 2.27-2.13 (m, 1H), 2.01-1.82 (m, 1H), 1.63-1.41 (m, 3H)

(490) MASS (ESI, Pos.): 453 (M+H)+.

Example 11(56)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-4,6-dimethyl-2-pyridinecarboxamide

(491) Description: white powder;

(492) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.57 min);

(493) TLC: Rf 0.48 (ethyl acetate:methanol=9:1, NH silica gel);

(494) NMR (300 MHz, CHLOROFORM-d): 10.79 (s, 1H), 9.76 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 6.90 (s, 2H), 2.98-2.87 (m, 2H), 2.62 (s, 3H), 2.60-2.49 (m, 3H), 2.44 (s, 3H), 2.38 (s, 6H), 1.87-1.61 (m, 4H), 1.48 (br. s, 2H);

(495) MASS (ESI, Pos.): 430 (M+H)+.

Example 11(57)

N-[4-(4-amino-1-piperazinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-dimethylbenzamide

(496) Description: white powder;

(497) Purity (UPLC-MS/ELSD): 99.7% (retention time: 0.61 min);

(498) TLC: Rf 0.63 (ethyl acetate:methanol=9:1, NH silica gel);

(499) NMR (300 MHz, CHLOROFORM-d): 9.70 (s, 1H), 9.03 (s, 1H), 8.13 (s, 1H), 7.58 (s, 2H), 7.23 (s, 1H), 7.05 (s, 1H), 6.89 (s, 2H), 2.85-2.79 (m, 4H), 2.73-2.53 (m, 4H), 2.43 (s, 6H), 2.38 (s, 6H), 1.58 (br. s, 2H);

(500) MASS (ESI, Pos.): 430 (M+H)+.

Example 11(58)

2-{4-[4-(aminomethyl)-1-piperidinyl]-5-(3,5-dimethylphenyl)-3-pyridinyl}-1H-isoindole-1,3(2H)-dione

(501) Description: yellow viscous oil;

(502) Purity (UPLC-MS/ELSD): 99.7% (retention time: 0.61 min);

(503) TLC: Rf 0.26 (ethyl acetate:methanol=9:1, NH silica gel);

(504) NMR (300 MHz, CHLOROFORM-d): 8.33 (s, 1H), 8.21 (s, 1H), 8.03-7.95 (m, 2H), 7.88-7.80 (m, 2H), 7.05 (s, 2H), 7.00 (s, 1H), 3.07-2.97 (m, 2H), 2.67-2.53 (m, 2H), 2.42-2.37 (m, 2H), 2.36 (s, 6H), 1.55-0.72 (m, 7H);

(505) MASS (ESI, Pos.): 441 (M+H)+.

Example 11(59)

N-{4-[(3-aminophenyl)amino]-5-(3,5-dimethylphenyl)-3-pyridinyl}-3,5-dimethylbenzamide

(506) Description: beige powder;

(507) Purity (UPLC-MS/ELSD): 100% (retention time: 0.75 min);

(508) TLC: Rf 0.64 (ethyl acetate:methanol=9:1, NH silica gel);

(509) NMR (300 MHz, CHLOROFORM-d): 9.53 (s, 1H), 8.33 (s, 1H), 7.73-7.68 (m, 1H), 7.13-7.04 (m, 3H), 7.00-6.96 (m, 2H), 6.93-6.89 (m, 2H), 6.39-6.35 (m, 1H), 6.31-6.26 (m, 1H), 6.19-6.15 (m, 1H), 5.65 (s, 1H), 3.68 (br. s, 2H), 2.33 (s, 6H), 2.25 (s, 6H);

(510) MASS (ESI, Pos.): 437 (M+H)+.

Example 11(60)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-dimethyl-1-piperidinecarboxamide

(511) Description: white powder;

(512) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.54 min);

(513) TLC: Rf 0.50 (ethyl acetate:methanol=9:1, NH silica gel);

(514) NMR (300 MHz, CHLOROFORM-d): 9.35 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.03 (s, 1H), 6.87 (s, 2H), 4.15-4.02 (m, 2H), 3.65-3.55 (m, 1H), 3.20-3.09 (m, 1H), 2.88-2.77 (m, 4H), 2.64-2.40 (m, 5H), 2.36 (s, 6H), 2.04-1.20 (m, 6H), 1.04-0.91 (m, 6H);

(515) MASS (ESI, Pos.): 436 (M+H)+.

Example 11(61)

N-[5-(3,5-dimethylphenyl)-4-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-3-pyridinyl]-3,5-dimethylbenzamide

(516) Description: white powder;

(517) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.59 min);

(518) TLC: Rf 0.69 (ethyl acetate:methanol=9:1, NH silica gel);

(519) NMR (300 MHz, METHANOL-d4): 8.78 (s, 1H), 8.14 (s, 1H), 7.42 (s, 1H), 7.38 (s, 2H), 7.22 (s, 1H), 7.06 (s, 1H), 7.03 (s, 2H), 4.00 (s, 2H), 3.51 (s, 3H), 3.08 (t, J=5.49 Hz, 2H), 2.45 (t, J=5.49 Hz, 2H), 2.31 (s, 6H), 2.31 (s, 6H);

(520) MASS (ESI, Pos.): 466 (M+H)+.

Example 11(62)

N-[2-(4-amino-1-piperidinyl)-2,5-difluoro-3-biphenylyl]-3-hydroxybenzamide

(521) Description: amber powder;

(522) TLC: Rf 0.48 (ethyl acetate:methanol=10:1, NH silica gel);

(523) NMR (300 MHz, CHLOROFORM-d): 9.97 (s, 1H), 8.70-8.60 (m, 1H), 7.71-7.58 (m, 1H), 7.49 (t, J=2.0 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.30-7.21 (m, 1H), 7.15-7.02 (m, 3H), 6.97 (ddd, J=8.1, 5.3, 2.7 Hz, 1H), 6.83 (dd, J=7.7, 1.5 Hz, 1H), 3.83-3.55 (m, 1H), 3.15-2.61 (m, 4H), 1.87-1.59 (m, 4H);

(524) MASS (ESI, Pos.): 424 (M+H)+.

Example 11(63)

N-[2-(4-amino-1-piperidinyl)-3,5-dimethyl-3-biphenylyl]-3-hydroxybenzamide

(525) Description: white powder;

(526) TLC: Rf 0.48 (ethyl acetate:methanol=10:1, NH silica gel);

(527) NMR (300 MHz, CHLOROFORM-d): 10.06 (s, 1H), 8.59 (dd, J=8.1, 1.4 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.09-6.98 (m, 2H), 6.90 (s, 2H), 6.86 (dd, J=7.6, 1.6 Hz, 1H), 2.96-2.77 (m, 3H), 2.62-2.44 (m, 2H), 2.37 (s, 6H), 1.84-1.68 (m, 4H);

(528) MASS (ESI, Pos.): 416 (M+H)+.

Example 11(64)

N-[2-(4-amino-1-piperidinyl)-3,5-dimethoxy-3-biphenylyl]-3-hydroxybenzamide

(529) Description: white powder;

(530) TLC: Rf 0.48 (ethyl acetate:methanol=10:1, NH silica gel);

(531) NMR (300 MHz, CHLOROFORM-d): 9.99 (s, 1H), 8.60 (dd, J=8.2, 1.5 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.05 (dd, J=8.1, 2.0 Hz, 1H), 6.91-6.84 (m, 1H), 6.51-6.47 (m, 1H), 6.44 (d, J=2.4 Hz, 2H), 3.82 (d, J=0.5 Hz, 6H), 2.96-2.82 (m, 3H), 2.63 (td, J=11.8, 2.8 Hz, 2H), 1.87-1.62 (m, 4H);

(532) MASS (ESI, Pos.): 448 (M+H)+.

Example 11(65)

N-[4-(4-acetamide-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-3,5-dimethylbenzamide

(533) Description: white powder;

(534) Purity (UPLC-MS/ELSD): 100% (retention time: 0.70 min);

(535) TLC: Rf 0.26 (ethyl acetate);

(536) NMR (300 MHz, CHLOROFORM-d): 9.67 (s, 1H), 8.96 (s, 1H), 8.13 (s, 1H), 7.54 (s, 2H), 7.22 (s, 1H), 7.07 (s, 1H), 6.88 (s, 2H), 5.21-5.13 (m, 1H), 3.79-3.64 (m, 1H), 2.93-2.82 (m, 2H), 2.71-2.59 (m, 2H), 2.42 (s, 6H), 2.38 (s, 6H), 2.01-1.80 (m, 2H), 1.94 (s, 3H), 1.29-1.45 (m, 2H);

(537) MASS (ESI, Pos.): 471 (M+H)+.

Example 11(66)

N-{5-(3,5-dimethylphenyl)-4-[4-(ethylamino)-1-piperidinyl]-3-pyridinyl}-3,5-dimethylbenzamide

(538) Description: white powder;

(539) Purity (UPLC-MS/ELSD): 100% (retention time: 0.58 min);

(540) TLC: Rf 0.59 (ethyl acetate:methanol=9:1, NH silica gel);

(541) NMR (300 MHz, CHLOROFORM-d): 9.68 (s, 1H), 8.97 (s, 1H), 8.13 (s, 1H), 7.55 (s, 2H), 7.20 (s, 1H), 7.06 (s, 1H), 6.89 (s, 2H), 2.97-2.85 (m, 2H), 2.66-2.49 (m, 3H), 2.41 (s, 6H), 2.38 (s, 6H), 1.92-1.80 (m, 2H), 1.48 (br. s., 1H), 1.42-1.24 (m, 3H), 1.06 (t, J=7.14 Hz, 3H);

(542) MASS (ESI, Pos.): 457 (M+H)+.

Example 11(67)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2,6-dimethylpyridine-4-carboxamide

(543) Description: yellow oil;

(544) TLC: Rf 0.58 (ethyl acetate:methanol=9:1, NH silica gel);

(545) NMR (300 MHz, METHANOL-d4): 8.47 (s, 1H), 8.06 (s, 1H), 7.61 (s, 2H), 7.07 (s, 1H), 6.98 (s, 2H), 3.08 (d, J=13.2 Hz, 2H), 2.61 (s, 9H), 2.37 (s, 6H), 1.69-1.50 (m, 2H), 1.33-1.03 (m, 2H);

(546) MASS (APCI, Pos.): 430 (M+H)+.

Example 11(68)

N-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-2-phenoxyacetamide

(547) Purity (LC-MS/ELSD): 100% (retention time: 0.54 min);

(548) MASS (ESI, Pos.): 431 (M+H)+.

Example 12

N-[5-(3,5-dimethylphenyl)-4-[3-hydroxypropyl(isobutyl)amino]-3-pyridyl]-3,5-dimethylbenzamide

(549) ##STR00091##

(550) Using 3-(isobutylamino)propan-1-ol (CAS#285124-45-0) in place of tert-butyl N-(4-piperidylmethyl)carbamate, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 14.fwdarw.Reference example 2.fwdarw.Reference example 16.fwdarw.Reference example 17.

(551) Description: white powder;

(552) TLC: Rf 0.32 (n-hexane:ethyl acetate=1:1);

(553) MASS (ESI, Pos.): 460 (M+H)+.

Reference Example 18

N-[5-(3,5-dimethylphenyl)-4-[isobutyl-[3-[(2-nitrophenyl)sulfonylamino]propyl]amino]-3-pyridyl]-3,5-dimethylbenzamide

(554) Using the compound (188 mg) produced in Example 12 and 2-nitrobenzenesulfonamide (CAS#5455-59-4) (404 mg), the title compound having the following physical property values was obtained by following the same procedure as in Reference example 9, and used for next reaction without further purification.

Example 13

N-[4-[3-aminopropyl(isobutyl)amino]-5-(3,5-dimethylphenyl)-3-pyridyl]-3,5-dimethylbenzamide dihydrochloride

(555) ##STR00092##

(556) To a acetonitrile (15 mL) solution of the compound produced in Reference example 18 and 4-chlorothiophenol (730 mg) was added cesium carbonate (1.65 g), the mixture was stirred at room temperature for 15 hours. After adding water, the reaction solution was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5), and treated with hydrogen chloride in ethyl acetate to obtain the present invention compound (60 mg) having the following physical property values.

(557) Description: white powder;

(558) Purity (UPLC-MS/ELSD): 99.2% (retention time: 0.72 min);

(559) TLC: Rf 0.61 (ethyl acetate:methanol=9:1, NH silica gel);

(560) MASS (ESI, Pos.): 459 (M+H)+.

Example 14

N-(2-aminoethyl)-3-[(3-chloro-4-fluorobenzoyl)amino]-5-(3,5-dimethylphenyl)pyridine-4-carboxamide

(561) ##STR00093##

(562) Using ethyl 3-amino-5-bromopyridine-4-carboxylate (purchased from ATLANTIC, catalog number: ES00288) in place of the compound produced in Reference example 16, using 3-chloro-4-fluorobenzoylchloride (CAS#157373-00-7) in place of 3,5-dimethylbenzoylchloride, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, using tert-butyl N-(2-aminoethyl)carbamate (CAS#57260-73-8) in place of 3,5-dimethylaniline, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 17.fwdarw.Reference example 2.fwdarw.Reference example 6.fwdarw.Reference example 7.fwdarw.Example 1.

(563) Description: beige powder;

(564) Purity (UPLC-MS/ELSD): 94.8% (retention time: 0.81 min);

(565) TLC: Rf 0.60 (ethyl acetate:methanol=9:1, NH silica gel);

(566) NMR (300 MHz, METHANOL-d4): 9.65 (s, 1H), 8.13 (s, 1H), 8.08 (dd, J=7.04, 2.29 Hz, 1H), 7.90-7.97 (m, 1H), 7.62 (s, 2H), 7.41 (t, J=8.78 Hz, 1H), 7.07 (s, 1H), 3.54 (t, J=6.13 Hz, 2H), 2.91 (t, J=6.10 Hz, 2H), 2.38 (s, 6H);

(567) MASS (ESI, Pos.): 441 (M+H)+.

Reference Example 19

[3-[[3-(3,5-dimethylphenyl)-5-nitro-4-pyridyl]amino]phenyl]methanol

(568) Using (3-aminophenyl)methanol (CAS#1877-77-6) in place of tert-butyl N-(4-piperidylmethyl)carbamate, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 14.fwdarw.Reference example 2.

(569) Description: yellow powder;

(570) TLC: Rf 0.28 (n-hexane:ethyl acetate=1:1);

(571) MASS (APCI, Pos.): 350 (M+H)+.

Reference Example 20

(3-((3-amino-5-(3,5-dimethylphenyl)pyridin-4-yl)amino)phenyl)methanol

(572) To a ethanol (30 mL) solution of the compound produced in Reference example 19 was added ammonium chloride (1.60 g) and water (3 mL), the mixture was heated to 50 degrees C. To the reaction solution was added zinc (784 mg), and stirred for 15 min. The reaction solution was diluted with tetrahydrofuran and cooled back to room temperature. The reaction solution was filtered and the filtrate was concentrated to obtain the title compound which was used for next reaction without further purification.

Example 15

N-(5-(3,5-dimethylphenyl)-4-((3-(hydroxymethyl)phenyl)amino)pyridin-3-yl)-3,5-dimethylbenzamide

(573) ##STR00094##

(574) Using the compound produced in Reference example 20 in place of the compound produced in Reference example 16, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 17:

(575) Description: pale brown amorphous;

(576) TLC: Rf 0.26 (ethyl acetate);

(577) MASS (APCI, Pos.): 452 (M+H)+.

Reference Example 21

N-(4-((3-(azidemethyl)phenyl)amino)-5-(3,5-dimethylphenyl)pyridin-3-yl)-3,5-dimethylbenzamide

(578) To a tetrahydrofuran (6 mL) solution of the compound (187 mg) produced in Example 15 and bis(p-nitrophenyl)azidophosphonate (CAS#51250-91-0) (365 mg) was added 1,5-diazabicyclo[4.3.0]non-5-ene (124 microL) at room temperature, and the mixture was stirred for 7 hours. The reaction solution was concentrated and the obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (156 mg) having the following physical property values.

(579) Description: colorless oil;

(580) TLC: Rf 0.44 (n-hexane:ethyl acetate=1:1);

(581) MASS (APCI, Pos.): 477 (M+H)+.

Example 16

N-(4-((3-(aminomethyl)phenyl)amino)-5-(3,5-dimethylphenyl)pyridin-3-yl)-3,5-dimethylbenzamide

(582) ##STR00095##

(583) Using the compound produced in Reference example 21 in place of the compound produced in Reference example 15, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 16.

(584) Description: white powder;

(585) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.59 min);

(586) TLC: Rf 0.51 (ethyl acetate:methanol=9:1, NH silica gel).

(587) NMR (300 MHz, CHLOROFORM-d): 9.43 (s, 1H), 8.34 (s, 1H), 7.56 (s, 1H), 7.30-7.21 (m, 1H), 7.05 (d, J=6.95 Hz, 2H), 6.98-6.91 (m, 3H), 6.83 (s, 2H), 6.80-6.71 (m, 2H), 5.85 (s, 1H), 3.75 (s, 2H), 2.32 (s, 6H), 2.22 (s, 6H), 1.49 (br. s, 2H); MASS (ESI, Pos.): 451 (M+H)+.

Reference Example 22

tert-butyl N-[1-[3-[(2-aminobenzoyl)amino]-5-(3,5-dimethylphenyl)-4-pyridyl]-4-piperidyl]carbamate

(588) Using the compound produced in Reference example 12 in place of the compound produced in Reference example 16, using 2-nitrobenzoyl chloride (CAS#610-14-0) in place of 3,5-dimethylbenzoylchloride, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 17.fwdarw.Reference example 6.fwdarw.Reference example 16.

(589) Description: colorless oil;

(590) TLC: Rf 0.64 (ethyl acetate);

(591) MASS (APCI, Pos.): 516 (M+H)+.

Reference Example 23

tert-butyl (1-(3-(3,5-dimethylphenyl)-5-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)pyridin-4-yl)piperidin-4-yl)carbamate

(592) To a dichloroethane (8 mL) solution of the compound (233 mg) produced in Reference example 22 was added diisopropylethylamine (78 microL) and triphosgene (CAS#32315-10-9) (67 mg) at room temperature, and the mixture was stirred for 15 hours. After adding water, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated after drying to obtain the title compound which was used for next reaction without further purification.

Example 17

3-[4-(4-amino-1-piperidyl)-5-(3,5-dimethylphenyl)-3-pyridyl]-1H-quinazoline-2,4-dione

(593) ##STR00096##

(594) Using the compound produced in Reference example 23 in place of the compound produced in Reference example 3, the present invention compound having the following physical property values was obtained by following the same procedure as in Example 1.

(595) Description: white powder;

(596) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.54 min);

(597) TLC: Rf 0.20 (ethyl acetate:methanol=9:1, NH silica gel);

(598) NMR (300 MHz, CHLOROFORM-d): 8.35 (s, 1H), 8.23 (s, 1H), 8.22-8.17 (m, 1H), 7.71-7.64 (m, 1H), 7.33-7.27 (m, 2H), 7.11-7.04 (m, 3H), 7.01 (s, 1H), 3.08-2.97 (m, 2H), 2.65-2.53 (m, 2H), 2.53-2.41 (m, 1H), 2.37 (s, 6H), 2.20-1.20 (br, 2H), 1.51-1.40 (m, 2H), 1.02-0.83 (m, 2H);

(599) MASS (ESI, Pos.): 442 (M+H)+.

Example 18

ethyl (1-(3-(3,5-dimethylbenzamide)-5-(3,5-dimethylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate

(600) ##STR00097##

(601) Using the compound produced in Reference example 11(39) in place of the compound produced in Reference example 16, using ethyl chloroformate (CAS#541-41-3) in place of 3,5-dimethylbenzoylchloride, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 17.

(602) Description: white powder;

(603) Purity (UPLC-MS/ELSD): 100% (retention time: 0.83 min);

(604) TLC: Rf 0.56 (ethyl acetate);

(605) NMR (300 MHz, CHLOROFORM-d): 9.68 (s, 1H), 8.98 (br. s., 1H), 8.14 (s, 1H), 7.54 (s, 2H), 7.22 (s, 1H), 7.07 (s, 1H), 6.88 (s, 2H), 4.46-4.34 (m, 1H), 4.09 (q, J=7.26 Hz, 2H), 3.52-3.35 (m, 1H), 2.93-2.82 (m, 2H), 2.69-2.55 (m, 2H), 2.42 (s, 6H), 2.38 (s, 6H), 2.00-1.89 (m, 2H), 1.48-1.31 (m, 2H), 1.23 (t, J=7.30 Hz, 3H);

(606) MASS (ESI, Pos.): 501 (M+H)+.

Reference Example 24

3-bromo-2-[3-(1,3-dioxoindolin-2-yl)propoxy]benzaldehyde

(607) To a dimethylformamide (10 mL) solution of 3-bromo-2-hydroxybenzaldehyde (CAS#1829-34-1) (1.00 g) and 2-(3-bromopropyl)isoindoline-1,3-dione (CAS#5460-29-7) (2.00 g) was added cesium carbonate (2.40 g) at room temperature, and the mixture was stirred at 80 degrees C. for 15 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and sequentially washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (1.84 g) having the following physical property values.

(608) Description: white powder;

(609) TLC: Rf 0.63 (n-hexane:ethyl acetate=1:1).

Reference Example 25

2-[3-[2-(1H-benzimidazol-2-yl)-6-bromophenoxy]propyl]isoindoline-1,3-dione

(610) To a dimethylformamide (3 mL)/ethanol (10 mL) solution of the compound (397 mg) produced in Reference example 24 and 2-nitroaniline (CAS#88-74-4) (141 mg) was added sodium hydrosulfite (871 mg) and water (5 mL) at room temperature, and the mixture was stirred at 80 degrees C. for 5 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and then sequentially washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was concentrated after drying to obtained title compound which was used for next reaction without further purification.

Reference Example 26

2-[3-[2-(1H-benzimidazol-2-yl)-6-(3,5-dimethylphenyl)phenoxy]propyl]isoindoline-1,3-dione

(611) Using the compound produced in Reference example 25 in place of the compound produced in Reference example 1, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 2.

(612) Description: beige powder;

(613) TLC: Rf 0.68 (ethyl acetate);

(614) MASS (ESI, Pos.): 502 (M+H)+.

Example 19

3-[2-(1H-benzimidazol-2-yl)-6-(3,5-dimethylphenyl)phenoxy]propan-1-amine hydrochloride

(615) ##STR00098##

(616) To a ethanol (10 mL) solution of the compound (220 mg) produced in Reference example 26 was added hydrazine monohydrate (0.5 mL) at room temperature, the mixture was stirred at 80 degrees C. for 3 hours, and then concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5), and then treated with hydrogen chloride in 1,4-dioxane solution to obtain the present invention compound (110 mg) having the following physical property values.

(617) Description: white powder;

(618) Purity (UPLC-MS/ELSD): 100% (retention time: 0.66 min);

(619) TLC: Rf 0.52 (ethyl acetate:methanol=9:1, NH silica gel);

(620) NMR (300 MHz, METHANOL-d4): 7.98-7.88 (m, 3H), 7.76 (dd, J=7.70, 1.70 Hz, 1H), 7.72-7.64 (m, 2H), 7.61-7.54 (m, 1H), 7.28 (s, 2H), 7.15 (s, 1H), 3.57 (t, J=6.04 Hz, 2H), 2.73-2.63 (m, 2H), 2.42 (s, 6H), 1.85-1.68 (m, 2H);

(621) MASS (ESI, Pos.): 372 (M+H)+.

Reference Example 27

tert-butyl (1-(3-amino-5-bromopyridin-4-yl)piperidin-4-yl)carbamate

(622) Using the compound produced in Reference example 1 in place of the compound produced in Reference example 5, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 6.fwdarw.Reference example 12.

(623) Description: ivory amorphous powder;

(624) TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1).

Example 20

N-(4-(4-aminopiperidin-1-yl)-5-(3,5-dimethylphenyl)pyridin-3-yl)-N-ethyl-3,5-dimethylbenzamide

(625) ##STR00099##

(626) Using acetaldehyde (CAS#75-07-0) in place of the compound produced in Reference example 9, using the compound produced in Reference example 27 in place of dimethylamine, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, using tetrakis(triphenylphosphine)palladium (Pd(PPh.sub.3).sub.4) in place of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), the present invention compound having the following physical property values was obtained by following the same procedure as in Example 10.fwdarw.Reference example 17.fwdarw.Reference example 2.fwdarw.Example 1.

(627) Description: colorless oil;

(628) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.67 min);

(629) TLC: Rf 0.50 (ethyl acetate:methanol=9:1, NH silica gel);

(630) MASS (ESI, Pos.): 457 (M+H)+.

Reference Example 28

tert-butyl N-[1-[3-[(2-amino-3,5-dimethylphenyl)carbamoyl]-5-(3,5-dimethylphenyl)-4-pyridyl]-4-piperidyl]carbamate

(631) Using 3,5-dimethylbenzene-1,2-diamine (CAS#3171-46-8) in place of 3,5-dimethylaniline, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 7.

(632) Description: pale brown powder;

(633) TLC: Rf 0.41 (ethyl acetate, NH silica gel);

Reference Example 29

tert-butyl N-[1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridyl]-4-piperidyl]carbamate

(634) To a toluene (7 mL) solution of the compound (750 mg) produced in Reference example 28 was added acetic acid (7 mL), and stirred at 90 degrees C. overnight. The reaction solution was sequentially washed with 1M aqueous solution of sodium hydroxide and saturated brine. The organic layer was concentrated after during. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5) to obtain the title compound having the following physical property values.

(635) TLC: Rf 0.70 (ethyl acetate:methanol=9:1).

Example 21(1)-Example 21(39)

(636) Using methyl 5-bromo-4-iodopyridine-3-carboxylate, or a corresponding reagent in place of it, using 4-tert-butoxycarbonylaminopiperidine, or a corresponding reagent in place of it, using a corresponding reagent in place of phenylboronic acid, using a corresponding benzene-1,2-diamine derivative, 2-aminothiophenol derivative or 2-aminophenol derivative in place of 3,5-dimethylaniline, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 1.fwdarw.Reference example 2.fwdarw.Reference example 6.fwdarw.Reference example 7.fwdarw.Reference Example 29.fwdarw.Example 1.

Example 21(1)

1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridyl]piperidin-4-amine

(637) ##STR00100##

(638) Description: pale yellow amorphous powder;

(639) TLC: Rf 0.49 (ethyl acetate:methanol=9:1, NH silica gel);

(640) NMR (300 MHz, METHANOL-d4): 8.43 (s, 1H), 8.23 (s, 1H), 7.26 (s, 1H), 7.09 (s, 1H), 7.05 (s, 2H), 6.96 (s, 1H), 3.15-3.04 (m, 2H), 2.78-2.62 (m, 1H), 2.56 (s, 3H), 2.56-2.48 (m, 2H), 2.45 (s, 3H), 2.40 (s, 6H), 1.56-1.43 (m, 2H), 1.31-1.09 (m, 2H);

(641) MASS (ESI, Pos.): 426 (M+H)+.

Example 21(2)

1-[3-(3,5-dimethoxyphenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(642) Description: white powder;

(643) TLC: Rf 0.30 (ethyl acetate:methanol=19:1, NH silica gel);

(644) NMR (300 MHz, CHLOROFORM-d): 11.25 and 10.64 (br. s, 1H), 9.37 and 9.19 (s, 1H), 8.33 (s, 1H), 7.50 and 7.15 (s, 1H), 6.95 (s, 1H), 6.52 (s, 1H), 6.46 (s, 2H), 3.84 (s, 6H), 3.18-2.94 (m, 2H), 2.80-2.51 (m, 6H), 2.48 (s, 3H), 1.88-1.64 (m, 2H), 1.61-1.19 (m, 4H);

(645) MASS (ESI, Pos.): 458 (M+H)+.

Example 21(3)

1-{1-[3-(3,5-dimethoxyphenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinyl}methanamine

(646) Description: white powder;

(647) TLC: Rf 0.16 (ethyl acetate:methanol=19:1, NH silica gel);

(648) NMR (300 MHz, CHLOROFORM-d): 11.35 and 10.78 (br. s., 1H), 9.41 and 9.21 (s, 1H), 8.33 (s, 1H), 7.50 and 7.08 (s, 1H), 6.94 (br. s., 1H), 6.52 (br. s., 1H), 6.47 (s, 2H), 3.84 (s, 6H), 3.08 (d, J=9.7 Hz, 2H), 2.80-2.50 (m, 6H), 2.48 (s, 3H), 1.82-1.58 (m, 2H), 1.58-0.98 (m, 4H);

(649) MASS (ESI, Pos.): 472 (M+H)+.

Example 21(4)

1-[3-(2,5-difluorophenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(650) Description: pale brown amorphous powder;

(651) TLC: Rf 0.30 (ethyl acetate:methanol=19:1, NH silica gel);

(652) NMR (300 MHz, CHLOROFORM-d): 10.93 and 10.37 (br. s., 1H), 9.27 and 9.07 (s, 1H), 8.27 (s, 1H), 7.55-6.93 (m, 5H), 3.02 (m, 2H), 2.78-2.52 (m, 6H), 2.48 (m, 3H), 1.83-1.09 (m, 6H),

(653) MASS (ESI, Pos.): 434 (M+H)+.

Example 21(5)

1-{1-[3-(2,5-difluorophenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinyl}methanamine

(654) Description: pale brown amorphous powder;

(655) TLC: Rf 0.16 (ethyl acetate:methanol=19:1, NH silica gel);

(656) NMR (300 MHz, CHLOROFORM-d): 11.07 and 10.42 (br. s., 1H), 9.37 and 9.13 (s, 1H), 8.29 (s, 1H), 7.57-6.98 (m, 4H), 6.95 (s, 1H), 3.07 (t, J=11.8 Hz, 2H), 2.77-2.38 (m, 9H), 1.81-0.97 (m, 6H);

(657) MASS (ESI, Pos.): 448 (M+H)+.

Example 21(6)

1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-3,5-dimethoxy-2-biphenylyl]-4-piperidinamine

(658) Description: ivory powder;

(659) TLC: Rf 0.48 (ethyl acetate:methanol=20:1, NH silica gel);

(660) NMR (300 MHz, METHANOL-d4): 7.53 (dd, J=7.3, 1.8 Hz, 1H), 7.30 (d, J=1.8 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.24-7.17 (m, 2H), 6.90 (s, 1H), 6.53-6.48 (m, 3H), 3.81 (s, 6H), 2.97 (d, J=12.4 Hz, 2H), 2.56 (s, 3H), 2.53-2.41 (m, 5H), 2.35-2.20 (m, 1H), 1.42 (d, J=11.7 Hz, 2H), 1.04-0.91 (m, 2H);

(661) MASS (ESI, Pos.): 457 (M+H)+.

Example 21(7)

1-[3-(1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine

(662) Description: white powder;

(663) TLC: Rf 0.50 (ethyl acetate:methanol=9:1, NH silica gel);

(664) NMR (300 MHz, CHLOROFORM-d): 11.52 (br. s., 1H), 9.19-8.92 (m, 1H), 8.35-8.17 (m, 1H), 7.67 (br. s., 2H), 7.42-7.15 (m, 2H), 7.04 (s, 1H), 6.90 (s, 2H), 2.96 (d, J=12.4 Hz, 2H), 2.80-2.48 (m, 3H), 2.46-1.84 (m, 8H), 1.63 (d, J=11.9 Hz, 2H), 1.40-1.09 (m, 2H);

(665) MASS (ESI, Pos.): 398 (M+H)+.

Example 21(8)

1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-2,5-difluoro-2-biphenylyl]-4-piperidinamine

(666) Description: amber powder;

(667) TLC: Rf 0.42 (ethyl acetate:methanol=20:1, NH silica gel);

(668) NMR (300 MHz, METHANOL-d4): 7.54 (dd, J=7.2, 1.9 Hz, 1H), 7.38-7.26 (m, 2H), 7.26-7.09 (m, 4H), 6.92 (s, 1H), 2.97 (d, J=12.4 Hz, 2H), 2.55 (s, 3H), 2.52-2.40 (m, 6H), 1.47 (d, J=11.3 Hz, 2H), 1.02-0.92 (m, 2H);

(669) MASS (ESI, Pos.): 433 (M+H)+.

Example 21(9)

1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-3,5-dimethyl-2-biphenylyl]-4-piperidinamine

(670) Description: pale orange powder;

(671) TLC: Rf 0.45 (ethyl acetate:methanol=20:1, NH silica gel);

(672) NMR (300 MHz, METHANOL-d4): 7.49 (dd, J=7.2, 1.9 Hz, 1H), 7.33-7.15 (m, 3H), 7.01 (s, 1H), 6.99 (s, 2H), 6.91 (s, 1H), 2.99-2.91 (m, 2H), 2.55 (s, 3H), 2.49-2.40 (m, 5H), 2.39-2.33 (m, 7H), 1.45-1.36 (m, 2H), 1.11-0.82 (m, 2H);

(673) MASS (ESI, Pos.): 425 (M+H)+.

Example 21(10)

1-[3-cyclopropyl-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine bis(trifluoroacetate

(674) Description: white powder;

(675) TLC: Rf 0.29 (ethyl acetate:methanol=9:1, NH silica gel);

(676) NMR (300 MHz, METHANOL-d4): 8.68 (s, 1H), 8.41 (s, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 3.82 (d, J=13.7 Hz, 2H), 3.42-3.25 (m, 1H), 3.12 (t, J=13.7 Hz, 2H), 2.64 (s, 3H), 2.51 (s, 3H), 2.16-1.94 (m, 3H), 1.75 (qd, J=12.2, 3.9 Hz, 2H), 1.32-1.20 (m, 2H), 1.08-0.97 (m, 2H);

(677) MASS (ESI, Pos.): 362 (M+H)+.

Example 21(11)

1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine

(678) Description: white amorphous powder;

(679) TLC: Rf 0.48 (ethyl acetate:methanol=9:1, NH silica gel);

(680) NMR (300 MHz, METHANOL-d4): 8.39 (s, 1H), 8.18 (s, 1H), 7.23 (br. s., 1H), 7.06 (s, 1H), 7.02 (s, 2H), 6.93 (s, 1H), 4.63 (t, J=6.9 Hz, 2H), 4.33 (t, J=6.5 Hz, 2H), 3.96-3.80 (m, 1H), 3.03 (d, J=12.8 Hz, 2H), 2.66-2.30 (m, 14H), 2.22 (s, 1H), 1.32 (d, J=10.1 Hz, 2H), 1.11-0.90 (m, 2H);

(681) MASS (ESI, Pos.): 482 (M+H)+.

Example 21(12)

4-(aminomethyl)-1-[3-(5,7-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinol

(682) Description: pale yellow powder;

(683) TLC: Rf 0.14 (ethyl acetate:methanol:28% ammonia water=90:10:1);

(684) NMR (300 MHz, METHANOL-d4): 8.42 (s, 1H), 8.23 (s, 1H), 7.30-7.20 (m, 1H), 7.07 (s, 3H), 6.95 (s, 1H), 2.99-2.75 (m, 4H), 2.65 (s, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.38 (s, 6H), 1.36-1.18 (m, 4H);

(685) MASS (ESI, Pos.): 456 (M+H)+.

Example 21(13)

1-[3-(1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-N,N-dimethyl-4-piperidinamine

(686) Description: brown powder;

(687) Purity (UPLC-MS/ELSD): unclear (retention time: 0.51 min);

(688) TLC: Rf 0.50 (ethyl acetate:methanol=9:1, NH silica gel);

(689) NMR (300 MHz, CHLOROFORM-d): 11.01 (br. s, 1H), 9.27 (s, 1H), 8.33 (s, 1H), 7.93-7.84 (m, 1H), 7.54-7.47 (m, 1H), 7.36-7.28 (m, 2H), 7.08 (s, 1H), 6.93 (s, 2H), 3.11-3.00 (m, 2H), 2.65-2.52 (m, 2H), 2.40 (s, 6H), 2.25 (s, 6H), 2.08-1.93 (m, 1H), 1.80-1.69 (m, 2H), 1.54-1.40 (m, 2H);

(690) MASS (ESI, Pos.): 426 (M+H)+.

Example 21(14)

(691) ##STR00101##

rac-(4aR,8aR)-6-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine

(692) Description: pale brown powder;

(693) TLC: Rf 0.52 (ethyl acetate:methanol=19:1, NH silica gel);

(694) NMR (300 MHz, METHANOL-d4): 8.42 (s, 1H), 8.23 (s, 1H), 7.25 (br. s., 1H), 7.09 (s, 1H), 7.02 (s, 2H), 6.94 (s, 1H), 3.62 (dd, J=11.5, 2.0 Hz, 1H), 3.41-3.29 (m, 1H), 3.01 (s, 3H), 2.83-2.49 (m, 6H), 2.44 (s, 3H), 2.39 (s, 6H), 2.27 (dd, J=11.3, 9.9 Hz, 1H), 2.10 (ddd, J=11.8, 8.8, 4.1 Hz, 1H), 1.33-1.17 (m, 1H), 1.16-0.98 (m, 1H);

(695) MASS (ESI, Pos.): 468 (M+H)+.

Example 21(15)

1-[3-(1,3-benzothiazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine

(696) Description: off-white powder;

(697) TLC: Rf 0.84 (ethyl acetate:methanol=19:1, NH silica gel);

(698) NMR (300 MHz, CHLOROFORM-d): 8.84 (s, 1H), 8.33 (s, 1H), 8.13 (ddd, J=8.1, 1.3, 0.6 Hz, 1H), 7.96 (ddd, J=8.0, 1.2, 0.6 Hz, 1H), 7.54 (ddd, J=8.1, 7.1, 1.2 Hz, 1H), 7.44 (ddd, J=8.0, 7.1, 1.3 Hz, 1H), 7.07-7.04 (m, 1H), 6.99-6.96 (m, 2H), 4.74 (t, J=6.9 Hz, 2H), 4.33 (t, J=6.9 Hz, 2H), 3.94 (quin, J=6.9 Hz, 1H), 3.05 (br. d, J=12.8 Hz, 2H), 2.65-2.54 (m, 2H), 2.39 (s, 6H), 2.37-2.24 (m, 1H), 1.46 (dd, J=12.3, 2.9 Hz, 2H), 1.38-1.20 (m, 2H);

(699) MASS (ESI, Pos.): 471 (M+H)+.

Example 21(16)

1-[3-(3,5-dimethylphenyl)-5-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(700) Description: orange amorphous powder;

(701) TLC: Rf 0.16 (ethyl acetate, NH silica gel);

(702) NMR (300 MHz, METHANOL-d4): 8.25 (s, 1H), 8.08 (s, 1H), 7.04 (d, J=0.7 Hz, 1H), 6.98 (t, J=0.7 Hz, 2H), 2.96 (br. d, J=13.0 Hz, 2H), 2.63 (br. s., 4H), 2.55-2.39 (m, 3H), 2.36 (s, 6H), 1.87 (br. s., 4H), 1.44 (dd, J=11.8, 2.5 Hz, 2H), 1.17-0.99 (m, 2H);

(703) MASS (ESI, Pos.): 402 (M+H)+.

Example 21(17)

1-[3-(3,5-dimethoxyphenyl)-5-(5,7-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-N-(2-fluoroethyl)-4-piperidinamine

(704) Description: pale brown amorphous powder;

(705) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.40 min);

(706) TLC: Rf 0.56 (ethyl acetate:methanol=9:1, NH silica gel);

(707) NMR (300 MHz, METHANOL-d4): 8.41 (s, 1H), 8.22 (s, 1H), 7.24 (br. s., 1H), 6.94 (s, 1H), 6.58-6.53 (m, 3H), 4.40 (ddd, J=47.8, 5.1, 4.8 Hz, 2H), 3.83 (s, 6H), 3.15-3.05 (m, 2H), 2.81-2.66 (m, 2H), 2.62-2.50 (m, 5H), 2.44 (s, 3H), 2.39-2.26 (m, 1H), 1.55-1.45 (m, 2H), 1.19-1.02 (m, 2H);

(708) MASS (ESI, Pos.): 504 (M+H)+.

Example 21(18)

1-[3-(3-cyclopropylphenyl)-5-(5-methyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(709) Description: pale brown amorphous powder;

(710) Purity (LC-MS/ELSD): 95.4% (retention time: 0.44 min);

(711) TLC: Rf 0.51 (ethyl acetate:methanol=9:1, NH silica gel);

(712) NMR (300 MHz, METHANOL-d4): 8.41 (s, 1H), 8.20 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.43 (s, 1H), 7.33-7.40 (m, 1H), 6.93-7.24 (m, 4H), 2.99 (br. d, J=13.0 Hz, 2H), 2.29-2.65 (m, 6H), 1.88-2.10 (m, 1H), 1.38 (br. d, J=11.7 Hz, 2H), 0.92-1.15 (m, 4H), 0.60-0.84 (m, 2H);

(713) MASS (ESI, Pos.): 424 (M+H)+.

Example 21(19)

1-[3-(2,5-dimethyl-3-furyl)-5-(5-methyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(714) Description: pale yellow amorphous powder;

(715) Purity (LC-MS/ELSD): 97.6% (retention time: 0.37 min);

(716) TLC: Rf 0.37 (ethyl acetate:methanol=9:1, NH silica gel);

(717) NMR (300 MHz, METHANOL-d4): 8.36 (s, 1H), 8.14 (s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.36-7.46 (m, 1H), 7.07-7.21 (m, 1H), 6.06 (s, 1H), 3.10 (br. d, J=12.6 Hz, 2H), 2.40-2.70 (m, 6H), 2.29 (s, 3H), 2.22 (s, 3H), 1.49 (br. d, J=12.4 Hz, 2H), 1.07-1.27 (m, 2H);

(718) MASS (ESI, Pos.): 402 (M+H)+.

Example 21(20)

(719) ##STR00102##

N-[3-(3,5-dimethoxyphenyl)-5-(5-methyl-1H-benzimidazol-2-yl)-4-pyridinyl]-N-methyl-1,3-propanediamine

(720) Description: pale brown powder;

(721) Purity (UPLC-MS/ELSD): 99.0% (retention time: 0.41 min);

(722) TLC: Rf 0.40 (ethyl acetate:methanol=10:1, NH silica gel);

(723) NMR (300 MHz, CHLOROFORM-d): 8.47 (s, 1H), 8.11 (s, 1H), 7.39-7.29 (m, 1H), 7.24-7.17 (m, 1H), 6.95 (dd, J=1.2, 8.3 Hz, 1H), 6.49 (t, J=2.2 Hz, 1H), 6.38 (d, J=2.2 Hz, 2H), 3.82 (s, 6H), 3.04-2.97 (m, 2H), 2.81-2.73 (m, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 1.77-1.66 (m, 2H)

(724) MASS (ESI, Pos.): 432 (M+H)+.

Example 21(21)

(725) ##STR00103##

rac-(3R,4S)-1-[3-(3,5-dimethylphenyl)-5-(6-methyl-1H-benzimidazol-2-yl)-4-pyridinyl]-3-fluoro-4-piperidinamine

(726) Description: pale brown amorphous powder;

(727) Purity (UPLC-MS/ELSD): 99.2% (retention time: 0.44 min);

(728) TLC: Rf 0.61 (ethyl acetate:methanol=20:1, NH silica gel);

(729) NMR (300 MHz, METHANOL-d4): 8.54 (s, 1H), 8.24 (s, 1H), 7.57-7.49 (m, 1H), 7.45 (s, 1H), 7.15 (dd, J=8.6, 1.3 Hz, 1H), 7.11 (s, 2H), 7.09 (s, 1H), 4.46-4.23 (m, 1H), 3.24-3.15 (m, 2H), 3.11-3.04 (m, 1H), 2.92-2.81 (m, 2H), 2.64-2.55 (m, 1H), 2.49 (s, 3H), 2.38 (s, 6H), 1.30-1.18 (m, 2H);

(730) MASS (ESI, Pos.): 430 (M+H)+.

Example 21(22)

1-[3-(3-cyclopropyl-5-methoxyphenyl)-5-(6-methyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(731) Description: ivory powder;

(732) Purity (UPLC-MS/ELSD): 100% (retention time: 0.45 min);

(733) TLC: Rf 0.52 (ethyl acetate:methanol=10:1, NH silica gel);

(734) NMR (300 MHz, CHLOROFORM-d): 11.54-11.37 (m, 1H), 9.08-8.94 (m, 1H), 8.26 (s, 1H), 7.73-7.64 and 7.39-7.31 (m, 1H), 7.62-7.56 and 7.29-7.24 (m, 1H), 7.10 (d, J=8.1 Hz, 1H), 6.67-6.55 (m, 3H), 3.80 (s, 3H), 3.02-2.91 (m, 2H), 2.66-2.52 (m, 3H), 2.48 (s, 3H), 1.95-1.81 (m, 1H), 1.68-1.54 (m, 2H), 1.32-1.12 (m, 2H), 1.03-0.92 (m, 2H), 0.75-0.64 (m, 2H);

(735) MASS (ESI, Pos.): 454 (M+H)+.

Example 21(23)

1-[3-(3-fluoro-5-methoxyphenyl)-5-(5-methyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(736) Description: green oil;

(737) Purity (UPLC-MS/ELSD): 100% (retention time: 0.41 min);

(738) TLC: Rf 0.63 (ethyl acetate:methanol=10:1, NH silica gel);

(739) NMR (300 MHz, CHLOROFORM-d): 10.77 (br. s., 1H), 9.19 (s, 1H), 8.30 (s, 1H), 7.86-7.31 (m, 2H), 7.14 (dd, J=1.1, 8.2 Hz, 1H), 6.73-6.62 (m, 3H), 3.85 (s, 3H), 3.08-2.97 (m, 2H), 2.75-2.59 (m, 3H), 2.51 (s, 3H), 1.77-1.51 (m, 2H), 1.40-1.17 (m, 2H);

(740) MASS (ESI, Pos.): 432 (M+H)+.

Example 21(24)

(741) ##STR00104##

1-[3-(3,5-dimethoxyphenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-N-(tetrahydro-3-furanyl)-4-piperidinamine

(742) Description: ivory amorphous powder;

(743) Purity (UPLC-MS/ELSD): 100% (retention time: 0.54 min);

(744) TLC: Rf 0.60 (ethyl acetate:methanol=10:1, NH silica gel);

(745) NMR (300 MHz, CHLOROFORM-d): 11.25 and 10.73 (br. s., 1H), 9.26 and 9.08 (br. s., 1H), 8.30 (s, 1H), 7.48 and 7.15 (br. s., 1H), 6.94 (s, 1H), 6.55-6.42 (m, 3H), 3.83 (s, 6H), 3.92-3.68 (m, 3H), 3.48-3.34 (m, 2H), 3.11-3.00 (m, 2H), 2.47 (s, 6H), 2.74-2.38 (m, 3H), 1.85-1.49 (m, 4H), 1.44-1.18 (m, 2H);

(746) MASS (ESI, Pos.): 528 (M+H)+.

Example 21(25)

(747) ##STR00105##

N-(2,2-difluoroethyl)-1-[3-(3,5-dimethoxyphenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-4-piperidinamine

(748) Description: yellow amorphous powder;

(749) Purity (UPLC-MS/ELSD): 98.0% (retention time: 0.49 min);

(750) TLC: Rf 0.50 (ethyl acetate, NH silica gel);

(751) NMR (300 MHz, METHANOL-d4): 8.42 (s, 1H), 8.23 (s, 1H), 7.24 (br. s., 1H), 6.93 (s, 1H), 6.58-6.53 (m, 3H), 5.76 (tt, J=15.5, 87.0 Hz, 1H), 3.83 (s, 6H), 3.14-3.05 (m, 2H), 2.78 (dt, J=4.2, 15.5 Hz, 2H), 2.57 (s, 3H), 2.62-2.49 (m, 2H), 2.44 (s, 3H), 2.39-2.26 (m, 1H), 1.55-1.42 (m, 2H), 1.18-0.99 (m, 2H);

(752) MASS (ESI, Pos.): 522 (M+H)+.

Example 21(26)

1-[3-(6-chloro-1,3-benzoxazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine

(753) Description: green amorphous powder;

(754) Purity (UPLC-MS/ELSD): 99.0% (retention time: 0.57 min);

(755) TLC: Rf 0.75 (ethyl acetate:methanol=100:6, NH silica gel);

(756) NMR (300 MHz, METHANOL-d4): 8.67 (s, 1H), 8.24 (s, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.47 (dd, J=2.0, 9.0 Hz, 1H), 7.10-7.03 (m, 3H), 3.15-3.04 (m, 2H), 2.77-2.64 (m, 3H), 2.39 (s, 6H), 1.59-1.46 (m, 2H), 1.34-1.15 (m, 2H);

(757) MASS (ESI, Pos.): 433 (M+H)+.

Example 21(27)

(758) ##STR00106##

rac-(3R,4S)-4-amino-1-[3-(3,5-dimethoxyphenyl)-5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-pyridinyl]-3-piperidinol

(759) Description: colorless oil;

(760) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(761) TLC: Rf 0.47 (ethyl acetate: methanol=9:1, NH silica gel);

(762) NMR (300 MHz, METHANOL-d4): 8.85 (s, 1H), 8.29 (s, 1H), 7.27 (s, 1H), 6.93 (s, 1H), 6.58 (t, J=2.2 Hz, 1H), 6.51 (d, J=2.2 Hz, 2H), 3.82 (s, 6H), 3.69 (br. s., 1H), 3.17-3.05 (m, 1H), 3.04-2.92 (m, 1H), 2.90-2.82 (m, 1H), 2.63-2.54 (m, 4H), 2.45-2.36 (m, 4H), 1.65-1.46 (m, 1H), 1.39-1.25 (m, 1H);

(763) MASS (ESI, Pos.): 474 (M+H)+.

Example 21(28)

rac-(3R,4S)-4-amino-1-[3-(6-fluoro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)-4-pyridinyl]-3-piperidinol

(764) Description: yellow amorphous powder;

(765) Purity (LC-MS/ELSD): 99.0% (retention time: 0.45 min);

(766) TLC: Rf 0.18 (ethyl acetate:methanol=19:1, NH silica gel);

(767) NMR (300 MHz, METHANOL-d4): 8.91 (s, 1H), 8.33 (s, 1H), 7.65 (dd, J=8.9, 4.7 Hz, 1H), 7.39 (dd, J=9.1, 2.2 Hz, 1H), 7.10 (ddd, J=9.7, 8.9, 2.2 Hz, 1H), 6.87-6.74 (m, 3H), 3.87 (s, 3H), 3.71 (br. s., 1H), 3.18-3.07 (m, 1H), 3.06-2.94 (m, 1H), 2.92-2.81 (m, 1H), 2.65-2.54 (m, 1H), 2.39 (dd, J=12.4, 1.0 Hz, 1H), 1.62-1.45 (m, 1H), 1.41-1.27 (m, 1H);

(768) MASS (ESI, Pos.): 452 (M+H)+.

Example 21(29)

rac-(3R,4S)-4-amino-1-[3-(6-chloro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)-4-pyridinyl]-3-piperidinol

(769) Description: yellow amorphous powder;

(770) Purity (LC-MS/ELSD): 99.0% (retention time: 0.51 min);

(771) TLC: Rf 0.18 (ethyl acetate:methanol=19:1, NH silica gel);

(772) NMR (300 MHz, METHANOL-d4): 8.92 (s, 1H), 8.34 (s, 1H), 7.70 (dd, J=2.0, 0.5 Hz, 1H), 7.65 (dd, J=8.6, 0.5 Hz, 1H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 6.87-6.74 (m, 3H), 3.87 (s, 3H), 3.74-3.69 (m, 1H), 3.17-3.07 (m, 1H), 3.06-2.95 (m, 1H), 2.91-2.83 (m, 1H), 2.60 (ddd, J=11.6, 5.0, 2.4 Hz, 1H), 2.39 (dd, J=12.4, 1.0 Hz, 1H), 1.62-1.44 (m, 1H), 1.42-1.27 (m, 1H);

(773) MASS (ESI, Pos.): 468 (M+H)+.

Example 21(30)

(774) ##STR00107##

rac-(4aR,8aR)-6-[3-(6-fluoro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine

(775) Description: off-white powder;

(776) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(777) TLC: Rf 0.35 (ethyl acetate:methanol=19:1, NH silica gel);

(778) NMR (300 MHz, METHANOL-d4): 8.48 (s, 1H), 8.30 (s, 1H), 7.66 (dd, J=8.8, 4.9 Hz, 1H), 7.38 (dd, J=9.1, 2.2 Hz, 1H), 7.12 (ddd, J=9.7, 8.9, 2.2 Hz, 1H), 6.86-6.75 (m, 3H), 3.88 (s, 3H), 3.66 (dd, J=11.6, 2.1 Hz, 1H), 3.45-3.34 (m, 1H), 3.13-2.90 (m, 3H), 2.88-2.61 (m, 3H), 2.42-2.27 (m, 1H), 2.25-2.11 (m, 1H), 1.38-1.26 (m, 2H), 1.23-1.06 (m, 1H);

(779) MASS (ESI, Pos.): 478 (M+H)+.

Example 21(31)

1-[3-(6-chloro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-4-piperidinamine

(780) Description: pale purple powder;

(781) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.47 min);

(782) TLC: Rf 0.20 (ethyl acetate:methanol=20:1, NH silica gel);

(783) NMR (300 MHz, METHANOL-d4): 8.44 (s, 1H), 8.25 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.31 (dd, J=8.5, 1.9 Hz, 1H), 7.09 (s, 1H), 7.03 (s, 1H), 7.00 (s, 1H), 3.07-2.95 (m, 2H), 2.62-2.49 (m, 2H), 2.47-2.43 (m, 4H), 1.42 (dd, J=12.5, 1.9 Hz, 2H), 1.07 (dd, J=11.6, 3.9 Hz, 2H);

(784) MASS (ESI, Pos.): 436 (M+H)+.

Example 21(32)

1-[3-(6-fluoro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-4-piperidinamine

(785) Description: pale brown amorphous powder;

(786) Purity (UPLC-MS/ELSD): 96.7% (retention time: 0.44 min);

(787) TLC: Rf 0.19 (ethyl acetate:methanol=20:1, NH silica gel);

(788) NMR (300 MHz, METHANOL-d4): 8.44 (s, 1H), 8.24 (s, 1H), 7.66-7.61 (m, 1H), 7.38-7.34 (m, 1H), 7.16-7.07 (m, 2H), 7.04-6.99 (m, 1H), 3.07-2.97 (m, 2H), 2.62-2.50 (m, 2H), 2.51-2.44 (m, 4H), 1.47-1.38 (m, 2H), 1.15-0.99 (m, 2H);

(789) MASS (ESI, Pos.): 420 (M+H)+.

Example 21(33)

1-[3-(5-fluoro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)-4-pyridinyl]-4-piperidinamine

(790) Description: pale yellow powder;

(791) Purity (LC-MS/ELSD): 95.0% (retention time: 0.43 min);

(792) TLC: Rf 0.45 (ethyl acetate:methanol=9:1, NH silica gel);

(793) NMR (300 MHz, METHANOL-d4): 8.44 (s, 1H), 8.25 (s, 1H), 7.63 (dd, J=8.8, 4.6 Hz, 1H), 7.36 (dd, J=9.1, 2.3 Hz, 1H), 7.10 (td, J=9.1, 2.4 Hz, 1H), 6.71-6.86 (m, 3H), 3.86 (s, 3H), 3.04 (br. d, J=12.4 Hz, 2H), 2.45-2.67 (m, 3H), 1.45 (br. d, J=10.8 Hz, 2H), 1.03-1.22 (m, 2H),

(794) MASS (ESI, Pos.): 436 (M+H)+.

Example 21(34)

rac-(4aR,8aR)-6-[3-(6-fluoro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine

(795) Description: brown amorphous powder;

(796) Purity (LC-MS/ELSD): 97.0% (retention time: 0.46 min);

(797) TLC: Rf 0.30 (ethyl acetate:methanol=19:1, NH silica gel);

(798) NMR (300 MHz, METHANOL-d4): 8.47 (s, 1H), 8.29 (s, 1H), 7.66 (dd, J=8.8, 4.9 Hz, 1H), 7.38 (dd, J=9.1, 2.3 Hz, 1H), 7.18-6.97 (m, 4H), 3.70-3.60 (m, 1H), 3.38 (td, J=11.5, 3.0 Hz, 1H), 3.10-2.89 (m, 3H), 2.87-2.60 (m, 3H), 2.46 (s, 3H), 2.39-2.26 (m, 1H), 2.23-2.10 (m, 1H), 1.36-1.25 (m, 1H), 1.20-1.03 (m, 1H);

(799) MASS (ESI, Pos.): 462 (M+H)+.

Example 21(35)

rac-(4aR,8aR)-6-[3-(6-chloro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine

(800) Description: brown amorphous powder;

(801) Purity (LC-MS/ELSD): 95.0% (retention time: 0.50 min);

(802) TLC: Rf 0.30 (ethyl acetate:methanol=19:1, NH silica gel);

(803) NMR (300 MHz, METHANOL-d4): 8.48 (s, 1H), 8.29 (s, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.33 (dd, J=8.7, 1.9 Hz, 1H), 7.11-7.08 (m, 1H), 7.07-6.97 (m, 2H), 3.65 (dd, J=11.4, 2.1 Hz, 1H), 3.39 (td, J=11.5, 3.2 Hz, 1H), 3.10-2.88 (m, 3H), 2.87-2.76 (m, 1H), 2.76-2.59 (m, 2H), 2.50-2.43 (m, 3H), 2.38-2.25 (m, 1H), 2.23-2.09 (m, 1H), 1.36-1.25 (m, 1H), 1.19-1.02 (m, 1H);

(804) MASS (ESI, Pos.): 478 (M+H)+.

Example 21(36)

1-[3-(5-fluoro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine

(805) Description: yellow amorphous powder;

(806) Purity (LC-MS/ELSD): 100% (retention time: 0.43 min);

(807) TLC: Rf 0.47 (ethyl acetate:methanol=9:1, NH silica gel);

(808) NMR (300 MHz, METHANOL-d4): 8.43 (s, 1H), 8.23 (s, 1H), 7.58-7.68 (m, 1H), 7.30-7.42 (m, 1H), 6.95-7.19 (m, 4H), 4.66 (t, J=7.0 Hz, 2H), 4.35 (t, J=6.5 Hz, 2H), 3.86-3.98 (m, 1H), 3.01 (br. d, J=13.0 Hz, 2H), 2.46-2.58 (m, 2H), 2.44 (s, 3H), 2.20-2.33 (m, 1H), 1.37 (br. d, J=11.2 Hz, 2H), 0.96-1.13 (m, 2H);

(809) MASS (ESI, Pos.): 476 (M+H)+.

Example 21(37)

(810) ##STR00108##

1-[3-fluoro-3-(5-fluoro-1H-benzimidazol-2-yl)-5-methyl-2-biphenylyl]-4-piperidinamine

(811) Description: off-white powder;

(812) Purity (LC-MS/ELSD): 99.8% (retention time: 0.61 min);

(813) TLC: Rf 0.56 (ethyl acetate:methanol=9:1, NH silica gel);

(814) NMR (300 MHz, METHANOL-d4): 7.60 (dd, J=8.9, 4.7 Hz, 1H), 7.49 (dd, J=7.3, 2.0 Hz, 1H), 7.22-7.37 (m, 3H), 6.89-7.13 (m, 4H), 3.02 (br. d, J=12.3 Hz, 2H), 2.57-2.72 (m, 1H), 2.39-2.54 (m, 5H), 1.53 (br. d, J=11.7 Hz, 2H), 1.04-1.20 (m, 2H);

(815) MASS (ESI, Pos.): 419 (M+H)+.

Example 21(38)

1-[3-(5-chloro-1H-benzimidazol-2-yl)-3-fluoro-5-methyl-2-biphenylyl]-4-piperidinamine

(816) Description: white powder;

(817) Purity (LC-MS/ELSD): 97.1% (retention time: 0.68 min);

(818) TLC: Rf 0.59 (ethyl acetate:methanol=9:1, NH silica gel);

(819) NMR (300 MHz, METHANOL-d4): 7.63 (d, J=1.5 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.51 (dd, J=7.3, 2.0 Hz, 1H), 7.22-7.35 (m, 3H), 6.89-7.04 (m, 3H), 2.97 (br. d, J=11.9 Hz, 2H), 2.38-2.56 (m, 6H), 1.48 (br. d, J=11.7 Hz, 2H), 0.97-1.13 (m, 2H);

(820) MASS (ESI, Pos.): 435 (M+H)+.

Example 21(39)

1-[3-(5-chloro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine

(821) Description: off-white powder;

(822) Purity (LC-MS/ELSD): 98.5% (retention time: 0.50 min);

(823) TLC: Rf 0.70 (ethyl acetate:methanol=9:1, NH silica gel);

(824) NMR (300 MHz, METHANOL-d4): 8.43 (s, 1H), 8.24 (s, 1H), 7.57-7.69 (m, 2H), 7.31 (dd, J=8.6, 2.0 Hz, 1H), 7.07 (br. s, 1H), 6.96-7.04 (m, 2H), 4.66 (t, J=6.9 Hz, 2H), 4.35 (t, J=6.6 Hz, 2H), 3.85-3.98 (m, 1H), 3.01 (br. d, J=12.6 Hz, 2H), 2.39-2.58 (m, 5H), 2.19-2.34 (m, 1H), 1.37 (br. d, J=11.3 Hz, 2H), 0.95-1.13 (m, 2H);

(825) MASS (ESI, Pos.): 492 (M+H)+.

Reference Example 30

methyl 5-bromo-4-hydroxypyridine-3-carboxylate

(826) To a suspension of methyl 4-hydroxypyridine-3-carboxylate (CAS#67367-24-2) (1.96 g) in acetonitrile (20 mL)/acetic acid (4 mL) was added N-bromosuccinimide (CAS#128-08-5) (2.39 g) at room temperature, and the mixture was stirred at 60 degrees C. for 4 hours followed by concentration. To the obtained residue was added acetone, and the mixture was stirred for 5 min. The insoluble matter was collected by filtration to obtain the title compound having the following physical property values.

(827) Description: white powder;

(828) TLC: Rf 0.53 (ethyl acetate:methanol=4:1);

Example 22(1)-Example 22(6)

(829) Using tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate (CAS#118811-03-3) in place of the compound produced in Reference example 8, using the compound produced in Reference example 30 in place of 3,5-dimethylphenol, using a corresponding reagent in place of phenylboronic acid, using a corresponding reagent in place of 3,5-dimethylaniline, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 9.fwdarw.Reference example 2.fwdarw.Reference example 6.fwdarw.Reference example 7.fwdarw.Example 1.

Example 22(1)

N,5-bis(3,5-dimethylphenyl)-4-[2-(2-piperidinyl)ethoxy]pyridine-3-carboxamide

(830) ##STR00109##

(831) Description: colorless oil;

(832) Purity (LC-MS/ELSD): 95.1% (retention time: 4.07 min);

(833) TLC: Rf 0.53 (ethyl acetate:methanol=9:1, NH silica gel);

(834) NMR (300 MHz, CHLOROFORM-d): 9.50 (br. s., 1H), 9.23 (s, 1H), 8.57 (s, 1H), 7.35 (s, 2H), 7.12 (s, 2H), 7.08 (s, 1H), 6.80 (s, 1H), 3.86-3.71 (m, 2H), 2.89 (d, J=12.08 Hz, 1H), 2.40 (s, 6H), 2.52-2.23 (m, 4H), 2.34 (s, 6H), 1.77-0.79 (m, 5H);

(835) MASS (ESI, Pos.): 458 (M+H)+.

Example 22(2)

5-(3,5-dimethylphenyl)-N-[3-(hydroxymethyl)phenyl]-4-[2-(2-piperidinyl)ethoxy]pyridine-3-carboxamide

(836) Description: colorless oil;

(837) Purity (LC-MS/ELSD): 100% (retention time: 3.66 min);

(838) TLC: Rf 0.46 (ethyl acetate:methanol=9:1, NH silica gel);

(839) NMR (300 MHz, CHLOROFORM-d): 9.72 (br. s., 1H), 9.23 (s, 1H), 8.59 (s, 1H), 7.77 (d, J=7.80 Hz, 1H), 7.63 (s, 1H), 7.36 (t, J=7.87 Hz, 1H), 7.17-7.03 (m, 5H), 4.71 (s, 2H), 3.92-3.65 (m, 2H), 2.92 (d, J=13.55 Hz, 1H), 2.65-2.27 (m, 8H), 1.80-1.64 (m, 2H), 1.65-1.47 (m, 2H), 1.42 (d, J=5.13 Hz, 1H), 1.36-1.11 (m, 2H), 1.01-0.78 (m, 1H);

(840) MASS (ESI, Pos.): 460 (M+H)+.

Example 22(3)

N-(3-carbamoylphenyl)-5-(3,5-dimethylphenyl)-4-[2-(2-piperidinyl)ethoxy]pyridine-3-carboxamide

(841) Description: white amorphous powder;

(842) Purity (LC-MS/ELSD): 98.6% (retention time: 3.78 min);

(843) TLC: Rf 0.43 (ethyl acetate:methanol=9:1);

(844) NMR (300 MHz, CHLOROFORM-d): 9.94 (br. s., 1H), 9.27 (s, 1H), 8.61 (s, 1H), 8.15-8.07 (m, 1H), 8.01 (t, J=1.83 Hz, 1H), 7.72-7.65 (m, 1H), 7.55-7.44 (m, 1H), 7.13 (s, 2H), 7.10 (s, 1H), 6.93 (br. s., 1H), 5.79-5.49 (m, 1H), 3.81 (t, J=6.13 Hz, 2H), 2.93 (d, J=2.93 Hz, 1H), 2.64-2.33 (m, 2H), 2.41 (s, 6H), 1.88-1.37 (m, 5H), 1.33-1.13 (m, 2H), 0.98-0.79 (m, 1H);

(845) MASS (ESI, Pos.): 473 (M+H)+.

Example 22(4)

N-benzyl-5-(3,5-dimethylphenyl)-4-[2-(2-piperidinyl)ethoxy]pyridine-3-carboxamide

(846) Description: pale yellow powder;

(847) Purity (LC-MS/ELSD): 100% (retention time: 3.78 min);

(848) TLC: Rf 0.43 (ethyl acetate);

(849) NMR (300 MHz, CHLOROFORM-d): 9.22 (s, 1H), 8.54 (s, 1H), 8.19-8.05 (m, 1H), 7.43-7.26 (m, 5H), 7.07 (s, 2H), 7.05 (s, 1H), 4.68 (d, J=5.68 Hz, 2H), 3.75-3.51 (m, 2H), 2.99-2.74 (m, 1H), 2.38-2.18 (m, 8H), 1.74-1.60 (m, 1H), 1.57-1.42 (m, 2H), 1.39-1.08 (m, 4H), 0.94-0.68 (m, 1H);

(850) MASS (ESI, Pos.): 444 (M+H)+.

Example 22(5)

5-(3,5-dimethylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-4-[2-(2-piperidinyl)ethoxy]pyridine-3-carboxamide

(851) Description: beige powder;

(852) Purity (LC-MS/ELSD): 100% (retention time: 3.59 min);

(853) TLC: Rf 0.70 (ethyl acetate:methanol=9:1, NH silica gel);

(854) NMR (300 MHz, CHLOROFORM-d): 9.66 (s, 1H), 9.21 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.57 (s, 1H), 7.11 (s, 2H), 7.09 (s, 1H), 3.88 (s, 3H), 3.85-3.69 (m, 2H), 3.09-2.87 (m, 1H), 2.63-1.82 (m, 9H), 1.77-1.51 (m, 2H), 1.49-1.19 (m, 4H), 1.10-0.91 (m, 1H);

(855) MASS (ESI, Pos.): 434 (M+H)+.

Example 22(6)

N-(3,5-dimethylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-4-[2-(2-piperidinyl)ethoxy]pyridine-3-carboxamide

(856) Description: pale yellow oil;

(857) Purity (LC-MS/ELSD): 100% (retention time: 3.64 min);

(858) TLC: Rf 0.63 (ethyl acetate:methanol=9:1, NH silica gel);

(859) NMR (300 MHz, CHLOROFORM-d): 8.99 (s, 2H), 8.74 (s, 1H), 7.86 (s, 2H), 7.32 (s, 2H).6.84 (s, 1H), 4.05-3.87 (m, 2H), 4.00 (s, 3H), 3.09-2.93 (m, 1H), 2.77-2.64 (m, 1H), 2.64-2.48 (m, 1H), 2.37-2.31 (m, 6H), 1.95-1.69 (m, 4H), 1.67-1.49 (m, 2H), 1.48-1.04 (m, 2H);

(860) MASS (ESI, Pos.): 434 (M+H)+.

Example 23

N-{5-(3,5-dimethylphenyl)-4-[2-(2-piperidinyl)ethoxy]-3-pyridinyl}-3,5-dimethylbenzamide

(861) ##STR00110##

(862) Using tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate in place of the compound produced in Reference example 8, using the compound produced in Reference example 30 in place of 3,5-dimethylphenol, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 9.fwdarw.Reference example 2.fwdarw.Reference example 6.fwdarw.Reference example 12.fwdarw.Reference Example 17.fwdarw.Example 1.

(863) Description: white powder;

(864) Purity (LC-MS/ELSD): 100% (retention time: 3.91 min);

(865) TLC: Rf 0.64 (ethyl acetate:methanol=9:1, NH silica gel);

(866) NMR (300 MHz, CHLOROFORM-d): 9.64 (s, 1H), 8.99 (br. s., 1H), 8.28 (s, 1H), 7.49 (s, 2H), 7.19 (s, 1H), 7.12 (s, 2H), 7.04 (s, 1H), 3.79-3.61 (m, 2H), 2.71 (d, J=9.1 Hz, 1H), 2.40 (s, 6H), 2.38 (s, 6H), 2.55-2.26 (m, 2H), 1.72-1.33 (m, 6H), 1.24-1.07 (m, 2H), 1.01-0.86 (m, 1H),

(867) MASS (ESI, Pos.): 458 (M+H)+.

Example 24(1)-Example 24(2)

(868) Using tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate in place of the compound produced in Reference example 8, using the compound produced in Reference example 30 in place of 3,5-dimethylphenol, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, using 3,5-dimethylbenzaldehyde, or a corresponding reagent in place of it, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 9.fwdarw.Reference example 2.fwdarw.Reference example 6.fwdarw.Reference example 12.fwdarw.Reference example 13.fwdarw.Example 1.

Example 24(1)

N-(3,5-dimethylbenzyl)-5-(3,5-dimethylphenyl)-4-[2-(2-piperidinyl)ethoxy]-3-pyridinamine

(869) ##STR00111##

(870) Description: colorless oil;

(871) Purity (LC-MS/ELSD): 100% (retention time: 3.82 min);

(872) TLC: Rf 0.70 (ethyl acetate:methanol=9:1, NH silica gel);

(873) NMR (300 MHz, CHLOROFORM-d): 7.91 (s, 1H), 7.87 (s, 1H), 7.14 (s, 2H), 7.02-6.97 (m, 3H), 6.90 (s, 1H), 5.90-5.41 (br, 1H), 4.33 (s, 2H), 3.73-3.63 (m, 1H), 3.63-3.53 (m, 1H), 2.97-2.87 (m, 1H), 2.64-2.40 (m, 2H), 2.36 (s, 6H), 2.31 (s, 6H), 1.76-1.42 (m, 6H), 1.36-1.22 (m, 2H), 1.09-0.93 (m, 1H);

(874) MASS (ESI, Pos.): 444 (M+H)+.

Example 24(2)

5-(3,5-dimethylphenyl)-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-[2-(2-piperidinyl)ethoxy]-3-pyridinamine

(875) Description: colorless oil;

(876) Purity (LC-MS/ELSD): 100% (retention time: 3.43 min);

(877) TLC: Rf 0.54 (ethyl acetate:methanol=4:1, NH silica gel);

(878) NMR (300 MHz, CHLOROFORM-d): 7.99 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 7.13 (s, 2H), 7.00 (s, 1H), 5.65-5.17 (br, 1H), 4.28 (s, 2H), 3.88 (s, 3H), 3.67-3.50 (m, 2H), 2.98-2.89 (m, 1H), 2.61-2.43 (m, 2H), 2.36 (s, 6H), 1.78-1.40 (m, 6H), 1.35-1.19 (m, 2H), 1.06-0.91 (m, 1H);

(879) MASS (ESI, Pos.): 420 (M+H)+.

Reference Example 31

ethyl 5-hydroxy-1-(quinolin-2-yl)-1H-pyrazole-4-carboxylate

(880) To a suspension of diethyl ethoxymethylenemalonate (CAS#87-13-8) (4.32 g) in water (40 mL) was added 2-hydrazinoquinoline (CAS#15793-77-8) (3.18 g) and potassium carbonate (2.76 g), and the mixture was refluxed for 5.5 hours. After cooling to room temperature, the precipitate was collected by filtration. The precipitate was suspended in the mixture of water and ethyl acetate and made weakly acidic with 2M hydrochloric acid. After being stirred, the precipitate was collected by filtration and dried to obtain the title compound (3.37 g) having the following physical property values.

(881) Description: beige powder;

(882) TLC: Rf 0.36 (dichloromethane: methanol=9:1)

Reference Example 32

ethyl 5-chloro-1-(quinolin-2-yl)-1H-pyrazole-4-carboxylate

(883) The compound (1.0 g) produced in Reference example 31 was mixed with phosphorus oxychloride (6 mL) under ice cooling, and stirred at 100 degrees C. for 16 hours. After cooling, the reaction solution was poured into the mixture of ice and ethyl acetate, and then washed with water and saturated brine sequentially. After drying, the organic layer was concentrated and treated with benzene as azeotropy four times. The obtained residue was purified by silica gel column chromatography (eluent hexane:ethyl acetate=95:5.fwdarw.75:25) to obtain the mixture of the title compound and mineral salt (2.2 g) having the following physical property values.

(884) TLC: Rf 0.71 (n-hexane:ethyl acetate=1:1);

Reference Example 33

ethyl 5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-1-(quinolin-2-yl)-1H-pyrazole-4-carboxylate

(885) To a dimethylacetamide (2.5 mL) solution of the mixture produced in Reference example 32 (500 mg) was added potassium phosphate (529 mg) and 4-(tert-butoxycarbonylamino)piperidine (365 mg), and stirred at 100 degrees C. for 21 hours. After cooling to room temperature, the reaction solution was added water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and concentrated after drying. The obtained residue was purified by silica gel column chromatography (eluent hexane:ethyl acetate=90:10.fwdarw.75:25) to obtain the title compound (58 mg) having the following physical property values.

(886) TLC: Rf 0.23 (n-hexane:ethyl acetate=3:1).

Example 25

5-(4-amino-1-piperidinyl)-N-(3,5-dimethylphenyl)-1-(2-quinolinyl)-1H-pyrazole-4-carboxamide

(887) ##STR00112##

(888) Using the compound produced in Reference example 33 in place of the compound produced in Reference example 5, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 6.fwdarw.Reference example 7.fwdarw.Example 1.

(889) Description: amber powder;

(890) TLC: Rf 0.67 (ethyl acetate:methanol=10:1, NH silica gel);

(891) NMR (300 MHz, CHLOROFORM-d): 9.92 (s, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.23 (s, 1H), 8.08-7.99 (m, 2H), 7.93-7.85 (m, 1H), 7.77 (ddd, J=8.4, 7.0, 1.5 Hz, 1H), 7.64-7.55 (m, 1H), 7.31 (s, 2H), 6.74 (s, 1H), 3.81-3.69 (m, 2H), 3.23 (d, J=12.1 Hz, 2H), 3.17-3.05 (m, 1H), 2.31 (s, 6H), 2.13-2.00 (m, 2H), 1.83-1.66 (m, 2H);

(892) MASS (ESI, Pos.): 441 (M+H)+.

Reference Example 34

benzyl (1-(3-amino-5-(3,5-dimethylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate

(893) Using benzyl piperidin-4-ylcarbamate (CAS#182223-54-7) in place of tert-butyl N-(4-piperidylmethyl)carbamate, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 14.fwdarw.Reference example 2.fwdarw.Reference example 16 and used for next reaction without further purification.

Reference Example 35

benzyl (1-(3-(3,5-dimethylphenyl)-5-iodopyridin-4-yl)piperidin-4-yl)carbamate

(894) To an anhydrous dichloromethane (36 mL) solution of the compound (1.68 g) produced in Reference example 34 was added boron trifluoride diethyl ether complex (BF.sub.3-Et.sub.2O) (2.05 mL) under ice cooling, and the mixture was stirred for 10 min. To the reaction solution was added amyl nitrite (1.87 mL) and stirred for 25 min under ice cooling. To the reaction solution was added the acetone (7.8 mL) solution of sodium iodide (CAS#7681-82-5) (1.8 g), and stirred for 30 min under ice-cooling. To the reaction solution was added saturated aqueous solution of sodium thiosulfate solution, and stirred at room temperature. After adding 1M aqueous solution of sodium hydroxide, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=1:1) to obtain the title compound (1.27 g) having the following physical property values.

(895) Description: pale yellow amorphous powder;

(896) TLC: Rf 0.72 (ethyl acetate);

Reference Example 36

benzyl (1-(3-(1,3-benzoxazol-2-yl)-5-(3,5-dimethylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate

(897) To a toluene (1.0 mL) solution of the compound (60 mg) produced in Reference example 35 was added potassium carbonate (38 mg), copper(II) acetate monohydrate (4.44 mg), palladium acetate (1.24 mg), triphenylphosphine (14.5 mg) and benzoxazole (CAS#273-53-0) (22 microL), and the mixture was stirred at 100 degrees C. overnight. To the reaction solution was added additional potassium carbonate (38 mg), copper(II) acetate monohydrate (6.2 mg), palladium acetate (1.2 mg), triphenylphosphine (15 mg) and benzoxazole (22 microL), and the mixture was stirred for 8 hours. After cooling to room temperature, the reaction solution was added water and ethyl acetate, and sequentially washed with water and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (n-hexane:ethyl acetate=1:1) to obtain the title compound (20 mg) having the following physical property values.

(898) TLC: Rf 0.25 (n-hexane:ethyl acetate=3:1, NH silica gel);

Example 26(1)-Example 26(89)

(899) Using 1-bromo-2-chloro-3-benzene in place of 3-bromo-4-chloro-5-nitropyridine or 3-bromo-4-chloro-5-nitropyridine, using a corresponding piperidine derivative in place of tert-butyl N-(4-piperidylmethyl)carbamate or tert-butyl N-(4-piperidylmethyl)carbamate, using a corresponding phenylboronic acid derivative in place of phenylboronic acid, using benzoxazole or a corresponding heterocyclic ring or a corresponding boronic acid derivative, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 14.fwdarw.Reference example 2.fwdarw.Reference example 16.fwdarw.Reference example 35.fwdarw.Reference example 36.fwdarw.Example 1 or Example 4.

Example 26(1)

1-[3-(1,3-benzoxazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine

(900) ##STR00113##

(901) Description: yellow oil;

(902) TLC: Rf 0.24 (ethyl acetate, NH silica gel);

(903) NMR (300 MHz, METHANOL-d4): 8.62 (s, 1H), 8.21 (s, 1H), 7.85-7.77 (m, 1H), 7.76-7.68 (m, 1H), 7.52-7.40 (m, 2H), 7.11-7.02 (m, 3H), 3.07 (d, J=12.6 Hz, 2H), 2.75-2.61 (m, 2H), 2.51 (s, 1H), 2.39 (s, 6H), 1.45 (dd, J=12.1, 2.0 Hz, 2H), 1.22-1.06 (m, 2H);

(904) MASS (ESI, Pos.): 399 (M+H)+.

Example 26(2)

1-[3-(1,3-benzothiazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine

(905) Description: yellow oil;

(906) TLC: Rf 0.57 (ethyl acetate:methanol=19:1, NH silica gel);

(907) NMR (300 MHz, METHANOL-d4): 8.68 (s, 1H), 8.22 (s, 1H), 8.16-7.96 (m, 2H), 7.62-7.53 (m, 1H), 7.53-7.44 (m, 1H), 7.10 (s, 1H), 7.03 (s, 2H), 3.13-3.00 (m, 2H), 2.70-2.57 (m, 2H), 2.53-2.34 (m, 7H), 1.55-1.42 (m, 2H), 1.41-1.24 (m, 2H);

(908) MASS (ESI, Pos.): 415 (M+H)+.

Example 26(3)

1-[5-(3,5-dimethylphenyl)-6-ethoxy-3,3-bipyridin-4-yl]-4-piperidinamine

(909) Description: colorless oil;

(910) Purity (UPLC-MS/ELSD): 99.6% (retention time: 0.45 min);

(911) TLC: Rf 0.69 (ethyl acetate:methanol=9:1, NH silica gel);

(912) NMR (300 MHz, CHLOROFORM-d): 8.26 (s, 1H), 8.21 (s, 1H), 8.18 (dd, J=2.4, 0.7 Hz, 1H), 7.63 (dd, J=8.4, 2.4 Hz, 1H), 7.02-7.00 (m, 1H), 6.97-6.94 (m, 2H), 6.82 (dd, J=8.4, 0.7 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.90-2.80 (m, 2H), 2.37 (s, 6H), 2.52-2.34 (m, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.45-1.38 (m, 2H), 1.02-0.86 (m, 2H);

(913) MASS (ESI, Pos.): 403 (M+H)+.

Example 26(4)

1-[3-(3,5-dimethylphenyl)-5-(2-methyl-2H-indazol-5-yl)-4-pyridinyl]-4-piperidinamine

(914) Description: pale brown amorphous powder;

(915) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.50 min);

(916) TLC: Rf 0.53 (ethyl acetate:methanol=9:1, NH silica gel);

(917) NMR (300 MHz, CHLOROFORM-d): 8.30 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.75-7.71 (m, 1H), 7.63-7.61 (m, 1H), 7.31-7.27 (m, 1H), 7.02-6.97 (m, 3H), 4.26 (s, 3H), 2.95-2.86 (m, 2H), 2.37 (s, 6H), 2.47-2.32 (m, 3H), 1.39-1.28 (m, 2H), 0.98-0.84 (m, 2H);

(918) MASS (ESI, Pos.): 412 (M+H)+.

Example 26(5)

1-[3-(3,5-dimethylphenyl)-5-(1-methyl-1H-benzimidazol-5-yl)-4-pyridinyl]-4-piperidinamine

(919) Description: white amorphous powder;

(920) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.41 min);

(921) TLC: Rf 0.28 (ethyl acetate:methanol=9:1, NH silica gel);

(922) NMR (300 MHz, CHLOROFORM-d): 8.29 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.82 (dd, J=1.6, 0.6 Hz, 1H), 7.46 (dd, J=8.3, 0.6 Hz, 1H), 7.34 (dd, J=8.3, 1.6 Hz, 1H), 7.03-6.98 (m, 3H), 3.91 (s, 3H), 2.92-2.83 (m, 2H), 2.37 (s, 6H), 2.47-2.29 (m, 3H), 1.37-1.24 (m, 2H), 0.97-0.82 (m, 2H);

(923) MASS (ESI, Pos.): 412 (M+H)+.

Example 26(6)

1-[3-(3,5-dimethoxyphenyl)-5-(5-fluoro-1H-indol-2-yl)-4-pyridinyl]-4-piperidinamine

(924) Description: deep yellow powder;

(925) Purity (UPLC-MS/ELSD): 98.9% (retention time: 0.52 min);

(926) TLC: Rf 0.52 (ethyl acetate:methanol=9:1, NH silica gel);

(927) NMR (300 MHz, CHLOROFORM-d): 9.51 (br. s., 1H), 8.67 (s, 1H), 8.25 (s, 1H), 7.36-7.27 (m, 2H), 7.01-6.90 (m, 1H), 6.73 (dd, J=2.0, 0.7 Hz, 1H), 6.51 (t, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 2H), 3.84 (s, 6H), 3.08-2.96 (m, 2H), 2.69-2.53 (m, 3H), 1.70-1.59 (m, 2H), 1.36-1.18 (m, 2H);

(928) MASS (ESI, Pos.): 447 (M+H)+.

Example 26(7)

1-[3-(3-fluoro-5-methoxyphenyl)-5-(6-methoxy-1H-indol-2-yl)-4-pyridinyl]-4-piperidinamine

(929) Description: pale brown powder;

(930) Purity (UPLC-MS/ELSD): 99.7% (retention time: 0.47 min);

(931) TLC: Rf 0.68 (ethyl acetate:methanol=9:1, NH silica gel);

(932) NMR (300 MHz, CHLOROFORM-d): 9.23 (br. s., 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.6, 2.2 Hz, 1H), 6.71-6.62 (m, 4H), 3.88 (s, 3H), 3.85 (s, 3H), 3.02 (d, J=12.8 Hz, 2H), 2.71-2.49 (m, 3H), 1.70-1.54 (m, 2H), 1.36-1.18 (m, 2H);

(933) MASS (ESI, Pos.): 447 (M+H)+.

Example 26(8)

(934) ##STR00114##

1-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-5-(3-fluoro-5-methoxyphenyl)-4-pyridinyl]-4-piperidinamine

(935) Description: pale brown powder;

(936) Purity (UPLC-MS/ELSD): 98.7% (retention time: 0.25 min);

(937) TLC: Rf 0.49 (ethyl acetate:methanol=20:1, NH silica gel);

(938) NMR (300 MHz, METHANOL-d4): 8.09 (s, 1H), 8.07 (s, 1H), 6.80-6.70 (m, 4H), 6.65 (d, J=1.8 Hz, 1H), 6.58 (dd, J=8.2, 2.2 Hz, 1H), 4.26-4.21 (m, 2H), 3.85 (s, 3H), 3.41-3.36 (m, 2H), 2.99 (d, 2H), 2.56-2.42 (m, 3H), 1.50-1.41 (m, 2H), 1.18-1.05 (m, 2H);

(939) MASS (ESI, Pos.): 435 (M+H)+.

Example 26(9)

1-[3-(3-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-indazol-5-yl)-4-pyridinyl]-4-piperidinamine

(940) Description: pale yellow powder;

(941) Purity (UPLC-MS/ELSD): 98.5% (retention time: 0.24 min);

(942) TLC: Rf 0.41 (ethyl acetate:methanol=20:1, NH silica gel);

(943) NMR (300 MHz, METHANOL-d4): 8.19 (s, 1H), 8.16 (s, 1H), 8.08 (d, J=0.9 Hz, 1H), 7.80 (dd, J=1.6, 0.8 Hz, 1H), 7.67 (dt, J=8.7, 0.8 Hz, 1H), 7.48 (dd, J=8.7, 1.6 Hz, 1H), 6.81-6.72 (m, 3H), 4.12 (s, 3H), 3.86 (s, 3H), 3.02-2.93 (m, 2H), 2.52-2.32 (m, 3H), 1.40-1.30 (m, 2H), 1.05-0.90 (m, 2H);

(944) MASS (ESI, Pos.): 432 (M+H)+.

Example 26(10)

(945) ##STR00115##

1-[3-(3-fluoro-5-methoxyphenyl)-5-(1H-indazol-6-yl)-4-pyridinyl]-4-piperidinamine

(946) Description: pale yellow powder;

(947) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.41 min);

(948) TLC: Rf 0.35 (ethyl acetate:methanol=20:1, NH silica gel);

(949) NMR (300 MHz, METHANOL-d4): 8.22 (s, 1H), 8.17 (s, 1H), 8.10 (d, J=0.9 Hz, 1H), 7.88 (dd, J=8.2, 0.5 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.19 (dd, J=8.4, 1.3 Hz, 1H), 6.83-6.72 (m, 3H), 3.86 (s, 3H), 3.04-2.94 (m, 2H), 2.53-2.33 (m, 3H), 1.52-1.32 (m, 2H), 1.08-0.91 (m, 2H),

(950) MASS (ESI, Pos.): 418 (M+H)+.

Example 26(11)

1-{3-(3,5-dimethoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(951) Description: white amorphous powder;

(952) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.50 min);

(953) TLC: Rf 0.73 (ethyl acetate:methanol=9:1, NH silica gel);

(954) NMR (300 MHz, CHLOROFORM-d): 8.30 (s, 1H), 8.23 (s, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 6.53-6.47 (m, 3H), 3.84 (s, 6H), 2.94-2.84 (m, 2H), 2.57-2.37 (s, 3H), 1.48-1.36 (m, 2H), 1.03-0.88 (m, 2H);

(955) MASS (ESI, Pos.): 458 (M+H)+.

Example 26(12)

(956) ##STR00116##

5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methoxyphenyl)-3-pyridinyl]-2-methylphenol

(957) Description: pale brown powder;

(958) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.44 min);

(959) TLC: Rf 0.59 (ethyl acetate:methanol=9:1, NH silica gel);

(960) NMR (300 MHz, METHANOL-d4): 8.14 (s, 2H), 7.18 (d, J=7.3 Hz, 1H), 6.82-6.72 (m, 5H), 3.85 (s, 3H), 3.16-3.00 (m, 2H), 2.97-2.79 (m, 1H), 2.62-2.47 (m, 2H), 2.24 (s, 3H), 1.66-1.52 (m, 2H), 1.36-1.16 (m, 2H);

(961) MASS (ESI, Pos.): 408 (M+H)+.

Example 26(13)

(962) ##STR00117##

5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methoxyphenyl)-3-pyridinyl]-2-methylphenyl acetate

(963) Description: yellow amorphous powder;

(964) Purity (UPLC-MS/ELSD): 99.8% (retention time: 0.48 min);

(965) TLC: Rf 0.40 (ethyl acetate:methanol=9:1);

(966) NMR (300 MHz, METHANOL-d4): 8.19 (s, 2H), 7.42 (d, J=7.9 Hz, 1H), 7.25 (dd, J=1.6, 7.9 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 6.86-6.67 (m, 3H), 3.85 (s, 3H), 3.12-2.98 (m, 2H), 2.98-2.81 (m, 1H), 2.64-2.45 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H), 1.64-1.48 (m, 2H), 1.35-1.15 (m, 2H);

(967) MASS (ESI, Pos.): 450 (M+H)+.

Example 26(14)

1-{3-(3,5-dimethoxyphenyl)-5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(968) Description: ivory amorphous powder;

(969) Purity (UPLC-MS/ELSD): 99.5% (retention time: 0.46 min);

(970) TLC: Rf 0.65 (ethyl acetate:methanol=9:1, NH silica gel);

(971) NMR (300 MHz, CHLOROFORM-d): 8.29 (s, 1H), 8.16 (s, 1H), 7.34-7.30 (m, 2H), 7.19 (s, 1H), 6.56 (d, J=2.2 Hz, 2H), 6.48 (t, J=2.2 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 6H), 2.94-2.84 (m, 2H), 2.53-2.33 (m, 3H), 1.47-1.33 (m, 2H), 0.94-0.74 (m, 2H);

(972) MASS (ESI, Pos.): 488 (M+H)+.

Example 26(15)

(973) ##STR00118##

1-{3-(3,5-dimethylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(974) Description: yellow amorphous powder;

(975) Purity (UPLC-MS/ELSD): 98.5% (retention time: 0.54 min);

(976) TLC: Rf 0.76 (ethyl acetate:methanol=9:1, NH silica gel);

(977) NMR (300 MHz, METHANOL-d4): 8.28 (s, 1H), 8.22 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.02 (s, 1H), 6.97 (s, 2H), 2.90-2.78 (m, 2H), 2.53-2.31 (m, 9H), 1.45-1.33 (m, 2H), 1.01-0.80 (m, 2H);

(978) MASS (ESI, Pos.): 426 (M+H)+.

Example 26(16)

1-{3-(3-fluoro-5-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(979) Description: white amorphous powder;

(980) Purity (UPLC-MS/ELSD): 98.9% (retention time: 0.52 min);

(981) TLC: Rf 0.76 (ethyl acetate:methanol=9:1, NH silica gel);

(982) NMR (300 MHz, METHANOL-d4): 8.18 (s, 1H), 8.17 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 6.81-6.70 (m, 3H), 3.85 (s, 3H), 3.00-2.88 (m, 2H), 2.54-2.38 (m, 3H), 1.47-1.36 (m, 2H), 1.10-0.92 (m, 2H); MASS (ESI, Pos.): 446 (M+H)+.

Example 26(17)

1-{3-(3-fluoro-5-methoxyphenyl)-5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(983) Description: white amorphous powder;

(984) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.50 min);

(985) TLC: Rf 0.65 (ethyl acetate:methanol=9:1, NH silica gel);

(986) NMR (300 MHz, CHLOROFORM-d): 8.26 (s, 1H), 8.17 (s, 1H), 7.33-7.29 (m, 2H), 7.18 (s, 1H), 6.78-6.71 (m, 2H), 6.67-6.60 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 2.92-2.80 (m, 2H), 2.54-2.31 (m, 3H), 1.46-1.35 (m, 2H), 0.95-0.73 (m, 2H);

(987) MASS (ESI, Pos.): 476 (M+H)+.

Example 26(18)

1-[3-(3,5-dimethoxyphenyl)-5-(1H-indazol-6-yl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine

(988) Description: yellow amorphous powder;

(989) Purity (LC-MS/ELSD): 100% (retention time: 0.45 min);

(990) TLC: Rf 0.52 (ethyl acetate:methanol=9:1, NH silica gel);

(991) NMR (300 MHz, METHANOL-d4): 8.19 (s, 1H), 8.16 (s, 1H), 8.10 (d, J=1.1 Hz, 1H), 7.84-7.91 (m, 1H), 7.57-7.61 (m, 1H), 7.20 (dd, J=8.3, 1.4 Hz, 1H), 6.51-6.56 (m, 3H), 4.65 (t, J=7.0 Hz, 2H), 4.35 (t, J=6.6 Hz, 2H), 3.87-3.99 (m, 1H), 3.77-3.87 (m, 6H), 3.01 (br. d, J=12.6 Hz, 2H), 2.37-2.51 (m, 2H), 2.18-2.32 (m, 1H), 1.31 (br. d, J=12.4 Hz, 2H), 0.91-1.07 (m, 2H);

(992) MASS (ESI, Pos.): 486 (M+H)+.

Example 26(19)

1-[3-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-indazol-5-yl)-4-pyridinyl]-N-(3-oxetanyl)-4-piperidinamine

(993) Description: deep yellow amorphous powder;

(994) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(995) TLC: Rf 0.12 (ethyl acetate:methanol=9:1);

(996) NMR (300 MHz, METHANOL-d4): 8.16 (s, 1H), 8.14 (s, 1H), 8.08 (d, J=1.1 Hz, 1H), 7.77-7.81 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.48 (dd, J=8.7, 1.6 Hz, 1H), 6.48-6.56 (m, 3H), 4.65 (t, J=7.0 Hz, 2H), 4.34 (t, J=6.6 Hz, 2H), 4.11 (s, 3H), 3.85-3.97 (m, 1H), 3.79-3.84 (m, 6H), 2.99 (br. d, J=12.6 Hz, 2H), 2.35-2.49 (m, 2H), 2.12-2.27 (m, 1H), 1.29 (br. d, J=11.0 Hz, 2H), 0.85-1.05 (m, 2H);

(997) MASS (ESI, Pos.): 500 (M+H)+.

Example 26(20)

1-{3-(3,5-dimethoxyphenyl)-5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}-N-(3-oxetanyl)-4-piperidinamine

(998) Description: white amorphous powder;

(999) Purity (LC-MS/ELSD): 100% (retention time: 0.56 min);

(1000) TLC: Rf 0.91 (ethyl acetate:methanol=9:1, NH silica gel);

(1001) NMR (300 MHz, METHANOL-d4): 8.13 (s, 1H), 8.02 (s, 1H), 7.30-7.47 (m, 3H), 6.52 (s, 3H), 4.67 (t, J=7.0 Hz, 2H), 4.36 (t, J=6.6 Hz, 2H), 3.89-3.98 (m, 1H), 3.87 (s, 3H), 3.82 (s, 6H), 2.85-3.05 (m, 2H), 2.30-2.53 (m, 2H), 2.14-2.28 (m, 1H), 1.32 (br. d, J=11.7 Hz, 2H), 0.76-0.95 (m, 2H);

(1002) MASS (ESI, Pos.): 544 (M+H)+.

Example 26(21)

1-[3-(3-fluoro-5-methoxyphenyl)-5-(3-methyl-1H-indazol-6-yl)-4-pyridinyl]-4-piperidinamine

(1003) Description: pale yellow amorphous powder;

(1004) Purity (LC-MS/ELSD): 100% (retention time: 0.44 min);

(1005) TLC: Rf 0.34 (ethyl acetate:methanol=9:1, NH silica gel);

(1006) NMR (300 MHz, METHANOL-d4): 8.21 (s, 1H), 8.17 (s, 1H), 7.81 (dd, J=8.3, 0.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.16 (dd, J=8.3, 1.4 Hz, 1H), 6.72-6.82 (m, 3H), 3.85 (s, 3H), 3.02 (br. d, J=12.6 Hz, 2H), 2.39-2.62 (m, 6H), 1.41 (br. d, J=11.2 Hz, 2H), 0.96-1.14 (m, 2H);

(1007) MASS (ESI, Pos.): 432 (M+H)+.

Example 26(22)

(1008) ##STR00119##

6-{5-(3,5-dimethoxyphenyl)-4-[4-(3-oxetanylamino)-1-piperidinyl]-3-pyridinyl}-1,3-dihydro-2H-indol-2-one

(1009) Description: pale yellow amorphous powder;

(1010) Purity (LC-MS/ELSD): 92.4% (retention time: 0.45 min);

(1011) TLC: Rf 0.17 (ethyl acetate:methanol=9:1, NH silica gel);

(1012) NMR (300 MHz, METHANOL-d4): 8.12 (br. s, 2H), 7.36 (d, J=7.1 Hz, 1H), 7.03 (dd, J=7.5, 1.5 Hz, 1H), 6.96 (s, 1H), 6.47-6.56 (m, 3H), 4.70 (t, J=7.0 Hz, 2H), 4.39 (t, J=6.5 Hz, 2H), 3.93-4.04 (m, 1H), 3.82 (s, 6H), 3.55-3.61 (m, 2H), 3.01 (br. d, J=12.4 Hz, 2H), 2.37-2.52 (m, 2H), 2.24-2.36 (m, 1H), 1.38 (br. d, J=12.1 Hz, 2H), 0.98-1.15 (m, 2H);

(1013) MASS (ESI, Pos.): 501 (M+H)+.

Example 26(23)

1-[3-(3-fluoro-5-methylphenyl)-5-(1-methyl-1H-indazol-5-yl)-4-pyridinyl]-4-piperidinamine

(1014) Description: pale orange powder;

(1015) Purity (USLC-MS/ELSD): 98.6% (retention time: 0.45 min);

(1016) TLC: Rf 0.33 (ethyl acetate:methanol=20:1, NH silica gel);

(1017) NMR (300 MHz, METHANOL-d4): 8.19 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.81-7.77 (m, 1H), 7.70-7.64 (m, 1H), 7.47 (dd, J=8.7, 1.6 Hz, 1H), 7.06-6.95 (m, 4H), 4.12 (s, 3H), 3.00-2.90 (m, 2H), 2.48-2.30 (m, 6H), 1.38-1.29 (m, 2H), 1.01-0.89 (m, 2H);

(1018) MASS (ESI, Pos.): 416 (M+H)+.

Example 26(24)

(1019) ##STR00120##

1-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(1020) Description: pale yellow powder;

(1021) Purity (USLC-MS/ELSD): 98.5% (retention time: 0.56 min);

(1022) TLC: Rf 0.51 (ethyl acetate:methanol=20:1, NH silica gel);

(1023) NMR (300 MHz, METHANOL-d4): 8.17 (s, 1H), 8.17 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.07-6.93 (m, 3H), 2.97-2.87 (m, 2H), 2.50-2.35 (m, 6H), 1.45-1.33 (m, 2H), 1.05-0.91 (m, 2H);

(1024) MASS (ESI, Pos.): 430 (M+H)+.

Example 26(25)

1-{3-(3-fluoro-5-methylphenyl)-5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(1025) Description: pale yellow powder;

(1026) Purity (USLC-MS/ELSD): 98.4% (retention time: 0.55 min);

(1027) TLC: Rf 0.51 (ethyl acetate:methanol=20:1, NH silica gel);

(1028) NMR (300 MHz, METHANOL-d4): 8.13 (s, 1H), 8.04 (s, 1H), 7.47-7.33 (m, 3H), 7.09-6.94 (m, 3H), 3.88 (s, 3H), 3.00-2.84 (m, 2H), 2.53-2.32 (m, 6H), 1.45-1.31 (m, 2H), 0.94-0.78 (m, 2H),

(1029) MASS (ESI, Pos.): 460 (M+H)+.

Example 26(26)

1-{3-(3-fluoro-5-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-N-methyl-4-piperidinamine

(1030) Description: pale yellow powder;

(1031) Purity (USLC-MS/ELSD): 99.4% (retention time: 0.53 min);

(1032) TLC: Rf 0.73 (ethyl acetate:methanol=9:1, NH silica gel);

(1033) NMR (300 MHz, CHLOROFORM-d): 8.28 (s, 1H), 8.24 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.71-6.61 (m, 3H), 3.85 (s, 3H), 2.96-2.84 (m, 2H), 2.50-2.37 (m, 2H), 2.32 (s, 3H), 2.27-2.12 (m, 1H), 1.58-1.44 (m, 2H), 1.04-0.84 (m, 2H);

(1034) MASS (ESI, Pos.): 460 (M+H)+.

Example 26(27)

2-{5-(3-fluoro-5-methoxyphenyl)-4-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}-5-(trifluoromethyl)phenol

(1035) Description: off-white powder;

(1036) Purity (USLC-MS/ELSD): 99.9% (retention time: 0.49 min);

(1037) TLC: Rf 0.43 (ethyl acetate:methanol=9:1, NH silica gel);

(1038) NMR (300 MHz, CHLOROFORM-d): 8.23 (s, 1H), 8.18 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.33-7.27 (m, 1H), 7.24 (s, 1H), 6.89-6.77 (m, 3H), 3.89 (s, 3H), 3.22-3.09 (m, 2H), 2.95-2.81 (m, 1H), 2.72-2.51 (m, 5H), 1.77-1.66 (m, 2H), 1.24-1.08 (m, 2H);

(1039) MASS (ESI, Pos.): 476 (M+H)+.

Example 26(28)

1-{3-(3-fluoro-5-methoxyphenyl)-5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}-N-methyl-4-piperidinamine

(1040) Description: pale yellow amorphous powder;

(1041) Purity (USLC-MS/ELSD): 98.8% (retention time: 0.54 min);

(1042) TLC: Rf 0.70 (ethyl acetate:methanol=9:1, NH silica gel);

(1043) NMR (300 MHz, CHLOROFORM-d): 8.26 (s, 1H), 8.16 (s, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 6.78-6.70 (m, 2H), 6.67-6.59 (m, 1H), 3.85 (s, 6H), 2.95-2.84 (m, 2H), 2.49-2.33 (m, 2H), 2.30 (s, 3H), 2.20-2.09 (m, 1H), 1.54-1.43 (m, 2H), 0.93-0.74 (m, 2H);

(1044) MASS (ESI, Pos.): 490 (M+H)+.

Example 26(29)

5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-2-methylphenol

(1045) Description: pale brown powder;

(1046) Purity (USLC-MS/ELSD): 99.9% (retention time: 0.44 min);

(1047) TLC: Rf 0.37 (ethyl acetate:methanol=10:1, NH silica gel);

(1048) NMR (300 MHz, METHANOL-d4): 8.10 (s, 1H), 8.09 (s, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.04-6.93 (m, 3H), 6.79-6.72 (m, 2H), 3.00-2.84 (m, 2H), 2.52-2.38 (m, 6H), 2.24 (s, 3H), 1.46-1.36 (m, 2H), 1.13-0.97 (m, 2H);

(1049) MASS (ESI, Pos.): 392 (M+H)+.

Example 26(30)

1-[5-(3-fluoro-5-methoxyphenyl)-2-methoxy-6-(trifluoromethyl)-3,3-bipyridin-4-yl]-4-piperidinamine

(1050) Description: pale yellow oil;

(1051) Purity (USLC-MS/ELSD): 100% (retention time: 0.54 min);

(1052) TLC: Rf 0.44 (ethyl acetate:methanol=20:1, NH silica gel);

(1053) NMR (300 MHz, METHANOL-d4): 8.19 (s, 1H), 8.11 (s, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.82-6.72 (m, 3H), 3.98 (s, 3H), 3.86 (s, 3H), 3.00-2.84 (m, 2H), 2.35-2.51 (m, 3H), 1.48-1.38 (m, 2H), 1.00-0.75 (m, 2H);

(1054) MASS (ESI, Pos.): 477 (M+H)+.

Example 26(31)

1-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-N-methyl-4-piperidinamine

(1055) Description: pale yellow amorphous powder;

(1056) Purity (USLC-MS/ELSD): 100% (retention time: 0.54 min);

(1057) TLC: Rf 0.73 (ethyl acetate:methanol=9:1, NH silica gel);

(1058) NMR (300 MHz, CHLOROFORM-d): 8.27 (s, 1H), 8.23 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.99-6.84 (m, 3H), 2.94-2.81 (m, 2H), 2.47-2.35 (m, 5H), 2.31 (s, 3H), 2.23-2.11 (m, 1H), 1.56-1.44 (m, 2H), 1.02-0.83 (m, 2H);

(1059) MASS (ESI, Pos.): 444 (M+H)+.

Example 26(32)

2-{5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}-5-(trifluoromethyl)phenol

(1060) Description: pale orange powder;

(1061) Purity (USLC-MS/ELSD): 100% (retention time: 0.50 min);

(1062) TLC: Rf 0.43 (ethyl acetate:methanol=9:1, NH silica gel);

(1063) NMR (300 MHz, METHANOL-d4): 8.18 (s, 1H), 8.14 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.30-7.23 (m, 1H), 7.21 (d, J=1.3 Hz, 1H), 7.12-6.99 (m, 3H), 3.13-3.01 (m, 2H), 2.65-2.41 (m, 6H), 2.39 (s, 3H), 1.64-1.52 (m, 2H), 1.12-0.95 (m, 2H);

(1064) MASS (ESI, Pos.): 460 (M+H)+.

Example 26(33)

rac-(4aR,8aR)-6-[3-(3-fluoro-5-methoxyphenyl)-5-(1H-indazol-6-yl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine

(1065) Description: white amorphous powder;

(1066) Purity (LC-MS/ELSD): 100% (retention time: 0.44 min);

(1067) TLC: Rf 0.32 (ethyl acetate:methanol=19:1, NH silica gel);

(1068) NMR (300 MHz, METHANOL-d4): 8.26 (s, 1H), 8.21 (s, 1H), 8.12 (d, J=0.9 Hz, 1H), 7.90 (dd, J=8.3, 0.9 Hz, 1H), 7.62-7.58 (m, 1H), 7.19 (dd, J=8.3, 1.5 Hz, 1H), 6.83-6.73 (m, 3H), 3.87 (s, 3H), 3.64 (dd, J=11.6, 2.1 Hz, 1H), 3.42-3.27 (m, 1H), 3.10-2.65 (m, 5H), 2.56 (td, J=12.3, 2.5 Hz, 1H), 2.22 (dd, J=11.3, 9.7 Hz, 1H), 2.16-2.05 (m, 1H), 1.33-1.17 (m, 1H), 1.12-0.95 (m, 1H);

(1069) MASS (ESI, Pos.): 460 (M+H)+.

Example 26(34)

rac-(4aR,8aR)-6-[3-(3-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-indazol-5-yl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine

(1070) Description: pale brown viscous oil;

(1071) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(1072) TLC: Rf 0.49 (ethyl acetate:methanol=19:1, NH silica gel);

(1073) NMR (300 MHz, METHANOL-d4): 8.23 (s, 1H), 8.19 (s, 1H), 8.10 (d, J=0.9 Hz, 1H), 7.81 (dd, J=1.6, 0.8 Hz, 1H), 7.69 (dt, J=8.7, 0.9 Hz, 1H), 7.47 (dd, J=8.7, 1.6 Hz, 1H), 6.84-6.71 (m, 3H), 4.13 (s, 3H), 3.87 (s, 3H), 3.64 (dd, J=11.4, 2.1 Hz, 1H), 3.44-3.32 (m, 1H), 3.10-2.66 (m, 5H), 2.56 (td, J=12.5, 2.4 Hz, 1H), 2.18 (dd, J=11.3, 9.6 Hz, 1H), 2.04-2.14 (m, 1H), 1.31-1.17 (m, 1H), 1.08-0.92 (m, 1H);

(1074) MASS (ESI, Pos.): 474 (M+H)+.

Example 26(35)

5-{5-(3-fluoro-5-methoxyphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}-2-methylphenol

(1075) Description: off-white amorphous powder;

(1076) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(1077) TLC: Rf 0.34 (ethyl acetate:methanol=19:1, NH silica gel);

(1078) NMR (300 MHz, METHANOL-d4): 8.14 (s, 2H), 7.19 (dd, J=7.9, 0.7 Hz, 1H), 6.82-6.69 (m, 5H), 3.86 (s, 3H), 3.75-3.65 (m, 1H), 3.45 (td, J=11.4, 2.9 Hz, 1H), 3.06-2.86 (m, 3H), 2.81 (dd, J=11.4, 3.6 Hz, 1H), 2.78-2.70 (m, 1H), 2.58 (td, J=12.4, 2.6 Hz, 1H), 2.31-2.21 (m, 4H), 2.20-2.10 (m, 1H), 1.35-1.25 (m, 1H), 1.20-1.05 (m, 1H);

(1079) MASS (ESI, Pos.): 450 (M+H)+.

Example 26(36)

1-[3-(4-chlorophenyl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine

(1080) Description: ivory powder;

(1081) Purity (USLC-MS/ELSD): 97.8% (retention time: 0.48 min);

(1082) TLC: Rf 0.67 (ethyl acetate:methanol=9:1, NH silica gel);

(1083) NMR (300 MHz, CHLOROFORM-d): 8.25 (s, 1H), 8.20 (s, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.02-6.94 (m, 3H), 2.90-2.77 (m, 2H), 2.37 (s, 6H), 2.52-2.28 (m, 3H), 1.46-1.34 (m, 2H), 1.00-0.85 (m, 2H);

(1084) MASS (ESI, Pos.): 392 (M+H)+.

Example 26(37)

2-{5-(3-fluoro-5-methoxyphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}-5-(trifluoromethyl)phenol

(1085) Description: white powder;

(1086) Purity (LC-MS/ELSD): 100% (retention time: 0.51 min);

(1087) TLC: Rf 0.50 (ethyl acetate:n-hexane=4:1, NH silica gel);

(1088) NMR (300 MHz, METHANOL-d4): 8.35 (s, 1H), 8.33 (s, 1H), 7.43-7.35 (m, 1H), 7.35-7.28 (m, 2H), 6.72-6.65 (m, 1H), 6.65-6.56 (m, 2H), 3.85 (s, 3H), 3.79-3.67 (m, 1H), 3.56-3.40 (m, 1H), 3.14-2.17 (m, 8H), 1.39 (br. s., 1H), 1.32-1.11 (m, 1H);

(1089) MASS (ESI, Pos.): 504 (M+H)+.

Example 26(38)

2-{5-(3-fluoro-5-methylphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}-5-(trifluoromethyl)phenol

(1090) Description: white amorphous powder;

(1091) Purity (LC-MS/ELSD): 100% (retention time: 0.51 min);

(1092) TLC: Rf 0.29 (ethyl acetate:methanol=19:1, NH silica gel);

(1093) NMR (300 MHz, CHLOROFORM-d): 8.35 (s, 1H), 8.32 (s, 1H), 7.43-7.35 (m, 1H), 7.35-7.28 (m, 2H), 6.95 (d, J=9.5 Hz, 1H), 6.90 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.73 (dd, J=11.1, 2.8 Hz, 1H), 3.58-3.39 (m, 1H), 3.12-2.16 (m, 11H), 1.40 (d, J=11.0 Hz, 1H), 1.22 (br. s., 1H),

(1094) MASS (ESI, Pos.): 488 (M+H)+.

Example 26(39)

4-(4-amino-1-piperidinyl)-5-(3-methoxy-5-methylphenyl)-N,N-dimethyl-3,3-bipyridin-6-amine

(1095) Description: white amorphous powder;

(1096) Purity (UPLC-MS/ELSD): 100% (retention time: 0.34 min);

(1097) TLC: Rf 0.35 (ethyl acetate:methanol=9:1, NH silica gel);

(1098) NMR (300 MHz, CHLOROFORM-d): 8.23 (s, 1H), 8.21 (s, 1H), 8.20 (dd, J=2.4, 0.7 Hz, 1H), 7.53 (dd, J=8.8, 2.4 Hz, 1H), 6.78-6.75 (m, 1H), 6.75-6.72 (m, 1H), 6.71-6.69 (m, 1H), 6.60 (dd, J=8.8, 0.7 Hz, 1H), 3.83 (s, 3H), 3.15 (s, 6H), 2.97-2.86 (m, 2H), 2.54-2.40 (m, 3H), 2.38 (s, 3H), 1.49-1.38 (m, 2H), 1.10-0.92 (m, 2H);

(1099) MASS (ESI, Pos.): 418 (M+H)+.

Example 26(40)

rac-(4aR,8aR)-6-[3-(3-fluoro-5-methylphenyl)-5-(1-methyl-1H-indazol-5-yl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine

(1100) Description: off-white powder;

(1101) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(1102) TLC: Rf 0.45 (ethyl acetate:methanol=19:1, NH silica gel);

(1103) NMR (300 MHz, CHLOROFORM-d): 8.33 (s, 1H), 8.29 (s, 1H), 8.04 (d, J=0.9 Hz, 1H), 7.70 (dd, J=1.4, 0.8 Hz, 1H), 7.51-7.45 (m, 1H), 7.41-7.35 (m, 1H), 7.00-6.95 (m, 1H), 6.95-6.85 (m, 2H), 4.13 (s, 3H), 3.69 (dd, J=11.4, 2.5 Hz, 1H), 3.42 (td, J=11.4, 2.7 Hz, 1H), 2.99-2.72 (m, 5H), 2.59-2.46 (m, 1H), 2.43 (s, 3H), 2.27-2.09 (m, 2H), 1.23-1.14 (m, 1H), 1.05-0.87 (m, 1H);

(1104) MASS (ESI, Pos.): 458 (M+H)+.

Example 26(41)

5-{5-(3-fluoro-5-methylphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}-2-methylphenol

(1105) Description: off-white powder;

(1106) Purity (LC-MS/ELSD): 99.0% (retention time: 0.48 min);

(1107) TLC: Rf 0.29 (ethyl acetate:methanol=19:1, NH silica gel);

(1108) NMR (300 MHz, CHLOROFORM-d): 8.37 (s, 1H), 8.24 (s, 1H), 7.17 (dd, J=7.7, 0.7 Hz, 1H), 6.97-6.81 (m, 4H), 6.79 (dd, J=7.6, 1.6 Hz, 1H), 3.74 (dd, J=11.4, 2.3 Hz, 1H), 3.49 (td, J=11.4, 2.6 Hz, 1H), 3.03-2.77 (m, 5H), 2.64-2.49 (m, 1H), 2.41 (s, 3H), 2.37-2.19 (m, 5H), 1.35-1.23 (m, 1H), 1.22-1.05 (m, 1H);

(1109) MASS (ESI, Pos.): 434 (M+H)+.

Example 26(42)

rac-(4aR,8aR)-6-{3-(3-fluoro-5-methylphenyl)-5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}octahydro-1H-pyrido[3,4-b][1,4]oxazine

(1110) Description: off-white powder;

(1111) Purity (LC-MS/ELSD): 98.0% (retention time: 0.58 min);

(1112) TLC: Rf 0.71 (ethyl acetate:methanol=19:1, NH silica gel);

(1113) NMR (300 MHz, CHLOROFORM-d): 8.29 (s, 1H), 8.19 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.20 (s, 1H), 6.97 (s, 1H), 6.90 (d, J=9.3 Hz, 2H), 3.85 (s, 3H), 3.72 (dd, J=11.4, 2.3 Hz, 1H), 3.40 (td, J=11.4, 2.1 Hz, 1H), 2.98-2.72 (m, 4H), 2.68-2.37 (m, 5H), 2.33-2.12 (m, 2H), 1.30-1.19 (m, 1H), 0.99-0.81 (m, 1H);

(1114) MASS (ESI, Pos.): 502 (M+H)+.

Example 26(43)

rac-(4aR,8aR)-6-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}octahydro-1H-pyrido[3,4-b][1,4]oxazine

(1115) Description: white powder;

(1116) Purity (LC-MS/ELSD): 99.0% (retention time: 0.58 min);

(1117) TLC: Rf 0.69 (ethyl acetate:methanol=19:1, NH silica gel);

(1118) NMR (300 MHz, CHLOROFORM-d): 8.31 (s, 1H), 8.27 (s, 1H), 7.80-7.70 (m, 2H), 7.51 (d, J=7.9 Hz, 2H), 6.97-6.81 (m, 3H), 3.73 (dd, J=11.5, 2.4 Hz, 1H), 3.45 (td, J=11.5, 2.4 Hz, 1H), 2.99-2.73 (m, 5H), 2.51 (td, J=12.5, 2.7 Hz, 1H), 2.43 (s, 3H), 2.32-2.15 (m, 2H), 1.32-1.21 (m, 1H), 1.01 (qd, J=12.2, 4.3 Hz, 1H);

(1119) MASS (ESI, Pos.): 472 (M+H)+.

Example 26(44)

rac-(4aR,8aR)-6-{3-(3-fluoro-5-methoxyphenyl)-5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}octahydro-1H-pyrido[3,4-b][1,4]oxazine Description: off-white amorphous powder

(1120) Purity (LC-MS/ELSD): 100% (retention time: 0.56 min);

(1121) TLC: Rf 0.45 (ethyl acetate:n-hexane=4:1, NH silica gel);

(1122) NMR (300 MHz, CHLOROFORM-d): 8.30 (s, 1H), 8.20 (s, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.20 (s, 1H), 6.74-6.60 (m, 3H), 3.85 (s, 6H), 3.76-3.66 (m, 1H), 3.48-3.33 (m, 1H), 2.99-2.72 (m, 4H), 2.72-2.41 (m, 2H), 2.38-2.25 (m, 1H), 2.25-2.12 (m, 1H), 1.31-1.19 (m, 1H), 0.92 (qd, J=12.4, 4.7 Hz, 1H);

(1123) MASS (ESI, Pos.): 518 (M+H)+.

Example 26(45)

5-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]-N,N-dimethyl-2-pyrimidinamine

(1124) Description: yellow amorphous powder;

(1125) Purity (UPLC-MS/ELSD): 96.3% (retention time: 0.46 min);

(1126) TLC: Rf 0.38 (ethyl acetate:methanol=9:1, NH silica gel);

(1127) NMR (300 MHz, CHLOROFORM-d): 8.40 (s, 2H), 8.25 (s, 1H), 8.19 (s, 1H), 7.03-7.00 (m, 1H), 6.96-6.91 (m, 2H), 3.25 (s, 6H), 2.94-2.81 (m, 2H), 2.56-2.39 (m, 3H), 2.37 (s, 6H), 1.54-1.30 (m, 2H), 1.09-0.89 (m, 2H);

(1128) MASS (ESI, Pos.): 403 (M+H)+.

Example 26(46)

rac-(3R,4S)-4-amino-1-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-3-piperidinol

(1129) Description: pale yellow viscous oil;

(1130) Purity (LC-MS/ELSD): 95.0% (retention time: 0.51 min);

(1131) TLC: Rf 0.46 (ethyl acetate:methanol=19:1, NH silica gel);

(1132) NMR (300 MHz, CHLOROFORM-d): 8.30 (s, 1H), 8.27 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.02 (d, J=0.5 Hz, 1H), 6.99-6.89 (m, 2H), 3.37-3.30 (m, 1H), 3.02-2.91 (m, 1H), 2.75-2.52 (m, 3H), 2.42 (s, 3H), 2.31 (dd, J=12.7, 2.3 Hz, 1H), 1.20-0.97 (m, 2H),

(1133) MASS (ESI, Pos.): 446 (M+H)+.

Example 26(47)

1-{3-[4-(difluoromethyl)phenyl]-5-(3-fluoro-5-methylphenyl)-4-pyridinyl}-4-piperidinamine

(1134) Description: white amorphous powder;

(1135) Purity (UPLC-MS/ELSD): 100% (retention time: 0.48 min);

(1136) TLC: Rf 0.61 (ethyl acetate:methanol=20:1, NH silica gel);

(1137) NMR (300 MHz, METHANOL-d4): 8.15 (s, 2H), 7.71-7.65 (m, 2H), 7.58-7.52 (m, 2H), 7.07-6.92 (m, 3H), 6.84 (t, J=56.2 Hz, 1H), 2.98-2.87 (m, 2H), 2.50-2.33 (m, 6H), 1.45-1.34 (m, 2H), 1.10-0.91 (m, 2H);

(1138) MASS (ESI, Pos.): 412 (M+H)+.

Example 26(48)

1-[3-(4-chlorophenyl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-4-piperidinamine

(1139) Purity (LC-MS/ELSD): 100% (retention time: 0.46 min);

(1140) NMR (600 MHz, ACETONITRILE-d3): 8.19 (s, 1H), 8.18 (s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.06 (br. s, 1H), 7.04 (br. d, J=10.1 Hz, 1H), 6.99 (br. d, J=9.4 Hz, 1H), 2.88 (br. d, J=13.0 Hz, 2H), 2.50-2.60 (m, 1H), 2.37-2.46 (m, 5H), 1.42 (br. d, J=13.2 Hz, 2H), 0.95-1.06 (m, 2H);

(1141) MASS (ESI, Pos.): 396 (M+H)+.

Example 26(49)

1-[3-(3-fluoro-5-methylphenyl)-5-(4-methoxyphenyl)-4-pyridinyl]-4-piperidinamine

(1142) Purity (LC-MS/ELSD): 99.0% (retention time: 0.44 min);

(1143) NMR (600 MHz, ACETONITRILE-d3): 8.17 (s, 1H), 8.16 (s, 1H), 7.38 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.07 (br. s, 1H), 7.04 (br. d, J=9.9 Hz, 1H), 6.99 (br. d, J=10.3 Hz, 1H), 3.88 (s, 3H), 2.90 (br. d, J=13.0 Hz, 2H), 2.56-2.65 (m, 1H), 2.38-2.45 (m, 5H), 1.43 (br. d, J=9.7 Hz, 2H), 1.02-1.10 (m, 2H);

(1144) MASS (ESI, Pos.): 392 (M+H)+.

Example 26(50)

(1145) ##STR00121##

1-{4-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]phenyl}ethanone

(1146) Purity (LC-MS/ELSD): 100% (retention time: 0.44 min);

(1147) NMR (600 MHz, ACETONITRILE-d3): 8.22 (s, 1H), 8.21 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 6.96-7.10 (m, 3H), 2.89 (br. d, J=12.5 Hz, 2H), 2.68 (s, 3H), 2.54-2.62 (m, 1H), 2.39-2.46 (m, 5H), 1.41 (br. d, J=10.1 Hz, 2H), 0.97-1.06 (m, 2H);

(1148) MASS (ESI, Pos.): 404 (M+H)+.

Example 26(51)

1-{3-[4-(dimethylamino)phenyl]-5-(3-fluoro-5-methylphenyl)-4-pyridinyl}-4-piperidinamine

(1149) Purity (LC-MS/ELSD): 100% (retention time: 0.43 min);

(1150) NMR (600 MHz, ACETONITRILE-d3): 8.16 (s, 1H), 8.12 (s, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.07 (br. s, 1H), 6.96-7.05 (m, 2H), 6.90 (d, J=8.8 Hz, 2H), 2.98 (s, 6H), 2.91 (br. d, J=12.7 Hz, 2H), 2.51-2.61 (m, 1H), 2.39-2.48 (m, 5H), 1.42 (br. d, J=15.0 Hz, 2H), 1.00-1.14 (m, 2H),

(1151) MASS (ESI, Pos.): 405 (M+H)+.

Example 26(52)

1-[3-(4-ethylphenyl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-4-piperidinamine

(1152) Purity (LC-MS/ELSD): 99.0% (retention time: 0.50 min);

(1153) NMR (600 MHz, ACETONITRILE-d3): 8.17 (s, 1H), 8.16 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 7.08 (br. s, 1H), 6.98-7.05 (m, 2H), 2.89 (br. d, J=13.0 Hz, 2H), 2.73 (q, J=7.9 Hz, 2H), 2.49-2.59 (m, 1H), 2.36-2.45 (m, 5H), 1.40 (br. d, J=12.7 Hz, 2H), 1.28 (t, J=7.9 Hz, 3H), 0.96-1.05 (m, 2H);

(1154) MASS (ESI, Pos.): 390 (M+H)+.

Example 26(53)

1-[3-(3-chlorophenyl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-4-piperidinamine

(1155) Purity (LC-MS/ELSD): 100% (retention time: 0.48 min);

(1156) NMR (600 MHz, ACETONITRILE-d3): 8.20 (s, 1H), 8.20 (s, 1H), 7.45-7.54 (m, 3H), 7.37-7.40 (m, 1H), 7.07 (br. s, 1H), 7.04 (br. d, J=9.9 Hz, 1H), 6.99 (br. d, J=9.9 Hz, 1H), 2.90 (br. d, J=12.8 Hz, 2H), 2.51-2.59 (m, 1H), 2.38-2.45 (m, 5H), 1.43 (br. d, J=10.8 Hz, 2H), 0.95-1.03 (m, 2H);

(1157) MASS (ESI, Pos.): 396 (M+H)+.

Example 26(54)

1-[3-(3-fluoro-5-methylphenyl)-5-(3-methoxyphenyl)-4-pyridinyl]-4-piperidinamine

(1158) Purity (LC-MS/ELSD): 100% (retention time: 0.45 min);

(1159) NMR (600 MHz, ACETONITRILE-d3): 8.20 (s, 1H), 8.18 (s, 1H), 7.44 (t, J=7.9 Hz, 1H), 6.97-7.09 (m, 6H), 3.86 (s, 3H), 2.93 (br. d, J=12.8 Hz, 2H), 2.55-2.62 (m, 1H), 2.39-2.46 (m, 5H), 1.43 (br. d, J=11.6 Hz, 2H), 0.99-1.07 (m, 2H);

(1160) MASS (ESI, Pos.): 392 (M+H)+.

Example 26(55)

1-[3-(3-fluoro-5-methylphenyl)-5-(3-methylphenyl)-4-pyridinyl]-4-piperidinamine

(1161) Purity (LC-MS/ELSD): 100% (retention time: 0.47 min);

(1162) NMR (600 MHz, ACETONITRILE-d3): 8.17 (s, 1H), 8.17 (s, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 7.25 (br. s, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.08 (br. s, 1H), 7.03 (br. d, J=10.3 Hz, 1H), 7.00 (br. d, J=9.9 Hz, 1H), 2.89 (br. d, J=12.3 Hz, 2H), 2.50-2.59 (m, 1H), 2.37-2.45 (m, 8H), 1.40 (br. d, J=10.3 Hz, 2H), 0.95-1.04 (m, 2H);

(1163) MASS (ESI, Pos.): 376 (M+H)+.

Example 26(56)

4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methoxyphenyl)-6-methyl-3,3-bipyridin-5-ol

(1164) Description: white powder;

(1165) Purity (UPLC-MS/ELSD): 91.0% (retention time: 0.35 min);

(1166) TLC: Rf 0.47 (ethyl acetate:methanol=1:1, NH silica gel);

(1167) NMR (300 MHz, METHANOL-d4): 8.18 (s, 1H), 8.17 (s, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.15 (d, J=1.8 Hz, 1H), 6.81-6.69 (m, 3H), 3.86 (s, 3H), 3.05-2.95 (m, 2H), 2.57-2.43 (m, 6H), 1.52-1.47 (m, 2H), 1.20-1.08 (m, 2H);

(1168) MASS (ESI, Pos.): 409 (M+H)+.

Example 26(57)

1-[3-(4-chloro-3-methylphenyl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-4-piperidinamine

(1169) Purity (LC-MS/ELSD): 100% (retention time: 0.53 min);

(1170) NMR (600 MHz, ACETONITRILE-d3): 8.18 (s, 1H), 8.17 (s, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.26 (dd, J=8.1, 2.2 Hz, 1H), 7.07 (br. s, 1H), 7.04 (br. d, J=11.0 Hz, 1H), 6.99 (br. d, J=9.4 Hz, 1H), 2.89 (br. d, J=12.7 Hz, 2H), 2.48-2.57 (m, 1H), 2.38-2.47 (m, 8H), 1.42 (br. d, J=11.7 Hz, 2H), 0.94-1.03 (m, 2H);

(1171) MASS (ESI, Pos.): 410 (M+H)+.

Example 26(58)

1-[3-(3-fluoro-5-methylphenyl)-5-(3-methoxy-4-methylphenyl)-4-pyridinyl]-4-piperidinamine

(1172) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(1173) NMR (600 MHz, ACETONITRILE-d3): 8.20 (s, 1H), 8.16 (s, 1H), 7.27 (d, J=7.5 Hz, 1H), 7.09 (br. s, 1H), 6.99-7.05 (m, 2H), 6.89-6.95 (m, 2H), 3.87 (s, 3H), 2.93 (br. d, J=12.5 Hz, 2H), 2.51-2.58 (m, 1H), 2.40-2.47 (m, 5H), 2.26 (s, 3H), 1.42 (br. d, J=12.3 Hz, 2H), 0.97-1.06 (m, 2H);

(1174) MASS (ESI, Pos.): 406 (M+H)+.

Example 26(59)

1-{3-[4-(difluoromethoxy)phenyl]-5-(3-fluoro-5-methylphenyl)-4-pyridinyl}-4-piperidinamine

(1175) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(1176) NMR (600 MHz, ACETONITRILE-d3): 8.19 (s, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H), 6.78-7.08 (m, 4H), 2.88 (br. d, J=12.1 Hz, 2H), 2.52-2.59 (m, 1H), 2.37-2.45 (m, 5H), 1.41 (br. d, J=9.7 Hz, 2H), 0.96-1.05 (m, 2H);

(1177) MASS (ESI, Pos.): 428 (M+H)+.

Example 26(60)

(1178) ##STR00122##

3-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-N-methylbenzamide

(1179) Purity (LC-MS/ELSD): 100% (retention time: 0.41 min);

(1180) NMR (600 MHz, ACETONITRILE-d3): 8.23 (s, 1H), 8.22 (s, 1H), 7.91 (br. s, 1H), 7.82-7.85 (m, 1H), 7.62-7.65 (m, 2H), 6.97-7.08 (m, 3H), 2.89-2.95 (m, 5H), 2.66-2.76 (m, 1H), 2.38-2.46 (m, 5H), 1.46 (br. d, J=11.9 Hz, 2H), 1.04-1.12 (m, 2H);

(1181) MASS (ESI, Pos.): 419 (M+H)+.

Example 26(61)

1-{3-(3-fluoro-5-methylphenyl)-5-[4-(1H-pyrazol-1-yl)phenyl]-4-pyridinyl}-4-piperidinamine

(1182) Purity (LC-MS/ELSD): 100% (retention time: 0.47 min);

(1183) NMR (600 MHz, ACETONITRILE-d3): 8.27 (d, J=2.6 Hz, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.80 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.07 (br. s, 1H), 7.05 (br. d, J=10.8 Hz, 1H), 7.00 (br. d, J=9.9 Hz, 1H), 6.58-6.62 (m, 1H), 2.93 (br. d, J=12.7 Hz, 2H), 2.58-2.67 (m, 1H), 2.41-2.49 (m, 5H), 1.44 (br. d, J=10.1 Hz, 2H), 1.03-1.12 (m, 2H);

(1184) MASS (ESI, Pos.): 428 (M+H)+.

Example 26(62)

1-[3-(3-fluoro-5-methylphenyl)-5-(3-methyl-1,2-benzoxazol-6-yl)-4-pyridinyl]-4-piperidinamine

(1185) Description: brown amorphous powder;

(1186) Purity (UPLC-MS/ELSD): 99.5% (retention time: 0.47 min);

(1187) TLC: Rf 0.35 (ethyl acetate:methanol=9:1, NH silica gel);

(1188) NMR (300 MHz, CHLOROFORM-d): 8.29 (s, 1H), 8.28 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.58-7.54 (m, 1H), 7.33 (dd, J=1.2, 8.1 Hz, 1H), 7.00-6.87 (m, 3H), 2.94-2.81 (m, 2H), 2.64 (s, 3H), 2.53-2.33 (m, 6H), 1.49-1.32 (m, 2H), 1.02-0.81 (m, 2H);

(1189) MASS (ESI, Pos.): 417 (M+H)+.

Example 26(63)

4-(4-amino-1-piperidinyl)-5-(3-chloro-5-methoxyphenyl)-N,N-dimethyl-3,3-bipyridin-6-amine

(1190) Purity (LC-MS/ELSD): 100% (retention time: 0.38 min);

(1191) MASS (ESI, Pos.): 438 (M+H)+.

Example 26(64)

4-(4-amino-1-piperidinyl)-5-(3-chloro-5-methylphenyl)-N,N-dimethyl-3,3-bipyridin-6-amine

(1192) Purity (LC-MS/ELSD): 100% (retention time: 0.39 min);

(1193) MASS (ESI, Pos.): 422 (M+H)+.

Example 26(65)

1-{3-(3-fluoro-5-methylphenyl)-5-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4-pyridinyl}-4-piperidinamine

(1194) Purity (LC-MS/ELSD): 100% (retention time: 0.48 min);

(1195) NMR (600 MHz, ACETONITRILE-d3): 8.25 (s, 1H), 8.22 (s, 1H), 8.11 (br. s, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.08 (br. s, 1H), 7.05 (br. d, J=10.5 Hz, 1H), 7.00 (br. d, J=8.8 Hz, 1H), 2.92 (br. d, J=13.0 Hz, 2H), 2.67 (s, 3H), 2.48-2.56 (m, 1H), 2.39-2.46 (m, 5H), 1.40 (d, J=12.5 Hz, 2H), 0.96-1.05 (m, 2H);

(1196) MASS (ESI, Pos.): 444 (M+H)+.

Example 26(66)

1-{3-(3-methoxy-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(1197) Description: white amorphous powder;

(1198) Purity (LC-MS/ELSD): 100% (retention time: 0.53 min);

(1199) TLC: Rf 0.53 (ethyl acetate:methanol=19:1, NH silica gel);

(1200) NMR (300 MHz, CHLOROFORM-d): 8.29 (s, 1H), 8.23 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.80-6.73 (m, 2H), 6.70 (s, 1H), 3.84 (s, 3H), 2.86 (d, J=13.2 Hz, 2H), 2.55-2.34 (m, 6H), 1.52-1.32 (m, 2H), 1.03-0.83 (m, 2H);

(1201) MASS (ESI, Pos.): 442 (M+H)+.

Example 26(67)

(1202) ##STR00123##

(3-{4-(4-amino-1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-3-pyridinyl}-5-fluorophenyl)methanol

(1203) Description: pale yellow amorphous powder;

(1204) Purity (LC-MS/ELSD): 100% (retention time: 0.47 min);

(1205) TLC: Rf 0.41 (ethyl acetate:methanol=19:1, NH silica gel);

(1206) NMR (300 MHz, CHLOROFORM-d): 8.30 (s, 1H), 8.28 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.28 (s, 1H), 7.12-6.99 (m, 2H), 4.71 (s, 2H), 2.84 (d, J=13.2 Hz, 2H), 2.75-2.26 (m, 3H), 1.38 (dd, J=12.5, 3.4 Hz, 2H), 1.01 (qd, J=11.6, 4.2 Hz, 2H);

(1207) MASS (ESI, Pos.): 446 (M+H)+.

Example 26(68)

(4-{5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}-2-methylphenyl)methanol

(1208) Purity (LC-MS/ELSD): 90.0% (retention time: 0.44 min);

(1209) NMR (600 MHz, ACETONITRILE-d3): 8.20 (s, 1H), 8.18 (s, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.23 (br. s, 1H), 7.07 (br. s, 1H), 7.04 (br. d, J=9.7 Hz, 1H), 7.00 (br. d, J=9.7 Hz, 1H), 4.69 (s, 2H), 2.95 (br. d, J=12.8 Hz, 2H), 2.45-2.55 (m, 1H), 2.37-2.45 (m, 8H), 2.35 (s, 3H), 1.51 (br. d, J=12.0 Hz, 2H), 1.00-1.08 (m, 2H);

(1210) MASS (ESI, Pos.): 420 (M+H)+.

Example 26(69)

(1211) ##STR00124##

2-{4-[4-(aminomethyl)-4-fluoro-1-piperidinyl]-5-(3-fluoro-5-methylphenyl)-3-pyridinyl}-5-(trifluoromethyl)phenol

(1212) Description: pale gray powder;

(1213) Purity (UPLC-MS/ELSD): 100% (retention time: 0.52 min);

(1214) TLC: Rf 0.24 (ethyl acetate:methanol=10:1, NH silica gel);

(1215) NMR (300 MHz, METHANOL-d4): 8.25 (s, 1H), 8.21 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.34-7.27 (m, 1H), 7.24 (s, 1H), 7.17 (s, 1H), 7.13-7.02 (m, 2H), 3.07-2.77 (m, 6H), 2.47 (s, 3H), 1.70-1.50 (m, 2H), 1.48-1.18 (m, 2H);

(1216) MASS (ESI, Pos.): 478 (M+H)+.

Example 26(70)

5-{4-[4-(aminomethyl)-4-fluoro-1-piperidinyl]-5-(3-fluoro-5-methylphenyl)-3-pyridinyl}-2-methylphenol

(1217) Description: pale brown powder;

(1218) Purity (UPLC-MS/ELSD): 100% (retention time: 0.48 min);

(1219) TLC: Rf 0.20 (ethyl acetate:methanol=10:1, NH silica gel);

(1220) NMR (300 MHz, CHLOROFORM-d): 8.37 (s, 1H), 8.23 (s, 1H), 7.15 (d, J=7.9 Hz, 1H), 6.99-6.85 (m, 4H), 6.79 (dd, J=1.6, 7.9 Hz, 1H), 2.83-2.72 (m, 4H), 2.70-2.59 (m, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 1.58-1.30 (m, 4H);

(1221) MASS (ESI, Pos.): 424 (M+H)+.

Example 26(71)

(1222) ##STR00125##

N-{3-[4-(4-amino-1-piperidinyl)-5-(3-chloro-5-fluorophenyl)-3-pyridinyl]phenyl}acetamide

(1223) Description: pale yellow amorphous powder;

(1224) Purity (LC-MS/ELSD): 100% (retention time: 0.44 min);

(1225) TLC: Rf 0.35 (ethyl acetate:methanol=9:1, NH silica gel);

(1226) NMR (300 MHz, CHLOROFORM-d): 8.26 (s, 1H), 8.23 (s, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.44-7.37 (m, 2H), 7.23-7.20 (m, 1H), 7.16-7.06 (m, 2H), 7.06-7.00 (m, 1H), 2.88 (d, J=12.8 Hz, 2H), 2.60-2.40 (m, 3H), 2.20 (s, 3H), 1.44 (dd, J=12.2, 3.0 Hz, 2H), 1.12-0.95 (m, 2H),

(1227) MASS (ESI, Pos.): 439 (M+H)+.

Example 26(72)

1-{3-(3-fluoro-5-methylphenyl)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(1228) Purity (LC-MS/ELSD): 100% (retention time: 0.55 min);

(1229) NMR (600 MHz, ACETONITRILE-d3): 8.23 (s, 1H), 8.21 (s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.09 (br. s, 1H), 7.05 (br. d, J=10.3 Hz, 1H), 7.01 (br. d, J=10.3 Hz, 1H), 3.96 (s, 3H), 2.93 (br. d, J=13.0 Hz, 2H), 2.51-2.59 (m, 1H), 2.41-2.48 (m, 5H), 1.43 (br. d, J=11.6 Hz, 2H), 0.96-1.04 (m, 2H);

(1230) MASS (ESI, Pos.): 460 (M+H)+.

Example 26(73)

3-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]phenol

(1231) Purity (LC-MS/ELSD): 100% (retention time: 0.42 min);

(1232) NMR (600 MHz, ACETONITRILE-d3): 8.18 (s, 1H), 8.17 (s, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.07 (br. s, 1H), 7.04 (br. d, J=10.3 Hz, 1H), 6.99 (br. d, J=10.3 Hz, 1H), 6.89-6.93 (m, 3H), 2.93 (br. d, J=12.8 Hz, 2H), 2.60-2.69 (m, 1H), 2.41-2.49 (m, 5H), 1.45 (br. d, J=12.8 Hz, 2H), 1.06-1.14 (m, 2H);

(1233) MASS (ESI, Pos.): 378 (M+H)+.

Example 26(74)

5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-2-fluorophenol

(1234) Purity (LC-MS/ELSD): 100% (retention time: 0.42 min);

(1235) NMR (600 MHz, ACETONITRILE-d3): 8.18 (s, 1H), 8.16 (s, 1H), 7.21 (dd, J=11.8, 8.5 Hz, 1H), 6.95-7.06 (m, 4H), 6.80-6.84 (m, 1H), 2.94 (br. d, J=12.3 Hz, 2H), 2.68-2.78 (m, 1H), 2.43 (s, 5H), 1.49 (br. d, J=12.3 Hz, 2H), 1.12-1.20 (m, 2H);

(1236) MASS (ESI, Pos.): 396 (M+H)+.

Example 26(75)

5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-2-chlorophenol

(1237) Purity (LC-MS/ELSD): 100% (retention time: 0.45 min);

(1238) NMR (600 MHz, ACETONITRILE-d3): 8.18 (s, 1H), 8.17 (s, 1H), 7.44 (d, J=8.3 Hz, 1H), 6.95-7.06 (m, 4H), 6.81-6.84 (m, 1H), 2.94 (br. d, J=12.8 Hz, 2H), 2.65-2.76 (m, 1H), 2.41-2.48 (m, 5H), 1.48 (br. d, J=12.8 Hz, 2H), 1.12-1.21 (m, 2H);

(1239) MASS (ESI, Pos.): 412 (M+H)+.

Example 26(76)

(1240) ##STR00126##

methyl 4-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]benzoate

(1241) Purity (LC-MS/ELSD): 100% (retention time: 0.48 min);

(1242) NMR (600 MHz, ACETONITRILE-d3): 8.21 (s, 1H), 8.21 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.07 (br. s, 1H), 7.05 (br. d, J=9.2 Hz, 1H), 7.00 (br. d, J=9.2 Hz, 1H), 3.95 (s, 3H), 2.89 (br. d, J=13.4 Hz, 2H), 2.51-2.61 (m, 1H), 2.38-2.46 (m, 5H), 1.41 (br. d, J=13.2 Hz, 2H), 0.96-1.05 (m, 2H);

(1243) MASS (ESI, Pos.): 420 (M+H)+.

Example 26(77)

methyl 3-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]benzoate

(1244) Purity (LC-MS/ELSD): 100% (retention time: 0.47 min);

(1245) NMR (600 MHz, ACETONITRILE-d3): 8.22 (s, 1H), 8.21 (s, 1H), 8.05-8.10 (m, 2H), 7.70-7.74 (m, 1H), 7.66 (t, J=7.5 Hz, 1H), 6.96-7.10 (m, 3H), 3.94 (s, 3H), 2.89 (br. d, J=12.5 Hz, 2H), 2.49-2.60 (m, 1H), 2.35-2.46 (m, 5H), 1.41 (br. d, J=12.4 Hz, 2H), 0.93-1.02 (m, 2H);

(1246) MASS (ESI, Pos.): 420 (M+H)+.

Example 26(78)

1-[3-(3-fluoro-5-methylphenyl)-5-(2-methyl-1,3-benzoxazol-5-yl)-4-pyridinyl]-4-piperidinamine

(1247) Purity (LC-MS/ELSD): 100% (retention time: 0.44 min);

(1248) NMR (600 MHz, ACETONITRILE-d3): 8.25 (s, 1H), 8.21 (s, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.42 (dd, J=8.4, 1.8 Hz, 1H), 7.07 (br. s, 1H), 7.05 (br. d, J=9.9 Hz, 1H), 6.99 (br. d, J=9.9 Hz, 1H), 2.91 (br. d, J=13.0 Hz, 2H), 2.68 (s, 3H), 2.55-2.64 (m, 1H), 2.44 (s, 3H), 2.35-2.42 (m, 2H), 1.40 (br. d, J=13.0 Hz, 2H), 0.98-1.07 (m, 2H);

(1249) MASS (ESI, Pos.): 417 (M+H)+.

Example 26(79)

N-{5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-2-methoxyphenyl}acetamide

(1250) Purity (LC-MS/ELSD): 100% (retention time: 0.44 min);

(1251) NMR (600 MHz, ACETONITRILE-d3): 8.18 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.19-7.23 (m, 1H), 7.15-7.19 (m, 1H), 7.07 (br. s, 1H), 7.04 (br. d, J=10.6 Hz, 1H), 6.99 (br. d, J=10.6 Hz, 1H), 3.94 (s, 3H), 2.93 (br. d, J=13.8 Hz, 2H), 2.65-2.79 (m, 1H), 2.46-2.54 (m, 2H), 2.43 (s, 3H), 2.17 (s, 3H), 1.46 (br. d, J=13.7 Hz, 2H), 1.18-1.26 (m, 2H);

(1252) MASS (ESI, Pos.): 449 (M+H)+.

Example 26(80)

(1253) ##STR00127##

6-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one

(1254) Purity (LC-MS/ELSD): 100% (retention time: 0.45 min);

(1255) NMR (600 MHz, ACETONITRILE-d3): 8.21 (s, 1H), 8.18 (s, 1H), 7.09-7.17 (m, 3H), 7.08 (br. s, 1H), 7.05 (br. d, J=9.4 Hz, 1H), 7.00 (br. d, J=9.4 Hz, 1H), 4.70 (s, 2H), 3.36 (s, 3H), 2.94 (br. d, J=13.2 Hz, 2H), 2.58-2.67 (m, 1H), 2.38-2.48 (m, 5H), 1.46 (br. d, J=13.2 Hz, 2H), 0.99-1.09 (m, 2H);

(1256) MASS (ESI, Pos.): 447 (M+H)+.

Example 26(81)

(1257) ##STR00128##

{4-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]phenyl}acetonitrile

(1258) Purity (LC-MS/ELSD): 100% (retention time: 0.45 min);

(1259) NMR (600 MHz, ACETONITRILE-d3): 8.19 (s, 1H), 8.19 (s, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.07 (br. s, 1H), 7.04 (br. d, J=9.5 Hz, 1H), 7.00 (br. d, J=9.5 Hz, 1H), 3.97 (s, 2H), 2.89 (br. d, J=12.5 Hz, 2H), 2.56-2.68 (m, 1H), 2.34-2.48 (m, 5H), 1.42 (br. d, J=12.5 Hz, 2H), 0.95-1.09 (m, 2H);

(1260) MASS (ESI, Pos.): 401 (M+H)+.

Example 26(82)

1-{3-[3-fluoro-5-(trifluoromethyl)phenyl]-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(1261) Purity (LC-MS/ELSD): 100% (retention time: 0.60 min);

(1262) NMR (600 MHz, ACETONITRILE-d3): 8.27 (s, 1H), 8.26 (s, 1H), 7.85 (d, J=7.9 Hz, 2H), 7.61-7.65 (m, 3H), 7.57 (br. d, J=8.8 Hz, 1H), 7.52 (br. d, J=8.8 Hz, 1H), 2.87 (br. d, J=13.2 Hz, 2H), 2.42-2.54 (m, 1H), 2.35-2.42 (m, 2H), 1.40 (br. d, J=13.2 Hz, 2H), 0.86-0.96 (m, 2H),

(1263) MASS (ESI, Pos.): 484 (M+H)+.

Example 26(83)

5-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]-2-(trifluoromethyl)phenol

(1264) Purity (LC-MS/ELSD): 100% (retention time: 0.50 min);

(1265) NMR (600 MHz, ACETONITRILE-d3): 8.20 (s, 1H), 8.19 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 6.88-7.10 (m, 5H), 2.94 (br. d, J=13.4 Hz, 2H), 2.60-2.74 (m, 1H), 2.40-2.50 (m, 5H), 1.46 (br. d, J=13.0 Hz, 2H), 1.09-1.19 (m, 2H);

(1266) MASS (ESI, Pos.): 446 (M+H)+.

Example 26(84)

(1267) ##STR00129##

1-{3-(3-fluoro-5-methylphenyl)-5-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-4-pyridinyl}-4-piperidinamine

(1268) Description: pale yellow oil;

(1269) Purity (UPLC-MS/ELSD): 100% (retention time: 0.51 min);

(1270) TLC: Rf 0.53 (ethyl acetate:methanol=20:1, NH silica gel);

(1271) NMR (300 MHz, CHLOROFORM-d): 8.17 (d, J=0.4 Hz, 1H), 8.13 (d, J=0.4 Hz, 1H), 6.97-6.80 (m, 3H), 5.76-5.68 (m, 1H), 3.18-2.96 (m, 2H), 2.75-2.53 (m, 3H), 2.52-2.28 (m, 8H), 2.21-2.11 (m, 1H), 1.82-1.56 (m, 3H), 1.22-1.03 (m, 2H); MASS (ESI, Pos.): 434 (M+H)+.

Example 26(85)

1-{3-(3-chloro-5-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(1272) Description: pale brown amorphous powder;

(1273) Purity (UPLC-MS/ELSD): 100% (retention time: 0.57 min);

(1274) TLC: Rf 0.65 (ethyl acetate:methanol=20:1, NH silica gel);

(1275) NMR (300 MHz, METHANOL-d4): 8.17 (s, 2H), 7.81 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.31-7.15 (m, 3H), 2.96-2.86 (m, 2H), 2.50-2.36 (m, 6H), 1.45-1.36 (m, 2H), 1.04-0.90 (m, 2H);

(1276) MASS (ESI, Pos.): 446 (M+H)+.

Example 26(86)

1-{3-(3-chloro-5-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridinyl}-4-piperidinamine

(1277) Description: colorless oil;

(1278) Purity (UPLC-MS/ELSD): 100% (retention time: 0.58 min);

(1279) TLC: Rf 0.58 (ethyl acetate:methanol=20:1, NH silica gel);

(1280) NMR (300 MHz, CHLOROFORM-d): 8.28 (s, 1H), 8.25 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H), 6.99 (t, J=1.6 Hz, 1H), 6.94-6.91 (m, 1H), 6.83-6.80 (m, 1H), 3.86 (s, 3H), 2.92-2.82 (m, 2H), 2.58-2.36 (m, 3H), 1.50-1.40 (m, 2H), 1.04-0.88 (m, 2H);

(1281) MASS (ESI, Pos.): 462 (M+H)+.

Example 26(87)

1-(3-{4-(4-amino-1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-3-pyridinyl}-5-fluorophenyl)ethanol

(1282) Description: white amorphous powder;

(1283) Purity (UPLC-MS/ELSD): 100% (retention time: 0.50 min);

(1284) TLC: Rf 0.56 (ethyl acetate:methanol=9:1, NH silica gel);

(1285) NMR (300 MHz, CHLOROFORM-d): 8.31 (s, 1H), 8.28 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.25-7.23 (m, 1H), 7.13-6.99 (m, 2H), 4.92 (q, J=6.2 Hz, 1H), 2.89-2.76 (m, 2H), 2.67-2.55 (m, 1H), 2.48-2.31 (m, 2H), 1.52 (d, J=6.2 Hz, 3H), 1.40-1.26 (m, 2H), 1.07-0.82 (m, 2H);

(1286) MASS (ESI, Pos.): 460 (M+H)+.

Example 26(88)

1-{4-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]phenyl}ethanol

(1287) Description: pale yellow amorphous powder;

(1288) Purity (UPLC-MS/ELSD): 94.1% (retention time: 0.45 min);

(1289) TLC: Rf 0.21 (ethyl acetate:methanol=9:1, NH silica gel);

(1290) NMR (300 MHz, CHLOROFORM-d): 8.23 (s, 1H), 8.20 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.86-7.02 (m, 3H), 4.98 (q, J=6.4 Hz, 1H), 2.85 (br. d, J=13.4 Hz, 2H), 2.28-2.52 (m, 6H), 1.56 (d, J=6.4 Hz, 3H), 1.39 (br. d, J=13.0 Hz, 2H), 0.84-1.01 (m, 2H);

(1291) MASS (ESI, Pos.): 406 (M+H)+.

Example 26(89)

[1-(4-{4-[4-(aminomethyl)-1-piperidinyl]-5-(3-fluoro-5-methoxyphenyl)-3-pyridinyl}phenyl)cyclopropyl]methanol

(1292) Purity (UPLC-MS/ELSD): 100% (retention time: 0.50 min);

(1293) MASS (ESI, Pos.): 462 (M+H)+.

Reference Example 37

2-(benzyloxy)-3-bromophenol

(1294) To a solution of 2-(benzyloxy)-3-bromobenzaldehyde (CAS#120980-85-0) (1.30 g) in chloroform (10 mL) was added 3-chloroperoxybenzoic acid (1.15 g), and stirred at 70 degrees C. for 15 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous solution of sodium thiosulfate. The organic layer was sequentially washed with water and saturated brine, and concentrated after drying. The obtained residue was dissolved in methanol (30 mL), added potassium carbonate (1.38 g) and then stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate and washed with 1M aqueous solution of potassium hydrogen sulfate. The organic layer was sequentially washed with water and saturated brine and concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=3:1) to obtain the title compound (1.24 g) having the following physical property values.

(1295) TLC: Rf 0.34 (n-hexane:ethyl acetate=3:1);

Reference Example 38

3,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methoxy)-[1,1-biphenyl]-2-ol

(1296) Using (1-methyl-1H-pyrazol-4-yl)methanol (CAS#112029-98-8) in place of the compound produced in Reference example 8, using the compound produced in Reference example 37 in place of 3,5-dimethylphenol, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 9.fwdarw.Reference example 2.fwdarw.Reference example 16, and used for next reaction without further purification.

Example 27

(2R)-2-[2-({3,5-dimethyl-3-[(1-methyl-1H-pyrazol-4-yl)methoxy]-2-biphenylyl}oxy)ethyl]piperidine

(1297) ##STR00130##

(1298) Using (R)-tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate (CAS#250249-85-5) in place of the compound produced in Reference example 8, using the compound produced in Reference example 38 in place of 3,5-dimethylphenol, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 9.fwdarw.Example 1.

(1299) Description: brown oil;

(1300) Purity (LC-MS/ELSD): 100% (retention time: 4.42 min);

(1301) TLC: Rf 0.20 (ethyl acetate, NH silica gel);

(1302) MASS (ESI, Pos.): 420 (M+H)+.

Reference Example 39

tert-butyl 2-(2-((3-bromo-5-(3,5-dimethylphenyl)pyridin-4-yl)oxy)ethyl)piperidine-1-carboxylate

(1303) Using tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate in place of the compound produced in Reference example 8, using 3-bromo-5-iodopyridin-4-ol (Synlett, 2003, vol. 11, p. 1678-1682) in place of 3,5-dimethylphenol, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 9.fwdarw.Reference example 2.

(1304) Description: orange solid;

(1305) TLC: Rf 0.48 (n-hexane:ethyl acetate=3:1);

(1306) NMR (300 MHz, CHLOROFORM-d): 8.61 (s, 1H), 8.38 (s, 1H), 7.12 (s, 2H), 7.03 (s, 1H), 4.29-4.16 (m, 1H), 3.96-3.82 (m, 1H), 3.82-3.67 (m, 1H), 3.60-3.43 (m, 1H), 2.63-2.46 (m, 1H), 2.36 (s, 6H), 2.03-1.87 (m, 1H), 1.75-1.29 (m, 7H), 1.37 (s, 9H).

Reference Example 40

tert-butyl 2-(2-((3-(3,5-dimethylphenyl)-5-vinylpyridin-4-yl)oxy)ethyl)piperidine-1-carboxylate

(1307) Using the compound produced in Reference example 39 in place of the compound produced in Reference example 1, using potassium vinyltrifluoroborate (CAS#13682-77-4) in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 2.

(1308) Description: orange solid;

(1309) TLC: Rf 0.43 (n-hexane:ethyl acetate=3:1);

(1310) NMR (300 MHz, CHLOROFORM-d): 8.61 (s, 1H), 8.38 (s, 1H), 7.16-7.10 (m, 2H), 7.05-6.86 (m, 2H), 5.86 (d, J=19.03 Hz, 1H), 5.40 (d, J=11.16 Hz, 1H), 4.29-4.07 (m, 1H), 3.95-3.79 (m, 1H), 3.72-3.56 (m, 1H), 3.51-3.37 (m, 1H), 2.58-2.43 (m, 1H), 2.37 (s, 6H), 1.97-1.80 (m, 1H), 1.68-1.23 (m, 16H).

Reference Example 41

(E)-tert-butyl 2-(2-((3-(3,5-dimethylphenyl)-5-(3,5-dimethylstyryl)pyridin-4-yl)oxy)ethyl)piperidine-1-carboxylate

(1311) To a solution of the compound produced in Reference example 40 (1.12 g) in dimethylformamide (10 mL) was added 1-bromo-3,5-dimethylbenzene (CAS#40032-73-3) (1.06 mL), 1,1-bis(diphenylphosphino)ferrocene-palladium(11) dichloride, complex with dichloromethane (PdCl.sub.2(dppf).sub.2CH.sub.2Cl.sub.2) (210 mg) and N,N-dicyclohexylmethylamine (1.65 mL), and the mixture was stirred at 130 degrees C. for 3 hours. After adding water, the reaction solution was extracted with ethyl acetate, and sequentially washed with water and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=3:1) to obtain the title compound (745 mg) having the following physical property values.

(1312) Description: dark red oil;

(1313) TLC: Rf 0.52 (n-hexane:ethyl acetate=3:1);

(1314) NMR (300 MHz, METHANOL-d4): 8.74 (s, 1H), 8.38 (s, 1H), 7.36 (s, 1H), 7.23-7.12 (m, 5H), 7.03 (s, 1H), 6.95 (s, 1H), 4.30-4.17 (m, 1H), 3.93-3.79 (m, 1H), 3.76-3.61 (m, 1H), 3.56-3.42 (m, 1H), 2.57-2.42 (m, 1H), 2.38 (s, 6H), 2.35 (s, 6H), 1.98-1.82 (m, 1H), 1.71-1.58 (m, 1H), 1.53-1.40 (m, 4H), 1.34 (br. s., 9H), 1.33-1.24 (m, 2H).

Example 28

3-(3,5-dimethylphenyl)-5-[(E)-2-(3,5-dimethylphenyl)vinyl]-4-[2-(2-piperidinyl)ethoxy]pyridine

(1315) ##STR00131##

(1316) Using the compound produced in Reference example 36 in place of the compound produced in Reference example 3, the present invention compound having the following physical property values was obtained by following the same procedure as in Example 1.

(1317) Description: beige powder;

(1318) TLC: Rf 0.60 (ethyl acetate, NH silica gel);

(1319) NMR (300 MHz, METHANOL-d4): 8.99 (br. s., 1H), 8.68 (s, 1H), 8.34 (s, 1H), 7.16-7.04 (m, 6H), 7.01 (s, 1H), 6.91 (s, 1H), 3.77-3.62 (m, 1H), 3.56-3.41 (m, 1H), 3.24-3.09 (m, 1H), 2.93-2.74 (m, 1H), 2.62-2.46 (m, 1H), 2.35 (s, 6H), 2.31 (s, 6H), 2.42-2.26 (m, 1H), 2.04-1.89 (m, 1H), 1.82-1.51 (m, 3H), 1.49-1.22 (m, 2H), 1.20-0.99 (m, 1H);

(1320) MASS (ESI, Pos.): 441 (M+H)+.

Reference Example 42

(Z)-tert-butyl (1-(3-((((amino(phenyl)methylene)amino)oxy)carbonyl)-5-(3,5-dimethylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate

(1321) To a solution of the compound produced in Reference example 6 (868 mg) in tetrahydrofuran (4 mL)/methanol (3 mL) was added 2M aqueous solution of sodium hydroxide (1.97 mL), and the mixture was stirred at 65 degrees C. for 6 hours. After cooling by ice-water, the reaction solution was neutralized by 2M hydrochloric acid (1.97 mL), and then concentrated under reduced pressure. The residue was dissolved in dimethylformamide, added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), triethylamine and benzamide oxime (CAS#1195196-49-6), and the mixture was stirred at room temperature overnight. The reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried followed by concentration. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (ethyl acetate) to obtain the title compound (58 mg) having the following physical property values.

(1322) Description: pale yellow powder;

(1323) TLC: Rf 0.23 (ethyl acetate);

Example 29

1-[3-(3,5-dimethylphenyl)-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-4-pyridinyl]-4-piperidinamine

(1324) ##STR00132##

(1325) A solution of the compound (58 mg) produced in Reference example 42 in dimethylformamide (1.0 mL) was stirred at 110 degrees C. overnight. To the reaction solution was added water, and extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in dichloromethane (1.0 mL). To the reaction solution was added trifluoroacetic acid (1.0 mL), and stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5) to obtain the present invention compound (17 mg) having the following physical property values.

(1326) Description: yellow viscous oil;

(1327) TLC: Rf 0.36 (ethyl acetate, NH silica gel);

(1328) NMR (300 MHz, CHLOROFORM-d): 8.77 (s, 1H), 8.37 (s, 1H), 8.26-8.09 (m, 2H), 7.63-7.41 (m, 3H), 7.14-6.91 (m, 3H), 3.04 (d, J=13.0 Hz, 2H), 2.83-2.53 (m, 3H), 2.39 (s, 6H), 1.77-1.37 (m, 2H), 1.31-1.03 (m, 2H);

(1329) MASS (APCI, Pos.): 426 (M+H)+.

Reference Example 43

tert-butyl ((1-(3-amino-5-(3,5-dimethylphenyl)pyridin-4-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate

(1330) Using tert-butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate (purchased from CHEMBASICS, catalog number: CMB1175) in place of tert-butyl N-(4-piperidylmethyl)carbamate, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 14.fwdarw.Reference example 2.fwdarw.Reference example 16, and used for next reaction without further purification.

Reference Example 44

tert-butyl ((1-(3-(3,5-dimethylphenyl)-5-(phenylamino)pyridin-4-yl)-4-hydroxypiperidin-4-yl)methyl)carbamate

(1331) To a solution of the compound (86 mg) produced in Reference example 43 in toluene (5 mL) was added iodobenzene (CAS#591-50-4) (45.24 mg), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (12.55 mg) and cesium carbonate (328.4 mg). Under the argon atmosphere, palladium(II) acetate (4.526 mg) was added to the reaction solution and stirred at 100 degrees C. for 14 hours. After cooling to room temperature, the reaction solution was added ethyl acetate and then concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (ethyl acetate) to obtain the title compound (65 mg) having the following physical property values.

(1332) Description: yellow viscous oil;

(1333) TLC: Rf 0.80 (ethyl acetate);

Example 30(1)-Example 30(5)

(1334) Using a corresponding reagent in place of tert-butyl N-(4-piperidylmethyl)carbamate, using 3,5-dimethylphenylboronic acid in place of phenylboronic acid, using a corresponding reagent in place of iodobenzene, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 14.fwdarw.Reference example 2.fwdarw.Reference example 16.fwdarw.Reference example 39.fwdarw.Example 1.

Example 30(1)

4-(aminomethyl)-1-[3-anilino-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinol

(1335) ##STR00133##

(1336) Description: yellow amorphous powder;

(1337) TLC: Rf 0.14 (ethyl acetate:methanol:28% ammonia water=90:10:1);

(1338) NMR (300 MHz, METHANOL-d4): 8.24 (s, 1H), 7.82 (s, 1H), 7.30-7.20 (m, 2H), 7.09-6.94 (m, 5H), 6.93-6.84 (m, 1H), 3.00-2.75 (m, 4H), 2.42 (s, 2H), 2.37 (s, 6H), 1.57-1.32 (m, 4H);

(1339) MASS (ESI, Pos.): 403 (M+H)+.

Example 30(2)

5-(3,5-dimethylphenyl)-4-[4-(methylamino)-1-piperidinyl]-N-phenyl-3-pyridinamine

(1340) Description: yellow amorphous powder;

(1341) TLC: Rf 0.76 (ethyl acetate:methanol=9:1, NH silica gel);

(1342) NMR (300 MHz, CHLOROFORM-d): 8.56 (s, 1H), 7.91 (s, 1H), 7.34-7.27 (m, 2H), 7.19-7.13 (m, 2H), 7.04 (s, 1H), 7.00-6.92 (m, 1H), 6.91-6.85 (m, 2H), 6.14 (s, 1H), 2.97 (d, J=12.26 Hz, 2H), 2.53-2.32 (m, 11H), 1.90 (m, 2H), 1.61-1.39 (m, 2H);

(1343) MASS (ESI, Pos.): 387 (M+H)+.

Example 30(3)

N-{5-(3,5-dimethylphenyl)-4-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}-6-quinazolinamine

(1344) Description: yellow amorphous powder;

(1345) TLC: Rf 0.58 (ethyl acetate:methanol=9:1, NH silica gel);

(1346) NMR (300 MHz, CHLOROFORM-d): 9.22 (s, 1H), 9.16 (s, 1H), 8.71 (s, 1H), 8.08 (s, 1H), 7.97 (d, J=8.97 Hz, 1H), 7.73 (dd, J=8.97, 2.40 Hz, 1H), 7.51 (d, J=2.40 Hz, 1H), 7.06 (s, 1H), 6.91 (s, 2H), 6.45 (s, 1H), 3.03-2.91 (m, 2H), 2.58-2.30 (m, 12H), 1.95-1.81 (m, 2H), 1.56-1.39 (m, 2H);

(1347) MASS (ESI, Pos.): 439 (M+H)+.

Example 30(4)

N-{5-(3,5-dimethylphenyl)-4-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}-6-quinazolinamine

(1348) Description: yellow powder;

(1349) TLC: Rf 0.58 (ethyl acetate:methanol=9:1, NH silica gel);

(1350) NMR (300 MHz, CHLOROFORM-d): 8.74 (dd, J=4.30, 1.65 Hz, 1H), 8.72 (s, 1H), 8.06-8.01 (m, 3H), 8.00-7.95 (m, 1H), 7.54-7.43 (m, 2H), 7.34 (dd, J=8.32, 4.30 Hz, 1H), 7.05 (s, 1H), 6.92 (s, 2H), 6.36 (s, 1H), 2.95 (d, J=12.62 Hz, 2H), 2.56-2.44 (m, 2H), 2.43-2.24 (m, 10H), 1.91-1.78 (m, 1H), 1.42-1.22 (m, 2H);

(1351) MASS (ESI, Pos.): 438 (M+H)+.

Example 30(5)

5-(3,5-dimethylphenyl)-4-[4-(methylamino)-1-piperidinyl]-N-[3-(trifluoromethoxy)phenyl]-3-pyridinamine

(1352) Description: yellow amorphous powder;

(1353) TLC: Rf 0.71 (ethyl acetate:methanol=9:1, NH silica gel);

(1354) NMR (300 MHz, CHLOROFORM-d): 8.55 (s, 1H), 7.98 (s, 1H), 7.28 (t, J=8.42 Hz, 1H), 7.06-7.00 (m, 2H), 6.98 (s, 1H), 6.93-6.87 (m, 2H), 6.83-6.75 (m, 1H), 6.18 (s, 1H), 2.93 (d, J=12.62 Hz, 2H), 2.54-2.33 (m, 12H), 1.91-1.80 (m, 2H), 1.47-1.30 (m, 2H);

(1355) MASS (ESI, Pos.): 471 (M+H)+.

Reference Example 45

(1356) tert-butyl (1-(3-(3,5-dimethylphenyl)-5-(3-phenyl-1H-1,2,4-triazol-5-yl)pyridin-4-yl)piperidin-4-yl)carbamate

(1357) To a sodium ethoxide (25 mg) in ethanol (1.0 mL) was added hydrazine monohydrate (0.5 mL), and stirred at 75 degrees C. overnight. The solvent and excess of hydrazine was removed under reduced pressure, and treated with toluene as azeotropy. The residue was dissolved in anhydrous ethanol (0.5 mL) and added benzamidine hydrochloride (CAS#1670-14-0) (59 mg), and then stirred at room temperature for 20 min. The reaction solution was added to the solution of the compound (100 mg) produced in Reference example 5 in toluene (1.0 mL)/ethanol (2.0 mL), and stirred at 110 degrees C. overnight and then additionally stirred at 130-150 degrees C. After cooling to room temperature, the reaction solution was filtered and concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (ethyl acetate) to obtain the title compound (77 mg) having the following physical property values.

(1358) TLC: Rf 0.27 (ethyl acetate);

Example 31

1-[3-(3,5-dimethylphenyl)-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-4-pyridinyl]-4-piperidinamine

(1359) ##STR00134##

(1360) Using the compound produced in Reference example 45 in place of the compound produced in Reference example 3, the present invention compound having the following physical property values was obtained by following the same procedure as in Example 1.

(1361) Description: pale yellow powder;

(1362) TLC: Rf 0.16 (ethyl acetate:methanol=9:1, NH silica gel);

(1363) NMR (300 MHz, CHLOROFORM-d): 8.95 (s, 1H), 8.38-8.25 (m, 1H), 8.21-8.07 (m, 2H), 7.55-7.38 (m, 3H), 7.03 (s, 1H), 6.93 (s, 2H), 4.12 (br. s, 2H), 2.98 (d, J=12.4 Hz, 2H), 2.70-2.53 (m, 3H), 2.37 (s, 6H), 1.65 (d, J=10.4 Hz, 2H), 1.34-1.15 (m, 2H);

(1364) MASS (ESI, Pos.): 425 (M+H)+.

Reference Example 46

tert-butyl (1-(3-(2-benzoylhydrazinecarbonyl)-5-(3,5-dimethylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate

(1365) To a solution of the compound (200 mg) produced in Reference example 5 in methanol (2.0 mL) was added 1M aqueous solution of sodium hydroxide (0.91 mL), and the mixture was stirred at room temperature overnight. To the reaction solution was added 1M aqueous solution of sodium hydroxide (0.455 mL), and after that methanol and tetrahydrofuran was added to the mixture until it became uniform layer, and the mixture was stirred at 65 degrees C. After cooling by ice-water, the reaction mixture was neutralized by 2M hydrochloric acid, concentrated under reduced pressure, and then treated with toluene as azeotropy. To the obtained residue was added N,N-dimethylacetamide (4 mL), N,N-diisopropylethylamine (235 microL), benzohydrazide (CAS#613-94-5) (260 mg) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (402 mg), and the mixture was stirred at room temperature overnight. After adding saturated brine, the reaction solution was extracted with tetrahydrofuran. After drying, the organic layer was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash NH) (ethyl acetate:methanol=95:5) to obtain the title compound having the following physical property values.

(1366) Description: white powder;

(1367) TLC: Rf 0.24 (ethyl acetate:methanol=9:1, NH silica gel).

Reference Example 47

tert-butyl (1-(3-(3,5-dimethylphenyl)-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)piperidin-4-yl)carbamate

(1368) To a solution of the compound (170 mg) produced in Reference example 46 in anhydrous tetrahydrofuran (2.0 mL) was added Burgess reagent (112 mg), and the mixture was stirred at room temperature for 2 hours and then at 50 degrees C. for 30 min. After cooling to room temperature, the solvent was removed under reduced pressure. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane:ethyl acetate=3:1) to obtain the title compound (160 mg) having the following physical property values.

(1369) Description: clear and colorless oil;

(1370) TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

Example 32(1)-Example 32(6)

(1371) Using 4-tert-butoxycarbonylaminopiperidine, or a corresponding reagent in place of it, using a corresponding boronic acid in place of phenylboronic acid, using benzohydrazide, or a corresponding reagent in place of it, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 1.fwdarw.Reference example 2.fwdarw.Reference example 41.fwdarw.Reference example 42.fwdarw.Example 1.

Example 32(1)

1-[3-(3,5-dimethylphenyl)-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-4-pyridinyl]-4-piperidinamine

(1372) ##STR00135##

(1373) Description: orange viscous oil;

(1374) TLC: Rf 0.66 (ethyl acetate:methanol=9:1, NH silica gel);

(1375) NMR (300 MHz, CHLOROFORM-d): 8.72 (s, 1H), 8.37 (s, 1H), 8.22-8.03 (m, 2H), 7.64-7.48 (m, 3H), 7.09-6.97 (m, 3H), 3.06 (d, J=12.8 Hz, 2H), 2.76-2.49 (m, 3H), 2.39 (s, 6H), 1.60-1.48 (m, 2H), 1.38 (br. s., 2H), 1.20-1.02 (m, 2H);

(1376) MASS (APCI, Pos.): 426 (M+H)+.

Example 32(2)

1-[3-(3,5-dimethylphenyl)-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)-4-pyridinyl]-4-piperidinamine

(1377) Description: pale yellow oil;

(1378) TLC: Rf 0.46 (ethyl acetate:methanol=20:1, NH silica gel);

(1379) NMR (300 MHz, METHANOL-d4): 8.50 (s, 1H), 8.24 (s, 1H), 7.08 (s, 1H), 7.06 (s, 2H), 3.40-3.32 (m, 1H), 3.04 (d, J=12.6 Hz, 2H), 2.67-2.44 (m, 3H), 2.39 (s, 6H), 1.57-1.49 (m, 2H), 1.47 (s, 3H), 1.45 (s, 3H), 1.12 (qd, J=11.8, 4.1 Hz, 2H);

(1380) MASS (ESI, Pos.): 392 (M+H)+.

Example 32(3)

1-[3-(3,5-dimethylphenyl)-5-(5-propyl-1,3,4-oxadiazol-2-yl)-4-pyridinyl]-4-piperidinamine

(1381) Description: yellow oil;

(1382) TLC: Rf 0.38 (ethyl acetate:methanol=20:1, NH silica gel);

(1383) NMR (300 MHz, METHANOL-d4): 8.49 (s, 1H), 8.23 (s, 1H), 7.11-7.01 (m, 3H), 3.13-2.92 (m, 4H), 2.69-2.45 (m, 3H), 2.38 (s, 6H), 1.97-1.79 (m, 2H), 1.51 (d, J=11.9 Hz, 2H), 1.22-0.99 (m, 5H);

(1384) MASS (ESI, Pos.): 392 (M+H)+.

Example 32(4)

1-[3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-(3,5-dimethylphenyl)-4-pyridinyl]-4-piperidinamine

(1385) Description: pale orange powder;

(1386) TLC: Rf 0.41 (ethyl acetate:methanol=20:1, NH silica gel);

(1387) NMR (300 MHz, METHANOL-d4): 8.55 (s, 1H), 8.26 (s, 1H), 7.09 (s, 1H), 7.03 (s, 2H), 3.09 (d, J=12.6 Hz, 2H), 2.86-2.71 (m, 1H), 2.69-2.54 (m, 2H), 2.44-2.27 (m, 7H), 1.62 (d, J=11.9 Hz, 2H), 1.41-1.12 (m, 6H);

(1388) MASS (ESI, Pos.): 390 (M+H)+.

Example 32(5)

1-[3-cyclopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-4-pyridinyl]-4-piperidinamine

(1389) Description: pale red powder;

(1390) TLC: Rf 0.70 (ethyl acetate:methanol=9:1, NH silica gel);

(1391) NMR (300 MHz, CHLOROFORM-d): 8.63 (s, 1H), 8.26 (s, 1H), 8.18-8.06 (m, 2H), 7.65-7.49 (m, 3H), 3.32 (d, J=12.62 Hz, 2H), 3.05-2.90 (m, 2H), 2.88-2.72 (m, 1H), 2.15-1.97 (m, 1H), 1.90-1.73 (m, 2H), 1.54-1.36 (m, 2H), 1.16-1.03 (m, 2H), 0.92-0.80 (m, 2H);

(1392) MASS (ESI, Pos.): 362 (M+H)+.

Example 32(6)

1-[3-cyclopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-4-pyridinyl]-N-ethyl-4-piperidinamine

(1393) Description: pale yellow amorphous powder;

(1394) TLC: Rf 0.85 (ethyl acetate:methanol=9:1, NH silica gel);

(1395) NMR (300 MHz, CHLOROFORM-d): 8.62 (s, 1H), 8.25 (s, 1H), 8.16-8.10 (m, 2H), 7.62-7.51 (m, 3H), 3.33 (d, J=12.60 Hz, 2H), 2.97 (td, J=12.60, 2.56 Hz, 2H), 2.73-2.57 (m, 3H), 2.15-2.00 (m, 1H), 1.90 (d, J=9.51 Hz, 2H), 1.50 (m, 2H), 1.14-1.02 (m, 5H), 0.92-0.79 (m, 2H)

(1396) MASS (ESI, Pos.): 390 (M+H)+.

Reference Example 48

ethyl 5-amino-1-(3,5-dimethylphenyl)-1H-pyrazole-4-carboxylate

(1397) To the solution of ethyl(ethoxymethylene)cyanoacetate (CAS#29096-99-9) (3.4 g) in ethanol (50 mL) was added (3,5-dimethylphenyl)hydrazine hydrochloride (CAS#60481-36-9) (3.5 g) and sodium acetate (1.8 g), and the mixture was stirred at 80 degrees C. for 1 hour. After cooling to room temperature, the reaction solution was filtered. The filtrate was concentrated and obtained the title compound which was used for next reaction without further purification.

Reference Example 49

ethyl 5-chloro-1-(3,5-dimethylphenyl)-1H-pyrazole-4-carboxylate

(1398) To a solution of the amyl nitrite (540 mg) and copper(I) chloride (570 mg) in acetonitrile (12 mL) stirring at 65 degrees C. was added a solution of the compound (1.0 g) produced in Reference example 48 in acetonitrile (12 mL), and the mixture was stirred at 65 degrees C. for 30 min. After cooling, the reaction solution was filtered and concentrated. The obtained residue was purified by silicagel column chromatography (eluent hexane:ethyl acetate=100:0.fwdarw.91:9) to obtain the title compound (187 mg) having the following physical property values.

(1399) TLC: Rf 0.61 (n-hexane:ethyl acetate=3:1).

Reference Example 50

ethyl 5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-1-(3,5-dimethylphenyl)-1H-pyrazole-4-carboxylate

(1400) Using the compound produced in Reference example 49 in place of the mixture produced in Reference example 32, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 33.

(1401) TLC: Rf 0.43 (n-hexane:ethyl acetate=3:1).

Example 33

1-[4-(4,6-dimethyl-1H-benzimidazol-2-yl)-1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl]-4-piperidinamine

(1402) ##STR00136##

(1403) Using the compound produced in Reference example 50 in place of the compound produced in Reference example 5, using 3,5-dimethylbenzene-1,2-diamine in place of 3,5-dimethylaniline, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference example 6.fwdarw.Reference example 7.fwdarw.Reference example 29.fwdarw.Example 1.

(1404) Description: amber powder;

(1405) TLC: Rf 0.41 (ethyl acetate:methanol=20:1, NH silica gel);

(1406) NMR (300 MHz, METHANOL-d4): 7.88-7.81 (m, 1H), 7.26 (s, 2H), 7.20 (s, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 3.10-2.99 (m, 4H), 2.72-2.59 (m, 1H), 2.56-2.51 (m, 3H), 2.44-2.40 (m, 3H), 2.40-2.38 (m, 6H), 1.67 (d, J=11.9 Hz, 2H), 1.42-1.25 (m, 2H); MASS (ESI, Pos.): 415 (M+H)+.

Reference Example 51

4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)-5-(3,5-dimethylphenyl)pyridine 1-oxide

(1407) ##STR00137##

(1408) tert-butyl (1-(3-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)-5-(3,5-dimethylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate (200 mg), which is Boc derivative of Example 21(1), was dissolved in a mixed solution of dichloromethane (5 mL), acetonitrile (2 mL), ethyl acetate (2 mL) and N,N-dimethylacetamide (10 mL). To the reaction mixture was added m-chloroperoxybenzoic acid (180 mg) and stirred at room temperature. After 1 hour, m-chloroperoxybenzoic acid (108 mg) and N,N-dimethylacetamide (5 mL) was added to it, and stirred. A saturated aqueous solution of sodium hydrogen sulfite was added to the reaction mixture, and stirred for a while. 0.5 mol/L aqueous solution of sodium hydroxide was added to the reaction mixture, and it was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative medium pressure liquid chromatography (NH silica gel, ethyl acetate:methanol=100:0.fwdarw.90:10) to obtain the title compound having the following physical property values.

(1409) TLC: Rf 0.59 (ethyl acetate:methanol=19:1, NH silica gel);

(1410) NMR (300 MHz, METHANOL-d4): 8.31 (d, J=2.2 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.27 (br. s, 1H), 7.14 (br. s, 1H), 7.09 (br. s, 2H), 6.98 (br. s, 1H), 3.15-3.02 (m, 1H), 2.95 (br. d, J=13.4 Hz, 2H), 2.61-2.47 (m, 4H), 2.45 (s, 3H), 2.40 (s, 6H), 1.35 (s, 11H), 1.20-1.03 (m, 2H).

Example 34

(1411) ##STR00138##

1-[3-(4,6-dimethyl-1H-benzimidazol-2-yl)-5-(3,5-dimethylphenyl)-1-oxide-4-pyridinyl]-4-piperidinamine

(1412) Using the compound produced in Reference example 51 in place of the compound produced in Reference example 3, the present invention compound having the following physical property values was obtained by following the same procedure as in Example 1.

(1413) Description: yellow powder;

(1414) Purity (LC-MS/ELSD): 100% (retention time: 0.45 min);

(1415) TLC: Rf 0.24 (ethyl acetate:methanol=9:1, NH silica gel);

(1416) NMR (300 MHz, METHANOL-d4): 8.32 (d, J=2.4 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 7.08 (s, 2H), 6.97 (s, 1H), 2.99 (br. d, J=13.4 Hz, 2H), 2.59-2.42 (m, 9H), 2.39 (s, 3H), 2.39 (s, 3H), 1.47-1.36 (m, 2H), 1.15-0.96 (m, 2H);

(1417) MASS (ESI, Pos.): 442 (M+H)+.

Reference Example 52

tert-butyl(1-(3-(3,5-dimethylphenyl)-5-vinylpyridin-4-yl)piperidin-4-yl)carbamate

(1418) ##STR00139##

(1419) Using tert-butyl(1-(3-(3,5-dimethylphenyl)-5-iodopyridin-4-yl)piperidin-4-yl)carbamate in place of the compound produced in Reference example 39, the title compound having the following physical property values was obtained by following the same procedure as in Reference example 40.

(1420) TLC: Rf 0.52 (n-hexane:ethyl acetate=1:1);

Example 35(1)-Example 35(3)

(1421) Using the compound produced in Reference example 52 in place of the compound produced in Reference example 40, using a corresponding bromobenzene derivative, or a corresponding bromopyridine derivative in place of 1-bromo-3,5-dimethylbenzene, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 41.fwdarw.Example 1.

Example 35(1)

(1422) ##STR00140##

3-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]vinyl}benzonitrile

(1423) Description: pale yellow powder;

(1424) Purity (UPLC-MS/ELSD): 99.3% (retention time: 0.54 min);

(1425) TLC: Rf 0.68 (ethyl acetate:methanol=9:1, NH silica gel);

(1426) NMR (300 MHz, DIMETHYL SULFOXIDE-d6): 8.63 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 8.07-8.00 (m, 1H), 7.83-7.77 (m, 1H), 7.71-7.63 (m, 1H), 7.44 (d, J=16.6 Hz, 1H), 7.28 (d, J=16.6 Hz, 1H), 7.07 (s, 1H), 6.95 (s, 2H), 3.03-2.90 (m, 2H), 2.67-2.56 (m, 3H), 2.37 (s, 3H), 1.71-1.54 (m, 2H), 1.43-1.24 (m, 2H);

(1427) MASS (ESI, Pos.): 409 (M+H)+.

Example 35(2)

(1428) ##STR00141##

5-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]vinyl}nicotinonitrile

(1429) Description: pale yellow powder;

(1430) Purity (UPLC-MS/ELSD): 99.4% (retention time: 0.51 min);

(1431) TLC: Rf 0.63 (ethyl acetate:methanol=9:1, NH silica gel);

(1432) NMR (300 MHz, METHANOL-d4): 9.03 (d, J=1.8 Hz, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.56 (s, 1H), 8.50-8.45 (m, 1H), 8.11 (s, 1H), 7.55 (d, J=16.6 Hz, 1H), 7.22 (d, J=16.6 Hz, 1H), 7.07 (s, 1H), 6.90 (s, 2H), 3.14-3.01 (m, 2H), 2.72-2.53 (m, 3H), 2.37 (s, 6H), 1.79-1.63 (m, 2H), 1.51-1.34 (m, 2H);

(1433) MASS (ESI, Pos.): 410 (M+H)+.

Example 35(3)

4-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]vinyl}-2-pyridinecarbonitrile

(1434) Description: pale yellow powder;

(1435) Purity (UPLC-MS/ELSD): 99.2% (retention time: 0.51 min);

(1436) TLC: Rf 0.63 (ethyl acetate:methanol=9:1, NH silica gel);

(1437) NMR (300 MHz, DIMETHYL SULFOXIDE-d6): 8.78 (d, J=5.1 Hz, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 7.97 (dd, J=1.7, 5.1 Hz, 1H), 7.71 (d, J=16.6 Hz, 1H), 7.28 (d, J=16.6 Hz, 1H), 7.07 (s, 1H), 6.95 (s, 2H), 3.02-2.89 (m, 2H), 2.70-2.57 (m, 3H), 2.37 (s, 6H), 1.68-1.56 (m, 2H), 1.43-1.24 (m, 2H); MASS (ESI, Pos.): 410 (M+H)+.

Example 36(1)-Example 36(14)

(1438) Using a corresponding vinylpyridine derivative in place of the compound produced in Reference example 40, using a corresponding bromobenzene derivative, or a corresponding bromopyridine derivative in place of 1-bromo-3,5-dimethylbenzene, the present invention compounds having the following physical property values were obtained by following the same procedure as in Reference example 41.fwdarw.Example 1.

Example 36(1)

5-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methoxyphenyl)-3-pyridinyl]vinyl}nicotinonitrile

(1439) Description: off-white powder;

(1440) Purity (UPLC-MS/ELSD): 100% (retention time: 0.46 min);

(1441) TLC: Rf 0.60 (ethyl acetate:methanol=9:1, NH silica gel);

(1442) NMR (300 MHz, CHLOROFORM-d): 8.78 (d, J=2.1 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.43 (s, 1H), 8.07 (s, 1H), 7.87 (t, J=2.1 Hz, 1H), 7.19 (d, J=16.6 Hz, 1H), 6.83 (d, J=16.6 Hz, 1H), 6.52-6.44 (m, 1H), 6.43-6.34 (m, 2H), 3.65 (s, 3H), 2.92-2.81 (m, 2H), 2.63-2.39 (m, 3H), 1.64-1.51 (m, 2H), 1.26-1.10 (m, 2H); MASS (ESI, Pos.): 430 (M+H)+.

Example 36(2)

4-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methoxyphenyl)-3-pyridinyl]vinyl}-2-pyridinecarbonitrile

(1443) Description: yellow amorphous powder;

(1444) Purity (UPLC-MS/ELSD): 100% (retention time: 0.47 min);

(1445) TLC: Rf 0.58 (ethyl acetate:methanol=9:1, NH silica gel);

(1446) NMR (300 MHz, CHLOROFORM-d): 8.71 (d, J=4.8 Hz, 1H), 8.63 (s, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.61 (dd, J=1.7, 5.2 Hz, 1H), 7.52 (d, J=16.5 Hz, 1H), 6.99 (d, J=16.5 Hz, 1H), 6.70-6.54 (m, 3H), 3.85 (s, 3H), 3.12-3.00 (m, 2H), 2.84-2.60 (m, 3H), 1.85-1.71 (m, 2H), 1.46-1.30 (m, 2H);

(1447) MASS (ESI, Pos.): 430 (M+H)+.

Example 36(3)

5-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]vinyl}nicotinonitrile

(1448) Description: yellow amorphous powder;

(1449) Purity (UPLC-MS/ELSD): 100% (retention time: 0.44 min);

(1450) TLC: Rf 0.62 (ethyl acetate:methanol=20:1, NH silica gel);

(1451) NMR (300 MHz, METHANOL-d4): 9.04 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.48 (t, J=2.2 Hz, 1H), 8.15 (s, 1H), 7.54 (d, J=16.5 Hz, 1H), 7.24 (d, J=16.5 Hz, 1H), 7.08-6.83 (m, 3H), 3.17-3.08 (m, 2H), 2.74-2.60 (m, 3H), 2.43 (s, 3H), 1.79-1.69 (m, 2H), 1.54-1.37 (m, 2H); MASS (ESI, Pos.): 414 (M+H)+.

Example 36(4)

4-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]vinyl}-2-pyridinecarbonitrile

(1452) Description: yellow amorphous powder;

(1453) Purity (UPLC-MS/ELSD): 100% (retention time: 0.46 min);

(1454) TLC: Rf 0.62 (ethyl acetate:methanol=20:1, NH silica gel);

(1455) NMR (300 MHz, METHANOL-d4): 8.68 (d, J=5.5 Hz, 1H), 8.61 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.88 (dd, J=5.4, 1.6 Hz, 1H), 7.70 (d, J=16.5 Hz, 1H), 7.22 (d, J=16.5 Hz, 1H), 7.06-6.85 (m, 3H), 3.17-3.06 (m, 2H), 2.75-2.62 (m, 3H), 2.44 (s, 3H), 1.81-1.71 (m, 2H), 1.55-1.40 (m, 3H);

(1456) MASS (ESI, Pos.): 414 (M+H)+.

Example 36(5)

(1457) ##STR00142##

3-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3-fluoro-5-methylphenyl)-3-pyridinyl]vinyl}benzonitrile

(1458) Description: pale brown powder;

(1459) Purity (UPLC-MS/ELSD): 100% (retention time: 0.50 min);

(1460) TLC: Rf 0.62 (ethyl acetate:methanol=20:1, NH silica gel);

(1461) NMR (300 MHz, METHANOL-d4): 8.58 (s, 1H), 8.13 (s, 1H), 8.00-7.93 (m, 2H), 7.70-7.63 (m, 1H), 7.62-7.55 (m, 1H), 7.43 (d, J=16.1 Hz, 1H), 7.21 (d, J=16.1 Hz, 1H), 7.05-6.83 (m, 3H), 3.18-3.04 (m, 2H), 2.75-2.59 (m, 3H), 2.43 (s, 3H), 1.81-1.70 (m, 2H), 1.56-1.39 (m, 2H),

(1462) MASS (ESI, Pos.): 413 (M+H)+.

Example 36(6)

(1463) ##STR00143##

5-[(E)-2-{5-(3-fluoro-5-methoxyphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}vinyl]nicotinonitrile

(1464) Description: pale brown amorphous powder;

(1465) Purity (LC-MS/ELSD): 100% (retention time: 0.47 min);

(1466) TLC: Rf 0.58 (ethyl acetate:methanol=19:1, NH silica gel);

(1467) NMR (300 MHz, CHLOROFORM-d): 8.96 (d, J=2.2 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 8.09-8.02 (m, 1H), 7.35 (d, J=16.5 Hz, 1H), 7.04 (d, J=16.5 Hz, 1H), 6.66 (dt, J=10.6, 2.3 Hz, 1H), 6.62-6.52 (m, 2H), 3.90-3.78 (m, 4H), 3.66 (td, J=11.4, 2.8 Hz, 1H), 3.34-3.22 (m, 1H), 3.17-2.97 (m, 3H), 2.96-2.85 (m, 1H), 2.78 (td, J=12.3, 2.9 Hz, 1H), 2.55 (dd, J=11.9, 10.1 Hz, 1H), 2.50-2.39 (m, 1H), 1.72-1.44 (m, 2H); MASS (ESI, Pos.): 472 (M+H)+.

Example 36(7)

3-[(E)-2-{5-(3-fluoro-5-methylphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}vinyl]benzonitrile

(1468) Description: pale yellow amorphous powder;

(1469) Purity (LC-MS/ELSD): 98.0% (retention time: 0.51 min);

(1470) TLC: Rf 0.58 (ethyl acetate:methanol=19:1, NH silica gel);

(1471) NMR (300 MHz, CHLOROFORM-d): 8.63 (s, 1H), 8.26 (s, 1H), 7.74-7.81 (m, 2H), 7.56-7.61 (m, 1H), 7.54-7.47 (m, 1H), 7.26 (d, J=16.3 Hz, 2H), 7.03 (d, J=16.3 Hz, 1H), 6.96-6.89 (m, 1H), 6.86 (s, 1H), 6.81-6.74 (m, 1H), 3.84 (dd, J=11.3, 2.4 Hz, 1H), 3.66 (td, J=11.5, 2.7 Hz, 1H), 3.29 (td, J=9.2, 4.6 Hz, 1H), 3.13-2.97 (m, 3H), 2.95-2.85 (m, 1H), 2.73 (td, J=12.2, 3.4 Hz, 1H), 2.54-2.37 (m, 5H), 1.61-1.46 (m, 2H);

(1472) MASS (ESI, Pos.): 455 (M+H)+.

Example 36(8)

(1473) ##STR00144##

5-[(E)-2-{5-(3-fluoro-5-methylphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}vinyl]nicotinonitrile

(1474) Description: off-white powder;

(1475) Purity (LC-MS/ELSD): 100% (retention time: 0.49 min);

(1476) TLC: Rf 0.61 (ethyl acetate:methanol=19:1, NH silica gel);

(1477) NMR (300 MHz, CHLOROFORM-d): 8.96 (d, J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 8.06 (t, J=2.1 Hz, 1H), 7.35 (d, J=16.6 Hz, 1H), 7.04 (d, J=16.6 Hz, 1H), 6.97-6.89 (m, 1H), 6.86 (d, J=0.7 Hz, 1H), 6.81-6.73 (m, 1H), 3.89-3.79 (m, 1H), 3.66 (td, J=11.4, 2.7 Hz, 1H), 3.27 (td, J=9.4, 4.3 Hz, 1H), 3.13-2.97 (m, 3H), 2.95-2.85 (m, 1H), 2.80-2.66 (m, 1H), 2.58-2.37 (m, 5H), 1.69-1.46 (m, 2H); MASS (ESI, Pos.): 456 (M+H)+.

Example 36(9)

4-[(E)-2-{5-(3-fluoro-5-methylphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}vinyl]-2-pyridinecarbonitrile

(1478) Description: yellow powder;

(1479) Purity (LC-MS/ELSD): 100% (retention time: 0.51 min);

(1480) TLC: Rf 0.50 (ethyl acetate:methanol=19:1, NH silica gel);

(1481) NMR (300 MHz, CHLOROFORM-d): 8.71 (dd, J=5.1, 0.5 Hz, 1H), 8.64 (d, J=0.7 Hz, 1H), 8.30 (s, 1H), 7.79-7.74 (m, 1H), 7.64-7.58 (m, 1H), 7.49 (d, J=16.3 Hz, 1H), 6.99 (d, J=16.3 Hz, 1H), 6.96-6.90 (m, 1H), 6.88-6.84 (m, 1H), 6.77 (d, J=9.0 Hz, 1H), 3.85 (dd, J=11.5, 2.2 Hz, 1H), 3.66 (td, J=11.3, 2.6 Hz, 1H), 3.34-3.24 (m, 1H), 3.11-2.98 (m, 3H), 2.95-2.86 (m, 1H), 2.74 (td, J=12.4, 2.7 Hz, 1H), 2.56-2.38 (m, 5H), 1.68-1.46 (m, 2H);

(1482) MASS (ESI, Pos.): 456 (M+H)+.

Example 36(10)

1-{3-(3-fluoro-5-methylphenyl)-5-[(E)-2-(3-fluorophenyl)vinyl]-4-pyridinyl}-4-piperidinamine

(1483) Description: pale brown powder;

(1484) Purity (UPLC-MS/ELSD): 99.9% (retention time: 0.53 min);

(1485) TLC: Rf 0.62 (ethyl acetate:methanol=20:1, NH silica gel);

(1486) NMR (300 MHz, METHANOL-d4): 8.56 (s, 1H), 8.10 (s, 1H), 7.47-7.32 (m, 3H), 7.34 (d, J=16.6 Hz, 1H), 7.16 (d, J=16.6 Hz, 1H), 7.07-6.82 (m, 4H), 3.16-3.06 (m, 2H), 2.71-2.58 (m, 3H), 2.43 (s, 3H), 1.79-1.69 (m, 2H), 1.55-1.39 (m, 2H);

(1487) MASS (ESI, Pos.): 406 (M+H)+.

Example 36(11)

1-{3-[(E)-2-(4-chlorophenyl)vinyl]-5-(3-fluoro-5-methylphenyl)-4-pyridinyl}-4-piperidinamine

(1488) Description: pale yellow powder;

(1489) Purity (UPLC-MS/ELSD): 99.2% (retention time: 0.55 min);

(1490) TLC: Rf 0.27 (ethyl acetate:methanol=9:1, NH silica gel);

(1491) NMR (300 MHz, CHLOROFORM-d): 8.61 (s, 1H), 8.20 (s, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 7.22 (d, J=16.6 Hz, 1H), 7.03 (d, J=16.6 Hz, 1H), 6.94-6.73 (m, 3H), 3.12-3.00 (m, 2H), 2.79-2.65 (m, 1H), 2.65-2.53 (m, 2H), 2.41 (s, 3H), 1.79-1.68 (m, 2H), 1.48-1.30 (m, 2H);

(1492) MASS (ESI, Pos.): 422 (M+H)+.

Example 36(12)

1-{3-[(E)-2-(3-chlorophenyl)vinyl]-5-(3-fluoro-5-methylphenyl)-4-pyridinyl}-4-piperidinamine

(1493) Description: pale yellow powder;

(1494) Purity (UPLC-MS/ELSD): 99.3% (retention time: 0.56 min);

(1495) TLC: Rf 0.25 (ethyl acetate:methanol=9:1, NH silica gel);

(1496) NMR (300 MHz, CHLOROFORM-d): 8.60 (s, 1H), 8.21 (s, 1H), 7.53-7.19 (m, 5H), 6.98 (d, J=16.6 Hz, 1H), 6.94-6.73 (m, 3H), 3.11-2.98 (m, 2H), 2.79-2.53 (m, 3H), 2.42 (s, 3H), 1.83-1.67 (m, 2H), 1.48-1.30 (m, 2H);

(1497) MASS (ESI, Pos.): 422 (M+H)+.

Example 36(13)

1-{3-(3-fluoro-5-methylphenyl)-5-[(E)-2-(4-fluorophenyl)vinyl]-4-pyridinyl}-4-piperidinamine

(1498) Description: pale brown powder;

(1499) Purity (UPLC-MS/ELSD): 100% (retention time: 0.54 min);

(1500) TLC: Rf 0.25 (ethyl acetate:methanol=9:1, NH silica gel);

(1501) NMR (300 MHz, METHANOL-d4): 8.55 (s, 1H), 8.09 (s, 1H), 7.66 (dd, J=8.6, 5.5 Hz, 2H), 7.26 (d, J=16.5 Hz, 1H), 7.19-7.08 (m, 3H), 7.04-6.82 (m, 3H), 3.17-3.04 (m, 2H), 2.71-2.56 (m, 3H), 2.43 (s, 3H), 1.79-1.67 (m, 2H), 1.54-1.41 (m, 2H);

(1502) MASS (ESI, Pos.): 406 (M+H)+.

Example 36(14)

5-{(E)-2-[4-(4-amino-1-piperidinyl)-5-(3,5-dimethylphenyl)-3-pyridinyl]vinyl}-3-pyridinol

(1503) Description: yellow amorphous powder;

(1504) Purity (UPLC-MS/ELSD): 91.2% (retention time: 0.42 min);

(1505) TLC: Rf 0.18 (ethyl acetate:methanol=9:1, NH silica gel);

(1506) NMR (300 MHz, METHANOL-d4): 8.55 (s, 1H), 8.07 (s, 1H), 7.97-7.85 (m, 2H), 7.38-7.27 (m, 2H), 7.14-7.04 (m, 2H), 6.90 (s, 2H), 3.14-3.01 (m, 2H), 2.70-2.54 (m, 3H), 2.37 (s, 6H), 1.81-1.68 (m, 2H), 1.57-1.40 (m, 2H);

(1507) MASS (ESI, Pos.): 401 (M+H)+.

Example 37

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl {1-[3-(6-chloro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]-4-piperidinyl}carbamate

(1508) ##STR00145##

(1509) The compound produced in Example 21 (50) was dissolved in 0.7 mL dimethylformamide and stirred at 0 degrees C. A solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenylcarbonate (81 mg) in 0.5 mL dimethylformamide was added to the reaction mixture and stirred at room temperature for 1 hour. To the reaction mixture was added water and ethyl acetate followed by extraction. The obtained organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silicagel column chromatography (hexane:ethyl acetate=75:25.fwdarw.20:80) to obtain the present invention compound having the following physical property values.

(1510) Description: pale purple powder;

(1511) Purity (UPLC-MS/ELSD): 100% (retention time: 0.73 min);

(1512) TLC: Rf 0.20 (ethyl acetate);

(1513) NMR (300 MHz, DIMETHYL SULFOXIDE-d6): 12.87 (br. s., 1H), 8.47 (s, 1H), 8.28 (s, 1H), 7.84-7.53 (m, 2H), 7.44 (d, J=7.1 Hz, 1H), 7.27 (br. s., 1H), 7.18-7.05 (m, 3H), 4.78 (s, 2H), 3.13-2.96 (m, 1H), 2.88-2.78 (m, 2H), 2.58-2.53 (m, 2H), 2.41 (s, 3H), 2.10 (s, 3H), 1.42-1.28 (m, 2H), 1.21-1.02 (m, 2H);

(1514) MASS (ESI, Pos.): 592 (M+H)+.

Example 38

1-{3-[(1E)-2-(3-chlorophenyl)-1-propen-1-yl]-5-(3-fluoro-5-methylphenyl)-4-pyridinyl}-4-piperidinamine

(1515) ##STR00146##

(1516) Using an iodopyridine derivative in place of the compound produced in Reference example 39, using (E)-2-(2-(3-chlorophenyl)-1-propen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in place of 3,5-dimethylphenylboronic acid, the present invention compound having the following physical property values was obtained by following the same procedure as in Reference Example 39.fwdarw.Example 1.

(1517) Description: brown powder;

(1518) Purity (UPLC-MS/ELSD): 100% (retention time: 0.55 min);

(1519) TLC: Rf 0.44 (ethyl acetate:methanol=20:1, NH silica gel);

(1520) NMR (300 MHz, CHLOROFORM-d): 8.34 (s, 1H), 8.21 (s, 1H), 7.55-7.53 (m, 1H), 7.48-7.43 (m, 1H), 7.37-7.29 (m, 2H), 6.95-6.71 (m, 4H), 3.10-2.99 (m, 2H), 2.71-2.55 (m, 3H), 2.43 (s, 3H), 2.26 (d, J=1.1 Hz, 3H), 1.72-1.62 (m, 2H), 1.31-1.14 (m, 2H);

(1521) MASS (ESI, Pos.): 436 (M+H)+.

Biological Example 1

Evaluation of SSTR2 Agonist Activity Using Human SSTR2 Expressing Cells

(1522) [Procedure]

(1523) (1) Isolation of Human SSTR2 Gene

(1524) Human brain cDNA was purchased from Ambion (catalog No.: 7962; lot No.: 040200121). PCR primer, hSSTR2_F1_XhoI: 5-CACCCTCGAGGACATGGCGGATGAGCCACTCAAT-3 (sequence number 1), and hSSTR2_R1_EcoRI:5-CCTTGAATTCGATACTGGTTTGGAGGTCTCCATT-3 (sequence number 2) are designed based on array of GenBank NM_001050.

(1525) Using human brain cDNA as a template, using KOD-plus-(TOYOBO), PCR is carried out (95 C. for 2 min, [98 C. for 10 sec., 60 C. for 30 sec., 68 C. for 90 sec.]30 times). After 1% agarose gel electrophoresis, amplified PCR products was purified by QIAquick Gel Extraction Kit (QIAGEN), and cut by restriction enzyme XhoI and EcoRI. The fragment was linked with expression vector (pIRESneo-Myc) using DNA Ligation Kit Ver.2 (Takara) to transform into Escherichia coli DH5a. The DNA sequence was determined with this plasmid pIRESneo-Myc/hSSTR2.

(1526) (2) Culture of CHO-K1 Cells

(1527) CHO-K1 () were cultured using Ham's F-12 (including FBS (10%), penicillin (100 U/mL) and streptomycin (0.1 mg/mL)) as medium. The transduced cells were cultured using the medium above with geneticin (1 mg/ml).

(1528) (3) Transduction into CHO-K1 Cells

(1529) The plasmid pIRESneo-Myc/hSSTR2 was transduced into CHO-K1 () cell using Lipofectamine 2000 (Invitrogen). After 48 hours, the medium was changed to the medium including 1 mg/mL Geneticin, overexpressing cells were selected and stably overexpressing cells (SSTR2-CHO-K1) were established.

(1530) (4) Evaluation of SSTR2 Agonist Activity

(1531) Human SSTR2 agonist activity of test compounds was evaluated by following procedure using inhibition activity against intracellular cyclic AMP (cAMP) production stimulated by Forskolin as an indicator. The SSTR2-CHO-K1 cells suspended in Ham's F-12 medium (including fetal bovine serum (10%), penicillin (100 U/mL), streptomycin (0.1 mg/mL)) including 0.25 mg/mL Geneticin was seeded in 96 wells plate (4.010.sup.4 cells/0.1 mL/1 well). After 1 day, the medium was removed and the cells were washed with 0.1 mL of wash buffer solution[0.1% bovine serum albumin (BSA), Hank's Balanced Salt Solution (HBSS) including 20 mmol/L 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES)] twice. To the cells added 0.06 mL/well assay buffer [500 nmol/L 3-isobutyl-1-methylxanthine (IBMX), 0.1% BSA, 20 mmol/L HBSS including HEPES], and incubated for 15 min. under 5% CO.sub.2 and 37 C. Next, to the cells added 0.06 mL/well assay buffer including test compounds of the double concentration of final concentration and 0.02 mmol/L Forskolin, and incubated for 30 min. under 5% CO.sub.2 and 37 C. After that, to the cells added 0.12 mL/well Assay/Lysis buffer included with cAMP-Screen kit (Applied Biosystems), and incubated for 30 min. under 5% CO.sub.2 and 37 C. The concentration of c-AMP is determined by ELISA test according to manual included with the kit. The reaction rate (%) of inhibition activity against c-AMP production stimulated by Forskolin are determined every each sample, and 50% effective concentration (EC.sub.50) of agonist activity of test compounds against human SSTR2 was calculated by non-linear regression analysis, where the reaction rate of 1000 nmol/L Octreotide is 100%, common logarithm concentration of the test compounds is independent variable, reaction rare of the corresponding concentration is dependent variable.

(1532) [Result]

(1533) The present invention compounds showed high SSTR2 agonist activity. For example, the compound produced in Example 5(1) showed 0.03 nmol/L, the compound produced in Example 2 (20) showed 0.006 nmol/L, the compound produced in Example 26(24) showed 0.049 nmol/L, the compound produced in Example 36(5) showed 0.016 nmol/L, the compound produced in Example 36(8) showed 0.034 nmol/L as EC.sub.50. In this evaluation method, Octreotide showed 0.24 nmol/L as EC.sub.50, and the compound which shown in WO2008/051272 as following formula (M):

(1534) ##STR00147##
showed 0.06 nmol/L as EC.sub.50.

Biological Example 2

Evaluation of Growth Hormone (GH) Secretory Inhibitory Activity Using Rat

(1535) [Procedure (A): Test Compounds are Administered 30 Min. Before.]

(1536) Test compounds dissolved in vehicle (distillated water (Otsuka jouryuusui, Otsuka Pharmaceutical Factory, Inc.) or vehicle only was administered to rat (7-week-old, male Crl: CD (SD) IGS rat (CHARLES RIVER LABORATORIES JAPAN, INC.)) orally, and 27 min. later, 50 mg/kg of sodium pentobarbital (Somunopentil Kyoritsu Seiyaku) was administered by tail vein injection to be anesthetized. Three minutes after administration of sodium pentobarbital, 0.01 mg/kg of growth hormone-releasing hormone (GHRH, Bachem) was administered by tail vein injection to evoke GH secretion. To measure blood concentration of GH, 0.2 mL blood sample from cervical vein was collected 5 minutes after administration of GHRH. The blood samples were treated with centrifugation at 13,000 g at 4 C. for 5 min. to obtain plasma sample. Blood concentration of GH was determined by Rat/Mouse Growth Hormone ELISA (Millipore) according to the procedure manual. Inhibition ratio of GH secretion (%) was determined by mathematical formula {[Inhibition ratio of GH secretion (%)]=([blood GH concentration of vehicle administered group]-[blood GH concentration of test compound administered group])/[blood GH concentration of vehicle administered group]100} using obtained value of blood GH concentration. In addition, vehicle administered group in the formula means vehicle administered animal group and test compound administered group means test compound dissolved in vehicle administered animal group.

(1537) [Procedure (B): Test Compounds are Administered 8 Hours Before]

(1538) Test compounds dissolved in vehicle (distillated water (Otsuka jouryuusui, Otsuka Pharmaceutical Factory, Inc.) or vehicle only was administered to rat (7-week-old, male Crl: CD (SD) IGS rat (CHARLES RIVER LABORATORIES JAPAN, INC.)) orally, and 7 hours 57 minutes later, 50 mg/kg of sodium pentobarbital (Somunopentil Kyoritsu Seiyaku) was administered by tail vein injection to be anesthetized. Three min. after administration of sodium pentobarbital, 0.01 mg/kg of growth hormone-releasing hormone (GHRH, Bachem) was given by tail vein injection to evoke GH secretion. Procedure after that was same as

(1539) [Procedure (A)]

(1540) [Result]

(1541) The present invention compounds showed high GH secretion inhibitory activity. For example, 10 mg/kg of the compound produced in Example 5(1) showed 92% (Procedure (A)), 3 mg/kg of the compound produced in Example 2(20) showed 97% (Procedure (A)), 3 mg/kg of the compound produced in Example 26(15) showed 92% (Procedure (B)), 1 mg/kg of the compound produced in Example 26(24) showed 91% (Procedure (B)), 1 mg/kg of the compound produced in Example 36(5) showed 92% (Procedure (B)), and 1 mg/kg of the compound produced in Example 36(8) showed 83% (Procedure (B)) as the ratio of GH secretion inhibition. In this evaluation method, for example, 0.003 mg/kg (s.c.) of Octreotide showed 98% (method (A)) as ratio of GH secretory inhibition.

Biological Example 3

Evaluation of the Gastric-Acid Secretion Inhibitory Activity Using Rat

(1542) [Procedure]

(1543) Rats (7-week-old, male Crl: CD (SD) IGS rat (CHARLES RIVER LABORATORIES JAPAN, INC.)), which were food-deprived a day before and water-deprived 2 hours before, were treated with abdominal operation under isoflurane anesthesia, and their gastric outlet was tied off. After closing the laparotomy department, vehicle only (saline (Otsuka seishokuchu, Otsuka Pharmaceutical Factory, Inc.) or test compounds which were dissolved in vehicle were administered subcutaneously immediately, and the rats were recovered from anesthesia. After 2 hours from tying gastric outlet, the rats were treated with abdominal operation under isoflurane anesthesia again, pinched cardiac end of the stomach with forceps and exsanguinated to death. After stomach contents were centrifugalized at 500 g for 15 min. and the supernatant was separated as gastric fluid, the volume of gastric fluid was determined based on weight (mL/100 g BW). Furthermore, acid concentration of gastric fluid (mmol/mL) was determined by back titration using COM-1600ST automatic titrator (Hitachi High-Technologies Corporation (Hiranuma sangyo Co., Ltd.)). Considering the product of a gastric fluid volume and the acid concentration as gastric acid output (mmol/100 g BW), inhibition ratio of stomach acid secretion was determined by mathematical formula [inhibition ratio of stomach acid secretion (%)]=([the gastric acid output of vehicle administered group]-[the gastric acid output of test compound administered group])/[the gastric acid output of vehicle administered group]100).

(1544) [Result]

(1545) The present invention compounds showed high gastric secretory inhibition activity. For example, the compounds manufactured in Example 5(1) showed 89% with a dose of 3 mg/kg, the compounds manufactured in Example 2(20) showed 89% with a dose of 0.3 mg/kg as the ratio of gastric acid secretion inhibition. In addition, for example, Octreotide showed 85% with a dose of 0.03 mg/kg, the compound represented by said formula (M) showed 74% with a dose of 10 mg/kg as the ratio of gastric acid secretion inhibition in this assay.

Biological Example 4

Evaluation of the Cell Toxicity Using Cultured Human Hepatocyte

(1546) [Procedure]

(1547) Frozen adherent human hepatocyte was thawed and suspended in hepatocyte cultured medium (HCM) purchased from Lonza, and then seeded in 96 wells plate coated by collagen. The hepatocytes were cultured overnight in the incubator (5% carbon dioxide, 95% air, 37 C.) and its medium was replaced with medium including test compounds (0, 12.5, 25, 50, 100, 200, or 40010.sup.6 mol/L) and cultured for 24 hours more. The cell toxicity was evaluated by measurement of ATP concentration in the cells. Specifically, using Promega Celltiter-Glo luminescent assay kit made by Promega KK, the cells were dissolved in an accompanying assay buffer and the ATP concentration released from the cells was determined by an emission of light of the luciferin-luciferase enzyme activity. The emission of light was measured by Molecular device's SpectraMax plate reader. A degree of toxicity was shown 50% inhibitory compound concentration of the emission of light (IC.sub.50).

(1548) [Result]

(1549) The present invention compounds showed low-toxicity against cultured human hepatocytes. For example, the compounds manufactured in Example 5 (1) showed 0.045 mmol/L, the compounds manufactured in Example 2(20) showed 0.040 mmol/L, the compounds manufactured in Example 26(24) showed 0.035 mmol/L, the compounds manufactured in Example 36(5) showed 0.019 mmol/L, the compounds manufactured in Example 36(8) showed 0.069 mmol/L as IC.sub.50. And the compounds represented by said formula (M) showed 0.013 mmol/L as IC.sub.50. Calculating a ratio of each IC.sub.50 divided by SSTR2 agonist activity described in Biological example 1, the compounds manufactured in Example 5(1) showed 1,500,000 times, the compounds manufactured in Example 2(20) showed 6,670,000 times, the compounds manufactured in Example 26(24) showed 710,000 times, the compounds manufactured in Example 36(5) showed 1,190,000 times, the compounds manufactured in Example 36(8) showed 2,030,000 times, so it was found that these compounds are superior in terms of separation of activity from toxicity.

Pharmaceutical preparation Example 1

Tablets including 5 mg of 4-[4-(aminomethyl)-1-piperidinyl]-N,5-bis(3,5-dimethyphenyl)pyridine-3-carboxamide

(1550) Mix each ingredients described below in the usual manner, then compress into tablets to obtain 10,000 tables which include 5 mg of active substances per a tablet.

(1551) 4-[4-(aminomethyl)-1-piperidinyl]-N,5-bis(3,5-dimethyphenyl)pyridine-3-carboxamide: 50 g

(1552) carboxymethyl cellulose calcium (disintegrators): 20 g

(1553) magnesium stearate (lubricant): 10 g

(1554) microcrystalline cellulose: 920 g

Pharmaceutical preparation Example 2

Injections including 20 mg of 4-[4-(aminomethyl)-1-piperidinyl]-N,5-bis(3,5-dimethyphenyl)pyridine-3-carboxamide

(1555) Mix each ingredients described below in the usual manner, sterilize in the usual manner, fill into ampules by 5 mL per a ampule, and freeze-dry in the usual manner to obtain 10,000 ampules which include 20 mg of active ingredient per a ampule.

(1556) 4-[4-(aminomethyl)-1-piperidinyl]-N,5-bis(3,5-dimethyphenyl)pyridine-3-carboxamide: 200 g

(1557) mannitol: 20 g

(1558) distillated water: 50 L

INDUSTRIAL APPLICABILITY

(1559) Since the present invention compounds have high agonist activity against somatostatin receptor, especially somatostatin receptor subtype 2, they are useful as a preventive and/or therapeutic agent for various diseases which may be related with somatostatin itself or hormones regulated by somatostatin, especially acromegaly and digestive symptom with gastrointestinal obstruction.