RU2353617C2 - Pyridin derivatives as dipeptidyl peptidase iv inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I,

where R¹ and R² are similar or different and each represents: (I) C_1-10alkyl group optionally substituted with 1-3 substituents selected from C_3-10cycloalkyl group, C_1-6alkoxycarbonyl group b C_1-6alkoxygroup; (2) C_6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C_1-6alkoxycabonyl group b carbamoyl group; or (3) C_7-13aralkyl group; R³ represents C_6-14aryl group optionally substituted with 1-3 substituents selected from C_1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C_1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C_1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R⁴ represents amino group; L represents C_1-10alkylene group; Q represents bond, C_1-10alkylene group or C_2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

Description

FIELD OF THE INVENTION

The present invention relates to a pyridine derivative having peptidase inhibiting activity, which is useful as an agent for the prevention or treatment of diabetes and the like.

BACKGROUND OF THE INVENTION

Peptidase is known to be associated with various diseases. Dipeptidyldipeptidase-IV (hereinafter sometimes abbreviated as DPP-IV), which is a type of peptidase, is a serine protease that specifically binds to a peptide containing proline (or alanine) in the 2nd position from the N-terminus and cleaves the bond at C-terminus of proline (or alanine) to form a dipeptide. DPP-IV has the same molecule as CD26, and has been reported to be involved in the immune system. Although the role of DPP-IV in mammals is not fully understood, it is believed that it plays an important role in the metabolism of neuropeptides, T-cell activation, cancer cell adhesion to endothelial cells, HIV (HIV) penetration into cells, and the like. In particular, from the point of view of carbohydrate metabolism, DPP-IV is involved in the inactivation of GLP-1 (glucagon-like peptide-1) and GIP (gastro-inhibiting peptide / glucose-dependent insulinotropic peptide), which are regulators of internal secretion. In addition, with regard to GLP-1, it is known that the physiological activity of GLP-1 is markedly reduced because it has a short, 1-2 minutes, plasma half-life, and GLP-1 (9-36) amide, which is a degradation product under the action of DPP-IV, acts on the GLP-1 receptor as an antagonist, as a result of which DPP-IV decomposes GLP-1. It is also known that inhibition of GLP-1 destruction by inhibition of DPP-IV activity leads to an increase in the physiological activity that GLP-1 exhibits, such as the effect of enhancing insulin secretion depending on glucose concentration and the like. In connection with these facts, it is expected that a compound having inhibitory DPP-IV activity will have an effect on impaired glucose tolerance, postprandial hyperglycemia, and fasting hyperglycemia observed in type I and type II diabetes and the like. , obesity or related diabetic complications and the like.

The following compounds have already been described as pyridine derivatives.

(1) A compound represented by the formula

where R ₂ and R ₆ each independently represents hydrogen, hydroxy, alkyl and the like; R ₃ represents hydroxy, amido and the like; R ₄ represents hydrogen, hydroxy, halogen and the like, and R ₅ represents hydrogen, hydroxy, halogen and the like, which has an inhibitory effect on cholesterol ester transfer protein (hereinafter abbreviated as CETP) (see WO99 / 41237) .

(2) A compound represented by the formula

where A is C _6-10 aryl, optionally substituted with halogen, and the like; D represents an unbranched or branched alkyl with 8 or less carbon atoms, optionally substituted by hydroxy; E and L are the same or different and each is straight or branched alkyl with 8 or less carbon atoms, optionally substituted with C _3-8 cycloalkyl, and the like; T is R ⁷ —X— or R ⁸ - (R ⁹ ) (R ¹⁰ ) C— (where R ⁷ and R ⁸ are the same or different and each is C _3-8 cycloalkyl, C _6-10 aryl, and the like the like; R ⁹ represents hydrogen and the like; R ¹⁰ represents hydrogen, halogen, azido and the like) which has an inhibitory effect on CETP or an antagonistic effect on glucagon;

a compound represented by the formula

where A represents C _6-10 aryl, optionally substituted with halogen, and the like; D and E are the same or different and each represents a straight or branched alkyl with 8 or less carbon atoms, optionally substituted with hydroxy; V represents O, S or NR ⁵ (where R ⁵ represents hydrogen, unbranched or branched alkyl containing 6 or less carbon atoms, or phenyl); R ¹ represents C _3-6 cycloalkyl, C _6-10 aryl and the like; L and T are the same or different and each represents trifluoromethyl and the like; and

a compound represented by the formula

where Ar is an optionally substituted aromatic or heteroaromatic group; R ⁴ and R ⁵ independently represent hydrogen, C _1-6 alkyl and the like; R ^1a and R ^1b independently represent trifluoromethyl, C _1-6 alkyl and the like (see WO98 / 04528, US patent No. 6218431).

(3) A compound represented by the formula

where A and E are the same or different and each represents C _6-10 aryl, optionally substituted with halogen, and the like; D represents an unbranched or branched alkyl with 8 or less carbon atoms, optionally substituted by hydroxy; L represents C _3-8 cycloalkyl, unbranched or branched alkyl containing 8 or less carbon atoms, and the like; T is R ³ —X— or R ⁴ - (R ⁵ ) (R ⁶ ) C— (where R ³ and R ⁴ are the same or different and each is C _3-8 cycloalkyl, C _6-10 aryl, and the like the like; R ⁵ is hydrogen and the like; R ⁶ is hydrogen, halogen, azido and the like), or a salt thereof having an inhibitory effect on CETP (see US Patent No. 5925645).

(4) A compound represented by the formula

where R ₂ and R ₆ independently represent bromoalkyl, chloralkyl and the like; R ₄ represents alkyl, cycloalkylalkyl, alkylthioalkyl, cycloalkyl, alkoxyalkyl or dialkylaminoalkyl; one of R ₃ and R ₅ represents CO-Y (where Y represents an alkylthio, alkoxy or N-containing heterocyclic group), and the other represents - (- C (R ⁹ ) (R ¹⁰ ) -) nX (where n is an integer of 1-3; R ⁹ and R ¹⁰ independently represent hydrogen, alkyl, and the like; X represents halogen, OH, and the like) and the like, or a salt thereof which (s) has a herbicidal effect (see WO92 / 20659).

(5) A compound represented by the formula

where R ¹ represents hydrogen or lower alkyl; R ² represents a heterocyclic group or an aryl group, each of which is optionally substituted with lower alkyl, and the like; R ³ and R ⁴ can form a phenyl ring and the like, each optionally substituted with halogen and the like, together with the carbon atoms associated with them, or a salt thereof which (s) has an inhibitory effect on DPP-4 (see WO03 / 068748 )

(6) A compound represented by the formula

where X represents N or CR ⁵ (where R ⁵ represents hydrogen or lower alkyl); R ¹ and R ² independently represent hydrogen or lower alkyl; R ³ represents a heterocyclic group or an aryl group, each of which is optionally substituted with lower alkyl, and the like; R ⁴ represents lower alkyl and the like, or its salt which (s) has an inhibitory effect on DPP-4 (see WO03 / 068757).

However, there are no reported compounds of the present invention.

Description of the invention

There is a need to develop a compound with an inhibitory effect on peptidase, useful as an agent for the prophylaxis or treatment of diabetes and the like, and excellent in terms of efficacy, duration of action, specificity, lower toxicity and the like.

The inventors of the present invention first found that the compound represented by the formula

Where

R ¹ and R ² are the same or different and each represents an optionally substituted hydrocarbon group or an optionally substituted hydroxy group;

R ³ represents an optionally substituted aromatic group;

R ⁴ represents an optionally substituted amino group;

L represents a divalent hydrocarbon group;

Q represents a bond or a divalent hydrocarbon group and

X represents a hydrogen atom, a cyano group, a nitro group, an acyl group, a substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted cyclic group;

with the proviso that when X represents an ethoxycarbonyl group, then Q represents a divalent hydrocarbon group, and that the compound is not

2,6-diisopropyl-3-methylaminomethyl-4- (4-fluorophenyl) -5-pentylpyridine;

2,6-diisopropyl-3-aminomethyl-4- (4-fluorophenyl) -5-pentylpyridine;

2,6-diisopropyl-3- (dimethylamino) methyl-4- (4-fluorophenyl) -5-pentylpyridine;

2,6-diisopropyl-3- (ethylamino) methyl-4- (4-fluorophenyl) -5-pentylpyridine and

3- (tert-butyldimethylsilyloxymethyl) -2,6-diisopropyl-4- (4-fluorophenyl) -5- (indolyl-5-aminomethyl) pyridine,

or its salt

[hereinafter sometimes abbreviated as compound (I)], characterized by a chemical structure in which an optionally substituted amino group is attached to position 3 of the pyridine ring through a divalent hydrocarbon group and an optionally substituted aromatic group is attached to position 4, has an excellent inhibitory effect on peptidase and is useful as a means for preventing or treating diabetes and the like. Based on this finding, the authors of the present invention conducted intensive research culminating in the present invention.

Thus, in accordance with the present invention, there are provided:

1) compound (I);

2) compound (I), where R ¹ and R ² are the same or different and each represents an optionally substituted hydrocarbon group and X represents a cyano group, a nitro group, an acyl group, a substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted a cyclic group;

3) compound (I), where the acyl group for X is a carboxyl group;

4) compound (I), where R ¹ and R ² are the same or different and each represents a C _1-10 alkyl group, optionally substituted with 1-3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxycarbonyl group and C _1-6 alkoxy groups;

5) compound (I), where R ³ represents a C _6-14 aryl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms and a halogen atom;

6) compound (I), where R ⁴ represents an amino group;

7) compound (I), where L represents a C _1-10 alkylene group;

8) compound (I), where Q is a bond;

9) compound (I), where X is an acyl group, a substituted hydroxy group, an optionally substituted thiol group, or an optionally substituted amino group;

10) compound (I), where X represents a carboxyl group;

11) compound (I), which is a

5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid;

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid;

methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate;

{[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl] methyl} amine;

methyl-3 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate;

N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide,

or its salt;

12) a prodrug of compound (I);

13) a pharmaceutical agent containing compound (I) or a prodrug thereof;

14) the pharmaceutical agent according to paragraph 13), which is a means for the prevention or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity;

15) a peptidase inhibitor containing compound (I) or a prodrug thereof;

16) the inhibitor according to paragraph 15), where the peptidase is dipeptidyldipeptidase-IV;

17) the use of compound (I) or its prodrug to obtain an agent for the prophylaxis or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity;

18) the use of compound (I) or its prodrug to obtain a peptidase inhibitor;

19) a method for the prevention or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity in a mammal, comprising administering to the mammal compound (I) or a prodrug thereof;

20) a method for inhibiting peptidase in a mammal, comprising administering to the mammal a compound (I) or a prodrug thereof;

21) a method for producing a compound represented by the formula

Where

R ¹ , R ² , R ³ and Q are as defined for compound (I);

La represents a bond or a divalent hydrocarbon group and

Xa represents a hydrogen atom, a nitro group, an acyl group, a substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted cyclic group;

or a salt thereof, comprising subjecting a compound represented by the formula

where each symbol is as defined above, or its salts of the reduction reaction; etc.

The compound of the present invention has an excellent inhibitory effect on peptidase and is useful as an agent for the prevention or treatment of diabetes and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

Further, each symbol in the formula (I) is described in more detail.

As the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R ¹ or R ² , for example, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _3-10 cycloalkyl group , A C _3-10 cycloalkenyl group, a C _4-10 cycloalkadienyl group, a C _6-14 aryl group, a C _7-13 aralkyl group, a C _8-13 arylalkenyl group, a C _3-10 cycloalkyl-C _1-6 alkyl group, and the like like that.

As the C _1-10 alkyl group in this description, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.

As the C _2-10 alkenyl group, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl , 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

As the C _2-10 alkynyl group, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentinyl , 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptinyl, 1-octinyl and the like.

As the C _3-10 cycloalkyl group, mention may be made, for example, of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl,

bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl,

bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and

things like that.

As the C _3-10 cycloalkenyl group, mention may be made, for example, of 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.

As the C _4-10 cycloalkadienyl group, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like can be mentioned.

As the C _6-14 aryl group, mention may be made, for example, of phenyl, naphthyl, antril, phenanthryl, acenaphthylenyl, biphenyl and the like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

As the C _7-13 aralkyl group, mention may be made, for example, of benzyl, phenethyl, naphthylmethyl, biphenylmethyl and the like.

As the C _8-13 arylalkenyl group, mention may be made, for example, of styryl and the like.

As the C _3-10 cycloalkyl-C _1-6 alkyl group, mention may be made, for example, of cyclohexylmethyl and the like.

Said C _1-10 alkyl group, C _2-10 alkenyl group and C _2-10 alkynyl group optionally contain 1-3 substituents at substituted positions. As these substituents can be called, for example:

(1) a C _3-10 cycloalkyl group (e.g. cyclopropyl, cyclohexyl);

(2) a C _6-14 aryl group (e.g. phenyl, naphthyl);

(3) an aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl) optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and C _{1 -6} alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);

(4) a non-aromatic heterocyclic group (e.g. tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl, oxooxadiazolyl), optionally substituted with a C _1-6 alkyl group, for example;

(5) an amino group optionally mono- or disubstituted with substituents selected from a C _1-6 alkyl group (e.g. methyl, ethyl), a C _1-6 alkylcarbonyl group (e.g. acetyl, isobutanoyl, isopentanoyl) and a C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);

(6) a C _1-6 alkylsulfonylamino group (e.g. methylsulfonylamino);

(7) an amidino group;

(8) a C _1-6 alkylcarbonyl group (e.g. acetyl, isobutanoyl, isopentanoyl);

(9) a C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);

(10) a C _1-6 alkylsulfonyl group (e.g. methylsulfonyl);

(11) a carbamoyl group, optionally mono- or disubstituted with a C _1-6 alkyl group (e.g. methyl, ethyl), optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(12) a thiocarbamoyl group, optionally mono- or disubstituted with a C _1-6 alkyl group (e.g. methyl, ethyl), optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(13) a sulfamoyl group, optionally mono- or disubstituted with a C _1-6 alkyl group (e.g. methyl, ethyl), optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(14) a carboxyl group;

(15) a hydroxy group;

(16) a C _1-6 alkoxy group (e.g. methoxy, ethoxy) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(17) a C _2-6 alkenyloxy group (e.g., ethenyloxy), optionally substituted with 1-3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);

(18) a C _3-10 cycloalkyloxy group (e.g. cyclohexyloxy);

(19) a C _7-13 aralkyloxy group (e.g. benzyloxy);

(20) a C _6-14 aryloxy group (e.g., phenyloxy, naphthyloxy);

(21) a C _1-6 alkylcarbonyloxy group (e.g., acetyloxy, tert-butylcarbonyloxy);

(22) a thiol group;

(23) a C _1-6 alkylthio group (e.g. methylthio, ethylthio) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(24) a C _7-13 aralkylthio group (e.g. benzylthio);

(25) a C _6-14 arylthio group (e.g., phenylthio, naphthylthio);

(26) a sulfo group;

(27) a cyano group;

(28) an azido group;

(29) a nitro group;

(30) a nitroso group;

(31) a halogen atom (e.g. fluorine, chlorine, bromine, iodine);

(32) a C _1-6 alkylsulfinyl group (e.g. methylsulfinyl) and the like.

C _3-10 Cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl group, C _6-14 aryl group, C _7-13 aralkyl group, C _8-13 arylalkenyl group and C _3-10 cycloalkyl-C _{1 -6} alkyl group, which are listed as examples of the above "hydrocarbon group", optionally contain 1-3 substituents in substituted positions.

As the indicated substituents, mention may be made, for example, of the groups listed as substituents for the above C _1-10 alkyl group and the like, for example:

C _1-6 alkyl group (e.g. methyl, ethyl) optionally substituted with 1-3 substituents selected from halogen atoms (e.g. fluorine, chlorine, bromine, iodine), carboxyl group, C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl , ethoxycarbonyl) and a carbamoyl group;

A C _2-6 alkenyl group (e.g. ethenyl, 1-propenyl) optionally substituted with 1-3 substituents selected from halogen atoms (e.g. fluorine, chlorine, bromine, iodine), a carboxyl group, a C _1-6 alkoxycarbonyl group (e.g. , methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group;

A C _7-13 aralkyl group (e.g. benzyl) and the like.

The “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R ¹ or R ² is preferably a C _1-10 alkyl group, a C _6-14 aryl group or a C _7-13 aralkyl group, more preferably a C _1-10 alkyl group.

An “optionally substituted hydrocarbon group” for R ¹ or R ^{2 is} preferably:

(1) a C _1-10 alkyl group optionally substituted with 1-3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkoxy group and the like;

(2) a C _6-14 aryl group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a carbamoyl group and the like; or

(3) a C _7-13 aralkyl group.

Of these, a C _1-10 alkyl group is optionally substituted with 1-3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkoxy group and the like.

As examples of a “substituted hydroxy group” of an “optionally substituted hydroxy group” for R ¹ or R ² , examples listed below for X may be used.

Each of R ¹ and R ² is preferably an “optionally substituted hydrocarbon group”, more preferably a C _1-10 alkyl group, optionally substituted with 1-3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxycarbonyl group, C _1-6 alkoxy groups and the like.

As the “aromatic group” of the “optionally substituted aromatic group” for R ³ , mention may be made, for example, of an aromatic hydrocarbon group, an aromatic heterocyclic group and the like.

As the aromatic hydrocarbon group, there can be mentioned, for example, a C _6-14 aryl group, which is exemplified for the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for the above R ¹ or R ² , and the like.

As an aromatic heterocyclic group, for example, a 5-7-membered monocyclic aromatic heterocyclic group containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as ring constituent atoms besides carbon atoms, and a condensed aromatic heterocyclic group . As a condensed aromatic heterocyclic group, for example, there can be mentioned a group in which said 5-7 membered monocyclic aromatic heterocyclic groups and a 6 membered ring containing 1 or 2 nitrogen atoms, a benzene ring or a 5 membered ring containing one sulfur atom , condensed, and the like.

Preferred examples of an aromatic heterocyclic group include monocyclic aromatic heterocyclic groups such as furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g. 2-pyrazinyl ), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4- midazolyl, 5-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, oxazolyl (e.g. 2-oxazolyl , 4-oxazolyl, 5-oxazolyl), isochazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g. 1,3,4 -thiadiazol-2-yl), triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1, 2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl) and the like; fused aromatic heterocyclic groups such as quinolyl (e.g. 2-quinolyl, 3-quinolyl, 4-quinolyl), quinazolyl (e.g. 2-quinazolyl, 4-quinazolyl), quinoxalil (e.g. 2-quinoxalyl), benzofuryl (e.g. 2-benzofuryl, 3-benzofuryl), benzothienyl (e.g. 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g. 2-benzoxazolyl), benzothiazolyl (e.g. 2-benzothiazolyl), benzimidazolyl (e.g. benzimidazol-1-yl, benzimidazol-2-yl), indolyl (e.g. indol-1-yl, indol-3-yl), indazolyl (e.g. 1H-indazol-3-yl), pyrrolopyrazinyl (e.g. ep, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl) imidazopyridinyl (eg 1H-imidazo [4,5-b] pyridine -2-yl, 1H-imidazo [4,5-c] pyridin-2-yl), imidazopyrazinyl (e.g., 1H-imidazo [4,5-b] pyrazin-2-yl) and the like, and the like.

The “aromatic group” of the “optionally substituted aromatic group” for R ³ is preferably an aromatic hydrocarbon group, more preferably a C _6-14 aryl group, even more preferably phenyl.

The "aromatic group" of the "optionally substituted aromatic group" for R ³ optionally contains 1-3 substituents at substituted positions.

As the indicated substituents, mention may be made, for example, of the groups indicated as examples of the substituents for the C _3-10 cycloalkyl group shown in the examples for the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for the above R ¹ or R ² .

These substituents are preferably

A C _1-6 alkyl group optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

a halogen atom (e.g. fluorine, chlorine, bromine, iodine);

A C _1-6 alkoxycarbonyl group;

carboxyl group;

hydroxy group;

C _1-6 alkoxy, optionally substituted with 1-3 halogen atoms, and the like, more preferably

A C _1-6 alkyl group (e.g. methyl, ethyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

a halogen atom (e.g. fluorine, chlorine, bromine, iodine) and the like.

An “optionally substituted aromatic group” for R ³ is preferably a C _6-14 aryl group (where the C _6-14 aryl group is preferably phenyl), optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (e.g. methyl , ethyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), a halogen atom (e.g. fluorine, chlorine, bromine, iodine) and the like.

As the “optionally substituted amino group” for R ^{4, there} may be mentioned, for example, an amino group optionally substituted with 1 or 2 substituents selected from a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, C _{3- 10} cycloalkenyl groups, C _6-14 aryl groups, C _7-13 aralkyl groups and C _8-13 arylalkenyl groups, each of which is optionally substituted; an acyl group and the like.

As a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a C _7-13 aralkyl group and a C _8-13 arylalkenyl group in this description, you can use these groups, given as examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R ¹ or R ² .

Each of these C _1-10 alkyl groups, C _2-10 alkenyl groups, C _3-10 cycloalkyl groups, C _3-10 cycloalkenyl groups, C _6-14 aryl groups, C _7-13 aralkyl groups and C _8-13 arylalkenyl the group optionally contains 1-3 substituents in substituted positions. As the indicated substituents, for example,

a halogen atom (e.g. fluorine, chlorine, bromine, iodine);

A C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl);

A C _1-6 alkylcarbonyl group;

cyano group;

a carbamoyl group optionally mono- or disubstituted with a C _1-10 alkyl group (e.g. methyl, ethyl, propyl, isopropyl, neopentyl);

hydroxy group;

carboxyl group; etc.

As the acyl group named as the example substituent of the “optionally substituted amino group”, the groups mentioned above as examples for X may be used. Of these, preferred are:

(1) a C _1-6 alkylcarbonyl group (e.g. acetyl, isobutanoyl, isopentanoyl);

(2) a C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) optionally substituted with a C _1-6 alkoxycarbonyl group;

(3) a C _3-10 cycloalkylcarbonyl group (e.g. cyclopentylcarbonyl, cyclohexylcarbonyl);

(4) a C _6-14 arylcarbonyl group (e.g. benzoyl) optionally substituted with 1-3 substituents selected from a halogen atom, a cyano group, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a carboxyl group, C _{1- 6} alkoxycarbonyl group, aromatic heterocyclic group (for example, tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (for example, oxooxadiazolyl) and carbamoyl group;

(5) a C _7-13 aralkyloxycarbonyl group (e.g. benzyloxycarbonyl) optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(6) a carbamoyl group;

(7) a mono- or diC _1-6 alkylcarbamoyl group (e.g. dimethylcarbamoyl);

(8) a C _1-6 alkylsulfonyl group (e.g. methylsulfonyl);

(9) a C _6-14 arylsulfonyl group optionally substituted with a C _1-6 alkylsulfonyl group (e.g. phenylsulfonyl, methylsulfonylphenylsulfonyl);

(10) an aromatic heterocyclic (e.g. pyridyl, thiazolyl, oxazolyl, indolyl) sulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group (e.g. 2-acetylamino-4-methyl-5-thiazolylsulfonyl);

(11) a C _7-13 aralkylcarbonyl group (e.g. benzylcarbonyl, phenethylcarbonyl);

(12) a C _8-13 arylalkenylcarbonyl group (e.g. styrylcarbonyl);

(13) an aromatic heterocyclic (e.g., furyl, thienyl, oxazolyl, thiazolyl, izohazolil, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) carbonyl group (e.g., furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, benzofurilkarbonil , benzothienylcarbonyl, quinoxalinylcarbonyl) optionally substituted by 1-3 substituents selected from a C _1-6 alkyl group, a C _6-14 aryl group, a C _7-13 aralkyl group, a C _1-6 alkoxy group, a carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group;

(14) a nitrogen-containing heterocyclic (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholino, oxopiperazinyl) carbonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (C _1-6 alkyl group optionally substituted with 1-3 substituents, selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(15) a C _6-14 arylazo-containing heterocyclic (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonyl group;

(16) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranylcarbonyl group;

(17) a tetrahydropyranylcarbonyl group;

(18) a C _6-14 aryloxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(19) a C _7-13 aralkylcarbamoyl group (e.g. benzylcarbamoyl);

(20) an aromatic heterocyclic (e.g. pyridyl, thiazolyl, oxazolyl, indolyl) carbamoyl group (e.g., thiazolylcarbamoyl, oxazolylcarbamoyl) optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group, and like that.

Preferred examples of the substituted amino group include:

(1) a mono- or diC _1-10 alkylamino group (e.g. methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino);

(2) a mono- or diC _2-10 alkenylamino group (e.g. diallylamino);

(3) a mono- or diC _3-10 cycloalkylamino group (e.g. cyclohexylamino);

(4) a C _6-14 arylamino group (e.g. phenylamino);

(5) a mono- or di (C _1-6 alkylcarbonyl) amino group (e.g. acetylamino, propionylamino, butanoylamino, isobutanoylamino, isopentanoylamino);

(6) a C _1-6 alkoxycarbonylamino group (e.g., methoxycarbonylamino) optionally substituted with a C _1-6 alkoxycarbonyl group;

(7) carbamoyl C _1-10 alkylamino group (e.g. carbamoylmethylamino);

(8) a C _1-6 alkoxycarbonyl C _1-10 alkylamino group (e.g. methoxycarbonylmethylamino, ethoxycarbonylmethylamino, tert-butoxycarbonylmethylamino);

(9) a carboxyC _1-10 alkylamino group (e.g. carboxymethylamino);

(10) a C _3-10 cycloalkylcarbonylamino group (e.g., cyclopentylcarbonylamino, cyclohexylcarbonylamino);

(11) a C _6-14 arylcarbonylamino group (e.g. benzoylamino) optionally substituted with 1-3 substituents selected from a halogen atom, a cyano group, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a carboxyl group, C _1-6 an alkoxycarbonyl group, an aromatic heterocyclic group (e.g., tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (e.g., oxooxadiazolyl) and a carbamoyl group;

(12) a C _7-13 aralkyloxycarbonylamino group (e.g., benzyloxycarbonylamino) optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(13) a carbamoylamino group;

(14) a mono- or diC _1-6 alkylcarbamoylamino group (e.g. dimethylcarbamoylamino);

(15) a C _1-6 alkylsulfonylamino group (e.g. methylsulfonylamino);

(16) a C _6-14 arylsulfonylamino group optionally substituted with a C _1-6 alkylsulfonyl group (e.g. phenylsulfonylamino, methylsulfonylphenylsulfonylamino);

(17) an aromatic heterocyclic (e.g. pyridyl, thiazolyl, oxazolyl, indolyl) sulfonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group (e.g. 2 -acetylamino-4-methyl-5-thiazolylsulfonylamino);

(18) a C _7-13 aralkylcarbonylamino group (e.g., benzylcarbonylamino, phenethylcarbonylamino);

(19) a C _8-13 arylalkenylcarbonylamino group (e.g. styrylcarbonylamino);

(20) aromatic heterocyclic (e.g., furyl, thienyl, oxazolyl, thiazolyl, isochazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) carbonylamino optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl A C _6-14 aryl group, a C _7-13 aralkyl group, a C _1-6 alkoxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(21) a nitrogen-containing heterocyclic (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholino, oxopiperazinyl) carbonylamino optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (a C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(22) a C _6-14 arylazo-containing heterocyclic (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonylamino group;

(23) tetrahydropyranylcarbonylamino group;

(24) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranylcarbonylamino group;

(25) a C _6-14 aryloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(26) a C _7-13 aralkylcarbamoylamino group (e.g. benzylcarbamoylamino);

(27) an aromatic heterocyclic (e.g. pyridyl, thiazolyl, oxazolyl, indolyl) carbamoylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; etc.

An “optionally substituted amino group” for R ^{4 is} preferably an amino group, optionally mono- or disubstituted with a C _1-6 alkyl group (eg methyl, ethyl, propyl, isopropyl). It is especially preferred when R ⁴ is an amino group.

As the “divalent hydrocarbon group” for L or Q, mention may be made, for example, of a divalent hydrocarbon group containing 1-10 carbon atoms. Specific examples include:

(1) a C _1-10 alkylene group (e.g., -CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -, - (CH ₂ ) ₅ -, - (CH ₂ ) ₆ -, -CHCH ₃ -, -C (CH ₃ ) ₂ -, - (CH (CH ₃ )) ₂ -, - (CH ₂ ) ₂ C (CH ₃ ) ₂ -, - (CH ₂ ) ₃ C (CH ₃ ) ₂ -);

(2) a C _2-10 alkenylene group (e.g., -CH = CH-, -CH ₂ -CH = CH-, -CH = CH-CH ₂ -, -CH = CH-CH ₂ -CH ₂ -, -C (CH ₃ ) ₂ -CH = CH-, -CH ₂ -CH = CH-CH ₂ -, -CH ₂ -CH ₂ -CH = CH-, -CH = CH-CH = CH-, -CH = CH- CH ₂ —CH ₂ —CH ₂ -);

(3) a C _2-10 alkynylene group (e.g., -C≡C-, -CH ₂ -C≡C-, -CH ₂ -C≡C-CH ₂ -CH ₂ -) and the like.

A “divalent hydrocarbon group” is preferably a C _1-10 alkylene group or a C _2-10 alkenylene group, more preferably —CH ₂ -, - (CH ₂ ) ₂ -, —CH = CH— and the like.

L represents preferably a C _1-10 alkylene group, more preferably —CH ₂ - and the like.

Q is preferably a bond, a C _1-10 alkylene group or a C _2-10 alkenylene group, more preferably a bond, —CH ₂ -, - (CH ₂ ) ₂ -, —CH = CH— and the like. It is especially preferred when Q is a bond.

As the “acyl group” for X, there can be mentioned, for example, a group represented by the formula: —COR ⁵ , —CO — OR ⁵ , —SO ₂ R ⁵ , —SOR ⁵ , —PO ₃ R ⁵ R ⁶ , —CO-NR ^5a R ^6a , —CS-NR ^5a R ⁶ [where R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R ⁵ and R ⁶ can form an optionally substituted nitrogen-containing heterocycle together with an adjacent nitrogen atom] and the like.

As the “optionally substituted hydrocarbon group” for R ⁵ , R ⁶ , R ⁵ or R ⁶ , the groups listed as examples for the above R ¹ or R ² can be used.

As the “heterocyclic group” of the “optionally substituted heterocyclic group” for R ⁵ , R ⁶ , R ⁵ or R ^{6, there} can be mentioned an aromatic heterocyclic group and a non-aromatic heterocyclic group.

As the aromatic heterocyclic group, mention may be made of the groups listed as examples of the “aromatic group” of the “optionally substituted aromatic group” for the above R ³ .

As a non-aromatic heterocyclic group, for example, a 5-7-membered monocyclic non-aromatic heterocyclic group containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as atoms making up the ring ring in addition to carbon atoms, and a condensed non-aromatic heterocyclic group . As a condensed non-aromatic heterocyclic group, for example, a group in which said 5-7-membered monocyclic non-aromatic heterocyclic groups and a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom can be mentioned , condensed, and the like.

Preferred examples of the non-aromatic heterocyclic group include pyrrolidinyl (e.g., 1-pyrrolidinyl), piperidinyl (e.g., piperidino), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g., 1-piperazinyl, e.g. hexamethyleneimin-1-yl), oxazolidinyl (e.g. oxazolidin-3-yl), thiazolidinyl (e.g. thiazolidin-3-yl), imidazolidinyl (e.g. imidazolidin-3-yl), oxoimidazolidinyl (e.g. 2-oxo-imidazolidinyl) 1-yl) dioxoimidazolidinyl (e.g. mer, 2,4-dioxoimidazolidin-3-yl), dioxooxazolidinyl (e.g. 2,4-dioxooxazolidin-3-yl, 2,4-dioxoxazolidin-5-yl, 2,4-dioxooxazolidin-1-yl), dioxothiazolidinyl ( e.g. 2,4-dioxothiazolidin-3-yl, 2,4-dioxothiazolidin-5-yl), dioxoisoindolyl (e.g. 1,3-dioxoisoindol-2-yl), oxooxadiazolyl (e.g. 5-oxooxadiazol-3-yl) , oxo-thiadiazolyl (e.g. 5-oxo-thiadiazol-3-yl), oxopiperazinyl (e.g. 3-oxopiperazin-1-yl), dioxopiperazinyl (e.g. 2,3-dioxopiperazin-1-yl, 2,5-dioxopiperazin-1-yl ), oxodioxolyl (e.g. 2-oxo-1,3-dioxol-4-yl), ox dioxolanyl (e.g. 2-oxo-1,3-dioxolan-4-yl), oxo-2-benzofuranyl (e.g. 3-oxo-2-benzofuran-1-yl), oxodihydrooxadiazolyl (e.g. 5-oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl), 4-oxo-2-thioxo-1,3-thiazolidin-5-yl, 4-oxo-2-thioxo-1,3-oxazolidin-5 -yl, tetrahydropyranyl (e.g. 4-tetrahydropyranyl), 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl (e.g. 4-oxo-4,5,6,7-tetrahydro-1-benzofuran- 3-yl), 1,3 (2H, 5H) -dioxotetrahydroimidazo [1,5-a] pyridinyl, 1,3 (2H, 5H) -dioxo-10,10a-dihydroimidazo [1,5-b] isoquinolinyl, and the like like that.

The “heterocyclic group” of the “optionally substituted heterocyclic group” for R ⁵ , R ⁶ , R ⁵ or R ⁶ optionally contains 1-3 substituents at substituted positions.

As the indicated substituents, mention may be made, for example, of those indicated as examples of substituents for the C _3-10 cycloalkyl group indicated as an example of a “hydrocarbon group” of an “optionally substituted hydrocarbon group” for the above R ¹ or R ² .

The substituents are preferably

A C _1-6 alkyl group (e.g. methyl, ethyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

a halogen atom (e.g. fluorine, chlorine, bromine, iodine);

A C _6-14 aryl group;

C _7-13 aralkyl group;

hydroxy group;

C _1-6 alkoxy;

carboxyl group;

A C _1-6 alkoxycarbonyl group;

carbamoyl group;

A C _1-6 alkyl group substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

a mono or di (C _1-6 alkylcarbonyl) amino group and the like.

As the “nitrogen-containing heterocycle” of the “optionally substituted nitrogen-containing heterocycle” formed by R ⁵ and R ⁶ together with an adjacent nitrogen atom, mention may be made, for example, of a 5-7 membered nitrogen-containing heterocycle containing at least one nitrogen atom and optionally additionally containing 1 -2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as constituting ring atoms in addition to carbon atoms. As preferred examples of the “nitrogen-containing heterocycle”, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like can be mentioned.

The nitrogen-containing heterocycle optionally contains 1-3 (preferably 1 or 2) substituents at substituted positions. As these substituents can be called

hydroxy group;

A C _1-6 alkyl group optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

A C _7-13 aralkyl group (e.g. benzyl, diphenylmethyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

A C _6-14 aryl group (e.g. phenyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

A C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl);

A C _1-6 alkyl group substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

carboxyl group;

carbamoyl group and the like.

Preferred examples of the “acyl group” include:

(1) a formyl group;

(2) a carboxyl group;

(3) a carbamoyl group;

(4) a C _1-6 alkylcarbonyl group (e.g. acetyl, isobutanoyl, isopentanoyl);

(5) C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from carboxyl group, carbamoyl group, thiocarbamoyl group, C _1-6 alkoxycarbonyl group and C _1-6 alkylcarbonyloxy groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

tert-butoxycarbonyl, carboxymethoxycarbonyl,

carboxyethoxycarbonyl, carboxybutoxycarbonyl,

carbamoylmethoxycarbonyl, thiocarbamoylmethoxycarbonyl,

ethoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl,

methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl,

tert-butylcarbonyloxymethoxycarbonyl);

(6) aromatic heterocyclic (e.g., furyl, thienyl, pyridyl, thiazolyl, oxazolyl, pyrazinyl, indolyl) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _{1- 6} alkoxycarbonyl group (e.g. pyridylmethoxycarbonyl,

carboxythiazolylmethoxycarbonyl,

carbamoylthiazolylmethoxycarbonyl,

ethoxycarbonylthiazolylmethoxycarbonyl);

(7) a non-aromatic heterocyclic (e.g., oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) C _1-6 alkoxycarbonyl group optionally substituted with a C _1-6 alkyl group (e.g.

methyloxydioxolylmethoxycarbonyl,

oxo-2-benzofuranylethoxycarbonyl);

(8) a C _3-10 cycloalkylcarbonyl group (e.g. cyclopentylcarbonyl, cyclohexylcarbonyl);

(9) a C _6-14 arylcarbonyl group (e.g. benzoyl, 1-naphthoyl, 2-naphthoyl) optionally substituted with 1-3 substituents selected from a halogen atom, a cyano group, an optionally halogenated C _1-6 alkyl group (i.e. A C _1-6 alkyl group optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine)), a C _1-6 alkoxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic group (e.g. tetrazolyl , oxadiazolyl), a non-aromatic heterocyclic group (e.g., oxooxadiazolyl) and carbam an oily group;

(10) a C _6-14 aryloxycarbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl) optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(11) a C _7-13 aralkyloxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, a halogen atom, a cyano group, a nitro group, a C _1-6 alkoxy group, C _{1 A -6} alkylsulfonyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group) (e.g. benzyloxycarbonyl,

phenethyloxycarbonyl, carboxybenzyloxycarbonyl,

methoxycarbonylbenzyloxycarbonyl, biphenylylmethoxycarbonyl);

(12) a carbamoyl group, a mono- or di-substituted C _1-6 alkyl group optionally substituted with 1-3 substituents selected from halogen atoms (e.g., fluoro, chloro, bromo, iodo) and C _1-6 alkoxy groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl;

(13) a carbamoyl C _1-6 alkylcarbamoyl group, optionally mono- or disubstituted with a C _1-6 alkyl group, optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) (e.g. carbamoylmethylcarbamoyl, carbamoyl ethyl carbamoyl, dimethylcarbamoylmethylamide );

(14) C _1-6 alkoksikarbonilS _1-6 alkylcarbamoyl group, an optionally substituted C _1-6 alkyl group (e.g., metoksikarbonilmetilkarbamoil, etoksikarboniletilkarbamoil, N-ethoxycarbonylmethyl-N-methylcarbamoyl);

(15) a C _6-14 arylcarbamoyl group (e.g. phenylcarbamoyl) optionally substituted with 1-3 substituents selected from an amino group, an optionally mono- or disubstituted C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic groups (e.g. tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (e.g., oxooxadiazolyl) and a carbamoyl group;

(16) a mono- or diC _3-10 cycloalkylcarbamoyl group optionally substituted with a C _1-6 alkyl group (e.g. cyclopropylcarbamoyl, cyclopentylcarbamoyl,

dicyclohexylcarbamoyl, N-cyclohexyl-N-methylcarbamoyl);

(17) C _7-13 aralkylcarbamoyl group, optionally substituted with 1-3 substituents selected from a halogen atom (e.g., fluorine, chlorine, bromine, iodine), hydroxy, carboxy, C _1-6 alkoxycarbonyl group and C _1-6 alkyl groups (e.g. benzylcarbamoyl, phenethylcarbamoyl,

phenylpropylcarbamoyl, hydroxyphenethylcarbamoyl,

chlorobenzylcarbamoyl, methoxycarbonylbenzylcarbamoyl,

N-benzyl-N-methylcarbamoyl);

(18) aromatic heterocyclic (e.g. pyridyl, thienyl, furyl, thiazolyl, oxazolyl, indolyl) C _1-6 alkylcarbamoyl group (e.g. indolylethylcarbamoyl,

pyridylmethylcarbamoyl, thienylmethylcarbamoyl,

thiazolylmethylcarbamoyl) optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(19) a C _1-6 alkylsulfonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group (e.g. methylsulfonyl, carboxymethylsulfonyl);

(20) a C _6-14 arylsulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylsulfonyl group (e.g. phenylsulfonyl, methylphenylsulfonyl,

carboxyphenylsulfonyl, methoxycarbonylphenylsulfonyl,

methylsulfonylphenylsulfonyl);

(21) a nitrogen-containing heterocyclic (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholino, oxopiperazinyl) carbonyl group optionally substituted with 1-3 substituents selected from a hydroxy group, a C _1-6 alkyl group (a C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group (e.g., pyrrolidinylcarbonyl,

piperidinylcarbonyl, piperazinylcarbonyl,

oxopiperazinylcarbonyl, morpholinocarbonyl,

methoxycarbonylpyrrolidinylcarbonyl);

(22) a C _6-14 aryl-nitrogen-containing heterocyclic (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonyl group (e.g. phenylpiperazinylcarbonyl, phenylpiperidinylcarbonyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine;

(23) a C _7-13 aralkyl-containing heterocyclic (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonyl group (e.g. benzylpiperazinylcarbonyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(24) an aromatic heterocyclic (e.g. pyridyl, thiazolyl, oxazolyl, indolyl) sulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group (e.g. 2-acetylamino-4-methyl-5-thiazolylsulfonyl);

(25) a non-aromatic heterocyclic (e.g., oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) hydroxycarbonyl group (e.g., oxodioxolanyloxycarbonyl, oxo-2-benzofuranyloxycarbonyl);

(26) a C _1-6 alkylsulfinyl group (e.g. methylsulfinyl);

(27) a thiocarbamoyl group;

(28) a phosphono group optionally mono- or disubstituted with a C _1-6 alkyl group (e.g., dimethylphosphono, diethylphosphono);

(29) a C _7-13 aralkylcarbonyl group (e.g., benzylcarbonyl, phenethylcarbonyl);

(30) a C _8-13 arylalkenylcarbonyl group (e.g. styrylcarbonyl);

(31) an aromatic heterocyclic (e.g. furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) carbonyl group (e.g. , benzothienylcarbonyl, quinoxalinylcarbonyl) optionally substituted by 1-3 substituents selected from a C _1-6 alkyl group, a C _6-14 aryl group, a C _7-13 aralkyl group, a C _1-6 alkoxy group, a carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group;

(32) a tetrahydropyranylcarbonyl group;

(33) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranylcarbonyl group;

(34) a C _3-10 cycloalkyl-C _1-6 alkoxycarbonyl group (e.g., cyclohexylmethoxycarbonyl) optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(35) aromatic heterocyclic (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, quinolyl, indolyl) C _7-13 aralkyloxycarbonyl group (e.g. tetrazolylbenzyloxycarbonyl);

(36) an aromatic heterocyclic (e.g., thienyl, furyl, pyridyl, thiazolyl, oxazolyl, indolyl) carbamoyl group (e.g., thienylcarbamoyl, furylcarbamoyl, thiazolylcarbamoyl, oxazolylcarbamoyl), optionally substituted with 1 to 3 substituents selected from _{1 to 6} carboxylic acid groups alkoxycarbonyl group and carbamoyl group, and the like.

The “acyl group” for X is preferably:

(1) a carboxyl group;

(2) a carbamoyl group;

(3) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkylcarbonyloxy group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

tert-butoxycarbonyl, carboxymethoxycarbonyl,

carboxyethoxycarbonyl, carboxybutoxycarbonyl,

carbamoylmethoxycarbonyl, thiocarbamoylmethoxycarbonyl,

ethoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl,

methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl,

tert-butylcarbonyloxymethoxycarbonyl);

(4) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a halogen atom and a C _1-6 alkoxy group (e.g. methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,

diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl,

isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,

trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl);

(5) a carbamoyl C _1-6 alkylcarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms (e.g. carbamoylmethylcarbamoyl, carbamoyl ethylcarbamoyl,

dimethylcarbamoylmethylcarbamoyl, dimethylcarbamoylethylcarbamoyl), and the like. Of these, a carboxyl group is preferred.

As the “substituted hydroxy group” for X, there can be mentioned, for example, a hydroxy group substituted with a substituent selected from a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, C _{6 -14} aryl groups, C _7-13 aralkyl groups, C _8-13 arylalkenyl groups, C _1-6 alkylcarbonyl groups (e.g. acetyl, isobutanoyl, isopentanoyl), 5- or 6-membered aromatic heterocyclic groups (e.g. furyl, thienyl , thiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyrimidinyl), condensed apo a heterocyclic group (e.g., indolyl) and the like, each of which is optionally substituted.

As the C _1-10 alkyl group, C _2-10 alkenyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl group, C _7-13 aralkyl groups and C _8-13 arylalkenyl group groups described as examples for the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for the above R ¹ or R ² can be used in this description.

Each of the above C _1-10 alkyl groups, C _2-10 alkenyl groups, C _3-10 cycloalkyl groups, C _3-10 cycloalkenyl groups, C _6-14 aryl groups, C _7-13 aralkyl groups, C _8-13 an arylalkenyl group, a C _1-6 alkylcarbonyl group, a 5- or 6-membered aromatic heterocyclic group, and a condensed aromatic heterocyclic group optionally contains 1-3 substituents at substituted positions. As the indicated substituents, for example,

a halogen atom (e.g. fluorine, chlorine, bromine, iodine);

hydroxy group;

cyano group;

A C _1-6 alkyl group optionally substituted with 1 or 2 substituents selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine), a carboxy group, a C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, tert-butoxycarbonyl) and carbamoyl groups

A C _1-6 alkoxy group optionally substituted with 1 or 2 substituents selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carboxyl group and a C _1-6 alkoxycarbonyl group (eg tert-butoxycarbonyl);

C _1-6 alkylthio group (e.g. methylthio, ethylthio);

A C _1-6 alkylcarbonyl group;

carboxyl group;

A C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl);

a carbamoyl group optionally mono- or disubstituted with a C _1-10 alkyl group (e.g. methyl, ethyl, propyl, isopropyl, neopentyl);

an amino group optionally mono- or disubstituted with a C _1-10 alkyl group (e.g. methyl, ethyl, propyl, isopropyl, neopentyl);

A C _1-6 alkylcarbonylamino group;

an aromatic heterocyclic group (e.g., furyl, thienyl, oxazolyl, thiazolyl, isochazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl) optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (e.g. methyl, ethyl), a carboxyl group , C _1-6 alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group;

A C _1-6 alkylsulfinyl group (e.g. methylsulfinyl);

A C _1-6 alkylsulfonyl group (e.g. methylsulfonyl) and the like.

As preferred examples of the “substituted hydroxy group”, mention may be made of:

(1) a C _1-6 alkylcarbonyloxy group;

(2) a C _1-10 alkoxy group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(3) a C _6-14 aryloxy group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a carbamoyl group, a C _1-6 alkoxy group, C _1-6 an alkylsulfonyl group, a C _1-6 alkylsulfinyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);

(4) a 5- or 6-membered aromatic heterocyclyloxy group (preferably thienyloxy, thiazolyloxy, oxazolyloxy, imidazolyloxy, triazolyloxy, pyrazolyloxy, pyridyloxy, pyrimidinyloxy) optionally substituted with 1-3 substituents selected from C _1-6 alkyl group (C _1-6 alkyl group the alkyl group is optionally substituted with 1-2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(5) a fused aromatic heterocyclyloxy group (preferably indolyloxy) optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(6) an aromatic heterocyclic (preferably pyridyl) C _1-6 alkoxy group, optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(7) an aromatic heterocyclic (preferably tetrazolyl) C _6-14 aryloxy group and the like.

As the “optionally substituted thiol group” for X, for example, a thiol group optionally substituted with a substituent selected from a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, C _6-14 aryl group, C _7-13 aralkyl groups, C _8-13 arylalkenyl group, C _1-6 alkylcarbonyl group (e.g., acetyl, isobutanoyl, izopentanoil), 5- or 6-membered aromatic heterocyclic groups (e.g. , furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, piri midinyl), a fused aromatic heterocyclic group (e.g. indolyl) and the like, each of which is optionally substituted.

As a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a C _7-13 aralkyl group and a C _8-13 arylalkenyl group in this case, you can use the groups indicated as examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R ¹ or R ² .

Each of the above C _1-10 alkyl groups, C _2-10 alkenyl groups, C _3-10 cycloalkyl groups, C _3-10 cycloalkenyl groups, C _6-14 aryl groups, C _7-13 aralkyl groups, C _8-13 an arylalkenyl group, a C _1-6 alkylcarbonyl group, a 5- or 6-membered aromatic heterocyclic group, and a condensed aromatic heterocyclic group optionally contains 1-3 substituents at substituted positions. As the indicated substituents, substituents for the C _1-10 alkyl group and the like for the “substituted hydroxy group” for the above X can be used.

As preferred examples of the “optionally substituted thiol group”, you can specify:

(1) a C _1-6 alkylthio group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(2) a C _6-14 arylthio group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group and a carbamoyl group;

(3) 5 or 6-membered aromatic heterocyclylthio (preferably thienylthio, thiazolylthio, oksazoliltio, imidazolylthio, triazoliltio, pirazoliltio, pyridylthio, pyrimidinylthio) optionally substituted by 1-3 substituents selected from C _1-6 alkyl, carboxyl, C _{1 -6} alkoxycarbonyl group and carbamoyl group, and the like.

As the “optionally substituted amino group” for X, the groups indicated as examples for the above R ⁴ can be used.

As the “cyclic group” of the “optionally substituted cyclic group” for X, for example, an aromatic hydrocarbon group, a non-aromatic cyclic hydrocarbon group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and the like can be mentioned.

As the aromatic hydrocarbon group and the aromatic heterocyclic group, the groups indicated as examples for the “aromatic group” of the “optionally substituted aromatic group” for the above R ^{3 can be used} .

In addition, as the non-aromatic heterocyclic group, the groups indicated as examples for the “heterocyclic group” of the “optionally substituted heterocyclic group” for the above R ^{5 can be used} .

As the nonaromatic cyclic hydrocarbon group can be mentioned, for example, C _3-10 cycloalkyl, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl groups and the like, each of which is optionally fused to a benzene ring.

As the C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group and the C _4-10 cycloalkadienyl group, the groups indicated as examples for the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for the above R ¹ or R ^{2 can be used} .

The “cyclic group” of the “optionally substituted cyclic group” for X optionally contains 1-3 substituents at substituted positions.

As substituents in this case, for example, substituents can be mentioned which are indicated as examples for the C _3-10 cycloalkyl group indicated as an example for the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for the above R ¹ or R ² .

The substituents is preferably

A C _1-6 alkyl group (e.g. methyl, ethyl) optionally substituted with 1-3 substituents selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine), a carbamoyl group, a carboxyl group and a C _1-6 alkoxycarbonyl group ( for example, methoxycarbonyl, ethoxycarbonyl);

a halogen atom (e.g. fluorine, chlorine, bromine, iodine);

carboxyl group;

A C _1-6 alkoxycarbonyl group;

carbamoyl group and the like.

X is preferably an acyl group, a substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, and more preferably an acyl group. Of these, preferred are:

(1) a carboxyl group;

(2) a carbamoyl group;

(3) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkylcarbonyloxy group;

(4) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a halogen atom and a C _1-6 alkoxy group;

(5) a carbamoyl C _1-6 alkylcarbamoyl group, optionally mono- or disubstituted with a C _1-6 alkyl group, optionally substituted with 1-3 halogen atoms, and the like, and a carboxyl group is particularly preferred.

When in compound (I) X is an ethoxycarbonyl group, Q is a divalent hydrocarbon group.

In addition, compound (I) does not include:

2,6-diisopropyl-3-methylaminomethyl-4- (4-fluorophenyl) -5-pentylpyridine [this compound is also called {[4- (4-fluorophenyl) -2,6-diisopropyl-5-pentylpyridin-3-yl] methyl} methylamine];

2,6-diisopropyl-3-aminomethyl-4- (4-fluorophenyl) -5-pentylpyridine [this compound is also called {[4- (4-fluorophenyl) -2,6-diisopropyl-5-pentylpyridin-3-yl] methyl} amine];

2,6-diisopropyl-3- (dimethylamino) methyl-4- (4-fluorophenyl) -5-pentylpyridine [this compound is also called 1- [4- (4-fluorophenyl) -2,6-diisopropyl-5-pentylpyridine- 3-yl] -N, N-dimethylmethanamine];

2,6-diisopropyl-3- (ethylamino) methyl-4- (4-fluorophenyl) -5-pentylpyridine [this compound is also called N - {[4- (4-fluorophenyl) -2,6-diisopropyl-5-pentylpyridine -3-yl] methyl} ethanamine] and

3- (tert-butyldimethylsilyloxymethyl) -2,6-diisopropyl-4- (4-fluorophenyl) -5- (indolyl-5-aminomethyl) pyridine [this compound is also called N - {[5 - ({[tert-butyl ( dimethyl) silyl] hydroxy} methyl) -4- (4-fluorophenyl) -2,6-diisopropylpyridin-3-yl] methyl} -1H-indol-5-amine].

As preferred examples of compound (I), the following compounds may be mentioned.

[Compound A]

A compound where:

R ¹ and R ² are the same or different and each represents a C _1-10 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl) optionally substituted with 1-3 substituents selected from C _3-10 cycloalkyl groups (preferably cyclopropyl), a C _1-6 alkoxycarbonyl group (preferably methoxycarbonyl) and the like;

R ³ represents a C _6-14 aryl group (the C _6-14 aryl group is preferably phenyl) optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (e.g. methyl, ethyl) optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and the like;

R ⁴ represents an amino group, optionally mono- or disubstituted with a C _1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl);

L represents a C _1-10 alkylene group (preferably —CH ₂ -);

Q is a bond, a C _1-10 alkylene group or a C _2-10 alkenylene group (preferably a bond, —CH ₂ -, - (CH ₂ ) ₂ -, —CH = CH—) and

X represents a carboxyl group, a carbamoyl group, a C _1-6 alkoxycarbonyl group, a carbamoyl group, a mono- or di-substituted C _1-6 alkyl group optionally substituted by 1-3 halogen atoms, or karbamoilC _1-6 alkylcarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms.

[Compound B]

A compound where:

R ¹ and R ² are the same or different and each represents:

(1) a C _1-10 alkyl group optionally substituted with 1-3 substituents selected from a C _3-10 cycloalkyl group (preferably cyclopropyl), a C _1-6 alkoxycarbonyl group, a C _1-6 alkoxy group and the like;

(2) a C _6-14 aryl group (preferably phenyl) optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a carbamoyl group and the like; or

(3) a C _7-13 aralkyl group (preferably benzyl);

R ³ represents a C _6-14 aryl group (the C _6-14 aryl group is preferably phenyl), optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, optionally substituted with 1-3 halogen atoms, a halogen atom, C _{A 1-6} alkoxycarbonyl group, a carboxyl group, a hydroxy group, a C _1-6 alkoxy group optionally substituted with 1-3 halogen atoms, and the like;

R ⁴ represents an amino group, optionally mono- or disubstituted by a C _1-6 alkyl group (preferably an amino group);

L represents a C _1-10 alkylene group (preferably —CH ₂ -);

Q is a bond, a C _1-10 alkylene group or a C _2-10 alkenylene group (preferably a bond, —CH ₂ -, - (CH ₂ ) ₂ -, —CH = CH—) and

X represents:

(1) a hydrogen atom;

(2) a cyano group;

(3) (3a) a carboxyl group;

(3b) a carbamoyl group;

(3c) a C _1-6 alkoxycarbonyl group optionally substituted with substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylcarbonyloxy group;

(3d) an aromatic heterocyclic (preferably pyridyl, thiazolyl, oxazolyl, indolyl) C _1-6 alkoxycarbonyl group optionally substituted with substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxycarbonyl group;

(3e) a non-aromatic heterocyclic (preferably oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) C _1-6 alkoxycarbonyl group optionally substituted with a C _1-6 alkyl group;

(3f) a C _7-13 aralkyloxycarbonyl group optionally substituted with substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxycarbonyl group;

(3g) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with substituents selected from 1-3 halogen atoms and a C _1-6 alkoxy group;

(3h) a carbamoyl C _1-6 alkylcarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms;

(3i) C _1-6 alkoksikarbonilS _1-6 alkylcarbamoyl group, an optionally substituted C _1-6 alkyl group;

(3j) a mono- or diC _3-10 cycloalkylcarbamoyl group optionally substituted with a C _1-6 alkyl group;

(3k) a C _7-13 aralkylcarbamoyl group optionally substituted with substituents selected from a halogen atom, a hydroxy group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkyl group;

(3l) aromatic heterocyclic (preferably pyridyl, thiazolyl, oxazolyl, indolyl) C _1-6 alkylcarbamoyl group;

(3m) a C _1-6 alkylsulfonyl group optionally substituted with substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(3n) a C _6-14 arylsulfonyl group optionally substituted with substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylsulfonyl group;

(3o) a nitrogen-containing heterocyclic (preferably pyrrolidinyl, piperidino, piperazinyl, morpholino) carbonyl group optionally substituted with substituents selected from a hydroxy group and a C _1-6 alkoxycarbonyl group;

(3p) a C _6-14 aryl azot-containing heterocyclic (preferably pyrrolidinyl, piperidino, piperazinyl, morpholino) carbonyl group optionally substituted with a halogen atom;

(3q) a C _7-13 aralkyl-containing heterocyclic (preferably pyrrolidinyl, piperidino, piperazinyl, morpholino) carbonyl group optionally substituted with a halogen atom;

(3r) non-aromatic heterocyclic (preferably oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) hydroxycarbonyl group; or

(3s) a phosphono group optionally mono- or disubstituted with a C _1-6 alkyl group;

(4) a C _1-6 alkylcarbonyloxy group;

(5) (5a) a C _1-6 alkylthio group optionally substituted with substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(5b) a C _6-14 arylthio group (preferably phenylthio) optionally substituted with substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkylthio group, or

(5c) a 5-membered aromatic heterocyclylthio group (preferably thiazolylthio, oxazolylthio, triazolylthio) optionally substituted with a C _1-6 alkyl group;

(6) (6a) an amino group;

(6b) C _1-6 alkoxycarbonyl C _1-10 alkylamino group

(preferably methoxycarbonylmethylamino,

ethoxycarbonylmethylamino, tert-butoxycarbonylmethylamino);

(6c) a carboxyC _1-10 alkylamino group;

(6d) a C _7-13 aralkyloxycarbonylamino group;

(6e) carbamoylamino group;

(6f) a mono- or diC _1-6 alkylcarbamoylamino group;

(6g) a C _1-6 alkylsulfonylamino group;

(6h) a C _6-14 arylsulfonylamino group optionally substituted with a C _1-6 alkylsulfonyl group; or

(6i) an aromatic heterocyclic (e.g. pyridyl, thiazolyl, oxazolyl, indolyl) sulfonylamino group optionally substituted with substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group; or

(7) tetrazolyl, oxoimidazolidinyl (preferably 2-oxoimidazolidin-1-yl), dioxoimidazolidinyl (preferably 2,4-dioxoimidazolidin-3-yl), oxopiperazinyl (preferably 3-oxopiperazin-1-yl), dioxopiperazinyl dioxopiperazin-1-yl, 2,5-dioxopiperazin-1-yl) or oxodihydrooxadiazolyl (preferably 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl).

[Compound C]

A compound wherein R ⁴ is an amino group and X is any of the above groups (3a) to (3s) in the above compound B.

[Compound D]

A compound where:

R ¹ , R ² , R ³ , R ⁴ , L and Q are as defined for the above compound B, X represents:

(1) a hydrogen atom;

(2) a cyano group;

(3) (3a) a carboxyl group;

(3b) a carbamoyl group;

(3c) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkylcarbonyloxy group;

(3d) aromatic heterocyclic (preferably furyl, thienyl, pyridyl, thiazolyl, oxazolyl, pyrazinyl, indolyl) C _1-6 alkoxycarbonyl group, optionally substituted with 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and C _1-6 alkoxycarbonyl group;

(3e) a non-aromatic heterocyclic (preferably oxodioxolyl, oxodioxolanyl, oxo-2-benzofuranyl) C _1-6 alkoxycarbonyl group optionally substituted with a C _1-6 alkyl group;

(3f) a C _7-13 aralkyloxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, a halogen atom, a cyano group, a nitro group, a C _1-6 alkoxy group, C _{1 A -6} alkyl sulfonyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);

(3g) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a halogen atom and a C _1-6 alkoxy group;

(3h) a carbamoyl C _1-6 alkylcarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms;

(3i) C _1-6 alkoksikarbonilS _1-6 alkylcarbamoyl group, an optionally substituted C _1-6 alkyl group;

(3j) a mono- or diC _3-10 cycloalkylcarbamoyl group optionally substituted with a C _1-6 alkyl group;

(3k) a C _7-13 aralkylcarbamoyl group optionally substituted with 1-3 substituents selected from a halogen atom, a hydroxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkyl group;

(3l) aromatic heterocyclic (preferably pyridyl, thienyl, furyl, thiazolyl, oxazolyl, indolyl) C _1-6 alkylcarbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, carbamoyl group and a C _1-6 alkoxycarbonyl group;

(3m) a C _1-6 alkylsulfonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(3n) a C _6-14 arylsulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylsulfonyl group;

(3o) a nitrogen-containing heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonyl group, optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group and a C _1-6 alkoxycarbonyl group;

(3p) a C _6-14 arylazo-containing heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonyl group optionally substituted with 1-3 halogen atoms;

(3q) a C _7-13 aralkyl-containing heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonyl group optionally substituted with 1-3 halogen atoms;

(3r) non-aromatic heterocyclic (preferably oxodioxolyl, oxodioxolanyl,

oxo-2-benzofuranyl) hydroxycarbonyl group;

(3s) a phosphono group optionally mono- or disubstituted with a C _1-6 alkyl group;

(3t) aromatic heterocyclic (preferably tetrazolyl) C _7-13 aralkyloxycarbonyl group;

(3u) a C _3-10 cycloalkyl-C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(3v) a C _6-14 arylcarbamoyl group optionally substituted with 1-3 substituents selected from an amino group, an optionally mono- or disubstituted C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic group (preferably tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (preferably oxooxadiazolyl) and a carbamoyl group; or

(3w) an aromatic heterocyclic (preferably thienyl, furyl) carbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(4) (4a) a C _1-6 alkylcarbonyloxy group;

(4b) a C _1-10 alkoxy group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(4c) a C _6-14 aryloxy group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a carbamoyl group, a C _1-6 alkoxy group, C _1-6 an alkylsulfonyl group, a C _1-6 alkylsulfinyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);

(4d) a 5- or 6-membered aromatic heterocyclyloxy group (preferably thienyloxy, thiazolyloxy, oxazolyloxy, imidazolyloxy, triazolyloxy, pyrazolyloxy, pyridyloxy, pyrimidinyloxy) optionally substituted with 1-3 substituents selected from C _1-6 alkyl group (C _1-6 alkyl group the alkyl group is optionally substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(4e) a fused aromatic heterocyclyloxy group (preferably indolyloxy) optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(4f) an aromatic heterocyclic (preferably pyridyl) C _1-6 alkoxy group, optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or

(4g) aromatic heterocyclic (preferably tetrazolyl) C _6-14 aryloxy group;

(5) (5a) a C _1-6 alkylthio group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;

(5b) a C _6-14 arylthio group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group and a carbamoyl group, or

(5c) a 5- or 6-membered aromatic heterocyclylthio group (preferably thienylthio, thiazolylthio, oxazolylthio, imidazolylthio, triazolylthio, pyrazolylthio, pyridylthio, pyrimidinylthio), optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group _1-6 alkoxycarbonyl group and carbamoyl group;

(6) (6a) an amino group;

(6b) a C _1-6 alkoxycarbonyl C _1-10 alkylamino group;

(6c) a carboxyC _1-10 alkylamino group;

(6d) a C _7-13 aralkyloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(6e) carbamoylamino group;

(6f) a mono- or diC _1-6 alkylcarbamoylamino group;

(6g) a C _1-6 alkylsulfonylamino group;

(6h) a C _6-14 arylsulfonylamino group optionally substituted with a C _1-6 alkylsulfonyl group;

(6i) an aromatic heterocyclic (e.g. pyridyl, thiazolyl, oxazolyl, indolyl) sulfonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group;

(6j) a mono- or di (C _1-6 alkylcarbonyl) amino group;

(6k) a C _3-10 cycloalkylcarbonylamino group;

(6l) a C _6-14 arylcarbonylamino group optionally substituted with 1-3 substituents selected from a halogen atom, a cyano group, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic groups (preferably tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (preferably oxooxadiazolyl) and a carbamoyl group;

(6m) a C _7-13 aralkylcarbonylamino group;

(6n) a C _8-13 arylalkenylcarbonylamino group;

(6o) aromatic heterocyclic (preferably furyl, thienyl, oxazolyl, thiazolyl, isochazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl) carbonylamino optionally substituted with 1-3 substituents selected from C _1-6 alkyl _6-14 aryl groups, C _7-13 aralkyl groups, C _1-6 alkoxy groups, carboxyl groups, C _1-6 alkoxycarbonyl groups and carbamoyl groups;

(6p) a nitrogen-containing heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholino) carbonylamino group optionally substituted with 1-3 substituents selected from a _C1-6 alkyl group (a _C1-6 alkyl group is optionally substituted with 1-3 substituents selected from a carboxyl group , C _1-6 alkoxycarbonyl group and carbamoyl group), carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group;

(6q) C _6-14 arylazotonic heterocyclic (e.g.

pyrrolidinyl, piperidinyl, piperazinyl,

morpholino) carbonylamino group;

(6r) tetrahydropyranylcarbonylamino group;

(6s) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranylcarbonylamino group;

(6t) C _1-6 alkoxycarbonylamino, optionally substituted C _1-6 alkoxycarbonyl group;

(6u) a C _6-14 aryloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;

(6v) a C _7-13 aralkylcarbamoylamino group or

(6w) an aromatic heterocyclic (preferably thiazolyl, oxazolyl) carbamoylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or

(7) (7a) tetrazolyl;

(7b) oxoimidazolidinyl (preferably 2-oxoimidazolidin-1-yl);

(7c) dioxoimidazolidinyl (preferably 2,4-dioxoimidazolidin-3-yl, 2,4-dioxoimidazolidin-1-yl) optionally substituted with a C _1-6 alkyl group, optionally substituted with 1-3 substituents selected from a carboxyl group and C _{1 -6} alkoxycarbonyl group;

(7d) oxopiperazinyl (preferably 3-oxopiperazin-1-yl);

(7e) dioxopiperazinyl (preferably 2,3-dioxopiperazin-1-yl, 2,5-dioxopiperazin-1-yl);

(7f) oxodihydrooxadiazolyl (preferably 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl);

(7g) dioxoisoisindolyl;

(7h) oxazolyl optionally substituted with a C _1-6 alkoxycarbonyl group;

(7i) dioxooxazolidinyl (preferably 2,4-dioxooxazolidin-5-yl) or dioxothiazolidinyl (preferably 2,4-dioxothiazolidin-5-yl), each of which is optionally substituted with a C _1-6 alkyl group, optionally substituted with 1-3 substituents, selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;

(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;

(7k) 1,3 (2H, 5H) -dioxotetrahydroimidazo [1,5-a] pyridinyl;

(7l) 1,3 (2H, 5H) -dioxo-10,10a-dihydroimidazo [1,5-b] isoquinolinyl or

(7m) a C _6-14 aryl group optionally substituted with a C _1-6 alkoxycarbonyl group.

[Compound E]

The above compound D, where:

R ¹ and R ² are the same or different and each represents a C _1-10 alkyl group (preferably R ¹ represents isobutyl or neopentyl; R ² represents methyl);

R ³ represents a C _6-14 aryl group optionally substituted with a C _1-6 alkyl group (R ³ preferably represents 4-methylphenyl);

R ⁴ represents an amino group and

X represents the above group (3a), (3c), (3f), (3o), (3v), (4d), (5b), (6l) or (6o) [preferably (3a), (3o) , (3v), (4d) or (6o)].

[Compound F]

5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (Example 22);

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (Example 40);

methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate (example 305 );

{[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl] methyl} amine (Example 312);

methyl-3 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate (example 336);

N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide (Example 350); or a salt thereof (preferably hydrochloride, trifluoroacetate, fumarate).

As a salt of compound (I), a pharmacologically acceptable salt is preferred. Examples of such a salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like.

Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt; ammonium salt and the like.

Preferred examples of salts with an organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine diamine, dicyclohexylamine diamine, dicyclohexylamine diben .

Preferred examples of the inorganic acid salt include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Preferred examples of salts with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenes toluenesulfonic acid and the like.

Preferred examples of a salt with a basic amino acid include a salt with arginine, lysine, ornithine, and the like.

Preferred examples of a salt with an acidic amino acid include a salt with aspartic acid, glutamic acid, and the like.

Of the above salts, an inorganic acid salt and an organic acid salt are preferred, and hydrochloride, trifluoroacetate, fumarate and the like are most preferred.

A prodrug of compound (I) is a compound that is converted to compound (I) as a result of interaction with an enzyme, stomach acid, and the like under physiological conditions in the body, that is, a compound that is converted to compound (I) as a result of enzymatic oxidation, reduction hydrolysis and the like, and a compound that is converted to compound (I) by hydrolysis and the like under the action of stomach acid and the like. Examples of the prodrugs of compound (I) include a compound in which the amino group of compound (I) is acylated, alkylated, phosphorylated (for example, a compound where the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3 -dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated and the like); a compound in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated, boronated (for example, a compound where the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethyl carbonylated and the like); a compound in which the carboxyl group of compound (I) is esterified or amidated (for example, a compound where the carboxyl group of compound (I) is ethyl esterified, phenyletherified, carboxymethyl esterified, dimethylaminomethyl esterified,

pivaloyloxymethyl etherified

ethoxycarbonyloxyethyl esterified, phthalidyletherified,

(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified,

cyclohexyloxycarbonylethyl etherified, methyl mediated and

things like that. These compounds can be obtained from compound (I) by methods known per se.

A prodrug of compound (I) can be a compound that is converted to compound (I) under physiological conditions, as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990).

Compound (I) can be labeled with an isotope (e.g., ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I and the like) and the like.

Compound (I) may be anhydrous or hydrate.

Compound (I) and its prodrug (hereinafter sometimes referred to simply as the compound of the present invention) exhibit low toxicity and can be used as agents for the prophylaxis or treatment of various diseases in the following mammals (e.g. human, mouse, rat, rabbit, dog, cat, cattle, horse, pig, monkey and the like) as such or mixed with a pharmacologically acceptable carrier and the like, forming a pharmaceutical composition.

In this case, organic or inorganic carriers conventionally used as materials for the manufacture of pharmaceutical preparations are used as a pharmacologically acceptable carrier, which are added in the form of an excipient, a lubricant, a binder, a disintegrant for solid preparations and a solvent, substances that promote dissolution, a suspending agent, means providing isotonicity of the solution, buffer, sedative, and the like for liquid preparations. If necessary, you can use such an additive to pharmaceutical preparations as a preservative, antioxidant, coloring matter, sweetener and the like.

Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium hydroxypropyl cellulose, powdered arabic gum, magnesium sulfate, siliculum, magnesium sulfate, siliculum like that.

Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide and the like.

Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, powdered arabian gum, methyl cellulose, carboxymethyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pulsulipropyl cellulose cellulose cellulose cellulose hydroxymethyl cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose cellulose

Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, light silicon anhydride, low substituted hydroxypropyl cellulose and the like.

Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

Preferred examples of dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.

Preferred examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.

Preferred examples of the solution isotonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.

Preferred examples of the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer and the like.

Preferred examples of a sedative include benzyl alcohol and the like.

Preferred examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Preferred examples of the antioxidant include sulfite, ascorbate and the like.

Preferred examples of the coloring matter include edible water-soluble resin pigments (for example, food colorings such as food color red No. 2 and 3, food color yellow No. 4 and 5, food color blue No. 1 and 2 and the like), water-insoluble colorful varnishes (for example , aluminum salt of the above edible water-soluble resin pigment and the like), natural pigments (e.g., betacarotene, chlorophyll, red iron oxide pigment, etc.) and the like.

Preferred examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.

The dosage form of the above pharmaceutical composition is, for example, an oral agent such as tablets (including sublingual tablets and chewable tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, suspensions and the like; or parenteral agent, such as injection forms (e.g., forms for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion, etc.), external agents (e.g., transdermal preparations, ointments, etc. .), suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pills, nasal preparations, pulmonary preparations (inhalation forms), ophthalmic preparations and the like. These dosage forms can be safely administered by oral or parenteral route.

These agents may be controlled release formulations such as quick release formulations and sustained release formulations (e.g., sustained release microcapsules).

The pharmaceutical composition can be obtained by a method commonly used in the pharmaceutical field, such as the method described in the Japanese Pharmacopoeia, and the like. Specific methods for the preparation of pharmaceutical preparations are described in detail below.

Although the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention and the like, it is, for example, about 0.1-100 wt.%.

An oral agent is obtained, for example, by adding excipients (e.g., lactose, sucrose, starch, D-mannitol and the like), disintegrants (e.g., calcium carboxymethyl cellulose and the like), binders (e.g., pregelatinized starch, powdered arabic gum) to the active ingredient. , carboxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and the like), lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000 and the like) and the like, by compression molding according to the irradiated mixture and, when necessary, covering it with a coating base for masking the taste, imparting the ability to dissolve in the intestine or the ability to prolong release in a manner known per se.

Examples of a coating base include a sugar coating base, a water-soluble film base, an enteric film base, and a film providing a sustained release of the active ingredient.

As a basis for obtaining a sugar coating, sucrose can be used, if necessary, together with one or more additives selected from talc, precipitated calcium carbonate, gelatin, powdered arabian gum, pullulan, carnauba wax and the like.

As the basis for the preparation of a water-soluble film, for example, cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E, trademark, Roehm Pharma], polyvinylpyrrolidone and the like; polysaccharides such as pullulan and the like; etc.

As the basis for the preparation of an enteric film, for example, cellulose polymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate and the like are used; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L, trademark, Roehm Pharma], methacrylic acid copolymer LD [Eudragit L-30D55, trademark, Roehm Pharma], methacrylic acid copolymer S [Eudragit S, trademark, Roehm Pharma] and the like; natural products such as shellac and the like; etc.

As the basis for coating to obtain a film providing a sustained release, for example, cellulose polymers such as ethyl cellulose and the like are used; acrylic acid polymers such as the aminoalkyl methacrylate copolymer RS [Eudragit RS, trademark, Roehm Pharma], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE, trademark, Roehm Pharma] and the like.

During use, two or more kinds of the above coating bases may be mixed in a suitable ratio. In addition, a light-shielding substance such as titanium oxide, iron oxide (3) and the like can be used during coating.

An injection dosage form is prepared by dissolving, suspending or emulsifying an active ingredient in an aqueous solvent (e.g., distilled water, physiological saline, Ringer's solution and the like) or an oil solvent (e.g., vegetable oil, such as olive oil, sesame oil, cottonseed oil, corn oil and the like, together with a dispersing agent (e.g., polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate and the like), a preservative (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol and the like), a substance that provides isotonicity of the solution (e.g. sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like). At this stage, if necessary, additives can be used, such as solubilizers (e.g. sodium salicylate, sodium acetate and the like), stabilizers (e.g. human serum albumin and the like), soothing f substances (e.g. benzyl alcohol and the like) and the like.

The compound of the present invention exhibits low toxicity (such as acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, vascular toxicity, carcinogenicity), causes minor side effects and can be used as a means for the prevention, treatment or diagnosis of various diseases in mammals (e.g. , man, cattle, horse, dog, cat, monkey, mouse, rat, especially man).

The compound of the present invention has a high peptidase inhibitory activity and can suppress peptidase-induced degradation of a physiologically active substance, such as peptide hormones, cytokines, neurotransmitters, and the like.

Examples of peptide hormones include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GIP, growth hormone release hormone (GHRH) and the like.

Examples of cytokines include a chemokine, such as RANTES, and the like.

Examples of neurotransmitters include neuropeptide Y and the like.

Examples of peptidases include

EC 3.4.11.1 (leucyl aminopeptidase),

EC 3.4.11.2 (membrane alanine aminopeptidase),

EC 3.4.11.3 (cystinyl aminopeptidase),

EC 3.4.11.4 (tripeptide aminopeptidase),

EC 3.4.11.5 (prolylamine peptidase),

EC 3.4.11.6 (aminopeptidase B),

EC 3.4.11.7 (glutamyl aminopeptidase),

EC 3.4.11.9 (Xaa-Pro aminopeptidase),

EC 3.4.11.10 (bacterial leisylaminopeitidase),

EC 3.4.11.13 (clostridial aminopeptidase),

EC 3.4.11.14 (cytosolic alanylamine peptidase),

EC 3.4.11.15 (lysylaminopeptidase),

EC 3.4.11.16 (Xaa-Trp aminopeptidase),

EC 3.4.11.17 (tryptophanyl aminopeptidase),

EC 3.4.11.18 (methionylaminopeptidase),

EC 3.4.11.19 (D-stereospecific aminopeptidase),

EC 3.4.11.20 (aminopeptidase Ey),

EC 3.4.11.21 (aspartylamine peptidase),

EC 3.4.11.22 (aminopeptidase I),

EC 3.4.13.3 (Xaa-His dipeptidase),

EC 3.4.13.4 (Xaa-Arg dipeptidase),

EC 3.4.13.5 (Xaa-methyl-His dipeptidase),

EC 3.4.13.7 (Glu-Glu dipeptidase),

EC 3.4.13.9 (Xaa-Pro dipeptidase),

EC 3.4.13.12 (Met-Xaa dipeptidase),

EC 3.4.13.17 (non-stereospecific dipeptidase),

EC 3.4.13.18 (cytosolic nonspecific dipeptidase),

EC 3.4.13.19 (membrane dipeptidase),

EC 3.4.13.20 (beta-Ala-His dipeptidase),

EC 3.4.14.1 (dipeptidyl peptidase I),

EC 3.4.14.2 (dipeptidyl peptidase II),

EC 3.4.14.4 (dipeptidyl peptidase III),

EC 3.4.14.5 (dipeptidyl peptidase IV),

EC 3.4.14.6 (dipeptidyl dipeptidase),

EC 3.4.14.9 (tripeptidyl peptidase I),

EC 3.4.14.10 (tripeptidyl peptidase II),

EC 3.4.14.11 (Xaa-Pro dipeptidyl dipeptidase) and the like in accordance with the classification of the International Union of Biochemistry and Molecular Biology. As peptidases, FAPα, DPP8, DPP9 and the like can also be mentioned.

Of these peptidase examples, EC 3.4.14.1, EC 3.4.14.2, EC 3.4.14.4, EC 3.4.14.5, EC 3.4.14.6, EC 3.4.14.9, EC 3.4.14.10 and EC 3.4.14.11 are preferred. Especially preferred is EC 3.4.14.5 (dipeptidyl peptidase IV).

The compound of the present invention may also, in addition to the inhibitory effect on peptidase, simultaneously have an antagonistic effect on glucagon and an inhibitory effect on CETP. When a compound of the present invention simultaneously possesses these effects, it is more effective as a means for the prevention or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes, pregnant diabetes mellitus, etc.) and hyperlipidemia (e.g. hypertriglyceridemia, hypercholesterolemia, hypoLVPemia, hyperlipidemia after eating, etc.).

The compound of the present invention is useful as an agent for the prophylaxis or treatment of diabetes (for example, type 1 diabetes, type 2 diabetes, pregnant diabetes and the like); agents for the prevention or treatment of hyperlipidemia (for example, hypertriglyceridemia, hypercholesterolemia, hypoLPVPemia, post-food hyperlipidemia and the like); agents for the prevention or treatment of arteriosclerosis; agents for the prevention or treatment of impaired glucose tolerance [IGT]; an insulin secretion enhancing agent; and an agent for preventing impaired glucose tolerance in diabetes.

Regarding diagnostic indicators, in 1999, the Japan Diabetes Society reported new diagnostic indicators.

According to this report, diabetes is a condition in which fasting blood glucose (glucose concentration in intravenous plasma) is not lower than 126 mg / dl, when determining glucose tolerance when taken orally 75 g glucose (75 g OGTT) level (concentration glucose in intravenous plasma) after 2 hours is not lower than 200 mg / dl and the blood glucose level (glucose concentration in intravenous plasma) is not fasting not lower than 200 ml / dl. A condition that does not meet the above criteria for diabetes and is different from “a condition in which the fasting glucose level (glucose concentration in the intravenous plasma) is not lower than 110 mg / dl or when determining glucose tolerance when taken orally 75 g of glucose ( 75 g OGTT) level (glucose concentration in intravenous plasma) after 2 hours is not lower than 140 mg / dL "(normal type), called the state of" borderline type ".

In addition, in 1997 reported new diagnostic indicators ADA (American Diabetes Association), and in 1998 - WHO (WHO).

According to these reports, diabetes is a condition in which fasting blood glucose (glucose concentration in intravenous plasma) is not lower than 126 mg / dl and when determining glucose tolerance when taken orally, 75 g glucose level (glucose concentration in intravenous plasma) after 2 hours is not lower than 200 mg / dl.

According to the above reports, impaired glucose tolerance is a condition in which the fasting blood glucose level (glucose concentration in intravenous plasma) is lower than 126 mg / dl and when determining glucose tolerance when taken orally, 75 g glucose level (glucose concentration during intravenous plasma) after 2 hours is not lower than 140 mg / dl and lower than 200 mg / dl. According to an ADA report, a condition in which fasting blood glucose (intravenous plasma glucose concentration) is not lower than 110 mg / dL and lower than 120 mg / dL is called IFG (impaired fasting glucose). According to a WHO report, among conditions of IFG (impaired fasting glucose), a condition in which when determining glucose tolerance by oral administration of 75 g of glucose, the level (glucose concentration in intravenous plasma) after 2 hours is lower than 140 mg / dl, is called IFG (impaired glycemia on an empty stomach).

The compound of the present invention can also be used as an agent for the prophylaxis or treatment of diabetes, borderline type condition, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glucose) as determined by the above new diagnostic indicators. In addition, the compound of the present invention can prevent the development of a borderline type disorder, impaired glucose tolerance, IFG (impaired fasting glucose) or IFG (impaired fasting glucose) in diabetes.

The compound of the present invention can also be used as an agent for the prophylaxis or treatment of, for example, diabetic complications [for example, neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (for example, respiratory infection, urinary tract infection, gastrointestinal infection, soft tissue infections of the skin, lower limb infection and the like), diabetic gangrene, xerostomia, hypacusia, cerebrovascular disorder , peripheral circulation disorder and the like], obesity, osteoporosis, cachexia (eg, tumor cachexia, tuberculous cachexia, diabetic cachexia, cachexia for blood disease, cachexia for endocrine disease, cachexia for infectious disease or cachexia due to acquired immune disease) liver, hypertension, polycystic ovary syndrome, kidney disease (e.g., diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal failure and the like), muscular dystrophy, myocardial infarction, angina pectoris, stroke (e.g. cerebral infarction, cerebral apoplexy), Alzheimer's disease, Parkinson's disease, fear, dementia, insulin resistance syndrome, metabolic syndrome, hyperinsulinemia caused by hyperinsulinemia of sensory impairment, tumors (e.g., leukemia, breast cancer, prostate cancer, skin cancer and the like), irritated bowel syndrome disease, acute or chronic diarrhea, inflammatory diseases (for example, chronic rheumatoid arthritis, deforming spondylitis, osteoarthritis, lumbago, gout, postoperative or traumatic inflammation, tumence, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including non-alcoholic steatreatitis, hepatitis) inflammatory bowel disease (including inflammatory bowel disease), ulcerative colitis, damage to the gastric mucosa (including damage to the gastric mucosa, causing my aspirin) and the like), a small injury to the intestinal mucosa, malabsorption, impaired testicular function, obesity syndrome of internal organs and the like.

The compound of the present invention can also be used to reduce the amount of internal fat, inhibit the accumulation of internal fat, improve glycometabolism, improve lipid metabolism, inhibit the production of oxidized LDL, improve metabolism of lipoproteins, improve metabolism in the coronary arteries, prevent and treat cardiovascular complications, prevent and treatment of complications of heart failure, reduction of blood balance, prevention and treatment of anovulation, prevention and treatment I have hypertrichosis, the prevention and treatment of hyperandrogenemia, improve pancreatic (β-cell) function, regenerate pancreatic β-cells, promote pancreatic β-cell regeneration, regulate appetite and the like.

The compound of the present invention can also be used for secondary prevention and prevention of the development of the above various diseases (for example, in the case of cardiovascular diseases such as myocardial infarction and the like).

The compound of the present invention is a glucose-dependent insulin secretion enhancing agent that selectively promotes insulin secretion in patients suffering from hyperglycemia (for example, patients with an fasting blood glucose of at least 126 mg / dl or when determining glucose tolerance by oral administration of 75 g glucose level after 2 hours at least 140 mg / dl, and the like). Thus, the compound of the present invention is useful as a safe means for preventing or treating diabetes with a low risk of insulin-induced vascular complications, induction of hypoglycemia and the like.

The compound of the present invention is also useful as a therapeutic agent for diabetes with an adverse reaction to sulfonylurea and has an excellent effect on insulin secretion and a hypoglycemic effect in diabetic patients in whom the sulfonylurea compounds and fast-acting insulin secretion enhancing agents are not sufficiently capable of providing an insulin secretion effect and therefore are not able to provide sufficient hypoglycemic effect.

As sulfonylurea, in this case, one can name a compound having a sulfonylurea skeleton or its derivative, such as tolbutuamide, glibenclamide, glyclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glibuzol and the like.

A quick-acting means of enhancing insulin secretion is a compound that promotes the secretion of insulin from pancreatic β-cells in the same way as sulfonylurea, although it does not have a sulfonylurea structure, such as clayides (e.g. repaglinide, senaglinide, nateglide, mitiglinide, their hydrate calcium salt, etc.) and the like.

The dose of the compound of the present invention varies depending on the subject of administration, route of administration, target disease, condition and the like, but the compound of the present invention as an active ingredient is prescribed in a unit dose, usually about 0.01-100 mg / kg body weight, preferably 0, 05-30 mg / kg body weight, more preferably 0.1-10 mg / kg body weight in the case of, for example, oral administration to adult diabetic patients. The indicated dose is preferably administered 1-3 times a day.

The compound of the present invention can be used in combination with such drugs as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipemic agent, an antihypertensive agent, an anti-obesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, a therapeutic agent for osteoporosis , remedy for dementia, remedy for improving erectile dysfunction, therapeutic agent for le incontinence or pollakiuria, a therapeutic agent for the treatment of dysuria and the like (hereinafter, such a drug is referred to as a combination drug). In this case, the time distribution of administration of the compound of the present invention and the combination drug is not limited. They can be administered to the subject of administration at the same time or alternately. In addition, the compound of the present invention and the combination drug can be administered as two types of drugs, each of which contains an active component, or as a single preparation containing both active components.

A suitable dose of the combination drug may be determined based on the clinically used dose. A suitable ratio of the compound of the present invention and the combination drug can be determined depending on the subject of administration, route of administration, target disease, condition, combination and the like. When, for example, the subject of administration is a human, the combination drug is used in an amount of 0.01-100 parts by weight per 1 part by weight of the compound of the present invention.

As a therapeutic agent for diabetes, insulin preparations can be mentioned (for example, animal insulin preparations extracted from the pancreas of a cow or a bull and a pig; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc-insulin; protamine-zinc-insulin; a fragment or derivative of insulin (e.g., INS-1, etc.), an oral preparation of insulin and the like), insulin sensitizers (e.g., pioglitazone or its salt (preferably hydrochloride), rosiglitazone or its salt (pr preferably maleate), reglixan (JTT-501), GI-262570, netoglitazone (MCC-555), YM-440, DRF-2593, BM-13.1258, KRP-297, R-119702, rivoglitazone (CS-011), FK -614, the compounds described in WO99 / 58510 (e.g., (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyamino] -4-phenylbutyric acid), the compounds described in WO01 / 38325, tezaglitazar (AZ-242), ragaglitazar (NN-622), muraglitazar (BMS-298585), ONO-5816, BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY -510929, balaglitazone (NN-2344), T-131 or its salt, THR-0921, etc.), PPARγ agonist, PPARγ antagonist, PPARγ / α double agonist, α-glucosidase inhibitors (e.g., voglibosis, acarbose, miglitol, emiglate, etc.), b iguanides (for example, phenformin, metformin, buformin or their salts (for example, hydrochloride, fumarate, succinate), etc.), insulin secretion enhancing agents [sulfonylurea (for example, tolbutamide, glibenclamide, glyclazide, chlorpropamide, tolazamide, acetohexamide glycopyramides, glimepiride, glipizide, glibuzole, etc.), repaglinide, senaglinide, nateglide, mitiglinide or their calcium salt hydrate], GPR40 agonist, GLP-1 receptor agonist [for example, GLP-1, GLP-1MR, NN-2211 , AC-2993 (exendin-4), BIM-51077, Aib (8.35) hGLP-1 (7.37) NH ₂ , CJC-1131], amylin agonists (eg, pramlintide, etc.), inhibitor s phosphotyrosine phosphatases (e.g. sodium vanadate, etc.), dipeptidyl peptidase IV inhibitors (e.g. NVP-DPP-278, PT-100, P32 / 98, LAF-237, P93 / 01, TS-021, MK-431, BMS-477118, etc.), β3 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.) , gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, etc.), SGLT inhibitors (sodium and glucose co-carrier) (e.g. T-1095, etc.), 11β- inhibitors hydroxysteroid dehydrogenase (e.g., BVT-3498, etc.), adiponectin or an agonist thereof, IKK inhibitors (e.g., AS -2868, etc.), drugs that increase resistance to leptin, somatostatin receptor agonists (compounds described in WO01 / 25228, WO03 / 42204, WO98 / 44921, WO98 / 45285, WO99 / 22735, etc.) glucokinase activators (e.g., Ro-28-1675) and the like.

Examples of a therapeutic agent for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, tsenrestat, tsopolrestat, minalrestat, fidarestat (SNK-860), CT-112, etc.), neurotrophic factors and drugs that increase them (e.g. NGF , NT-3, BDNF, neurotropin production and secretion promoters described in WO01 / 14372 (e.g. 4- (4-chlorophenyl) -2- (2-methyl-1-imiazolyl) -5- [3- (2-methylphenoxy ) propyl] oxazole, etc.) and the like), nerve regeneration stimulants (eg, Y-128, etc.), PKC inhibitors (eg, cutting mesylate Istaurine; LY-333531, etc.), AGE inhibitors (e.g., ALT946, pimagedin, piratoxanthin, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorine, pyridoxamine, etc.), reactive acceptors oxygen (e.g., thioctic acid, etc.), cerebral vasodilators (e.g., tiapride, mechiletine, etc.), somatostatin receptor agonists (BIM23190) and kinase-1 inhibitors that regulate apoptosis signal (ASK-1).

Examples of antihyperlipemic agents include statins, which are inhibitors of cholesterol synthesis (e.g., cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin and their salts (e.g. sodium salt, potassium salt, etc.) squalene synthase inhibitors (for example, the compounds described in WO97 / 10224, such as N - [[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3- dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic acid, etc.), fibrates (e.g. zafibrate, clofibrate, simfibrate, clinofibrate, etc.), ACAT inhibitors (e.g. avasimib, eflusimib, etc.), anion exchange resins (e.g., colestyramine, etc.), probucol, nicotinic acid-based drugs (e.g. nicomol, niceritrol and the like), ethyl glycosapentate, plant sterols (e.g., soysterol, γ-oryzanol, etc.) and the like.

Examples of an antihypertensive agent include angiotensin converting enzyme inhibitors (e.g. captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g. candesartan cilexetil, losartan, eprozartan, valzartan, telmisartan, irbesartan-1, (2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid, etc. .), calcium antagonists (e.g., manidipine, nifedipine, amplodipine, efonidipine, nicardipine, etc.), potassium channel activators (e.g., levkromakalim, L-27152, AL 0671, NIP-121, etc.), clonidine and the like.

Examples of anti-obesity agents include anti-obesity agents acting on the central nervous system (for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramone, dexamphetamine, mazindole, phenylpropanolamine, clobenzorex; MCH receptor antagonists (for example, SB-568849; SN; described in WO01 / 82925 and WO01 / 87834. etc.); antagonists of the neuropeptide Y (e.g. CP-422935 etc.); cannabinoid receptor antagonists (e.g. SR-141716, SR-147778, etc. d.); ghrelin antagonist; 11β-hydroxysteroid dihydrogenase inhibitors (e.g. BVT-3498 etc.) and the like), pancreatic lipase inhibitors (e.g., orlistat, ATL-962, etc.), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.), apetite-lowering peptides (e.g. leptin, CNTF (ciliary neurotropic factor), etc.), cholecystokinin agonists (e.g. lintitript, FPL-15849, etc.), a food moderation inhibitor (e.g., P-57, etc.) and the like.

Examples of a diuretic include xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine, etc.), thiazide preparations (e.g., etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutazidide and polit, .), anti-aldosterone preparations (e.g., spironolactone, triamteren, etc.), carbonate dehydratase inhibitors (e.g., acetazolamide and the like), chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruzide, indapamide, etc.), azosemide, isosorbide, ethacrylic acid, pyrethanide, bumetanide, furosemide and the like.

Examples of chemotherapeutic agents include alkylating agents (e.g. cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g. methotrexate, 5-fluorouracil or a derivative thereof, etc.), anti-tumor antibiotics (e.g. mitomycin, adriamycin, etc.). e.), anticancer drugs of plant origin (for example, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide and the like. Of these, furtulon and neofurtulon, which are derivatives of 5-fluorouracil and the like, are preferred.

Examples of an immunotherapeutic agent include a microorganism or bacterial components (for example, a derivative of muruamyldipeptide, picybanil, etc.), polysaccharides with potentiating immunity activity (for example, lentinan, sisofiran, christening, etc.), cytokines obtained by genetic engineering ( for example, interferon, interleukin (IL), etc.), colony stimulating factors (e.g. granulocyte colony stimulating factor, erythropoietin, etc.) and the like, of which interleukins are preferred, such as IL-1, IL-2, IL-12 and the like.

Examples of an antithrombotic agent include heparin (e.g., heparin-sodium, calcium heparin, dalteparin-sodium, etc.), warfarin (e.g., warfarin-potassium, etc.), antithrombin drugs (e.g., aragatroban, etc. e.), thrombolytic agents (e.g., urokinase, tizokinase, alteplase, nateplase, monteplase, pamiteplase, etc.), platelet aggregation inhibitors (e.g. ticlopidine hydrochloride, cilostazol, ethyl glycopentate, beraprost-sodium, hydrochloride tardaparde .) etc.

Examples of a therapeutic agent for osteoporosis include alfacalcidol, calcitriol, elcatonin, salcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium and the like.

Examples of anti-dementia drugs include tacrine, donepezil, rivastigmine, galantamine and the like.

Examples of agents for improving erectile dysfunction include apomorphine, sildenafil citrate and the like.

Examples of a therapeutic agent for incontinence or pollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.

Examples of a therapeutic agent for dysuria include acetylcholinesterase inhibitors (e.g., distigmine) and the like.

In addition, drugs created in animal models and in a clinical setting that have a cachexia-improving effect, such as cyclooxygenase inhibitors (e.g., indomethacin, etc.), progesterone derivatives (e.g., mesterol acetate, can be used in combination with the compound of the present invention. ), glucose steroid (e.g. dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs, drugs that improve fat metabolism (e.g. eicosapentaenoic acid, etc.), hormones p hundred, IGF-1 or antibodies to the cachexia-induced factor such as TNF-α, LIF, IL-6, oncostatin M and the like.

Preferably, the combination drug is an insulin preparation, an insulin sensitizer, an α-glucosidase inhibitor, biguanide, an insulin secretion enhancing agent (preferably sulfonylurea), and the like.

Two or more of the above combination drugs may be used in combination in an appropriate ratio. Preferred combinations in the case of using two or more combination drugs are, for example, such as shown below:

1) an agent that enhances insulin secretion (preferably sulfonylurea) and an α-glucosidase inhibitor;

2) an agent that enhances the secretion of insulin (preferably sulfonylurea), and biguanide;

3) an agent that enhances the secretion of insulin (preferably sulfonylurea), biguanide and an α-glucosidase inhibitor;

4) an insulin sensitizer and an α-glucosidase inhibitor;

5) insulin sensitizer and biguanide;

6) an insulin sensitizer, biguanide and an α-glucosidase inhibitor.

When a compound of the present invention is used in combination with combination drugs, their amount can be reduced within safe limits given the counteraction of said drugs. In particular, the dose of an insulin sensitizer, an agent that enhances the secretion of insulin (preferably sulfonylurea), and biguanide can be reduced compared to a normal dose. Thus, the side effect that may be caused by these agents can be reduced to a safe level. In addition, it is possible to reduce the dose of a therapeutic agent for diabetic complications, an antihyperlipemic agent and an antihypertensive agent, whereby a side effect that may be caused by said agents can be effectively prevented.

The following explains the methods of obtaining the compounds of the present invention.

The compound of the present invention can be obtained by a method known per se, such as the method described in detail below, or a similar method.

Compound (Ia), which is a compound of formula (I), where L is La-CH ₂ - (where La is a bond or a divalent hydrocarbon group), X is Xa (where Xa is a hydrogen atom, nitro group, acyl group , a substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted cyclic group) and R ⁴ represents an amino group, can be obtained by the following method A or a similar method.

As the “divalent hydrocarbon group” for La, there can be mentioned groups similar to the “divalent hydrocarbon groups” listed as examples for the above group L. Preferably, La is a bond or a C _1-9 alkylene group.

In addition, as the “acyl group”, “substituted hydroxy group”, “optionally substituted thiol group”, “optionally substituted amino group” and “optionally substituted cyclic group” for each Xa, the groups listed as examples for the above group X can be used .

When Xa is an ethoxycarbonyl group, Q is preferably a divalent hydrocarbon group.

[Method A]

where the characters are as defined above.

In this method, the compound is subjected to a reduction reaction to give compound (Ia).

The reduction reaction is carried out in the presence of a reducing agent in a solvent which does not adversely affect the reaction, in accordance with a conventional method.

As the reducing agent, for example, metal hydrides such as sodium bis (2-methoxyethoxy) aluminum hydride, diisobutyl aluminum hydride and the like; complexes with metal hydrides such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium aluminum hydride and the like; etc.

The amount of reducing agent used is usually 0.1-20 equivalents relative to compound (II).

As a solvent which does not adversely affect the reaction, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, tert-butanol and the like can be used; aromatic hydrocarbons such as benzene, toluene, xylene and the like; aliphatic hydrocarbons such as hexane, heptane and the like; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like; esters such as methyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate and the like; amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone and the like. These solvents can be used in a mixture of two or more kinds thereof, mixed in a suitable ratio.

The reaction temperature is usually from −70 ° C. to 150 ° C., preferably from −20 ° C. to 100 ° C.

The reaction time is usually 0.1-100 hours, preferably 0.1-40 hours.

The reduction reaction can also be carried out in the presence of a metal catalyst such as palladium on carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt and the like, and a hydrogen source in a solvent that is not has a harmful effect on the reaction.

The amount of metal catalyst used is usually 0.001-1000 equivalents, preferably 0.01-100 equivalents relative to compound (II).

As the source of hydrogen, for example, hydrogen gas, formic acid, an amine salt of formic acid, a salt of phosphinic acid, hydrazine and the like can be mentioned.

As a solvent that does not adversely affect the reaction, solvents used in the reduction reaction described above using a reducing agent can be mentioned.

The reaction temperature and reaction time are as described above for the reduction reaction using a reducing agent.

This reaction, if necessary, can be carried out in the presence of ammonia (for example, aqueous ammonia, a mixture of ammonia-ethanol and the like). When carrying out the reaction in the presence of ammonia, a side reaction can be suppressed and compound (Ia) can be obtained in high yield.

The compound (Ia) obtained in the described manner can be isolated and purified by known separation and purification methods, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Compound (II) used as a starting compound in method A described above can be prepared by a method known per se.

For example, compound (II-a), which is compound (II), where Q and La are a bond and Xa is an acyl group, can be obtained by the following method B.

[Method B]

where the characters are as defined above.

Compound (II-a) can be obtained by a method known per se, for example, by reacting (III) and an oxidizing agent, such as diluted nitric acid, diammonium cerium nitrate and the like, in a solvent that does not adversely affect the reaction, such as 1, 4-dioxane, acetone and the like.

Compound (III) can be prepared by a method known per se, for example from compound (IV) and compound (VII) according to the Hantzch pyridine synthesis method as described in “Shin Jikken Kagaku Kouza (The Chemical Society of Japan ed.) , Vol. 14, Synthesis and Reaction of Organic Compound IV, Maruzen (1978), page 2057, or a similar method.

Compound (IV) can be obtained by a method known per se, for example, by reacting compound (VI) and compound (V) according to the well-known Knoevenagel method.

Compound (VII) can be prepared by a method known per se, for example, from compound (VIII) by the method described in Synthesis (1999), vol. 11, pages 1951-1960; Journal of Chemical Society Perkin Transactions 1, (2002), pages 1663-1671, and the like, or in a similar manner.

The above compound (V), compound (VI) and compound (VIII) can be obtained by a method known per se.

Compound (Ib), which is a compound of formula (I), where R ⁴ is an amino group, mono - or disubstituted with a C _1-10 alkyl group, can be obtained by alkylation reaction of compound (I-c), which is a compound of formula (I) where R ⁴ represents an amino group.

The specified reaction is carried out (1) in the presence of a base, when necessary, using an alkylating agent in a solvent that does not adversely affect the reaction, or (2) in the presence of a reducing agent, when necessary, using a carbonyl compound in a solvent which does not adversely affect the reaction, in accordance with a known method.

As the alkylating agent in this case, for example, C _1-10 alkyl halide, C _1-10 alkyl sulfonate and the like.

As the carbonyl compound, for example, aldehydes, ketones and the like.

The amount of alkylating agent and carbonyl compound used is preferably from about 1 to about 5 equivalents relative to compound (Ic).

As the base, for example, alkali metal salts such as sodium hydroxide, potassium carbonate and the like; amines such as pyridine, triethylamine and the like; metal hydrides such as sodium hydride and the like; alkali metal alkoxides such as sodium methoxide, potassium tert-butoxide and the like, and the like.

The amount of base used is preferably from about 1 to about 5 equivalents relative to compound (Ic).

As the reducing agent, for example, metal hydrides such as diisobutylaluminum hydride and the like; complexes with metal hydrides such as sodium cyanoborohydride and the like, and the like.

The amount of reducing agent used is usually 0.1-20 equivalents relative to compound (Ic).

The reaction using the specified carbonyl compound can also be carried out in the presence of a metal catalyst, such as palladium on carbon and the like, and a hydrogen source, without a reducing agent, in a solvent that does not adversely affect the reaction.

The amount of metal catalyst used is preferably 0.01-100 equivalents relative to compound (Ic).

As the source of hydrogen, for example, hydrogen gas, formic acid, the amine salt of formic acid and the like can be mentioned.

As the “solvent which does not adversely affect the reaction” used for the alkylation reaction, for example, aromatic hydrocarbons such as toluene and the like; ethers such as tetrahydrofuran and the like; halogenated hydrocarbons such as chloroform and the like; amides such as N, N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like, and the like. These solvents can be used as a mixture of solvents mixed in an appropriate ratio.

The temperature of the alkylation reaction is preferably from about −10 ° C. to about 100 ° C.

The alkylation reaction time is usually from about 0.5 hours to about 20 hours.

The compound (I-b) obtained as described above can be isolated and purified by known separation and purification methods, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the preparation of a compound of the present invention, when the starting compound may contain an amino group, a carboxyl group, a hydroxy group or a carbonyl group as a substituent, a protecting group commonly used in peptide chemistry and the like can be introduced into these groups. Removal, when necessary, of the protective group after the reaction, the target compound can be obtained.

An amino protecting group includes, for example, a formyl group, a C _1-6 alkylcarbonyl group (e.g., acetyl, propionyl and the like), a C _1-6 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like), a benzoyl group, C _7-13 aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl and the like), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, a silyl group (e.g. trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-Buti dimethylsilyl, tert-butyldiethylsilyl and the like), C _2-6 alkenyl group (e.g., 1-allyl and the like) and the like. These groups are optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), a C _1-6 alkoxy group (e.g. methoxy, ethoxy, propoxy and the like), nitro group and the like.

A carboxy protecting group is, for example, a C ₁ -alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), a C _7-13 aralkyl group (e.g. benzyl and the like), a phenyl group a trityl group, a silyl group (e.g. trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like), a C _2-6 alkenyl group (e.g. 1-allyl and the like) and the like. These groups are optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), a C _1-6 alkoxy group (e.g. methoxy, ethoxy, propoxy and the like) or nitro group and the like.

The hydroxy protecting group is, for example, a C ₁ -alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), a phenyl group, a trityl group, a C _7-13 aralkyl group (e.g. benzyl and the like), formyl group, C _1-6 alkylcarbonyl group (e.g. acetyl, propionyl and the like), benzoyl group, C _7-13 aralkylcarbonyl group (e.g. benzylcarbonyl and the like), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl group (e.g. trimethylsilyl, t diethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like), a C _2-6 alkenyl group (e.g. 1-allyl and the like) and the like. These groups are optionally substituted with 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), a _C1-6 alkyl group (e.g. methyl, ethyl, propyl and the like), a _C1-6 alkoxy group ( for example, methoxy, ethoxy, propoxy and the like) or a nitro group and the like.

The carbonyl protecting group is, for example, cyclic acetal (e.g., 1,3-dioxane and the like), non-cyclic acetal (e.g., diC _1-6 alkylacetal and the like) and the like.

The introduction and removal of these protective groups can be carried out by a method known per se, for example, described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980), and the like. For example, a method is used using acid, base, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g. trimethylsilyl iodide, trimethylsilyl bromide and the like) and the like, reduction, and the like.

When a starting compound can form a salt in the preparation of a compound of the present invention, a compound in salt form can be used. As such a salt, the salts of compound (I) given above as examples can be used.

When compound (I) contains an optical isomer, a stereoisomer, a position isomer or a rotational isomer, they are also encompassed by compound (I) and can be obtained as a separate product by known methods of synthesis and separation. For example, when compound (I) contains an optical isomer, compound (I) also covers the optical isomer separated from it.

The optical isomer can be obtained by a method known per se. In particular, an optically active synthetic intermediate is used or the final racemic product is subjected to conventional optical resolution methods to give an optical isomer.

The optical separation method may be known per se, such as a fractional recrystallization method, a chiral column method, a diastereomeric method and the like.

1) The method of fractional recrystallization

A racemate salt with an optically active compound is formed (for example, (+) - mandelic acid, (-) - mandelic acid, (+) - tartaric acid, (-) - tartaric acid, (+) - 1-phenethylamine, (-) - 1-phenethylamine, cichonin, (-) - cichonidine, brucin and the like), which are separated by fractional recrystallization, and, if necessary, a free optical isomer is obtained by carrying out the neutralization step.

2) Chiral column method

The racemate or its salt is applied to a column to separate the optical isomer (chiral column) to allow separation. In the case of liquid chromatography, for example, a mixture with an optical isomer is applied to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or the CHIRAL series (manufactured by Daicel Chemical Industries, Ltd.) and the like, and elute with water, various buffer solutions (e.g., phosphate buffered saline) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine and the like) individually or in a mixture to separate the optical isomer. In the case of gas chromatography, for example, a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like are used for separation.

3) Diastereomeric method

The racemic mixture is converted by chemical reaction with an optically active reagent into a diastereomeric mixture, which is converted into a separate substance by a typical separation method (e.g., fractional recrystallization, chromatographic method and the like) and subjected to chemical treatment such as hydrolysis and the like to separate the optically active reagent resulting in an optical isomer. For example, when compound (I) contains a hydroxy group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (-) - methoxyacetic acid and the like ) and the like are subjected to a condensation reaction to obtain an ester form diastereomer or an amide form diastereomer, respectively. When compound (I) contains a carboxyl group, the compound and the reactant in the form of an optically active amine or optically active alcohol are subjected to a condensation reaction to obtain an amide form diastereomer or an ester form diastereomer, respectively. The separated diastereomer is converted into the optical isomer of the parent compound by acid or basic hydrolysis.

Compound (I) may be in the form of a crystal.

A crystal of compound (I) (hereinafter sometimes referred to as a crystal of the present invention) can be obtained by crystallization of compound (I) by a crystallization method known per se.

Examples of the crystallization method include crystallization from solution, crystallization from steam, crystallization from melt and the like.

“Crystallization from solution" is a typical method, which involves shifting an unsaturated state to a supersaturated state by changing factors characterizing the solubility of the compounds (solvent composition, pH, temperature, ionic strength, oxidation-reduction state, etc.), or the amount of solvent. In particular, one can name, for example, the concentration method, the annealing method, the reaction method (diffusion method, electrolysis method), hydrothermal growth method, flux method, and the like. Examples of the solvent used include aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc. .), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (e.g. acetonitrile, etc.), ketones (e.g. acetone, etc.), sulfoxides ( e.g. dimethyl sulfoxide, etc.), acid amides (e.g. N, N-dimethylformamide and the like), esters (n example, ethyl acetate, etc.), alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents are used individually or in combination of two or more solvents in a suitable ratio (for example, 1: 1-1: 100 (volume ratio)).

“Crystallization from steam” is, for example, an evaporation method (a sealed tube method, a gas flow method), a gas-phase reaction method, a chemical transport method, and the like.

“Melt crystallization” is, for example, the normal solidification method (Czockralski method, temperature gradient method, Bridgman method), zone melting method (zone alignment method, floating zone method), a special growing method (VLS method (П-Ж-Т), liquid phase epitaxy method) and the like.

Preferred examples of the crystallization method include a method comprising dissolving compound (I) in a suitable solvent (for example, alcohols such as methanol, ethanol, etc., and the like) at a temperature of 20-120 ° C and cooling the resulting solution to a temperature not higher than the dissolution temperature (for example, 0-50 ° C, preferably 0-20 ° C) and the like.

The crystals of the present invention thus obtained can be isolated, for example, by filtration and the like.

In this specification, the melting point is a melting point measured using, for example, a microfusion temperature measuring apparatus (Yanako, MP-500D or Buchi, B-545) or a DSC (differential scanning calorimeter) device (SEIKO, EXSTAR6000) and the like. .

Typically, the melting temperature varies depending on the measuring instruments, measurement conditions and the like. The crystal in this description may show different melting points given in this description, if only it was in the General error range.

The crystal of the present invention is excellent in physicochemical properties (e.g., melting point, solubility, stability, etc.) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), expression of potency, etc.) and very useful as a pharmaceutical.

Examples

The present invention is described in more detail with the following examples, experimental examples, and composition examples. These examples do not limit the present invention, which may be changed within the scope of the invention.

Abbreviations in the examples have the following meanings:

(c): singlet, (d): doublet, (t): triplet, (q): quartet, (m): multiplet, (broad s): wide singlet, J: interaction constant, 4-Mephenyl: 4-methylphenyl, 4-F-phenyl: 4-fluorophenyl, 2,6-di-F-phenyl: 2,6-difluorophenyl.

In the examples, room temperature means a temperature of 1-30 ° C. and% means a percentage by weight, unless otherwise indicated.

Example 1

Methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

1) A suspension of sodium hydride (60% in oil, 8.0 g, 0.2 mol) in tetrahydrofuran (80 ml) was heated under reflux with vigorous stirring. A mixture of methyl isovalerate (11.6 g, 0.1 mol), acetonitrile (10.5 ml, 0.2 mol) and tetrahydrofuran (25 ml) was added dropwise to the resulting suspension over 30 minutes, and the mixture was heated under reflux. for 5 hours. The reaction mixture was allowed to cool to room temperature and 2-propanol (5 ml) was added to it. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (100 ml) and washed successively with hexane and a mixed solution of hexane-diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-methyl-3-oxohexannitrile (12.6 g, 100% yield) as a yellow oil. The resulting yellow oil was used in the next step without further purification.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.05-2.30 (1H, m), 2.50 (2H, d, J = 7 , 0 Hz), 3.43 (2H, s).

2) A mixture of 5-methyl-3-oxohexannitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), piperidine (0.34 g, 4.0 mmol), acetic acid (0 , 48 g, 8.0 mmol) and toluene (200 ml) were heated at the boil under reflux for 12 h using a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methanol (50 ml). Methyl 3-aminocrotonate (4.6 g, 40 mmol) was added to the solution, and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain methyl 5-cyano -6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (7.45 g, yield 57%) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.80-2.00 ( 1H, m), 2.10-2.35 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 3.58 (3H, s), 4.57 (1H , s), 5.68 (1H, br s), 7.00-7.20 (4H, m).

3) Methyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (7.3 g, 22.5 mmol) was dissolved in 1,4- dioxane (20 ml), 2N was added to the solution. nitric acid (100 ml) and the mixture was stirred at 70 ° C for 1 hour. While stirring in an ice bath, ethyl acetate (100 ml) and 2N were added to the mixture. aqueous sodium hydroxide solution (100 ml). The aqueous layer was separated and extracted with ethyl acetate. The organic layer and the extract were combined, the mixture was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain methyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (5.94 g, 82% yield) as a white powder .

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.41 (3H, s), 2, 63 (3H, s), 2.95 (2H, d, J = 7.4 Hz), 3.60 (3H, s), 7.20-7.30 (4H, m).

4) A mixture of methyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.00 g, 3.10 mmol), Raney nickel (4 ml), 25% aqueous ammonia (6 ml), tetrahydrofuran (15 ml), methanol (45 ml) was stirred in a hermetically sealed tube in an atmosphere of hydrogen at 0.5 MPa at room temperature for 6 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a 10% aqueous potassium carbonate solution. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.97 g, 95% yield) as yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (2H, br.s), 2.15-2.30 (1H, m), 2.39 (3H, s), 2.53 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 3.50 (3H, s), 3.66 (2H, s ), 7.11 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz).

Mp: 56-57 ° C

Example 2

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride

1) To a solution of methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.90 g, 2.76 mmol) in tetrahydrofuran (25 ml) was added di-tert- butyl dicarbonate (0.76 ml, 3.31 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give methyl 5 - {[(tert-butoxycarbonyl) amino ] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.16 g, yield 98%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.10-2.30 (1H, m), 2, 39 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.50 (3H, s), 4.15 (2H, d, J = 4.9 Hz), 4.24 (1H, t, J = 4.9 Hz), 7.06 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7 9 Hz).

2) To a solution of methyl 5 - {[(tert-butoxycarbonnyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.0 g, 2.34 mmol) in methanol ( 30 ml) was added 1N. an aqueous solution of sodium hydroxide (10 ml) and the mixture was heated at the boil under reflux for 3 days. The reaction mixture was allowed to cool to room temperature, acidified with 0.5N. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from water-methanol to give 5 - {[(tert-butoxycarbonnyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.58 g, yield 60%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.87 (6H, d, J = 6.4 Hz), 1.39 (9H, s), 1.95-2.10 (1H, m), 2, 38 (3H, s), 2.67 (3H, s), 2.75 (2H, d, J = 7.2 Hz), 4.13 (2H, d, J = 4.7 Hz), 4, 30 (1H, t, J = 4.7 Hz), 7.15 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz).

3) To a solution of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.20 g, 0.48 mmol) in 1.4 dioxane (4 ml) was added 4N. A 1,4-dioxane solution of hydrogen chloride (4 ml, 16 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting white solid was washed with diisopropyl ether to give 5- (aminomethyl) -6 dihydrochloride -isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.18 g, 95% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.05-2.30 (1H, m), 2.38 (3H, s), 2.65 (3H, s), 3.02 (2H, s), 3.83 (2H, d, J = 5.5 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 8.45 (3H, br s).

Example 3

5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride

1) A mixture of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.11 g, 0.27 mmol), 1- ammonium salt hydroxy-1H-benzotriazole (0.10 g, 0.65 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.13 g, 0.65 mmol) and N, N-dimethylformamide (10 ml ) was stirred at room temperature for 2.5 days. The reaction mixture was partitioned between ethyl acetate (100 ml) and 0.1 M aqueous citric acid solution (50 ml). The organic layer and the extract obtained by extracting the aqueous layer with ethyl acetate were combined and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl {[5- (aminocarbonyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate ( 0.090 g, 82% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.10-2.30 (1H, m), 2, 39 (3H, s), 2.61 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.14 (2H, d, J = 4.7 Hz), 4, 15-4.30 (1H, broad s), 5.21 (1H, broad s), 7.11 (2H, d, J = 7.9 Hz), 7 23 (2H, d, J = 7.9 Hz).

2) 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride (0.050 g, 82% yield) was obtained as a white powder from tert-butyl {[5- (aminocarbonyl) - 2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.065 g, 0.16 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.05-2.30 (1H, m), 2.37 (3H, s), 2.66 (3H, s), 3.02 (2H, s), 3.82 (2H, d, J = 4.9 Hz), 7.20-7.35 (4H, m), 7.54 (1H, br.s), 7.84 (1H, br.s), 8.32 (3H, br.s).

Example 4

5- (Aminomethyl) -N- (3-amino-3-oxopropyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride

1) A mixture of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.12 g, 0.29 mmol), β-alaninamide hydrochloride (0.055 g, 0.44 mmol), 1-hydroxy-1H-benzotriazole (0.059 g, 0.44 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.084 g, 0.44 mmol), triethylamine (0.061 ml, 0.44 mmol) and N, N-dimethylformamide (5 ml) was stirred at room temperature for 14 hours. The reaction mixture was partitioned between ethyl acetate-tetrahydrofuran (1: 1, 100 ml) and 0.1 M aqueous citric acid solution (100 ml). The organic layer and the extract obtained by extracting the aqueous layer with ethyl acetate were combined and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl {[5 - [(3-amino-3-oxopropyl) amino] carbonyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.075 g, 54% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 1.98 (2H, t, J = 6.0 Hz) , 2.10-2.25 (1H, m), 2.38 (3H, s), 2.55 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 3, 36 (2H, q, J = 6.0 Hz), 4.11 (2H, d, J = 5.5 Hz), 4.23 (1H, br.s), 5.23 (1H, br.s ), 5.38 (1H, br.s), 6.22 (1H, t, J = 5.5 Hz), 7.09 (2H, d, J = 8.1 Hz), 7.19 (2H d, J = 8.1 Hz).

2) 5- (Aminomethyl) -N- (3-amino-3-oxopropyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride (0.048 g, 99%) was obtained as a white powder from tert-butyl {[5 - [(3-amino-3-oxopropyl) amino] carbonyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.050 g, 0 , 10 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.98 (2H, t, J = 6.7 Hz), 2.10-2, 25 (1H, m), 2.37 (3H, s), 2.57 (3H, s), 2.96 (2H, br.s), 3.09 (2H, q, J = 6.7 Hz ), 3.82 (2H, d, J = 5.3 Hz), 6.82 (1H, br.s), 7.21 (2H, d, J = 8.0 Hz), 7.27 (2H d, J = 8.0 Hz), 7.28 (1H, br.s), 8.24 (3H, br.s), 8.36 (1H, br.s).

Example 5

[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetonitrile

1) Suspension of methyl 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (3.4 g, 7.9 mmol) in toluene (80 ml) was cooled to -78 ° C and a toluene diisobutylammonium hydride solution (33 ml, 32 mmol) was added dropwise to it at 0.95 M over 15 minutes. After stirring at -78 ° C for 1.5 hours, the mixture was allowed to warm to 0 ° C and was further stirred for 30 minutes. Methanol (1 ml) and sodium sulfate 10-hydrate (10.2 g, 32 mmol) were successively added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.9 g, yield 60%) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.32 (9H, s), 2.13-2.25 (1H, m), 2, 42 (3H, s), 2.68 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 4.05 (2H, d, J = 4.7 Hz), 4, 19 (1H, br.s), 4.36 (2H, d, J = 5.7 Hz), 7.05 (2H, d, J = 7.9 Hz), 7.24-7.26 (2H , m).

2) A mixture of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.50 g, 1.3 mmol), triethylamine (0.35 ml, 2.5 mmol) and tetrahydrofuran (10 ml) were cooled to 0 ° C and methanesulfonyl chloride (0.22 g, 1.9 mmol) was added dropwise to it. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 ml) and potassium cyanide (0.41 g, 6.3 mmol) was added to the solution. The mixture was stirred at 60 ° C for 30 minutes. Ethyl acetate was added to the reaction mixture, the mixture was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate ( 0.36 g, yield 72%) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 43 (3H, s), 2.66 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 3.31 (2H, s), 4.07 (2H, d, J = 4.7 Hz), 7.04 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz).

3) Trifluoroacetic acid (5 ml) was added to tert-butyl {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.11 g 0.27 mmol) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetonitrile (0.084 g, 99% yield) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.22 (1H, m), 2.45 (3H, s), 2, 66 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 3.47 (2H, s), 3.74 (2H, br.s), 7.17 (2H, d , J = 7.8 Hz), 7.42 (2H, d, J = 7.8 Hz).

Example 6

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride

1) To a solution of tert-butyl {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.90 g, 2.2 mmol) in ethanol (20 ml) was added 2N. an aqueous solution of sodium hydroxide (5.5 ml, 11 mmol) and the mixture was heated under reflux for 2 hours. 6N was added. hydrochloric acid to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain tert-butyl {[5- (2-amino-2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0 25 g, 27% yield) as a colorless solid.

2) Trifluoroacetic acid (5 ml) was added to tert-butyl {[5- (2-amino-2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.25 g, 0.59 mmol) and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 4N was added to the residue. A 1,4-dioxane solution of hydrogen chloride (4 ml, 16 mmol) was added to the residue, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to obtain 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride (0.19 g, 81% yield) as white powder.

¹ H-NMR (CD ₃ OD) δ: 1.09-1.13 (6H, m), 2.09-2.22 (1H, m), 2.46 (3H, s), 2.77- 2.80 (3H, m), 3.00-3.09 (2H, m), 3.51-3.55 (2H, m), 4.08 (2H, br.s), 7.15- 7.22 (2H, m); 7.47 (2H, d, J = 8.1 Hz).

Example 7

Methyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate dihydrochloride

1) To a solution of tert-butyl {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.90 g, 2.2 mmol) in ethanol (20 ml) was added 2N. an aqueous solution of sodium hydroxide (5.5 ml, 11 mmol) and the mixture was heated at the boil under reflux for 1.5 days. 6N was added. hydrochloric acid to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in N, N-dimethylformamide (5 ml). Methyl iodide (0.65 g, 4.4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) were added to the solution, and the mixture was stirred at room temperature for 1 h. Ethyl acetate was added to the reaction mixture and the mixture was washed successively with water. and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain methyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] acetate (0.097 g, 10% yield) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.28 (1H, m), 2, 40 (3H, s), 2.49 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.36 (2H, s), 3.61 (3H, s), 4.04-4.05 (2H, m), 4.27 (1H, br.s), 6.98 (2H, d, J = 7.8 Hz), 7.23 (2H, d, J = 7.8 Hz).

2) Methyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate dihydrochloride (0.069 g, 76% yield) was obtained as a white powder from methyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (0.097 g, 0.22 mmol) in a manner similar to the method of example 2- 3).

¹ H-NMR (CD ₃ OD) δ: 1.09-1.13 (6H, m), 2.12-2.26 (1H, m), 2.47 (3H, s), 2.84 ( 3H, s), 3.12 (2H, d, J = 7.4 Hz), 3.29-3.31 (2H, m), 3.63 (3H, s), 4.08 (2H, s ), 7.19 (2H, d, J = 7.7 Hz), 7.48 (2H, d, J = 7.7 Hz).

Example 8

Ethyl (2E) -3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylate

1) To a solution of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.95 g, 4.9 mmol) manganese dioxide (4.9 g, 56 mmol) was added in tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 19 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.25 g, yield 65% ) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.21-2.35 (1H, m), 2, 43 (3H, s), 2.79 (3H, s), 2.82 (2H, d, J = 7.2 Hz), 4.15 (2H, d, J = 4.9 Hz), 4, 38 (1H, br s), 7.10 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 9.71 (1H, s).

2) To a solution of triethylphosphonoacetate (0.033 g, 1.5 mmol) in tetrahydrofuran (10 ml) was added sodium hydride (60% in oil, 0.060 g, 1.5 mmol) at 0 ° C and the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of tert-butyl {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.38 g, 0.98 mmol) in tetrahydrofuran (5 ml) and the mixture was stirred at room temperature for 45 minutes. Ethyl acetate was added to the reaction mixture, the mixture was washed successively with brine, saturated aqueous ammonium chloride and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain ethyl (2E) -3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] acrylate (0.44 g, 96% yield) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.23 (3H, t, J = 7.2 Hz), 1.39 (9H, s) , 2.16-2.27 (1H, m), 2.40 (3H, s), 2.64 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 4, 08-4.17 (4H, m), 4.21 (1H, br.s), 5.76 (1H, d, J = 16.4 Hz), 6.95 (2H, d, J = 8, 1 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.37 (1H, d, J = 16.4 Hz).

3) A mixture of ethyl- (2E) -3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylate (0 12 g, 0.25 mmol) and 4n. A 1,4-dioxane solution of hydrogen chloride (5 ml, 20 mmol) was stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate-tetrahydrofuran and saturated aqueous sodium hydrogen carbonate. The organic layer and the extract obtained by extracting the aqueous layer with ethyl acetate-tetrahydrofuran were combined and the mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl (2E) -3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylate (0.059 g, 64% yield).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.23 (3H, t, J = 7.2 Hz), 1.30 (2H, br. s), 2.18-2.33 (1H, m), 2.40 (3H, s), 2.63 (3H, s), 2.79 (2H, d, J = 7.1 Hz), 3.60 (2H, s), 4.13 (2H, q, J = 7.2 Hz), 5.76 (1H, d, J = 16.4 Hz), 7.01 (2H, d, J = 8.0 Hz), 7.24 (2H, d, J = 8.0 Hz), 7.39 (1H, d, J = 16.4 Hz).

Example 9

(2E) -3- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylic acid dihydrochloride

1) To a solution of ethyl- (2E) -3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylate ( 0.32 g, 0.69 mmol) in tetrahydrofuran (10 ml) was added 1N. aqueous sodium hydroxide solution (3.4 ml, 3.4 mmol) and the mixture was stirred at 60 ° C for 12 hours. The reaction mixture was acidified with 1N. hydrochloric acid and was extracted with ethyl acetate. The extracts were combined and the mixture was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give (2E) -3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylic acid (0.28 g, 93% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.4 Hz), 1.39 (9H, s), 2.10-2.20 (1H, m), 2, 39 (3H, s), 2.64 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 4.00-4.20 (2H, m), 4.34 (1H , br.s), 5.76 (1H, d, J = 16.4 Hz), 6.97 (2H, d, J = 7.5 Hz), 7.22 (2H, d, J = 7, 5 Hz), 7.41 (1H, d, J = 16.4 Hz).

2) Dihydrochloride (2E) -3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylic acid (0.077 g, 90% yield) was obtained as white powder from (2E) -3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylic acid (0.093 g , 0.21 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.10 (6H, d, J = 6.6 Hz), 2.12-2.27 (1H, m), 2.46 (3H, br.s) , 2.84 (3H, s), 3.05 (2H, d, J = 7.5 Hz), 4.13 (2H, s), 5.98 (1H, d, J = 16.3 Hz) 7.20 (2H, d, J = 8.0 Hz), 7.25 (1H, d, J = 16.3 Hz), 7.46 (2H, d, J = 8.0 Hz).

Example 10

(2E) -3- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylamide dihydrochloride

1) tert-Butyl {[5 - [(1E) -3-amino-3-oxoprop-1-en-1-yl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3- yl] methyl} carbamate (0.19 g, 99% yield) was obtained from (2E) -3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -methylphenyl) pyridin-3-yl] acrylic acid (0.19 g, 0.43 mmol) in a manner similar to the method of example 3-1).

¹ H-NMR (CD ₃ OD) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.09-2.20 (1H, m), 2 , 37 (3H, s), 2.59 (3H, s), 2.74 (2H, d, J = 7.2 Hz), 3.99 (2H, s), 4.34 (1H, br. s), 6.00 (1H, d, J = 16.2 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.22-7.28 (3H, m).

2) Dihydrochloride (2E) -3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylamide (0.078 g, 99% yield) was obtained from tert- butyl {[5 - [(1E) -3-amino-3-oxoprop-1-en-1-yl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.083 g, 0.19 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.11 (6H, d, J = 6.6 Hz), 2.13-2.22 (1H, m), 2.45 (3H, s), 2 87 (3H, s), 3.10 (2H, d, J = 7.5 Hz), 4.15 (2H, s), 6.12 (1H, d, J = 16.2 Hz), 7 11 (1H, d, J = 16.2 Hz), 7.23 (2H, d, J = 7.9 Hz), 7.45 (2H, d, J = 7.9 Hz).

Example 11

Methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4-phenylnicotinate

1) Methyl 5-cyano-6-isobutyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylate (10.7 g, 86% yield) was obtained as a white powder from 5-methyl-3 -oxohexannitrile (5.0 g, 40 mmol), benzaldehyde (4.2 g, 40 mmol) and methyl 3-aminocrotonate (4.6 g, 40 mmol) in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 1.82-1.97 ( 1H, m), 2.18-2.34 (2H, m), 2.38 (3H, s), 3.57 (3H, s), 4.61 (1H, s), 5.69 (1H , br.s), 7.18-7.32 (5H, m).

2) Methyl 5-cyano-6-isobutyl-2-methyl-4-phenylnicotinate (8.4 g, 80% yield) was obtained as a white powder from methyl 5-cyano-6-isobutyl-2-methyl-4 -phenyl-1,4-dihydropyridine-3-carboxylate (10.7 g, 34 mmol) in a manner similar to the method of example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.8 Hz), 2.21-2.35 (1H, m), 2.64 (3H, s), 2, 96 (2H, d, J = 7.2 Hz), 3.57 (3H, s), 7.33-7.39 (2H, m), 7.44-7.50 (3H, m).

3) Methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4-phenylnicotinate (0.21 g, yield 2.5%) was obtained as a white powder from methyl-5-cyano-6-isobutyl-2 methyl 4-phenylnicotinate (8.4 g, 27 mmol) in a manner similar to the method of example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.6 Hz), 2.17-2.33 (1H, m), 2.54 (3H, s), 2, 81 (2H, d, J = 7.4 Hz), 3.46 (3H, s), 3.65 (2H, s), 7.20-7.25 (2H, m), 7.38-7 46 (3H, m).

Example 12

Methyl 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate

1) A mixture of methyl 3-oxohexanoate (7.2 g, 50 mmol), ammonium acetate (19.3 g, 250 mmol), acetic acid (3.0 g, 50 mmol) and toluene (500 ml) was heated under reflux under reflux using a Dean-Stark trap for 11 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain methyl 3-aminohex-2-enoate as a colorless oil.

Methyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-propyl-1,4-dihydropyridine-3-carboxylate (11.8 g, 84% yield) was obtained as an oil from 5-methyl- 3-oxohexannitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the above colorless methyl 3-aminohex-2-enoate oil, in a manner similar to the method of Example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.93-1.05 (6H, m), 1.26 (3H, q, J = 7.2 Hz), 1.59-1.69 (2H, m ), 1.83-1.96 (1H, m), 2.23-2.47 (2H, m), 2.30 (3H, s), 2.69-2.74 (2H, m), 3.57 (3H, s), 4.58 (1H, s), 5.65 (1H, br.s), 7.09 (2H, d, J = 8.1 Hz), 7.13 (2H d, J = 8.1 Hz).

2) Methyl-5-cyano-6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (9.4 g, 80% yield) was obtained as an oil from methyl-5-cyano-6-isobutyl-4- (4-methylphenyl) -2-propyl-1,4-dihydropyridine-3-carboxylate (11.8 g, 33 mmol) in a manner similar to the method of example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.4 Hz), 1.01 (6H, d, J = 6.6 Hz), 1.73-1.85 ( 2H, m), 2.22-2.35 (1H, m), 2.41 (3H, s), 2.78 (2H, m), 2.96 (2H, d, J = 7.4 Hz ), 3.58 (3H, s), 7.23-7.32 (4H, m).

3) Methyl 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (0.78 g, 88% yield) was obtained as an oil from methyl 5-cyano-6-isobutyl- 4- (4-methylphenyl) -2-propylnicotinate (0.88 g, 2.6 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.94-0.99 (9H, m), 1.70-1.83 (2H, m), 2.18-2.31 (1H, m), 2 , 39 (3H, s), 2.69-2.74 (2H, m), 2.81 (2H, d, J = 7.2 Hz), 3.48 (3H, s), 3.65 ( 2H, s), 7.12 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).

Example 13

[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid dihydrochloride

1) To a solution of methyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (0.25 g, 0, 56 mmol) in tetrahydrofuran (15 ml) was added ethanol (10 ml) and 8N. an aqueous solution of sodium hydroxide (3.0 ml, 24 mmol) and the mixture was heated at the boil under reflux for 3 hours. The reaction mixture was acidified with 6n. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (0.16 g, yield 65%) as a white powder.

2) [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid dihydrochloride (0.15 g, 99% yield) was obtained as a white powder from [ 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (0.16 g, 0.36 mmol) in a similar manner the method of example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.10 (6H, d, J = 6.4 Hz), 2.09-2.25 (1H, m), 2.48 (3H, s), 2 84 (3H, s), 3.10 (2H, d, J = 7.4 Hz), 3.60 (2H, s), 4.09 (2H, s), 7.20 (2H, d, J = 7.9 Hz), 7.49 (2H, d, J = 7.9 Hz).

Example 14

Methyl 5- (aminomethyl) -6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) nicotinate

1) Dimethyl-3-aminopent-2-endioate was obtained from dimethyl-1,3-acetone dicarboxylate (7.0 g, 40 mmol) in a manner similar to the method of example 12-1).

Methyl 5-cyano-6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (11.5 g, 75% yield) was obtained in the form of a yellow oil from the obtained dimethyl-3-aminopent-2-endioate, 5-methyl-3-oxohexannitrile (5.0 g, 40 mmol) and p-tolualdehyde (4.8 g, 40 mmol).

¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.85-2.00 ( 1H, m), 2.20-2.40 (2H, m), 2.31 (3H, s), 3.58 (3H, s), 3.77 (3H, s), 3.85-4 10 (2H, m), 4.59 (1H, s), 7.01 (1H, br.s), 7.10 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz).

2) Methyl-5-cyano-6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) nicotinate (3.2 g, 28% yield) was obtained as a yellow-orange oil from methyl 5-cyano-6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (11.5 g, 30 mmol) in a similar manner the method of example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.41 (3H, s), 2, 97 (2H, d, J = 7.2 Hz), 3.54 (3H, s), 3.71 (3H, s), 4.04 (2H, s), 7.20-7.30 (4H , m).

3) Methyl 5- (aminomethyl) -6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) nicotinate (2.5 g, 77% yield) was obtained as a pale yellow oils from methyl 5-cyano-6-isobutyl-2- (2-methoxy-2-oxoethyl) -4- (4-methylphenyl) nicotinate (3.2 g, 8.4 mmol) in a manner similar to the method of example 1-4 )

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.39 (2H, br.s), 2.15-2.35 (1H, m), 2.39 (3H, s), 2.82 (2H, d, J = 7.4 Hz), 3.45 (3H, s), 3.67 (2H, s), 3.70 (3H, s ), 3.94 (2H, s), 7.05-7.25 (4H, m).

Example 15

Methyl 5- (aminomethyl) -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate

1) Methyl 5-cyano-4- (2,6-difluorophenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (14.8 g, 36% yield) was obtained as yellow crystals from 5-methyl-3-oxohexannitrile (15.0 g, 120 mmol), 2,6-difluorobenzaldehyde (17.0 g, 120 mmol) and methyl-3-aminocrotonate (13.8 g, 120 mmol) in a similar manner to the method Example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.05 (6H, m), 1.80-2.05 (1H, m), 2.10-2.45 (2H, m), 2 , 31 (3H, s), 3.56 (3H, s), 5.21 (1H, s), 5.87 (1H, br.s), 6.75-6.90 (2H, m), 7.05-7.25 (1H, m).

2) Methyl 5-cyano-4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (11.7 g, 80% yield) was obtained as yellow crystals from methyl 5-cyano-4- ( 2,6-difluorophenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (14.8 g, 43 mmol) in a manner similar to that of Example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 1.15 (6H, d, J = 6.6 Hz), 2.15-2.40 (1H, m), 2.72 (3H, s), 2, 97 (2H, d, J = 7.0 Hz), 3.65 (3H, s), 6.95-7.10 (2H, m), 7.35-7.55 (1H, m).

3) Methyl 5- (aminomethyl) -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (9.8 g, 83% yield) was obtained as a pale yellow solid from methyl 5- cyano-4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (11.7 g, 34 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.51 (2H, br.s), 2.15-2.35 (1H, m), 2.60 (3H, s), 2.83 (2H, d, J = 7.5 Hz), 3.56 (3H, s), 3.62 (2H, s), 6.95-7.05 (2H, m), 7.35-7.50 (1H, m).

Mp: 48-49 ° C

Example 16

Methyl 5- (aminomethyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate

1) Methyl 5-cyano-4- (4-fluorophenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (27.4 g, 70% yield) was obtained as a yellow oil from 5 methyl 3-oxohexannitrile (15.0 g, 120 mmol), 4-fluorobenzaldehyde (14.9 g, 120 mmol) and methyl 3-aminocrotonate (13.8 g, 120 mmol) in a manner similar to the method of example 1-2 )

2) Methyl 5-cyano-4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (24.0 g, 61% yield) was obtained as a yellow oil from methyl 5-cyano-4- (4- fluorophenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (27 g, 82 mmol) in a manner similar to that of Example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.15-2.40 (1H, m), 2.64 (3H, s), 2, 96 (2H, d, J = 7.2 Hz), 3.61 (3H, s), 7.10-7.40 (4H, m).

3) Methyl 5- (aminomethyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (11.2 g, 85% yield) was obtained as a pale yellow solid from methyl 5-cyano- 4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (13.0 g, 40 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.26 (2H, br.s), 2.15-2.35 (1H, m), 2.54 (3H, s), 2.81 (2H, d, J = 7.2 Hz), 3.51 (3H, s), 3.65 (2H, s), 7.00-7.30 (4H, m).

Mp: 55-57 ° C

Example 17

5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid dihydrochloride

1) Methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (0.71 g, 71% yield) was obtained as a white solid from methyl 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (0.78 g, 2.2 mmol) in a manner similar to that of Example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 0.94-0.99 (9H, m), 1.39 (9H, s), 1.70-1.83 (2H, m), 2.16-2 , 27 (1H, m), 2.38 (3H, s), 2.70-2.75 (2H, m), 2.79 (2H, d, J = 7.2 Hz), 3.48 ( 3H, s), 4.14 (2H, d, J = 4.9 Hz), 4.24 (1H, br.s), 7.06 (2H, d, J = 7.9 Hz), 7, 20 (2H, d, J = 7.9 Hz) .2)

2) 5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid (0.59 g, 86% yield) was obtained from methyl-5 - {[ (tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (0.71 g, 1.6 mmol) in a manner similar to that of Example 2-2).

¹ H-NMR (CDCl ₃ ) δ: 0.94-1.05 (9H, m), 1.39 (9H, s), 1.72-1.84 (2H, m), 2.12-2 22 (1H, m), 2.38 (3H, s), 2.81-2.92 (4H, m), 4.40-4.09 (2H, m), 7.20 (2H, d , J = 8.3 Hz), 7.26 (2H, d, J = 8.3 Hz).

3) 5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid dihydrochloride (0.50 g, 90% yield) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinic acid (0.59 g, 1.3 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.04-1.13 (9H, m), 1.76-1.91 (2H, m), 2.13-2.25 (1H, m), 2.44 (3H, s), 3.01-3.18 (4H, m), 4.20 (2H, br.s), 7.28-7.36 (2H, m), 7.43 ( 2H, d, J = 7.9 Hz).

Example 18

5- (Aminomethyl) -6-isobutyl-2-methyl-4-phenylnicotinic acid dihydrochloride

1) Methyl 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinate (9.4 g, 83% yield) was obtained as a white solid from methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4-phenylnicotinate (8.5 g, 27 mmol) in a manner similar to that of Example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.20 (1H, m), 2, 55 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 3.46 (3H, s), 4.14 (2H, d, J = 4.9 Hz), 4, 24 (1H, br s), 7.14-7.21 (2H, m), 7.37-7.44 (3H, m).

2) 5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinic acid (0.39 g, 40% yield) was obtained as a white solid from methyl 5- { [(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinate (1.0 g, 2.4 mmol) in a manner similar to that of Example 2-2).

3) 5- (Aminomethyl) -6-isobutyl-2-methyl-4-phenylnicotinic acid dihydrochloride (0.25 g, 86% yield) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4-phenylnicotinic acid (0.39 g, 0.98 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.04-1.15 (6H, m), 2.12-2.28 (1H, m), 2.78-2.89 (3H, m), 3.01-3.14 (2H, m), 4.13-4.20 (2H, m), 7.38-7.47 (2H, m), 7.56-7.63 (3H, m) )

Example 19

Methyl 5 - [(dimethylamino) methyl] -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

A mixture of methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.50 g, 1.6 mmol), formic acid (5 ml) and formalin (5 ml) was stirred at 100 ° C for 12 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5 - [(dimethylamino) methyl] -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.10 g, 19% yield).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.97 (6H, s), 2.14-2.28 (1H, m), 2, 39 (3H, s), 2.53 (3H, s), 2.89 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.48 (3H, s), 7.04 (2H, d, J = 8.0 Hz); 7.17 (2H, d, J = 8.0 Hz).

Example 20

Methyl 5- (aminomethyl) -2-methyl-6-isobutyl [4,4'-bipyridine] -3-carboxylate

1) Methyl 5-cyano-6-isobutyl-2-methyl-1,4-dihydro-4,4'-bipyridine-3-carboxylate (26.4 g, 71% yield) was obtained as a yellow oil from 5- methyl 3-oxohexannitrile (15.0 g, 120 mmol), isonicotinaldehyde (12.8 g, 120 mmol) and methyl 3-aminocrotonate (13.8 g, 120 mmol) in a manner similar to the method of Example 1-2).

2) To a solution of methyl 5-cyano-6-isobutyl-2-methyl-1,4-dihydro-4,4'-bipyridine-3-carboxylate (20 g, 64 mmol) in acetone (150 ml) was added diammonium cerium nitrate ( 45 g, 82 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 ° C and partitioned between ethyl acetate and 2N. sodium hydroxide. The organic layer and the extract obtained by extracting the aqueous layer with ethyl acetate were combined and the mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain methyl 5-cyano-6-isobutyl-2-methyl-4,4'-bipyridine-3-carboxylate (10.2 g, 51% yield) as yellow oil.

3) Methyl 5- (aminomethyl) -2-methyl-6-isobutyl [4,4'-bipyridine] -3-carboxylate (10.9 g, 72% yield) was obtained as a pale yellow solid from methyl- 5-cyano-6-isobutyl-2-methyl-4,4'-bipyridine-3-carboxylate (15.0 g, 48 mmol) in a manner similar to the method of example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.33 (2H, br.s), 2.15-2.40 (1H, m), 2.57 (3H, s), 2.82 (2H, d, J = 7.2 Hz), 3.49 (3H, s), 3.61 (2H, s), 7.15-7.25 (2H, m), 8.65-8.70 (2H, m).

Mp: 63-65 ° C

Example 21

Methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate

1) 5,5-Dimethyl-3-oxohexannitrile (92.0 g, 99% yield) was obtained as an oil from methyl 3,3-dimethylbutanoate (86.0 g, 0.66 mol) in a manner similar to that of Example 1- one).

¹ H-NMR (CDCl ₃ ) δ: 1.05 (9H, s), 2.49 (2H, s), 3.43 (2H, s).

2) A mixture of 5,5-dimethyl-3-oxohexannitrile (22.0 g, 158 mmol), p-tolualdehyde (19 g, 158 mmol), piperidine (1.3 g, 15.8 mmol), acetic acid (1 9 g, 31.6 mmol) and toluene (300 ml) were heated under reflux for 12 hours using a Dean-Stark trap. After allowing to cool to room temperature, the reaction mixture was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methanol (50 ml). Methyl 3-aminocrotonate (18.2 g, 158 mmol) was added to the solution, and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain methyl 5-cyano -2-methyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (23 g, 43% yield) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 0.98 (3H, d, J = 6.6 Hz), 1.80-2.00 (1H, m), 2, 14-2.41 (2H, m), 2.31 (3H, s), 2.37 (3H, s), 3.58 (3H, s), 4.57 (1H, s), 5.56 (1H, br s), 7.06-7.16 (4H, m).

3) Methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (12 g, 60% yield) was obtained as colorless crystals from methyl 5-cyano-2-methyl-4- ( 4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (20 g, 59.4 mmol) in a manner similar to that of Example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (9H, s), 2.41 (3H, s), 2.63 (3H, s), 3.01 (2H, s), 3.61 ( 3H, s), 7.26 (4H, m).

Mp: 139-140 ° C

4) Methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.3 g, 56% yield) was obtained as colorless crystals from methyl 5-cyano-2-methyl -4- (4-methylphenyl) -6-neopentylnicotinate (4 g, 11.9 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.44 (2H, br s), 2.39 (3H, s), 2.53 (3H, s), 2, 88 (2H, s), 3.50 (3H, s), 3.72 (2H, s), 7.12 (2H, m), 7.21 (2H, m).

Mp: 119-120 ° C

Example 22

5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride

1) To a solution of methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (1.0 g, 2.9 mmol) in tetrahydrofuran (25 ml) was added di-tert-butyl dicarbonate (0.65 g, 3.0 mmol) and the mixture was stirred at room temperature for 1 h. 8N was added to the reaction mixture. an aqueous solution of sodium hydroxide (2 ml) and methanol (10 ml) and the mixture was heated at the boil under reflux for 3 days. The reaction mixture was allowed to cool to room temperature, acidified with 1N. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether to give 5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (0.5 g, yield 42%) as crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.88 (9H, s), 1.36 (9H, s), 2.38 (3H, s), 2.72 (3H, s), 2.88 ( 2H, s), 4.21 (2H, br.s), 4.29 (1H, br.s), 7.18 (2H, d, J = 8.3 Hz), 7.23 (2H, d , J = 8.3 Hz).

Mp: 216-217 ° C

2) 4n. A 1,4-dioxane solution of hydrogen chloride (5 ml) was added to 5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (0.30 g, 0.7 mmol) and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure and the resulting white solid was washed with diethyl ether to give 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) dihydrochloride -6-neopentylnicotinic acid (0.2 g, 71% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.37 (3H, s), 2.59 (3H, s), 3.04 (2H, s), 3, 86 (2H, d, J = 5.5 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.24 ( 3H, broad s).

Example 23

tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinate

1) A mixture of tert-butyl acetoacetate (580 ml, 3.5 mol), 25% aqueous ammonia (1200 ml) and methanol (1000 ml) was stirred at room temperature for 14 hours. After concentration under reduced pressure, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl-3-aminocrotonate (550 g, 99% yield) as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.87 (3H, s), 4.46 (1H, s).

2) tert-Butyl 4- (4-chlorophenyl) -5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (7.6 g, yield 62%) was obtained as a white powder from 5-methyl-3-oxohexannitrile (4.0 g, 32 mmol), 4-chlorobenzaldehyde (4.5 g, 32 mmol) and tert-butyl-3-aminocrotonate (5.0 g, 32 mmol) in a similar manner to the method Example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 1.29 (9H, s) 1.80-1.95 (1H, m), 2.10-2.30 (2H, m), 2.34 (3H, s), 4.54 (1H, s), 5.56 (1H , broad s), 7.10-7.20 (2H, m), 7.25-7.30 (2H, m).

Mp: 185-186 ° C

3) To a solution of tert-butyl 4- (4-chlorophenyl) -5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (7.6 g, 20 mmol) in acetone (200 ml) was added an aqueous solution (40 ml) of diammonium cerium nitrate (27 g, 49 mmol) at room temperature over 5 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer and the extract obtained by extracting the aqueous layer with ethyl acetate were combined and the mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl 4- (4-chlorophenyl) -5-cyano-6-isobutyl-2-methylnicotinate (7.2 g, 95% yield) as white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.8 Hz), 1.27 (9H, s), 2.15-2.35 (1H, m), 2, 65 (3H, s), 2.94 (2H, d, J = 7.2 Hz), 7.30-7.35 (2H, m), 7.40-7.50 (2H, m).

Mp: 70-72 ° C

4) A mixture of tert-butyl 4- (4-chlorophenyl) -5-cyano-6-isobutyl-2-methylnicotinate (1.0 g, 2.6 mmol), Raney cobalt (4 ml), 25% aqueous ammonia ( 2 ml), tetrahydrofuran (20 ml) and methanol (40 ml) were stirred in a hermetically sealed tube in a hydrogen atmosphere at 0.5 MPa at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a 10% aqueous potassium carbonate solution. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl-5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinate (0.98 g, yield 97%) in in the form of a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.22 (9H, s), 1.42 (2H, br.s), 2.15- 2.30 (1H, m), 2.55 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 3.61 (2H, s), 7.21 (2H, d , J = 8.3 Hz), 7.41 (2H, d, J = 8.3 Hz).

Mp: 81-83 ° C

Example 24

5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinic acid hydrochloride

1) A mixture of tert-butyl-5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinate (0.60 g, 1.5 mmol) and trifluoroacetic acid (4 ml) was stirred at 50 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1,4-dioxane (4 ml). 4n A 1,4-dioxane solution of hydrogen chloride (4 ml, 16 mmol) was added to the resulting solution, and the mixture was concentrated under reduced pressure. The residue was washed with diisopropyl ether to give 5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride (0.63 g, 99% yield) as a colorless oil.

2) 5- (Aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride (0.63 g, 1.5 mmol) was dissolved in isopropanol (10 ml) and propylene oxide (0) was added to the solution 27 g, 4.6 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting oil was crystallized from isopropanol-diisopropyl ether to give 5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-methylnicotinic hydrochloride acid (0.43 g, 76%) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.49 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.75 (2H, s), 7.34 (2H, d, J = 7.5 Hz), 7.54 (2H, d, J = 7.5 Hz), 8.43 (1H, br s).

Example 25

tert-Butyl-5- (aminomethyl) -6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinate

1) To a solution of Meldrum acid (14.41 g, 0.1 mol) and pyridine (16.2 ml, 0.2 mol) in dichloromethane (100 ml) was added isobutyryl chloride (13.4 ml, 0.11 mol) dropwise ) at 0 ° C for 30 minutes and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was poured into 0.5N. hydrochloric acid and the mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of the obtained residue, tert-butanol (11.2 g, 150 mmol) and toluene (100 ml) was heated under reflux for 6 hours. After cooling to room temperature, the reaction mixture was washed with brine and dried over anhydrous sulfate. magnesium. The solvent was evaporated under reduced pressure to obtain tert-butyl-4-methyl-3-oxopentanoate as a crude product (9.31 g). A mixture of the crude product (9.31 g), 25% aqueous ammonia (100 ml) and methanol (100 ml) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl-3-amino-4-methylpent-2-enoate as a crude product (9.26 g).

2) tert-Butyl-5-cyano-6-isobutyl-2-isopropyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (12.11 g, 76% yield) was obtained as colorless crystals from 5-methyl-3-oxohexannitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (9.26 g) tert-butyl-3-amino-4-methylpent -2-enoate obtained in the above stage 1), in a manner similar to the method of example 1-2).

3) tert-Butyl-5-cyano-6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinate (2.88 g, 73% yield) was obtained as an oil from tert-butyl-5-cyano-6 isobutyl-2-isopropyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (3.94 g, 10 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.25 (9H, s), 1.32 (6H, d, J = 6.6 Hz) 2.26-2.35 (1H, m), 2.40 (3H, s), 2.94 (2H, d, J = 7.2 Hz), 3.14-3.23 (1H, m ), 7.26-7.35 (4H, m).

4) tert-Butyl-5- (aminomethyl) -6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinate (2.15 g, 77% yield) was obtained as a white powder from tert-butyl-5- cyano-6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinate (2.74 g, 7 mmol) in a manner similar to the method of example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.18 (9H, s), 1.30 (6H, d, J = 6.6 Hz) 1.39 (2H, br.s), 2.26-2.35 (1H, m), 2.39 (3H, s), 2.78 (2H, d, J = 6.9 Hz), 3.04-3.14 (1H, m), 3.60 (2H, s), 7.13 (2H, d, J = 8.2 Hz), 7.20 (2H, d, J = 8, 2 Hz).

Example 26

5- (aminomethyl) -6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinic acid dihydrochloride

5- (aminomethyl) -6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.37 g, 90% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) - 6-isobutyl-2-isopropyl-4- (4-methylphenyl) nicotinate (0.40 g, 1 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.03 (6H, d, J = 6.6 Hz), 2.23-2, 37 (4H, m), 2.85 (2H, d, J = 6.9 Hz), 3.04-3.13 (1H, m), 3.77 (2H, d, J = 5.4 Hz ), 7.22 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.21 (3H, br.s).

Example 27

tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2-methyl-6-neopentylnicotinate

1) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2-methyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (2.5 g, 38% yield) was obtained as a white powder from 5,5-dimethyl-3-oxohexannitrile (2.6 g, 18.0 mmol), 4-chlorobenzaldehyde (2.3 g, 16.0 mmol) and tert-butyl-3-aminocrotonate (2.5 g, 16.0 mmol) in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.29 (9H, s), 2.17 (1H, d, J = 13.9 Hz), 2.34 (3H, s), 2.35 (1H, d, J = 13.9 Hz), 4.55 (1H, s), 5.46 (1H, br.s), 7.10-7.35 (4H, m )

Mp: 208-210 ° C

2) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2-methyl-6-neopentylnicotinate (2.1 g, 90% yield) was obtained as a pale yellow powder from tert-butyl-4- ( 4-chlorophenyl) -5-cyano-2-methyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (2.4 g, 5.9 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (9H, s), 1.28 (9H, s), 2.65 (3H, s), 3.00 (2H, s), 7.30- 7.35 (2H, m); 7.45-7.50 (2H, m).

Mp: 94-95 ° C

3) tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2-methyl-6-neopentylnicotinate (0.93 g, yield 92%) was obtained as a white powder from tert-butyl-4- ( 4-chlorophenyl) -5-cyano-2-methyl-6-neopentylnicotinate (1.0 g, 2.5 mmol) in a manner similar to that of Example 23-4).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.22 (9H, s), 1.43 (2H, br s), 2.55 (3H, s), 2, 86 (2H, s), 3.66 (2H, s), 7.15-7.25 (2H, m), 7.35-7.45 (2H, m).

Mp: 116-118 ° C

Example 28

5- (aminomethyl) -4- (4-chlorophenyl) -2-methyl-6-neopentylnicotinic acid dihydrochloride

5- (aminomethyl) -4- (4-chlorophenyl) -2-methyl-6-neopentylnicotinic acid dihydrochloride (1.0 g, yield 98%) was obtained as a white powder from tert-butyl-5- (aminomethyl) -4 - (4-chlorophenyl) -2-methyl-6-neopentylnicotinate (0.95 g, 2.4 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.56 (3H, s), 2.94 (2H, s), 3.84 (2H, d, J = 5 5 Hz), 7.35-7.40 (2H, m), 7.55-7.60 (2H, m), 8.20 (3H, br.s).

Mp: 246-248 ° C

Example 29

tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinate

1) To a solution (30 ml) of piperidine (0.94 g, 11 mmol) and acetic acid (0.66 g, 11 mmol) in isopropanol was added dropwise a solution (300 ml) of 5,5-dimethyl-3-oxohexannitrile ( 17.0 g, 110 mmol) and p-chlorobenzaldehyde (15.5 g, 110 mmol) in isopropanol at room temperature for 30 minutes and the mixture was stirred for 3 days. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3- (4-chlorophenyl) -2- (3,3-dimethylbutanoyl) acrylonitrile as a crude product (35.2 g).

2) tert-Butyl-3-amino-5,5-dimethylhex-2-enoate was obtained as a crude product (13 g) from Meldrum acid (8.65 g, 60 mmol) and tert-butyl acetyl chloride (9.2 ml, 66 mmol) in a manner similar to the method of example 25-1).

3) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate (2.03 g, 15% yield) was obtained as a yellow oil from a crude the product (11.7 g) obtained in the above step 1), and the crude product (13.0 g) obtained in the above step 2), in a manner similar to the method of example 1-2). Namely, these two types of crude products were dissolved in methanol (40 ml) and the mixture was heated under reflux for 3.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl-4 - (4-chlorophenyl) -5-cyano-2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate.

¹ H-NMR (CDCl ₃ ) δ: 1.00 (9H, s), 1.03 (9H, s), 1.29 (9H, s), 2.24 (4H, s), 4.58 ( 1H, br.s), 5.37 (1H, br.s), 7.20-7.32 (4H, m).

4) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2,6-dineopentylnicotinate (0.75 g, 38% yield) was obtained from tert-butyl-4- (4-chlorophenyl) -5-cyano -2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate (2.03 g, 4.44 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.07 (9H, s), 1.24 (9H, s), 2.84 (2H, s), 3.00 ( 2H, s), 7.31 (2H, d, J = 8.67 Hz), 7.45 (2H, d, J = 8.67 Hz).

5) tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinate (0.35 g, 46% yield) was obtained as a pale yellow solid from tert-butyl-4- (4-chlorophenyl) -5-cyano-2,6-dineopentylnicotinate (0.75 g, 1.65 mmol) in a manner similar to that of Example 23-4).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.04 (9H, s), 1.18 (9H, s), 2.74 (2H, s), 2.86 ( 2H, s), 3.64 (2H, s), 7.21 (2H, d, J = 8.48 Hz), 7.40 (2H, d, J = 8.48 Hz).

Example 30

5- (aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinic acid dihydrochloride

5- (aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinic acid dihydrochloride (0.21 g, 69% yield) was obtained as a white solid from tert-butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2,6-dineopentylnicotinate (0.30 g, 0.653 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (9H, s), 1.03 (9H, s), 2.77 (2H, s), 2.91 (2H, s), 3.83 ( 2H, d, J = 5.65 Hz), 7.35 (2H, d, J = 8.48 Hz), 7.54 (2H, d, J = 8.29 Hz), 8.12 (2H, ears.s).

Example 31

5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid hemifumarate (sometimes referred to herein as bis [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) fumarate -6-neopentylnicotinic acid])

1) To a mixture of 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (5.99 g, 15.0 mmol), tetrahydrofuran (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml) benzyl chloroformate (95%, 2.48 ml, 16.5 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 2 hours and 0.1 M hydrochloric acid (100 ml) was added. The mixture was extracted with ethyl acetate-tetrahydrofuran (1: 1). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran to give 5 - ({[(benzyloxy) carbonyl] amino} methyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (5.57 g, 81%) as a colorless powder crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (9H, s), 2.33 (3H, s), 2.44 (3H, s), 2.70 (2H, s), 3, 97 (2H, d, J = 4.1 Hz), 4.98 (2H, s), 7.15-7.20 (4H, m), 7.27-7.42 (6H, m), 12 96 (1H, br s).

2) Mixture of 5 - ({[(benzyloxy) carbonyl] amino} methyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (5.5 g, 12 mmol), 5% palladium on carbon ( 11.0 g), tetrahydrofuran (100 ml) and ethanol (100 ml) were stirred overnight in a hydrogen atmosphere at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (2.46 g, 63%) as colorless powdery crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (9H, s), 2.33 (3H, s), 2.36 (3H, s), 2.76 (2H, s), 3, 56 (2H, s), 7.12-7.18 (4H, m).

3) 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (1.14 g, 3.50 mmol) and fumaric acid (0.203 g, 1.75 mmol) were dissolved in water (150 ml) when heated. The resulting aqueous solution was concentrated under reduced pressure. The residue was washed with ethanol and recrystallized from water to give 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid hemifumarate (0.902 g, 67%) as colorless powdery crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (9H, s), 2.34 (3H, s), 2.40 (3H, s), 2.77 (2H, s), 3, 65 (2H, s), 6.45 (1H, s), 7.14-7.21 (4H, m).

Example 32

tert-Butyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

1) tert-Butyl-5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (159 g, 27% yield) was obtained as a white solid from tert-butyl-3-aminocrotonate (253 g, 1.60 mol) by a method similar to that of Example 1-2). Then, tert-butyl-5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (40.8 g, 99% yield) was obtained as a yellow solid from tert-butyl-5-cyano- 6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (41.0 g, 112 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.9 Hz), 1.26 (9H, s), 2.21-2.32 (1H, m), 2, 41 (3H, s), 2.64 (3H, s), 2.93 (2H, d, J = 7.5 Hz), 7.18-7.32 (4H, m).

2) tert-Butyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (502 g, 96% yield) was obtained as a white solid from tert-butyl-5-cyano -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (515 g, 1.42 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.19 (9H, s), 2.13-2.31 (1H, m), 2, 39 (3H, s), 2.56 (3H, s), 2.79 (2H. D, J = 7.4 Hz), 3.64 (2H, br.s), 7.13 (2H, d , J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz).

Example 33

Dihydrochloride ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) acetic acid

1) To a solution (10 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (510 mg, 1.24 mmol) in N , N-dimethylformamide was added benzyl bromoacetate (568 mg, 2.48 mmol) and potassium carbonate (343 mg, 2.48 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 2- (benzyloxy) -2-oxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-methylphenyl) nicotinate (690 mg, 99% yield) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.26 (1H, m), 2, 36 (3H, s), 2.59 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.11-4.17 (2H, m), 4.22 (1H , br.s), 4.40 (2H, s), 5.16 (2H, s), 7.05 (2H, d, J = 8.1 Hz), 7.17 (2H, d, J = 7.9 Hz), 7.29-7.39 (5H, m).

2) Mixture of 2- (benzyloxy) -2-oxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (690 mg, 1.23 mmol), palladium on carbon (10%, dry) (132 mg, 0.124 mmol) and ethanol (10 ml) were stirred in a hydrogen atmosphere at room temperature for 30 min. After filtration, the solvent was evaporated under reduced pressure to obtain ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy ) acetic acid as a crude product (580 mg).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.37 (3H, s), 2.62 (3H, s), 2.81 (2H, d, J = 7.0 Hz), 4.11-4.17 (2H, m), 4.30 (1H, br.s), 4.36 (2H, s ), 7.06 (2H, d, J = 7.7 Hz), 7.19 (2H, d, J = 7.7 Hz).

3) Dihydrochloride ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) acetic acid (517 mg, 94% yield) was obtained as white powder from a crude product (580 mg) obtained in the above Step 2), in a manner similar to the method of Example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.11 (6H, d, J = 6.6 Hz), 2.15-2.27 (1H, m), 2.45 (3H, s), 2 94 (3H, s), 3.11 (2H, d, J = 7.5 Hz), 4.20 (2H, s), 4.50 (2H, s), 7.30 (2H, d, J = 8.1 Hz), 7.42 (2H, d, J = 7.9 Hz).

Example 34

2-amino-2-oxoethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

1) To a solution (10 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (500 mg, 1.22 mmol) in N , N-dimethylformamide, 2-iodoacetamide (673 mg, 3.64 mmol) and potassium carbonate (337 mg, 2.44 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2-amino-2-oxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (570 mg yield 99%) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.17-2.31 (1H, m), 2, 39 (3H, s), 2.57 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 4.13-4.18 (2H, m), 4.23 (1H , br.s), 4.40 (2H, s), 5.12 (2H, br.s), 7.12 (2H, d, J = 7.7 Hz), 7.25 (2H, d, J = 7.9 Hz).

2) 2-amino-2-oxoethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (370 mg, 82% yield) was obtained as an oil from 2-amino-2 -oxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (570 mg, 1.21 mmol) in a manner similar to the method of example 8-3) .

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.17-2.32 (1H, m), 2.40 (3H, s), 2, 57 (3H, s), 2.82 (2H, d, J = 7.2 Hz), 3.70 (2H, s), 4.39 (2H, s), 5.20 (2H, br.s ), 7.19 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 7.9 Hz).

Example 35

4-Ethoxy-4-oxobutyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) A mixture of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.41 g, 1.0 mmol), ethyl 4- bromobutyrate (0.21 g, 1.1 mmol), potassium carbonate (0.15 g, 1.1 mmol) and N, N-dimethylformamide (20 ml) were stirred at room temperature for 1 h and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 4-ethoxy-4-oxobutyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) nicotinate (0.45 g, yield 85%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.39 (9H, s) 1.55-1.70 (2H, m), 2.08 (2H, t, J = 7.5 Hz), 2.15-2.30 (1H, m), 2.38 (3H, s ), 2.54 (3H, s), 2.78 (2H, d, J = 7.3 Hz), 3.95 (2H, t, J = 6.2 Hz), 4.11 (2H, q , J = 7.2 Hz), 4.53 (2H, d, J = 5.3 Hz), 4.23 (1H, br.s), 7.07 (2H, d, J = 8.0 Hz ), 7.21 (2H, d, J = 8.0 Hz).

2) 4-Ethoxy-4-oxobutyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (0.12 g, 95% yield) was obtained as a white powder from 4 -ethoxy-4-oxobutyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.13 g, 0.25 mmol) in a similar manner the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.17 (3H, t, J = 7.2 Hz), 1.45-1, 60 (2H, m), 2.05 (2H, t, J = 7.4 Hz), 2.15-2.30 (1H, m), 2.36 (3H, s), 2.51 (3H , br.s), 2.85 (2H, t, J = 6.3 Hz), 3.82 (2H, d, J = 5.7 Hz), 3.92 (2H, t, J = 6, 3 Hz), 4.03 (2H, q, J = 7.2 Hz), 7.19 (2H, d, J = 7.9 Hz), 7.28 (2H, d, J = 7.9 Hz ), 8.21 (3H, br s).

Mp: 193-195 ° C

Example 36

4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) butanoic acid dihydrochloride

1) 4-Ethoxy-4-oxobutyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.30 g, 0.57 mmol ) was dissolved in ethanol (20 ml) and 1N was added. aqueous sodium hydroxide solution (4.0 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5N. hydrochloric acid (20 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting crude crystals were recrystallized from diisopropyl ether-ethyl acetate to give 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] carbonyl} hydroxy) butanoic acid (0.23 g, 82% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.4 Hz), 1.39 (9H, s), 1.55-1.70 (2H, m), 2, 12 (2H, t, J = 7.1 Hz), 2.15-2.30 (1H, m), 2.39 (3H, s), 2.75 (3H, br.s), 2.85 -3.20 (2H, m), 4.00 (2H, t, J = 6.2 Hz), 4.20 (2H, d, J = 3.6 Hz), 4.37 (1H, br. s), 7.10 (2H, d, J = 7.7 Hz), 7.26 (2H, d, J = 7.7 Hz).

2) 4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) butanoic acid dihydrochloride (0.20 g, 99% yield ) was obtained as a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy ) butanoic acid (0.20 g, 0.40 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.40-1.55 (2H, m), 2.00 (2H, t, J = 7.4 Hz), 2.15-2.30 (1H, m), 2.36 (3H, s), 2.52 (3H, br.s), 2.80-2.95 (2H, m), 3.83 (2H, d, J = 4.3 Hz), 3.92 (2H, t, J = 6.2 Hz), 7.20 (2H, d, J = 7.7 Hz) 7.29 (2H, d, J = 7.7 Hz); 8.29 (3H, br s).

Mp: 221-223 ° C

Example 37

Pyridin-2-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride

1) To a solution (15 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol) in N, N-dimethylformamide, 2- (bromomethyl) pyridine hydrobromide (0.92 g, 3.64 mmol) and potassium carbonate (66.9 mg, 4.84 mmol) were added and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain pyridin-2-ylmethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.20 g yield 98%) as a pale pink solid.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.25 (1H, m), 2, 35 (3H, s), 2.56 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 4.14 (2H, br.s), 4.25 (1H, br c), 5.06 (2H, s), 6.89 (1H, d, J = 7.7 Hz), 7.06 (2H, d, J = 7.9 Hz), 7.13 (2H d, J = 7.9 Hz), 7.17-7.22 (1H, m), 7.57 (1H, t, J = 7.7 Hz), 8.52 (1H, d, J = 4.7 Hz).

2) Pyridin-2-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride (1.22 g, 99% yield) was obtained as a pale pink solid from pyridin-2-ylmethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.20 g, 2.38 mmol) in a similar manner to the method Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.4 Hz), 2.17-2.28 (1H, m), 2.34 (3H, s), 2.61 (3H, s), 2.94 (2H, d, J = 6.8 Hz), 3.81 (2H, d, J = 4.9 Hz), 5.20 (2H, s), 7.19 (4H, s), 7.23 (1H, br.s), 7.62-7.66 (1H, m), 8.06 (1H, t, J = 7.9 Hz), 8 39 (3H, br s), 8.68 (1H, d, J = 4.9 Hz).

Example 38

2-Ethoxy-1-methyl-2-oxoethyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate dihydrochloride

1) 2-Ethoxy-1-methyl-2-oxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.35 g, yield 56%) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (0.5 g, 1.2 mmol) and ethyl 2-bromopropionate (0.43 g, 2.4 mmol) in a manner similar to that of Example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.11 (3H, d, J = 7.0 Hz), 1.25 (3H, t, J = 7.1 Hz) 1.37 (9H, s), 2.38 (3H, s), 2.62 (3H, d, J = 4.9 Hz), 2.83-2.93 (2H, m), 4, 17 (2H, q, J = 7.0 Hz), 4.21 (3H, s), 4.82 (1H, q, J = 7.1 Hz), 7.04-7.12 (2H, m ), 7.19-7.21 (2H, m).

2) 2-Ethoxy-1-methyl-2-oxoethyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate dihydrochloride (0.16 g, 85% yield) was obtained as white powder from 2-ethoxy-1-methyl-2-oxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.2 g, 0 , 38 mmol) in a manner similar to the method of example 22-2).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 1.06 (3H, d, J = 7.0 Hz), 1.16 (3H, t, J = 7.1 Hz), 2.37 (3H, s), 2.58 (3H, s), 2.95 (2H, s), 3.88 (2H, s), 4.11 (2H, q, J = 7 , 0 Hz), 4.77 (1H, q, J = 7.1 Hz), 7.13-7.16 (1H, m), 7.23-7.32 (3H, m), 8.24 (3H, s).

Example 39

(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate dihydrochloride

1) (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6 -neopentylnicotinate (0.9 g, 73% yield) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (1 , 0 g, 2.3 mmol) and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (0.42 g, 2.8 mmol) in a manner similar to the method of example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.36 (9H, s), 1.97 (3H, s), 2.39 (3H, s), 2.53 ( 3H, s), 2.88 (2H, s), 4.16 (3H, s), 4.74 (2H, s), 7.02 (2H, d, J = 7.8 Hz), 7, 17 (2H, d, J = 7.8 Hz).

2) To a solution (2 ml) of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- ( 4-methylphenyl) -6-neopentylnicotinate (0.8 g, 1.5 mmol) in ethyl acetate was added 4N. an ethyl acetate solution of hydrogen chloride (8 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting white solid was recrystallized from methanol-ethyl acetate to give dihydrochloride (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.6 g, yield 77%) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (9H, s), 1.99 (3H, s), 2.34 (3H, s), 2.52 (3H, s), 2, 93 (2H, s), 3.83 (2H, d, J = 5.5 Hz), 4.93 (2H, s), 7.13 (2H, d, J = 7.9 Hz), 7, 20 (2H, d, J = 7.9 Hz), 8.18 (3H, s).

Example 40

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid hemifumarate (sometimes referred to herein as bis [5- (aminomethyl) -6-isobutyl-2-methyl-4- fumarate (4-methylphenyl) nicotinic acid])

1) A mixed solution of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (53.7 g, 130 mmol) and 4N. A 1,4-dioxane solution of hydrogen chloride (400 ml) was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and washed with diisopropyl ether (200 ml). The resulting white solid was dissolved in isopropanol (500 ml) and the mixture was stirred at 50 ° C for 30 minutes. The resulting mixture was allowed to cool to room temperature and the mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and washed with propanol (50 ml) to obtain 5- (aminomethyl) dihydrochloride propane-2-solvate (1: 1) ) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (46.5 g, 80% yield) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.04 (6H, d, J = 6.0 Hz), 2.16-2, 27 (1H, m), 2.37 (3H, s), 2.58 (3H, s), 2.90 (2H, d, J = 7.0 Hz), 3.73-3.86 (3H , m), 7.23 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 7.9 Hz), 8.26 (3H, br.s).

2) The propan-2-ol solvate (1: 1) of 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid hydrochloride (35.6 g, 80 mmol) was suspended in water ( 80 ml) and 1N was added. aqueous sodium hydroxide solution (160 ml, 160 mmol) at room temperature. The mixture was stirred for 1 h. The precipitated solid was collected by filtration and washed with ethanol (10 ml) to obtain 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (13.3 g, yield 53%) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (6H, d, J = 6.8 Hz), 2.14-2.25 (1H, m), 2.34 (3H, s), 2.38 (3H, s), 2.70 (2H, d, J = 7.2 Hz), 3.49 (2H, s), 7.14-7.20 (4H, m).

3) 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (15.4 g, 49.3 mmol) was suspended in water (400 ml) and the mixture was heated under reflux with stirring for 30 minutes. Fumaric acid (3.43 g, 29.6 mmol) was added to the resulting suspension and the mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and the filtrate was washed with water (50 ml) to obtain 5- (aminomethyl hemifumarate) ) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (13.9 g, yield 76%) as white crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (6H, d, J = 6.6 Hz), 2.26-2.28 (1H, m), 2.35 (3H, s), 2.42 (3H, s), 2.72 (2H, d, J = 7.2 Hz), 3.55 (2H, s), 6.49 (1H, s), 7.17 (2H, d , J = 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz).

Example 41

3- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionamide dihydrochloride

Mixture of tert-butyl {[5 - [(1E) -3-amino-3-oxoprop-1-en-1-yl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl ] methyl} carbamate (97.6 mg, 0.223 mmol), 10% palladium on carbon (24 mg, 0.0223 mmol) and ethanol (5 ml) were stirred under a hydrogen atmosphere at room temperature for 16 hours. After filtration, the solvent was evaporated under reduced pressure to obtain tert-butyl {[5- (3-amino-3-oxopropyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate as a crude product . The crude product was dissolved in 4n. A 1.4-dioxane solution of hydrogen chloride (10 ml) and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained white solid was washed with diisopropyl ether to obtain 3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionamide dihydrochloride (72, 7 mg, yield 79%) as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.09 (6H, d, J = 6.2 Hz), 2.07-2.19 (1H, m), 2.24-2.29 (2H, m), 2.48 (3H, s), 2.84 (2H, t, J = 7.8 Hz), 2.90 (3H, s), 3.06 (2H, d, J = 7.7 Hz), 4.04 (2H, s), 7.29 (2H, d, J = 7.9 Hz), 7.50 (2H, d, J = 7.7 Hz).

Example 42

Ethyl 3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionate dihydrochloride

1) A mixture of ethyl- (2E) -3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acrylate (700 mg, 1.50 mmol), 10% palladium on carbon (160 mg, 0.15 mmol) and ethanol (15 ml) were stirred in a hydrogen atmosphere at room temperature for 1 h. After filtration, the solvent was evaporated under reduced pressure and the obtained residue purified by silica gel column chromatography to obtain ethyl 3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionate (480 mg, 68% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.18 (3H, t, J = 7.2 Hz), 1.38 (9H, s) , 2.11-2.30 (3H, m), 2.40 (3H, s), 2.57 (3H, s), 2.62-2.68 (2H, m), 2.72 (2H d, J = 7.4 Hz), 3.96-4.07 (4H, m), 4.18 (1H, br.s), 6.98 (2H, d, J = 7.91), 7.24 (2H, d, J = 7.9 Hz).

2) Ethyl 3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionate dihydrochloride (58.3 mg, 85% yield) was obtained as white powder from ethyl 3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionate (73.0 mg, 0.156 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.08 (6H, d, J = 6.6 Hz), 1.17 (3H, t, J = 7.2 Hz), 2.08-2.21 (1H, m), 2.34-2.39 (2H, m), 2.48 (3H, s), 2.82-2.85 (2H, m), 2.88 (3H, s), 3.05 (2H, d, J = 7.5 Hz), 4.00-4.07 (4H, m), 7.27 (2H, d, J = 7.9 Hz), 7.50 (2H d, J = 7.9 Hz).

Example 43

3- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionic acid dihydrochloride

1) To a mixed solution (10 ml) of ethyl 3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionate (407 mg, 0.868 mmol) in tetrahydrofuran was added 1N. aqueous sodium hydroxide solution (4.30 ml, 4.30 mmol) and the mixture was stirred at 50 ° C for 5 hours. The reaction mixture was neutralized with 6N hydrochloric acid (0.8 ml) and was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] propionic acid (255 mg, 60% yield) as a yellow powder.

¹ H-NMR (CD ₃ OD) δ: 1.04 (6H, d, J = 6.6 Hz), 2.05-2.17 (1H, m), 2.26-2.36 (2H, m), 2.44 (3H, s), 2.75-2.87 (5H, m), 2.97 (2H, d, J = 7.5 Hz), 4.05 (2H, s), 7.17 (2H, d, J = 8.1 Hz); 7.40 (2H, d, J = 7.7 Hz).

2) 3- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionic acid dihydrochloride (94.2 mg, 97% yield) was obtained as a white powder from 3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propionic acid (100 mg, 0.234 mmol) in a similar manner the method of example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.09 (6H, d, J = 6.6 Hz), 2.09-2.22 (1H, m), 2.30-2.38 (2H, m), 2.48 (3H, s), 2.80-2.88 (2H, m), 2.90 (3H, s), 3.05 (2H, d, J = 7.5 Hz), 4.05 (2H, s), 7.26 (2H, d, J = 7.9 Hz), 7.51 (2H, d, J = 8.1 Hz).

Example 44

2- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylpyridin-3-yl] acetamide

1) tert-Butyl {[5- (hydroxymethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate (1.40 g, 60% yield) was obtained as a pale of pink powder from methyl 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-propylnicotinate (2.50 g, 5.50 mmol) in a manner similar to the example method 5-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.02 (3H, d, J = 7.4 Hz), 1.38 (9H, s) 1.73-1.86 (2H, m), 2.14-2.28 (1H, m), 2.41 (3H, s), 2.76 (2H, d, J = 7.2 Hz ), 2.88-2.93 (2H, m), 4.04 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 4.36 (2H, d, J = 5.8 Hz), 7.06 (2H, d, J = 7.9 Hz), 7.26 (2H, d, J = 7.35 Hz).

2) tert-Butyl {[5- (cyanomethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate (0.82 g, 67% yield) was obtained as an oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate (1.20 g, 2.81 mmol) in a manner similar to the example method 5-2).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.05 (3H, t, J = 7.4 Hz), 1.38 (9H, s) , 1.78-1.90 (2H, m), 2.18-2.27 (1H, m), 2.43 (3H, s), 2.77 (2H, d, J = 7.4 Hz ), 2.81-2.86 (2H, m), 3.33 (2H, s), 4.05-4.06 (2H, m), 4.20 (1H, br.s), 7, 05 (2H, d, 7.9 Hz), 7.30 (2H, d, J = 7.7 Hz),

3) tert-Butyl {[5- (2-amino-2-oxoethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate (814 mg, 95% yield) obtained as a white powder from tert-butyl {[5- (cyanomethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate (0.82 g, 1.88 mmol ) in a manner similar to the method of example 6-1).

¹ H-NMR (CD ₃ OD) δ: 0.98-1.05 (9H, m), 1.38 (9H, s), 1.66-1.77 (2H, m), 2.08- 2.19 (1H, m), 2.39 (3H, s), 2.76-2.80 (4H, m), 3.37 (2H, s), 3.92-3.97 (2H, m), 4.59 (1H, br.s), 7.70 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 7.7 Hz).

4) 2- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-propylpyridin-3-yl] acetamide (31 mg, 10% yield) was obtained as an oil from tert-butyl {[ 5- (2-amino-2-oxoethyl) -2-isobutyl-4- (4-methylphenyl) -6-propylpyridin-3-yl] methyl} carbamate (300 mg, 0.84 mmol) in a manner similar to the method of example 8- 3).

¹ H-NMR (CD ₃ OD) δ: 0.99 (6H, d, J = 6.6 Hz), 1.01 (3H, t, J = 7.4 Hz), 1.63-1.71 (2H, m), 2.04-2.18 (1H, m), 2.40 (3H, s), 2.71-2.76 (2H, m), 2.79 (2H, d, J = 7.4 Hz), 3.33 (2H, s), 3.53 (2H, s), 7.11 (2H, d, J = 7.9 Hz), 7.30 (2H, d, J = 7.9 Hz).

Example 45

tert-Butyl-5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) nicotinate

1) tert-Butyl-3-amino-5-methylhex-2-enoate was obtained as a crude product (10 g) from Meldrum acid (14.41 g, 100 mmol) and isovaleryl chloride (11.5 ml, 110 mmol) by the method similar to the method of example 25-1).

2) tert-Butyl-5-cyano-2,6-diisobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (12.11 g, 74% yield) was obtained as an oil from 5- methyl 3-oxohexannitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (9.96 g) obtained in the above step 1), in a manner similar to the method of example 1 -2).

3) tert-Butyl-5-cyano-2,6-diisobutyl-4- (4-methylphenyl) nicotinate (3.39 g, 83% yield) was obtained from tert-butyl-5-cyano-2,6-diisobutyl- 4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.09 g, 10 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.00 (6H, d, J = 6.6 Hz), 1.23 (9H, s) , 2.19-2.33 (1H, m), 2.41 (3H, s), 2.76 (2H, d, J = 7.5 Hz), 2.94 (2H, d, J = 7 , 2 Hz), 7.20-7.35 (4H, m).

4) tert-Butyl-5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) nicotinate (2.85 g, 86% yield) was obtained as an oil from tert-butyl-5-cyano-2 , 6-diisobutyl-4- (4-methylphenyl) nicotinate (3.25 g, 8 mmol) in a manner similar to the method of example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.6 Hz), 0.97 (6H, d, J = 6.6 Hz), 1.17 (9H, s) 1.38 (2H, br.s), 2.16-2.30 (2H, m), 2.39 (3H, s), 2.67 (2H, d, J = 7.5 Hz), 2.79 (2H, d, J = 7.2 Hz), 3.62 (2H, s), 7.13 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).

Example 46

5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride

5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.39 g, 92% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -2, 6-diisobutyl-4- (4-methylphenyl) nicotinate (0.41 g, 1 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (6H, d, J = 6.6 Hz), 0.96 (6H, d, J = 6.6 Hz), 2.16-2, 29 (2H, m), 2.37 (3H, s), 2.68 (2H, d, J = 7.2 Hz), 2.88 (2H, d, J = 7.2 Hz), 3, 79 (2H, d, J = 5.1 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 8.12 ( 3H, broad s).

Example 47

({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine p-toluenesulfonate

1) To a suspension of sodium p-toluenesulfinate (9.0 g, 50.5 mmol) in ethanol (50 ml) was added dropwise bromoacetone (6.92 g, 50.5 mmol). The resulting mixture was heated under reflux for 30 minutes, allowed to cool to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1 - [(4-methylphenyl) sulfonyl] acetone (8.0 g, 75% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.46 (3H, s), 4.14 (2H, s), 7.37 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

2) A mixture of 1 - [(4-methylphenyl) sulfonyl] acetone (2.0 g, 9.4 mmol), p-tolualdehyde (1.14 g, 9.4 mmol), piperidine (0.093 ml, 0.94 mmol) ), acetic acid (0.11 ml, 1.9 mmol) and toluene (100 ml) were heated under reflux using a Dean-Stark trap for 3 hours. The reaction mixture was allowed to cool to room temperature, washed with saturated solution salts and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4- (4-methylphenyl) -3 - [(4-methylphenyl) sulfonyl] but-3-en-2-one as a crude product (3.5 g).

3) A mixture of 5-methyl-3-oxohexannitrile (14.3 g, 100 mmol), acetic acid (6.0 g, 10 mmol), ammonium acetate (38.5 g, 500 mmol) and toluene (200 ml) was heated at reflux, using a Dean-Stark trap, for 17 hours. The reaction mixture was allowed to cool to room temperature, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 3-amino-5-methylhex-3-ennitrile as a mixture (8.2 g). The mixture (0.65 g) and the crude product (1.7 g) obtained in the above Step 2) were dissolved in ethanol (50 ml) and the mixture was heated under reflux for 12 hours. The reaction mixture was concentrated under reduced temperature. pressure and the obtained residue was purified by silica gel column chromatography to obtain 2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] -1,4-dihydropyridin-3-carbonitrile (1, 3 g, 64% yield) as a white powder.

EIMC (M + 1): 421

4) 2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] nicotinonitrile (0.77 g, 68% yield) was obtained as a white powder from 2-isobutyl-6 -methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] -1,4-dihydropyridin-3-carbonitrile (1.13 g, 2.7 mmol) in a manner similar to the method of example 23-3) .

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.38 (3H, s), 2, 39 (3H, s), 2.91 (2H, d, J = 7.2 Hz), 3.07 (3H, s), 6.86 (2H, d, J = 8.1 Hz), 7, 08 (4H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz).

Mp: 129-131 ° C

5) ({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.64 g, yield 93%) was obtained as a colorless oil from 2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] nicotinonitrile (0.69 g, 1.6 mmol) in a manner similar to the method of Example 1-4 )

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.41 (2H, br.s), 2.20-2.35 (1H, m), 2.38 (6H, s), 2.79 (2H, d, J = 7.2 Hz), 2.96 (3H, s), 3.40 (2H, s), 6.76 (2H, d , J = 8.1 Hz), 7.03 (2H, d, J = 8.3 Hz), 7.09 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.3 Hz).

6) To a solution of ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.64 g, 1.5 mmol) in ethanol (5 ml) was added dropwise a solution of p-toluenesulfonic acid monohydrate (0.29 g, 1.5 mmol) in ethanol (5 ml) at room temperature. The precipitated crystals were collected by filtration, washed with cold ethanol and dried to obtain p-toluenesulfonate ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl } methyl) amine (0.57 g, 63% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.29 (3H, s), 2.37 (6H, s), 2.78 (2H, d, J = 7.0 Hz), 2.84 (3H, s), 3.57 (2H, s), 6.87 (2H, d , J = 7.9 Hz), 7.11 (4H, d, J = 8.5 Hz), 7.25-7.30 (4H, m), 7.47 (2H, d, J = 7, 9 Hz), 7.76 (3H, br s).

Mp: 234-235 ° C

Example 48

tert-Butyl-5- (aminomethyl) -2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinate

1) tert-Butyl-3-amino-4-phenylbut-2-enoate was obtained as a crude product (16 g) from Meldrum acid (14.41 g, 100 mmol) and phenylacetyl chloride (14.5 ml, 110 mmol) by the method similar to the method of example 25-1).

2) tert-Butyl-2-benzyl-5-cyano-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (14.1 g, 79% yield) was obtained as an oil from 5-methyl-3-oxohexannitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (16 g) obtained in the above step 1), in a manner similar to the method of example 1 -2).

3) tert-Butyl-2-benzyl-5-cyano-6-isobutyl-4- (4-methylphenyl) nicotinate (2.92 g, 66% yield) was obtained from tert-butyl-2-benzyl-5-cyano- 6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.43 g, 10 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.10 (9H, s), 2.19-2.35 (1H, m), 2, 40 (3H, s), 2.94 (2H, d, J = 7.2 Hz), 4.28 (2H, s), 7.16-7.32 (9H, m).

4) tert-Butyl-5- (aminomethyl) -2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinate (2.45 g, 55% yield) was obtained as an oil from tert-butyl-2-benzyl -5-cyano-6-isobutyl-4- (4-methylphenyl) nicotinate (4.40 g, 10 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.05 (9H, s), 1.26 (2H, br.s), 2.21- 2.30 (1H, m), 2.38 (3H, s), 2.79 (2H, d, J = 7.5 Hz), 3.62 (2H, s), 4.20 (2H, s ), 7.11-7.31 (9H, m).

Example 49

5- (aminomethyl) -2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride

5- (aminomethyl) -2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.38 g, 82% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) - 2-benzyl-6-isobutyl-4- (4-methylphenyl) nicotinate (0.44 g, 1 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (6H, d, J = 6.3 Hz), 2.16-2.29 (1H, m), 2.37 (3H, s), 2.82 (2H, d, J = 6.6 Hz), 3.77 (2H, d, J = 4.8 Hz), 4.13 (2H, s), 7.15-7.31 (9H m) 8.16 (3H, br s).

Example 50

5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinic acid dihydrochloride

1) Ethyl 3-amino-3-phenylacrylate was obtained as a crude product (9.5 g) from ethyl 3-oxo-3-phenylpropanoate (9.61 g, 50 mmol) and ammonium acetate (19.27 g, 250 mmol) in a manner similar to the method of example 12-1).

2) Ethyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-phenyl-1,4-dihydropyridine-3-carboxylate (9.52 g, 59% yield) was obtained as an oil from 5- methyl 3-oxohexannitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (9.5 g) obtained in the above step 1), in a manner similar to the method of example 1 -2).

3) Ethyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinate (4.11 g, 85% yield) was obtained as an oil from ethyl 5-cyano-6-isobutyl-4- (4-methylphenyl) -2-phenyl-1,4-dihydropyridine-3-carboxylate (4.81 g, 12 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7.2 Hz), 1.05 (6H, d, J = 6.6 Hz), 2.29-2.44 ( 4H, m), 3.05 (2H, d, J = 7.2 Hz), 3.91 (2H, q, J = 7.2 Hz), 7.26-7.33 (4H, m), 7.43-7.48 (3H, m); 7.624-7.69 (2H, m).

4) Ethyl 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinate (3.63 g, 90% yield) was obtained as an oil from ethyl 5-cyano-6-isobutyl- 4- (4-methylphenyl) -2-phenylnicotinate (4.40 g, 10 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.80 (3H, t, J = 7.2 Hz), 1.03 (6H, d, J = 6.6 Hz), 1.36 (2H, br. s), 2.29-2.42 (4H, m), 2.90 (2H, d, J = 7.2 Hz), 3.70 (2H, s), 3.81 (2H, q, J = 7.2 Hz), 7.17 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.35-7.43 (3H, m ), 7.62-7.65 (2H, m).

5) A mixture of ethyl 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinate (0.80 g, 2 mmol), 6N. hydrochloric acid (20 ml) and acetic acid (10 ml) were heated at the boil under reflux for 3 days. The reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (20 ml) and 1N were added to the residue. aqueous sodium hydroxide solution (30 ml). Di-tert-butyl dicarbonate (0.55 ml, 2.4 mmol) was added to the resulting mixture, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinic acid (0.38 g, 0.8 mmol) as an oil. Then, 5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) -2-phenylnicotinic acid dihydrochloride (0.31 g, 88% yield) was obtained from the oil as a white powder in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.24-2.35 (1H, m), 2.38 (3H, s), 2.93 (2H, d, J = 6.9 Hz), 3.82 (2H, d, J = 5.1 Hz), 7.26-7.32 (4H, m), 7.44-7 52 (3H, m), 7.66-7.69 (2H, m), 8.38 (3H, br s).

Example 51

Methyl 5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate

1) Methyl 3-aminopent-2-enoate was obtained as a crude product (6.4 g) from methyl 3-oxopentanoate (6.50 g, 50 mmol) and ammonium acetate (19.27 g, 250 mmol) by the method similar to the method of example 12-1).

2) Methyl 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.12 g, 48% yield) was obtained as an oil from 5- methyl 3-oxohexannitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (3.2 g) obtained in the above step 1), in a manner similar to the method of example 1 -2).

3) Methyl-5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (3.41 g, 84% yield) was obtained from methyl-5-cyano-2-ethyl-6-isobutyl- 4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (4.06 g, 12 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.32 (3H, t, J = 7.5 Hz), 2.24-2.36 ( 1H, m), 2.41 (3H, s), 2.85 (2H, q, J = 7.5 Hz), 2.96 (2H, d, J = 6.9 Hz), 3.59 ( 3H, s), 7.24-7.30 (4H, m).

4) Methyl 5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (2.49 g, 73% yield) was obtained as a white powder from methyl 5-cyano-2- ethyl 6-isobutyl-4- (4-methylphenyl) nicotinate (4.40 g, 10 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.29 (3H, t, J = 7.5 Hz), 2.18-2.31 ( 1H, m), 2.34 (3H, s), 2.77 (2H, q, J = 7.5 Hz), 2.81 (2H, d, J = 7.2 Hz), 3.49 ( 3H, s), 3.65 (2H, s), 7.11 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz).

Example 52

5- (Aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride

5- (Aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.30 g, 82% yield) was obtained as a white powder from methyl 5- (aminomethyl) -2- ethyl 6-isobutyl-4- (4-methylphenyl) nicotinate (0.34 g, 1 mmol) in a manner similar to that of Example 50-5).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.26 (3H, t, J = 7.5 Hz), 2.17-2, 26 (1H, m), 2.37 (3H, s), 2.89 (2H, q, J = 7.3 Hz), 3.00 (2H, d, J = 6.9 Hz), 3, 81 (2H, d, J = 6.0 Hz), 7.25 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 8.38 ( 3H, broad s).

Example 53

5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid maleate

To a mixed solution of 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (114 mg, 0.350 mmol), acetonitrile (2 ml) and water (2 ml) was added maleic acid (40, 6 mg, 0.350 mmol) and the mixture was stirred at room temperature. After the maleic acid was dissolved, acetonitrile (8 ml) was added and the mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure and acetonitrile (10 ml) was added to the residue. The mixture was stirred at room temperature for 1 h. The precipitated crystals were collected by filtration to obtain 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid maleate (92.6 mg, 60%) in the form of colorless powdery crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (9H, s), 2.36 (3H, s), 2.49 (3H, s), 2.81 (2H, s), 3, 84 (2H, s), 6.01 (2H, s), 7.17-7.21 (2H, m), 7.27-7.31 (2H, m).

Example 54

5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tartrate

To a mixed solution of 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (114 mg, 0.350 mmol), acetonitrile (2 ml) and water (2 ml) was added tartaric acid (40, 6 mg, 0.350 mmol) and the mixture was stirred at room temperature. After the tartaric acid was dissolved, acetonitrile (8 ml) was added and the mixture was stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure, and acetonitrile (10 ml) was added to the residue. The mixture was stirred at room temperature for 1 h. The precipitated crystals were collected by filtration to obtain 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid tartrate (129 mg, 77%) as colorless powdery crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (9H, s), 2.35 (3H, s), 2.44 (3H, s), 2.79 (2H, s), 3, 75 (2H, s), 3.96 (2H, s), 7.15-7.19 (2H, m), 7.21-7.25 (2H, m).

Example 55

tert-Butyl-5- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate

1) tert-Butyl-3-amino-5-methylhex-2-enoate was obtained as a crude product (10 g) from Meldrum acid (14.41 g, 100 mmol) and isovaleryl chloride (11.5 ml, 110 mmol) by the method similar to the method of example 25-1).

2) tert-Butyl-5-cyano-2-isobutyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (3.75 g, 22% yield) was obtained as an oil from 5,5-dimethyl-3-oxohexannitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol) and the crude product (10 g) obtained in the above step 1), in a manner similar to the method Example 1-2).

3) tert-Butyl-5-cyano-2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate (1.66 g, 49% yield) was obtained from tert-butyl-5-cyano-2-isobutyl-4 - (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (3.38 g, 10 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.06 (9H, s), 1.24 (9H, s), 2.22-2, 35 (1H, m), 2.40 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 3.00 (2H, s), 7.19-7.35 (4H , m).

4) tert-Butyl-5- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate (1.34 g, 89% yield) was obtained as white crystals from tert-butyl-5-cyano -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate (3.25 g, 8 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.6 Hz), 1.02 (9H, s), 1.17 (9H, s), 1.24 (2H, br.s), 2.22-2.31 (1H, m), 2.39 (3H, s), 2.66 (2H, d, J = 7.5 Hz), 2.87 (2H, s ), 3.68 (2H, s), 7.13 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz).

Example 56

tert-Butyl-5- (aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinate

1) tert-Butyl-3-amino-4-phenylbut-2-enoate was obtained as a crude product (16 g) from Meldrum acid (14.41 g, 100 mmol) and phenylacetyl chloride (14.5 ml, 110 mmol) by the method similar to the method of example 25-1).

2) tert-Butyl-2-benzyl-5-cyano-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (12.5 g, 68% yield) was obtained as an oil from 5,5-dimethyl-3-oxohexannitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol) and the crude product (11.6 g) obtained in the above step 1), by the method similar to the method of example 1-2).

3) tert-Butyl-2-benzyl-5-cyano-4- (4-methylphenyl) -6-neopentylnicotinate (6.8 g, 100% yield) was obtained from tert-butyl-2-benzyl-5-cyano-4 - (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (6.8 g, 10 mmol) in a manner similar to the method of example 23-3).

4) tert-Butyl-5- (aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.48 g, 15% yield) was obtained as white crystals from tert-butyl-2-benzyl -5-cyano-4- (4-methylphenyl) -6-neopentylnicotinate (3.18 g, 7 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (9H, s), 1.07 (9H, s), 2.39 (3H, s), 2.85 (2H, s), 3.67 ( 2H, s), 4.18 (2H, s), 7.11-7.32 (9H, m).

Example 57

tert-Butyl-5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate

1) tert-Butyl-3-aminopent-2-enoate was obtained as a crude product (8.5 g) from Meldrum acid (14.41 g, 100 mmol) and propionyl chloride (9.6 ml, 110 mmol) in a similar manner to the method Example 25-1).

2) tert-Butyl-5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (6.0 g, 38% yield) was obtained as an oil from 5,5-dimethyl-3-oxohexannitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol) and the crude product (8.5 g) obtained in the above step 1), by the method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.58 g, 43% yield) was obtained as a pale yellow solid from tert-butyl-5- cyano-2-ethyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (5.92 g, 15 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.26 (9H, s), 1.34 (3H, t, J = 7.5 Hz), 2.41 (3H, s), 2.89 (2H, q, J = 7.5 Hz), 3.01 (2H, s), 7.20-7.29 (4H, m).

4) tert-Butyl-5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (1.56 g, yield 65%) was obtained as an oil from tert-butyl-5-cyano- 2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.36 g, 6 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.19 (9H, s), 1.28 (2H, br s), 1.32 (3H, t, J = 7 5 Hz), 2.39 (3H, s), 2.80 (2H, q, J = 7.5 Hz), 2.87 (2H, s), 3.68 (2H, s), 7, 13 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).

Example 58

5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride

5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.37 g, 90% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -2 ethyl 4- (4-methylphenyl) -6-neopentylnicotinate (0.39 g, 1 mmol) in a manner similar to the method of example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 1.26 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 2.78 ( 2H, q, J = 7.5 Hz), 2.92 (2H, s), 3.83 (2H, d, J = 5.4 Hz), 7.21 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 8.13 (3H, br.s).

Example 59

tert-Butyl-5- (aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate

1) tert-Butyl-3-aminohex-2-enoate was obtained as a crude product (9.2 g) from Meldrum acid (14.41 g, 100 mmol) and butyryl chloride (11.4 ml, 110 mmol) in a similar manner to the method Example 25-1).

2) tert-Butyl-5-cyano-4- (4-methylphenyl) -6-neopentyl-2-propyl-1,4-dihydropyridine-3-carboxylate (10.1 g, 61% yield) was obtained as an oil from 5,5-dimethyl-3-oxohexannitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol) and the crude product (16 g) obtained in the above step 1), in a manner similar to the method Example 1-2).

3) tert-Butyl-5-cyano-4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate (5.74 g, 58% yield) was obtained as an oil from tert-butyl-5-cyano-4- (4-methylphenyl) -6-neopentyl-2-propyl-1,4-dihydropyridine-3-carboxylate (9.8 g, 24 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.5 Hz), 1.06 (9H, s), 1.26 (9H, s), 1.75-1, 88 (2H, m), 2.41 (3H, s), 2.81-2.86 (2H, m), 3.00 (2H, s), 7.18-7.30 (4H, m) .

4) tert-Butyl-5- (aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate (3.36 g, 74% yield) was obtained as white crystals from tert-butyl-5-cyano -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinate (4.47 g, 11 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.3 Hz), 1.02 (9H, s), 1.14 (2H, br.s), 1.14 ( 9H, s), 1.73-1.86 (2H, m), 2.39 (3H, s), 2.72-2.77 (2H, m), 2.87 (2H, s), 3 68 (2H, s), 7.13 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).

Example 60

5- (aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinic acid dihydrochloride

5- (aminomethyl) -4- (4-methylphenyl) -6-neopentyl-2-propylnicotinic acid dihydrochloride (0.38 g, 90% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -4 - (4-methylphenyl) -6-neopentyl-2-propylnicotinate (0.41 g, 1 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.02 (9H, s), 1.69-1.81 (2H, m), 2.37 (3H, s), 2.74-2.79 (2H, m), 2.94 (2H, br.s), 3.84 (2H, d, J = 5.1 Hz), 7 22 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 8.14 (3H, br.s).

Example 61

tert-Butyl-5- (aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate

1) tert-Butyl-3-amino-4-methylpent-2-enoate was obtained as a crude product (9.2 g) from Meldrum acid (14.41 g, 100 mmol) and isobutyryl chloride (11.4 ml, 110 mmol) ) in a manner similar to the method of example 25-1).

2) tert-Butyl-5-cyano-2-isopropyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (4.91 g, 30% yield) was obtained as an oil from 5,5-dimethyl-3-oxohexannitrile (5.57 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol) and the crude product (9.2 g) obtained in the above step 1), by the method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate (2.48 g, 50% yield) was obtained from tert-butyl-5-cyano-2-isopropyl-4 - (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (4.90 g, 12 mmol) in a manner similar to the method of example 23-3).

4) tert-Butyl-5- (aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate (1.26 g, 51% yield) was obtained as white crystals from tert-butyl-5-cyano -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate (3.25 g, 8 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.18 (9H, s), 1.30 (6H, d, J = 6.9 Hz), 1.32 (2H, broad s), 2.39 (3H, s), 2.85 (2H, s), 3.04-3.13 (1H, m), 3.66 (2H, s), 7.13 (2H d, J = 8.0 Hz), 7.20 (2H, d, J = 8.0 Hz).

Example 62

5- (aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride

5- (aminomethyl) -2-isopropyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.37 g, 88% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -2 -isopropyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.42 g, 1 mmol) in a manner similar to the method of example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 1.25 (6H, d, J = 6.6 Hz), 2.36 (3H, s), 2.90 ( 2H, s), 3.03-3.13 (1H, m), 3.81 (2H, d, J = 5.4 Hz), 7.22 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz); 8.18 (3H, br s).

Example 63

5- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride

5- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.41 g, 93% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -2 -isobutyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.42 g, 1 mmol) in a manner similar to the method of example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (6H, d, J = 6.6 Hz), 1.02 (9H, s), 2.18-2.31 (1H, m), 2.37 (3H, s), 2.66 (2H, d, J = 7.2 Hz), 2.91 (2H, s), 3.84 (2H, d, J = 5.1 Hz), 7.21 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 8.08 (3H, br.s).

Example 64

5- (aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride

5- (aminomethyl) -2-benzyl-4- (4-methylphenyl) -6-neopentylnicotinic acid dihydrochloride (0.43 g, 91% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -2 -benzyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.45 g, 1 mmol) in a manner similar to the method of example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (9H, s), 2.37 (3H, s), 2.89 (2H, s), 3.82 (2H, d, J = 5 4 Hz), 4.14 (2H, s), 7.18-7.31 (9H, m), 8.17 (3H, br.s).

Example 65

Methyl 5- (aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) Methyl-6-butyl-5-cyano-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridin-3-carboxylate (39 g, 24% yield) was obtained as crystals from 3-oxoheptanenitrile ( 64 g, 500 mmol) in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.30-1.42 (2H, m), 1.49-1.60 (2H, m ), 2.30 (3H, s), 2.34-2.39 (2H, m), 2.35 (3H, s), 3.58 (3H, s), 4.56 (1H, s) 5.77 (1H, s), 7.07-7.14 (4H, m)

2) Methyl-6-butyl-5-cyano-2-methyl-4- (4-methylphenyl) nicotinate (25 g, yield 65%) was obtained as crystals from methyl-6-butyl-5-cyano-2-methyl -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (25 g, 77 mmol) in a manner similar to that of Example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.3 Hz), 1.40-1.52 (2H, m), 1.74-1.84 (2H, m ), 2.41 (3H, s), 2.62 (3H, s), 3.04-3.09 (2H, m), 3.60 (3H, s), 7.23-7.29 ( 4H, m).

3) Methyl-5- (aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate (17 g, 68% yield) was obtained as an oil from methyl-6-butyl-5-cyano-2 methyl 4- (4-methylphenyl) nicotinate (4 g, 11.9 mmol) in a manner similar to the method of example 1-4). An oil (3 g) was dissolved in ethyl acetate (10 ml) and 4N was added. ethyl acetate solution of hydrogen chloride (10 ml). The mixture was concentrated under reduced pressure to obtain methyl 5- (aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride in powder form.

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (3H, t, J = 7.3 Hz), 1.38-1.51 (2H, m), 1.65-1.75 (2H , m), 2.37 (3H, s), 2.53 (3H, s), 2.98-3.03 (2H, m), 3.47 (3H, s), 3.82 (2H, d, J = 5.5 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.38 (3H, s) .

Example 66

5- (Aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride

1) Methyl 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate (16.3 g, 89% yield) was obtained as crystals from methyl -5- (aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate (14 g, 42.9 mmol) in a manner similar to that of Example 2-1).

2) 5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-butyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.5 g, yield 77%) was obtained as crystals from methyl- 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-butyl-2-methyl-4- (4-methylphenyl) nicotinate (2.0 g, 4.7 mmol) in a manner similar to that of Example 2-2).

3) 5- (Aminomethyl) -6-butyl-2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (0.56 g, 86% yield) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl ) amino] methyl} -6-butyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.7 g, 1.7 mmol) in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (3H, t, J = 7.4 Hz), 1.39-1.49 (2H, m), 1.65-1.75 (2H , m), 2.37 (3H, s), 2.61 (3H, s), 3.03-3.08 (2H, m), 3.81 (2H, d, J = 5.3 Hz) 7.24 (2H, d, J = 8.1 Hz); 7.31 (2H, d, J = 8.1 Hz); 8.40 (3H, s).

Example 67

Methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinate dihydrochloride

1) Methyl-5-cyano-2-methyl-4- (4-methylphenyl) -6-propyl-1,4-dihydropyridine-3-carboxylate (60 g, 39% yield) was obtained as an oil from 3-oxohexannitrile ( 60 g, 500 mmol) in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.4 Hz), 1.54-1.66 (2H, m), 2.30 (3H, s), 2, 32-2.41 (2H, m), 2.35 (3H, s), 3.58 (3H, s), 4.56 (1H, s), 5.80 (1H, s), 7.09 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

2) Methyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-propylnicotinate (34.8 g, 58% yield) was obtained as crystals from methyl-5-cyano-2-methyl-4- (4-methylphenyl) -6-propyl-1,4-dihydropyridine-3-carboxylate (60 g, 193 mmol) in a manner similar to that of Example 1-3).

¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7.4 Hz), 1.79-1.91 (2H, m), 2.41 (3H, s), 2, 62 (3H, s), 3.02-3.07 (2H, m), 3.60 (3H, s), 7.23-7.29 (4H, m).

3) Methyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinate (15 g, 67% yield) was obtained as an oil from methyl-5-cyano-2-methyl-4- (4-methylphenyl) -6-propylnicotinate (22 g, 71.3 mmol) in a manner similar to that of Example 1-4). An oil (2 g) was dissolved in ethyl acetate (10 ml) and 4N was added. ethyl acetate solution of hydrogen chloride (10 ml). The mixture was concentrated under reduced pressure to obtain methyl 5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinate dihydrochloride in powder form.

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (3H, t, J = 7.4 Hz), 1.69-1.82 (2H, m), 2.37 (3H, s), 2.53 (3H, s), 2.96-3.02 (2H, m), 3.47 (3H, s), 3.82 (2H, d, J = 5.5 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 8.38 (3H, s).

Example 68

5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinic acid dihydrochloride

1) Methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotinate (12 g, 70% yield) was obtained as crystals from methyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinate (13 g, 41.6 mmol) in a manner similar to that of Example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.4 Hz), 1.39 (9H, s), 1.72-1.79 (2H, m), 2, 38 (3H, s), 2.53 (3H, s), 2.84-2.90 (2H, m), 3.49 (3H, s), 4.15 (2H, d, J = 5, 1 Hz), 4.25 (1H, s), 7.05 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 8.1 Hz).

2) 5 - {[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotinic acid (1.6 g, 83% yield) was obtained as crystals from methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotinate (2 g, 4.8 mmol) in a manner similar to that of Example 2-2).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (3H, t, J = 7.4 Hz), 1.35 (9H, s), 1.64-1.76 (2H, m), 2.33 (3H, s), 2.44 (3H, s), 2.67-2.72 (2H, m), 3.87 (2H, d, J = 4.5 Hz), 6.99 (1H, s), 7.16-7.22 (4H, m), 12.92 (1H, s).

3) 5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-propylnicotinic acid dihydrochloride (0.75 g, 96% yield) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-propylnicotinic acid (0.7 g, 2.1 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (3H, t, J = 7.4 Hz), 1.69-1.82 (2H, m), 2.37 (3H, s), 2.62 (3H, s), 3.01-3.07 (2H, m), 3.82 (2H, d, J = 5.3 Hz), 7.24 (2H, d, J = 8, 1 Hz), 7.31 (2H, d, J = 8.1 Hz), 8.41 (3H, s).

Example 69

5- (aminomethyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride

1) Methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (2.60 g, 99% yield) was obtained as a white solid from methyl 5- (aminomethyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (2.00 g, 6.05 mmol) in a manner similar to that of Example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.16-2.26 (1H, m), 2, 54 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.51 (3H, s), 4.08-4.17 (2H, m), 4.22 (1H , broad s), 7.07-7.20 (4H, m).

2) 5 - {[(tert-Butoxycarbonyl) amino] methyl} -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinic acid (2.01 g, 79% yield) was obtained as a yellow solid from methyl -5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinate (2.60 g, 6.24 mmol) in a manner similar to that of Example 2-2).

¹ H-NMR (CD ₃ OD) δ: 1.04 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.12-2.22 (1H, m), 2 71 (3H, s), 2.94 (2H, d, J = 7.4 Hz), 4.13 (2H, s), 7.17-7.25 (2H, m), 7.32- 7.39 (2H, m).

3) 5- (Aminomethyl) -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride (0.20 g, 76% yield) was obtained as a white solid from 5 - {[(tert-butoxycarbonyl ) amino] methyl} -4- (4-fluorophenyl) -6-isobutyl-2-methylnicotinic acid (0.28 g, 0.673 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.04-1.13 (6H, m), 2.13-2.28 (1H, m), 2.78-2.86 (3H, m), 3.02-3.11 (2H, m), 4.13-4.20 (2H, m), 7.30-7.38 (2H, m), 7.42-7.51 (2H, m) )

Example 70

5- (aminomethyl) -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride

1) Methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (2.49 g, 87% yield) was obtained as a white solid substances from methyl 5- (aminomethyl) -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (2.00 g, 6.38 mmol) in a manner similar to that of Example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2, 61 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 3.57 (3H, s), 4.13 (2H, d, J = 5.3 Hz), 4, 36 (1H, br s), 6.97-7.02 (2H, m), 7.34-7.44 (1H, m).

2) 5 - {[(tert-Butoxycarbonyl) amino] methyl} -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinic acid (2.22 g, 92% yield) was obtained as a yellow solid from methyl 5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinate (2.49 g, 5.55 mmol) in a manner similar to the method of example 2 -2).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.11-2.26 (1H, m), 2, 64 (3H, s), 2.81 (2H, d, J = 7.2 Hz), 4.11-4.16 (2H, m), 4.37 (1H, br.s), 6.96 -7.01 (2H, m), 7.34-7.43 (1H, m).

3) 5- (Aminomethyl) -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride (185 mg, 70% yield) was obtained as a white solid from 5 - {[(tert-butoxycarbonyl ) amino] methyl} -4- (2,6-difluorophenyl) -6-isobutyl-2-methylnicotinic acid (0.28 g, 0.635 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (CD ₃ OD) δ: 1.08 (6H, d, J = 6.8 Hz), 2.19-2.29 (1H, m), 2.81-2.88 (3H, m), 2.98-3.08 (2H, m), 4.09-4.16 (2H, m), 7.20-7.27 (2H, m), 7.64-7.72 ( 1H, m).

Example 71

tert-Butyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate

1) 2- (3-Methylbutanoyl) -3- [4- (trifluoromethyl) phenyl] acrylonitrile was obtained as the crude product (9.8 g) from 5-methyl-3-oxohexannitrile (4.0 g, 32 mmol) and 4- (trifluoromethyl) benzaldehyde (5.6 g, 32 mmol) in a manner similar to that of Example 29-1).

2) tert-Butyl-5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] -1,4-dihydropyridine-3-carboxylate (4.8 g, 36% yield) was obtained in as a white powder from a crude product (9.8 g) obtained in the above Step 1) and tert-butyl-3-aminocrotonate (5.47 g, 35 mmol) in a manner similar to the method of Example 1-2). Namely, the above crude product and tert-butyl 3-aminocrotonate were dissolved in methanol (200 ml) and the mixture was heated under reflux for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl-5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] -1,4-dihydropyridine-3-carboxylate.

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.5 Hz), 1.28 (9H, s) 1.75-2.00 (1H, m), 2.10-2.35 (2H, m), 2.36 (3H, s), 4.64 (1H, s), 5.60 (1H , br.s), 7.36 (2H, d, J = 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz).

Mp: 199-201 ° C

3) tert-Butyl-5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (3.5 g, 76% yield) was obtained as a white powder from tert-butyl-5 -cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] -1,4-dihydropyridine-3-carboxylate (4.7 g, 11 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.6 Hz), 1.23 (9H, s), 2.20-2.40 (1H, m), 2, 67 (3H, s), 2.95 (2H, d, J = 7.4 Hz), 7.51 (2H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8 , 2 Hz).

Mp: 108-110 ° C

4) tert-Butyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (3.3 g, 96% yield) was obtained as a white powder from tert-butyl -5-cyano-6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (3.5 g, 8.2 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.17 (9H, s), 1.38 (2H, br.s), 2.15- 2.35 (1H, m), 2.57 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 3.60 (2H, s), 7.42 (2H, d , J = 8.0 Hz), 7.70 (2H, d, J = 8.0 Hz).

Mp: 88-90 ° C

Example 72

5- (Aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinic acid hydrochloride

5- (Aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinic acid hydrochloride (0.51 g, 53% yield) was obtained as a white powder from tert-butyl-5- ( aminomethyl) -6-isobutyl-2-methyl-4- [4- (trifluoromethyl) phenyl] nicotinate (1.0 g, 2.3 mmol) in a manner similar to that of Example 24.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.15-2.35 (1H, m), 2.51 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.75 (2H, s), 7.56 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.0 Hz), 8.01 (2H, br s).

Example 73

tert-Butyl-5- (aminomethyl) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate

1) Methyl-4- (2-cyano-5-methyl-3-oxohex-1-en-1-yl) benzoate was obtained as a crude product (10.1 g) from 5-methyl-3-oxohexannitrile (4, 0 g, 32 mmol) and methyl 4-formyl benzoate (5.3 g, 32 mmol) in a manner similar to the method of example 29-1).

2) tert-Butyl-5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methyl-1,4-dihydropyridine-3-carboxylate (5.9 g, 45% yield) was obtained in as a white powder from a crude product (10.1 g) obtained in the above Step 1) and tert-butyl-3-aminocrotonate (5.25 g, 33 mmol) in a manner similar to the method of Example 1-2). Namely, the above crude product and tert-butyl-3-aminocrotonate were dissolved in methanol (200 ml) and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl-5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methyl-1,4-dihydropyridine-3-carboxylate.

¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.26 (9H, s) 1.75-2.00 (1H, m), 2.15-2.35 (2H, m), 2.36 (3H, s), 3.90 (3H, s), 4.63 (1H , s), 5.69 (1H, br.s), 7.32 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.3 Hz).

Mp: 191-193 ° C

3) tert-Butyl-5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate (5.4 g, 95% yield) was obtained as a white powder from tert-butyl-5- cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methyl-1,4-dihydropyridine-3-carboxylate (5.7 g, 14 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.23 (9H, s), 2.20-2.35 (1H, m), 2, 67 (3H, s), 2.94 (2H, d, J = 7.4 Hz), 3.96 (3H, s), 7.40-7.50 (2H, m), 8.10-8 , 20 (2H, m).

Mp: 108-109 ° C

4) tert-Butyl-5- (aminomethyl) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate (5.0 g, 94% yield) was obtained as a white powder from tert-butyl- 5-cyano-6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate (5.3 g, 13 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.17 (9H, s), 1.49 (2H, br.s), 2.15- 2.35 (1H, m), 2.57 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 3.59 (2H, s), 3.96 (3H, s ), 7.30-7.40 (2H, m), 8.05-8.15 (2H, m).

Mp: 77-81 ° C

Example 74

5- (aminomethyl) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinic acid hydrochloride

5- (aminomethyl) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinic acid hydrochloride (0.50 g, 66% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl ) -6-isobutyl-4- [4- (methoxycarbonyl) phenyl] -2-methylnicotinate (0.80 g, 1.9 mmol) in a manner similar to that of Example 24.

¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (6H, d, J = 6.6 Hz), 2.05-2.25 (1H, m), 2.41 (3H, s), 2.70 (2H, d, J = 7.0 Hz), 3.54 (2H, s), 3.88 (3H, s), 7.41 (2H, d, J = 8.1 Hz), 7.95 (2H, d, J = 8.1 Hz).

Example 75

tert-Butyl-5- (aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate

1) 3- (4-Ethylphenyl) -2- (3-methylbutanoyl) acrylonitrile was obtained as a crude product (8.8 g) from 5-methyl-3-oxohexannitrile (4.0 g, 32 mmol) and 4-ethylbenzaldehyde (4.3 g, 32 mmol) in a manner similar to that of Example 29-1).

2) tert-Butyl-5-cyano-4- (4-ethylphenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (7.8 g, 64% yield) was obtained as a white powder from the crude product (8.8 g) obtained in the above Step 1) and tert-butyl-3-aminocrotonate (5.47 g, 35 mmol) in a manner similar to the method of Example 1-2). Namely, the above crude product and tert-butyl 3-aminocrotonate were dissolved in methanol (200 ml) and the mixture was heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl-5-cyano-4- (4-ethylphenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate.

¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, d, J = 6.5 Hz), 0.99 (3H, d, J = 6.5 Hz), 1.20 (3H, t, J = 7.6 Hz), 1.28 (9H, s), 1.80-2.00 (1H, m), 2.10-2.30 (2H, m), 2.32 (3H, s ), 2.61 (2H, q, J = 7.6 Hz), 4.52 (1H, s), 5.55 (1H, br.s), 7.10 (2H, d, J = 8, 3 Hz), 7.14 (2H, d, J = 8.3 Hz).

Mp: 165-166 ° C

3) tert-Butyl-5-cyano-4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate (5.2 g, 67% yield) was obtained as a white powder from tert-butyl-5-cyano-4 - (4-ethylphenyl) -6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (7.8 g, 21 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.23 (9H, s), 1.26 (3H, t, J = 7.6 Hz) , 2.20-2.35 (1H, m), 2.64 (3H, s), 2.71 (2H, q, J = 7.6 Hz), 2.94 (2H, d, J = 7 4 Hz), 7.20-7.35 (4H, m).

Mp: 85-86 ° C

4) tert-Butyl-5- (aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate (7.0 g, 97% yield) was obtained as a white powder from tert-butyl-5-cyano -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinate (7.2 g, 19 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.17 (9H, s), 1.25 (3H, t, J = 7.5 Hz) 1.38 (2H, br.s), 2.15-2.30 (1H, m), 2.55 (3H, s), 2.69 (2H, q, J = 7.5 Hz), 2.78 (2H, d, J = 7.4 Hz), 3.63 (2H, s), 7.15 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz).

Mp: 50-52 ° C

Example 76

5- (aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinic acid hydrochloride

5- (Aminomethyl) -4- (4-ethylphenyl) -6-isobutyl-2-methylnicotinic acid hydrochloride (0.52 g, 79% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -4 - (4-ethylphenyl) -6-isobutyl-2-methylnicotinate (0.70 g, 1.8 mmol) in a manner similar to the method of example 24.

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 7.5 Hz), 1.23 (3H, t, J = 7.5 Hz), 2.10-2, 30 (1H, m), 2.47 (3H, s), 2.67 (2H, q, J = 7.5 Hz), 2.77 (2H, d, J = 7.0 Hz), 3, 74 (2H, s), 7.22 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 8.81 (1H, br.s).

Example 77

Methyl 5- (aminomethyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate

1) Methyl-3-aminopent-2-enoate was obtained as a crude product (20 g) from methyl 3-oxopentanoate (13 g, 100 mmol) and ammonium acetate (38.5 g, 500 mmol) in a manner similar to the method of example 12 -one).

2) Methyl 4- (4-chlorophenyl) -5-cyano-2-ethyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (1.4 g, 23% yield) was obtained as a yellow powder from 5 , 5-dimethyl-3-oxohexannitrile (5.1 g, 32 mmol), 4-chlorobenzaldehyde (4.5 g, 32 mmol) and the crude product (3.2 g) obtained in the above step 1), in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.05 (3H, m), 1.01 (9H, s), 2.20 (1H, d, J = 13.8 Hz), 2, 37 (1H, d, J = 13.8 Hz), 2.77 (2H, q, J = 7.5 Hz), 3.58 (3H, s), 4.60 (1H, s), 5, 63 (1H, br s), 7.10-7.20 (2H, m), 7.25-7.30 (2H, m).

3) Methyl 4- (4-chlorophenyl) -5-cyano-2-ethyl-6-neopentylnicotinate (0.58 g, 43% yield) was obtained as a pale yellow powder from methyl 4- (4-chlorophenyl) -5-cyano-2-ethyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (1.4 g, 3.7 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.33 (3H, t, J = 7.5 Hz), 2.87 (2H, q, J = 7.5 Hz) 3.03 (2H, s), 3.61 (3H, s), 7.25-7.35 (2H, m), 7.45-7.50 (2H, m).

Mp: 120-121 ° C

4) Methyl 5- (aminomethyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate (0.49 g, 85% yield) was obtained as a pale yellow oil from methyl 4- (4- chlorophenyl) -5-cyano-2-ethyl-6-neopentylnicotinate (0.57 g, 1.5 mmol) in a manner similar to that of Example 23-4).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.30 (3H, t, J = 7.5 Hz), 1.42 (2H, br.s), 2.77 ( 2H, q, J = 7.5 Hz), 2.89 (2H, s), 3.51 (3H, s), 3.69 (2H, s), 7.15-7.25 (2H, m ), 7.35-7.45 (2H, m).

Example 78

5- (aminomethyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinic acid dihydrochloride

1) Methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate (0.52 g, 97% yield) was obtained as a white powder from methyl -5- (aminomethyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate (0.42 g, 1.1 mmol) in a manner similar to that of Example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.30 (3H, t, J = 7.5 Hz), 1.38 (9H, s), 2.78 (2H, q, J = 7.5 Hz), 2.87 (2H, s), 3.51 (3H, s), 4.18 (3H, br.s), 7.10-7.20 (2H, m ), 7.30-7.45 (2H, m).

2) 5 - {[(tert-Butoxycarbonyl) amino] methyl} -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinic acid (0.37 g, 81% yield) was obtained as a white powder from methyl- 5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinate (0.47 g, 0.99 mmol) in a manner similar to the method of Example 2-2).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.24 (3H, t, J = 7.4 Hz), 1.33 (9H, s), 2.73 (2H, q, J = 7.4 Hz), 2.73 (2H, s), 3.92 (2H, d, J = 4.5 Hz), 6.96 (1H, t, J = 4.5 Hz) , 7.25-7.35 (2H, m), 7.47 (2H, d, J = 8.3 Hz), 13.05 (1H, br.s).

Mp: 71-72 ° C

3) 5- (Aminomethyl) -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinic acid dihydrochloride (0.24 g, 83% yield) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (4-chlorophenyl) -2-ethyl-6-neopentylnicotinic acid (0.30 g, 0.65 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 1.26 (3H, t, J = 7.4 Hz), 2.79 (2H, q, J = 7.4 Hz), 2.90 (2H, br.s), 3.83 (2H, d, J = 5.7 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.50- 7.60 (2H, m), 8.12 (3H, br s).

Mp: 230-235 ° C

Example 79

tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinate

1) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2-isopropyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (2.00 g, 16% yield) was obtained as a white solid substances from 5,5-dimethyl-3-oxohexannitrile (5.67 g, 36.7 mmol), 4-chlorobenzaldehyde (5.16 g, 36.7 mmol) and tert-butyl-3-amino-4-methylpent- 2-enoate (5.98 g, 30 mmol) in a manner similar to that of Example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.04 (3H, d, J = 6.8 Hz), 1.21 (3H, d, J = 7.0 Hz) , 1.28 (9H, s), 2.20 (1H, d, J = 13.9 Hz), 2.33 (1H, d, J = 14.1 Hz), 4.07-4.30 ( 1H, m), 4.55 (1H, s), 5.65 (1H, s), 7.16 (2H, d, J = 8.3 Hz), 7.22-7.35 (2H, m )

2) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2-isopropyl-6-neopentylnicotinate (1.91 g, 96% yield) was obtained as a yellow solid from tert-butyl-4- (4 -chlorophenyl) -5-cyano-2-isopropyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate (2.00 g, 4.66 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (9H, s), 1.27 (9H, s), 1.32 (6H, d, J = 6.6 Hz), 3.00 (2H, s), 3.13-3.25 (1H, m), 7.32 (2H, d, J = 8.5 Hz), 7.45 (2H, d, J = 8.5 Hz).

3) tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinate (1.24 g, 67% yield) was obtained as a white solid from tert-butyl-4- (4-chlorophenyl) -5-cyano-2-isopropyl-6-neopentylnicotinate (1.80 g, 4.27 mmol) in a manner similar to the method of Example 23-4).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.21 (9H, s), 1.30 (6H, d, J = 6.6 Hz), 2.85 (2H, s), 3.01-3.16 (1H, m), 3.64 (2H, s), 7.22 (2H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.5 Hz).

Example 80

5- (aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinic acid dihydrochloride

5- (aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinic acid dihydrochloride (393 mg, 93% yield) was obtained as a yellow solid from tert-butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2-isopropyl-6-neopentylnicotinate (406 mg, 0.941 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 1.25 (6H, d, J = 6.8 Hz), 2.88 (2H, s), 3.05- 3.14 (1H, m), 3.81 (2H, d, J = 5.3 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.55 (2H, d, J = 8.5 Hz), 8.11 (3H, br s).

Example 81

tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-isopropyl nicotinate

1) tert-Butyl-4- (4-chlorophenyl) -5-cyano-6-isobutyl-2-isopropyl-1,4-dihydropyridine-3-carboxylate (6.18 g, 50% yield) was obtained as a yellow solid substances from 5-methyl-3-oxohexannitrile (4.14 g, 33 mmol), 4-chlorobenzaldehyde (4.64 g, 33 mmol) and tert-butyl-3-amino-4-methylpent-2-enoate (5, 98 g, 30 mmol) in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, dd, J = 8.5, 6.8 Hz), 1.14 (3H, d, J = 7.0 Hz), 1.22 ( 3H, d, J = 7.0 Hz), 1.28 (9H, s), 1.81-1.98 (1H, m), 2.25 (2H, d, J = 7.4 Hz), 4.09-4.26 (1H, s), 4.55 (1H, s), 5.71 (1H, s), 7.15 (2H, d, J = 8.3 Hz), 7.25 -7.27 (2H, m).

2) tert-Butyl 4- (4-chlorophenyl) -5-cyano-6-isobutyl-2-isopropyl nicotinate (6.10 g, 99% yield) was obtained as a yellow oil from tert-butyl 4- (4- chlorophenyl) -5-cyano-6-isobutyl-2-isopropyl-1,4-dihydropyridine-3-carboxylate (6.16 g, 14.8 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.26 (9H, s), 1.32 (6H, d, J = 6.8 Hz) 2.22-2.39 (1H, m), 2.95 (2H, d, J = 7.2 Hz), 3.19-3.25 (1H, m), 7.33 (2H, d , J = 8.7 Hz), 7.46 (2H, d, J = 8.7 Hz).

3) tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-isopropyl nicotinate (5.52 g, 89% yield) was obtained as a white solid from tert-butyl-4- (4-Chlorophenyl) -5-cyano-6-isobutyl-2-isopropyl nicotinate (6.10 g, 1.48 mmol) in a manner similar to the method of Example 23-4).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 1.21 (9H, s), 1.30 (6H, d, J = 6.8 Hz) 2.23-2.39 (1H, m), 2.78 (2H, d, J = 7.2 Hz), 3.01-3.16 (1H, m), 3.59 (1H, s ), 7.22 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz).

Example 82

5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-isopropylnicotinic acid dihydrochloride

5- (aminomethyl) -4- (4-chlorophenyl) -6-isobutyl-2-isopropylnicotinic acid dihydrochloride (263 mg, 62% yield) was obtained as a yellow solid from tert-butyl-5- (aminomethyl) -4- (4-Chlorophenyl) -6-isobutyl-2-isopropyl nicotinate (404 mg, 0.969 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.25 (6H, d, J = 6.8 Hz), 2.20-2, 39 (1H, m), 2.83 (2H, d, J = 7.0 Hz), 3.01-3.19 (1H, m), 3.77 (2H, d, J = 5.3 Hz ), 7.36 (2H, d, 8.5 Hz), 7.55 (2H, d, J = 8.3 Hz), 8.14 (3H, br.s).

Example 83

tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2,6-diisobutylnicotinate

1) tert-Butyl-3-amino-5-methylhex-2-enoate was obtained as a crude product (20.2 g) from Meldrum acid (17.3 g, 120 mmol) and isovaleryl chloride (15.8 ml, 132 mmol) ) in a manner similar to the method of example 25-1).

2) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2,6-diisobutyl-1,4-dihydropyridine-3-carboxylate (10.2 g, 72% yield) was obtained as a pale yellow powder from 5-methyl-3-oxohexannitrile (4.1 g, 33 mmol), 4-chlorobenzaldehyde (4.6 g, 33 mmol) and the crude product (10.1 g) obtained in the above step 1), in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.05 (12H, m), 1.29 (9H, s), 1.80-2.05 (2H, m), 2.15-2 35 (2H, m), 2.55-2.70 (2H, m), 4.60 (1H, s), 5.51 (1H, br.s), 7.15-7.25 (2H m) 7.25-7.30 (2H, m).

Mp: 166-168 ° C

3) tert-Butyl 4- (4-chlorophenyl) -5-cyano-2,6-diisobutylnicotinate (9.6 g, 99% yield) was obtained as a white powder from tert-butyl 4- (4-chlorophenyl) -5-cyano-2,6-diisobutyl-1,4-dihydropyridine-3-carboxylate (9.8 g, 23 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.8 Hz), 1.00 (6H, d, J = 6.6 Hz), 1.25 (9H, s) , 2.15-2.40 (2H, m), 2.76 (2H, d, J = 7.2 Hz), 2.95 (2H, d, J = 7.4 Hz), 7.30- 7.35 (2H, m); 7.40-7.50 (2H, m).

4) tert-Butyl 5- (aminomethyl) -4- (4-chlorophenyl) -2,6-diisobutylnicotinate (0.97 g, 96% yield) was obtained as a white powder from tert-butyl 4- (4- chlorophenyl) -5-cyano-2,6-diisobutylnicotinate (1.0 g, 2.3 mmol) in a manner similar to that of Example 23-4).

¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 6.6 Hz), 0.98 (6H, d, J = 6.6 Hz), 1.20 (9H, s) , 1.48 (2H, br.s), 2.15-2.35 (2H, m), 2.67 (2H, d, J = 7.4 Hz), 2.80 (2H, d, J = 7.4 Hz), 3.61 (2H, s), 7.20-7.25 (2H, m), 7.35-7.45 (2H, m).

Example 84

5- (aminomethyl) -4- (4-chlorophenyl) -2,6-diisobutylnicotinic acid dihydrochloride

5- (aminomethyl) -4- (4-chlorophenyl) -2,6-diisobutylnicotinic acid dihydrochloride (0.92 g, 98% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -4- ( 4-chlorophenyl) -2,6-diisobutylnicotinate (0.90 g, 2.1 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (6H, d, J = 6.6 Hz), 0.97 (6H, d, J = 6.6 Hz), 2.10-2, 35 (2H, m), 2.66 (2H, d, J = 6.4 Hz), 2.84 (2H, d, J = 6.2 Hz), 3.79 (2H, d, J = 5 5 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.50-7.60 (2H, m), 8.17 (3H, br.s).

Mp: 205 ° C (decomposition)

Example 85

tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinate

1) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2-isobutyl-6-neopentyl-1,4-dihydropyridine-3-carboxylate was obtained as a crude product (7.9 g) from 5.5 dimethyl-3-oxohexannitrile (4.6 g, 33 mmol), 4-chlorobenzaldehyde (4.6 g, 33 mmol) and the crude product (10.1 g) tert-butyl-3-amino-5-methylhex-2 -enoate obtained in example 83-1), in a manner similar to the method of example 1-2).

2) tert-Butyl-4- (4-chlorophenyl) -5-cyano-2-isobutyl-6-neopentylnicotinate (5.5 g, 37% yield) was obtained as a white powder from a crude product (7.9 g), obtained in the above stage 1), in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.06 (9H, s), 1.26 (9H, s), 2.20-2, 35 (1H, m), 2.76 (2H, d, J = 7.2 Hz), 3.01 (2H, s), 7.30-7.35 (2H, m), 7.40-7 50 (2H, m).

3) tert-Butyl-5- (aminomethyl) -4- (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinate (4.5 g, 86% yield) was obtained as a yellow powder from tert-butyl-4- ( 4-chlorophenyl) -5-cyano-2-isobutyl-6-neopentylnicotinate (5.2 g, 12 mmol) in a manner similar to that of Example 23-4).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.8 Hz), 1.02 (9H, s), 1.20 (9H, s), 1.86 (2H, broad s), 2.15-2.35 (1H, m), 2.67 (2H, d, J = 7.4 Hz), 2.87 (2H, s), 3.71 (2H, s ), 7.20-7.25 (2H, m), 7.35-7.45 (2H, m).

Example 86

5- (aminomethyl) -4- (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinic acid dihydrochloride

5- (aminomethyl) -4- (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinic acid dihydrochloride (0.29 g, 56% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl) -4 - (4-chlorophenyl) -2-isobutyl-6-neopentylnicotinate (0.50 g, 1.1 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (6H, d, J = 6.6 Hz), 1.02 (9H, s), 2.15-2.30 (1H, m), 2.66 (2H, q, J = 7.2 Hz), 2.91 (2H, s), 3.84 (2H, d, J = 5.5 Hz), 7.30-7.40 (2H , m), 7.50-7.60 (2H, m), 8.12 (3H, br s).

Mp: 251 ° C (decomposition)

Example 87

[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetonitrile dihydrochloride

1) tert-Butyl {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (4.5 g, yield 48%) was obtained as white powder from methyl 5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentyl nicotinate (10 g, 22.7 mmol) in a manner similar to the method of example 5-1) .

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.37 (9H, s), 2.41 (3H, s), 2.67 (3H, s), 2.84 ( 2H, s), 4.10 (2H, d, J = 4.9 Hz), 4.16 (1H, s), 4.36 (2H, d, J = 5.7 Hz), 7.05 ( 2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz).

2) A mixture of tert-butyl {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.9 g, 2.2 mmol), triethylamine (0.4 g, 4.0 mmol) and tetrahydrofuran (30 ml) were cooled to 0 ° C and methanesulfonyl chloride (0.3 g, 2.6 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (0.85 g, yield 79%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.37 (9H, s), 2.41 (3H, s), 2.67 (3H, s), 2.75 ( 3H, s), 2.86 (2H, s), 4.11 (2H, d, J = 4.9 Hz), 4.17 (1H, s), 4.91 (2H, s), 7, 04 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz).

3) [5 - {[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (0.84 g, 1.7 mmol) was dissolved in dimethyl sulfoxide (10 ml) and potassium cyanide (0.14 g, 2.0 mmol) was added. The mixture was stirred at 60 ° C for 1 h. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl {[5- (cyanomethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.45 g, yield 63 %) in the form of a powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.37 (9H, s), 2.43 (3H, s), 2.65 (3H, s), 2.85 ( 2H, s), 3.30 (2H, s), 4.11 (2H, d, J = 4.5 Hz), 4.17 (1H, s), 7.05 (2H, d, J = 8 0 Hz), 7.30 (2H, d, J = 8.0 Hz).

4) [5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetonitrile dihydrochloride (0.28 g, 76%) was obtained as a powder from tert-butyl {[ 5- (cyanomethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.4 g, 0.95 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.42 (3H, s), 2.76 (3H, s), 3.06 (2H, s), 3, 59 (2H, s), 3.80 (2H, d, J = 5.3 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.42 (2H, d, J = 7 9 Hz), 8.20 (3H, s).

Example 88

2- [5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetamide dihydrochloride

1) tert-Butyl {[5- (2-amino-2-oxoethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.3 g, 82% ) was obtained in powder form from tert-butyl {[5- (cyanomethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.35 g, 0.83 mmol ) in a manner similar to the method of example 6-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.40 (3H, s), 2.56 (3H, s), 2.84 ( 2H, s), 3.30 (2H, s), 4.10 (2H, d, J = 4.9 Hz), 4.19 (1H, s), 5.15 (1H, s), 5, 20 (1H, s), 7.00 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz).

2) 2- [5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetamide dihydrochloride (0.18 g, 85%) was obtained as a powder from tert-butyl {[5- (2-amino-2-oxoethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.22 g, 0.5 mmol) in a similar manner the method of example 6-2).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.41 (3H, s), 2.77 (2H, s), 3.29 (3H, s), 3, 87 (2H, s), 4.28 (2H, s), 7.03 (1H, s), 7.20 (2H, d, J = 7.8 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.39 (1H, s), 8.24 (3H, s).

Example 89

[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl acetate dihydrochloride

1) A mixture of tert-butyl {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.3 g, 0.73 mmol), triethylamine (0.1 g, 1.0 mmol) and tetrahydrofuran (20 ml) were cooled to 0 ° C and acetyl chloride (0.06 g, 0.8 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl acetate (0.26 g, yield 76%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.00 (3H, s), 2.40 (3H, s), 2.57 ( 3H, s), 2.85 (2H, s), 4.11 (2H, d, J = 4.9 Hz), 4.17 (1H, s), 4.76 (2H, s), 7, 00 (2H, d, J = 8.1 Hz), 7.22 (2H, d, J = 8.1 Hz).

2) [5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl acetate dihydrochloride (99 mg, 90%) was obtained in powder form from [5 - {[(t β-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl acetate (0.12 g, 0.26 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 1.96 (3H, s), 2.40 (3H, s), 2.78 (3H, s), 3, 14 (2H, s), 3.82 (2H, s), 4.72 (2H, s), 7.21 (2H, d, J = 7.8 Hz), 7.36 (2H, d, J = 7.8 Hz), 8.23 (3H, s).

Example 90

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[[4- (methylthio) phenyl] thio} methyl) pyridin-3-yl] methyl} amine dihydrochloride

1) A mixture of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (3.06 g, 7.68 mmol), triethylamine (1.8 ml, 12.9 mmol) and tetrahydrofuran (30 ml) were cooled to 0 ° C and methanesulfonyl chloride (0.89 ml, 11.5 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate as a crude product. The crude product was dissolved in N, N-dimethylformamide (30 ml). Potassium carbonate (1.77 g, 12.8 mmol) and 4- (methylthio) benzenethiol (1.00 g, 6.40 mmol) were added and the mixture was stirred under heating at 50 ° C for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[4- (methylthio) phenyl] thio} methyl) pyridin-3- yl] methyl} carbamate (3.43 g, 99% yield) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.24 (1H, m), 2, 40 (3H, s), 2.45 (3H, s), 2.63 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.75 (2H, s), 4.02 (2H, d, J = 5.1 Hz), 4.18 (1H, br.s), 6.98 (2H, d, J = 8.1 Hz), 7.03 (2H, d , J = 8.7 Hz), 7.08 (2H, d, J = 8.7 Hz), 7.20 (2H, d, J = 7.9 Hz).

2) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[4- (methylthio) phenyl] thio} methyl) pyridin-3-yl] methyl} amine dihydrochloride (380 mg, yield 79%) was obtained as a yellow solid from tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[4- (methylthio) phenyl] thio} methyl) pyridine- 3-yl] methyl} carbamate (508 mg, 0.947 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.13-2.22 (1H, m), 2.40 (3H, s), 2.46 (3H, s), 2.78 (3H, s), 3.11 (2H, br.s), 3.76 (2H, d, J = 4.5 Hz), 3.87 (2H , s), 7.12 (2H, d, J = 8.7 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.22 (2H, d, J = 7.9 Hz ), 7.33 (2H, d, J = 7.9 Hz), 8.38 (3H, br s).

Example 91

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[[4- (methylsulfonyl) phenyl] sulfonyl} methyl) pyridin-3-yl] methyl} amine dihydrochloride

1) To a solution of tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[4- (methylthio) phenyl] thio} methyl) pyridin-3-yl] methyl} carbamate (1.10 g, 2.05 mmol) in methanol (15 ml), water (1.5 ml) and tetrahydrofuran (1.5 ml) were added sulfuric acid (121 mg, 1.23 mmol) and Oxon (trademark , 3.78 g, 6.15 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed successively with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting white solid was washed with diisopropyl ether to obtain tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[[4- (methylsulfonyl) phenyl] sulfonyl} methyl) pyridin-3- silt] methyl} carbamate (1.06 g, 86% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.17-2.27 (1H, m), 2, 42 (3H, s), 2.70 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.09 (3H, s), 4.00 (2H, d, J = 5.1 Hz), 4.19 (1H, br.s), 4.36 (2H, s), 6.87 (2H, d, J = 7.9 Hz), 7.19 (2H, d , J = 7.9 Hz), 7.69 (2H, d, J = 8.3 Hz), 8.00 (2H, d, J = 8.5 Hz).

2) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[4- (methylsulfonyl) phenyl] sulfonyl} methyl) pyridin-3-yl] methyl} amine dihydrochloride (480 mg, yield 98%) was obtained as a white powder from tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - ({[4- (methylsulfonyl) phenyl] sulfonyl} methyl) pyridin-3 -yl] methyl} carbamate (511 mg, 0.851 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.17-2.27 (1H, m), 2.38 (3H, s), 2.81 (3H, br.s), 3.00 (2H, br.s), 3.34 (3H, s), 3.68 (2H, br.s), 7.03 (2H, d, J = 7.4 Hz), 7.22 (2H, d, J = 7.9 Hz), 7.77 (2H, d, J = 7.0 Hz), 8.11 (2H, d, J = 8.5 Hz), 8.26 (3H, br s).

Example 92

Dihydrochloride (6-methyl-4- (4-methylphenyl) -5 - {[(4-methyl-4H-1,2,4-triazol-3-yl) thio] methyl} -2-neopentylpyridin-3-yl) methylamine

1) tert-Butyl [(6-methyl-4- (4-methylphenyl) -5 - {[(4-methyl-4H-1,2,4-triazol-3-yl) thio] methyl} -2-neopentylpyridine -3-yl) methyl] carbamate (0.28 g, 77%) was obtained as a powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6 -neopentylpyridin-3-yl] methyl methanesulfonate (0.35 g, 0.71 mmol) and 4-methyl-4H-1,2,4-triazole-3-thiol (99 mg, 0.86 mmol) in a manner similar to the example method 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.39 (3H, s), 2.65 (3H, s), 2.84 ( 2H, s), 3.41 (3H, s), 4.07 (2H, d, J = 5.3 Hz), 4.17 (3H, s), 7.02 (2H, d, J = 7 9 Hz), 7.22 (2H, d, J = 7.9 Hz), 8.08 (1H, s).

2) Dihydrochloride (6-methyl-4- (4-methylphenyl) -5 - {[(4-methyl-4H-1,2,4-triazol-3-yl) thio] methyl} -2-neopentylpyridin-3- il) methylamine (0.12 g, 72%) was obtained in powder form from tert-butyl [(6-methyl-4- (4-methylphenyl) -5 - {[(4-methyl-4H-1,2,4 -triazol-3-yl) thio] methyl} -2-neopentylpyridin-3-yl) methyl] carbamate (0.18 g, 0.35 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.39 (3H, s), 2.80 (3H, s), 3.19 (2H, s), 3, 41 (3H, s), 3.79 (2H, s), 4.05 (2H, s), 7.13 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 8.25 (3H, s), 8.74 (1H, s).

Example 93

{6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(1,3-thiazol-2-ylthio) methyl] pyridin-3-yl} methylamine dihydrochloride

1) tert-Butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(1,3-thiazol-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (0 , 25 g, 69%) was obtained in powder form from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (0 , 35 g, 0.71 mmol) and 2-mercaptothiazole (100 mg, 0.86 mmol) in a manner similar to the method of example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.38 (3H, s), 2.64 (3H, s), 2.84 ( 2H, s), 4.08 (2H, d, J = 5.1 Hz), 4.17 (3H, s), 7.03 (2H, d, J = 7.9 Hz), 7.18 ( 1H, d, J = 3.4 Hz), 7.20 (2H, d, J = 7.9 Hz), 7.60 (1H, d, J = 3.4 Hz).

2) {6-Methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(1,3-thiazol-2-ylthio) methyl] pyridin-3-yl} methylamine dihydrochloride (0.11 g, 80 %) was obtained in powder form from tert-butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(1,3-thiazol-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (0.15 g, 0.29 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.38 (3H, s), 2.78 (3H, s), 3.10 (2H, s), 3, 78 (2H, s), 4.20 (2H, s), 7.20 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 7, 69 (1H, d, J = 3.4 Hz), 7.71 (1H, d, J = 3.4 Hz), 8.17 (3H, s).

Example 94

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinonitrile dihydrochloride

1) To a solution (20 ml) of tert-Butyl {[5- (aminocarbonyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1750 mg, 4.2 mmol) in dichloromethane, triethylamine (1.2 ml, 8.4 mmol) was added and trifluoromethanesulfonic anhydride (780 ml, 8.4 mmol) was added dropwise under ice-cooling. The mixture was stirred for 30 minutes, then the reaction mixture was washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl {[5-cyano-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1130 mg, 68% yield) in the form of white crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.40 (9H, s), 2.20-2.29 (1H, m), 2, 43 (3H, s), 2.77 (3H, s), 2.83 (2H, d, J = 9.0 Hz), 4.18 (2H, s), 4.20 (1H, br.s ), 7.13 (2H, d, J = 6.0 Hz), 7.31 (2H, d, J = 6.0 Hz).

2) 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinonitrile dihydrochloride (81 mg, 88% yield) was obtained as a white powder from tert-butyl {[5-cyano-2- isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (100 mg, 0.25 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.21-2.27 (1H, m), 2.42 (3H, s), 2.71 (3H, s), 2.89 (2H, d, J = 6.9 Hz), 3.82 (2H, d, J = 5.4 Hz), 7.33-7.40 (4H , m), 8.50 (3H, br s).

Example 95

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] urea dihydrochloride

1) To a solution (3 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) in N , N-dimethylformamide was added triethylamine (170 μl, 1.5 mmol) and diphenylphosphoryl azide (260 μl, 1.5 mmol) was added dropwise under ice-cooling. The mixture was stirred for 30 minutes and water was added to it. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in toluene (3 ml). The mixture was heated under reflux with stirring for 1 h. 25% aqueous ammonia (3 ml) was added to the reaction mixture and the mixture was stirred at 100 ° C for 1 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl {[5 - [(aminocarbonyl) amino] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (101 mg, 24% yield) as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.26 (1H, m), 2, 39 (3H, s), 2.56 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 4.10 (2H, d, J = 5.1 Hz), 4, 24 (1H, br.s), 4.38 (2H, s), 5.50 (1H, s), 7.01 (2H, d, J = 7.5 Hz), 7.24 (2H, d , J = 7.5 Hz).

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] urea dihydrochloride (84 mg, 92% yield) was obtained as a white powder from tert- butyl {[5 - [(aminocarbonyl) amino] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (100 mg, 0.23 mmol) in a manner similar to the method of example 2 -3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 5.4 Hz), 2.14-2.19 (1H, m), 2.40 (3H, s), 2.53 (3H, s), 3.0, (2H, br.s), 3.80 (2H, br.s), 3.83 (1H, br.s), 5.94 (1H, br s), 7.20 (2H, d, J = 7.8 Hz), 7.36 (2H, d, J = 7.8 Hz), 8.28 (3H, br.s).

Example 96

N '- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N, N-dimethylurea dihydrochloride

1) tert-Butyl {[5 - {[(dimethylamino) carbonyl] amino] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (158 mg, 35% yield ) was obtained as a white powder from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and 2M tetrahydrofuran dimethylamine solution (0.6 ml, 1.2 mmol) in a manner similar to the method of example 95-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.25 (1H, m), 2, 41 (3H, s), 2.51 (3H, s), 2.71 (6H, s), 2.75 (2H, d, J = 9.0 Hz), 4.08 (2H, d, J = 5.1 Hz), 4.23 (1H, br.s), 5.32 (1H, s), 7.02 (2H, d, J = 7.8 Hz), 7.24 (2H, d , J = 7.8 Hz).

2) N '- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N, N-dimethylurea dihydrochloride (108 mg, 73% yield) was obtained in as a white powder from tert-butyl {[5 - {[(dimethylamino) carbonyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (158 mg, 0 , 35 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.3 Hz), 2.17-2.20 (1H, m), 2.39 (3H, s), 2.64 (9H, s), 3.09 (2H, br.s), 3.83 (2H, br.s), 7.20 (2H, d, J = 7.8 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.86 (1H, br.s), 8.39 (3H, br.s).

Example 97

Benzyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate dihydrochloride

1) Benzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate (1600 mg, 35% yield) was obtained in as a white powder of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (3700 mg, 8.9 mmol) and benzyl alcohol (2, 3 ml, 10.7 mmol) in a manner similar to the method of example 95-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.16 (1H, m), 2, 39 (3H, s), 2.51 (3H, s), 2.75 (2H, d, J = 7.2 Hz), 4.08 (2H, s), 4.22 (1H, br.s ), 5.07 (2H, broad s), 5.70 (1H, broad s), 6.95 (2H, broad s), 7.17 (2H, d, J = 7.8 Hz), 7 20-7.26 (2H, m); 7.31-7.36 (3H, m).

2) Benzyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate dihydrochloride (54 mg, 76% yield) was obtained as a white powder from benzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate (75 mg, 0.14 mmol) in a manner similar to the method of example 2- 3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.3 Hz), 2.15-2.22 (1H, m), 2.39 (3H, s), 2.56 (3H, s), 2.99 (2H, s), 3.79 (2H, s), 5.00 (2H, s), 7.14-7.18 (4H, m), 7 29-7.35 (5H, m), 8.29 (3H, br s), 9.08 (1H, br s).

Example 98

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -3-pyridinamine trihydrochloride

1) To a solution (100 ml) of benzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate (1500 mg, 2.9 mmol) in ethanol, 5% palladium-carbon (150 mg) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1000 mg, 90% yield) in the form of a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.09-2.16 (1H, m), 2, 41 (3H, s), 2.42 (3H, s), 2.65 (2H, d, J = 7.2 Hz), 3.28 (2H, s), 4.02 (2H, br.s ), 4.22 (1H, br.s), 7.06 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 7.7 Hz).

2) 5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -3-pyridinamine trihydrochloride (34 mg, 62% yield) was obtained as a white powder from tert-butyl {[5-amino -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (50 mg, 0.13 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (6H, d, J = 6.6 Hz), 1.97-2.08 (1H, m), 2.42 (3H, s), 2.65 (3H, s), 2.99 (2H, s), 3.69 (2H, s), 5.40 (3H, br s), 7.26 (2H, d, J = 8, 1Hz), 7.44 (2H, d, J = 8.1 Hz), 8.38 (3H, br.s).

Example 99

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methanesulfonamide dihydrochloride

To a solution of tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (100 mg, 0.26 mmol) in tetrahydrofuran (2 ml) triethylamine (54 μl, 0.39 mmol) was added and methanesulfonyl chloride (30 μl, 0.39 mmol) was added at room temperature. The mixture was then stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. To a solution of an oil in ethyl acetate (1 ml) was added 4N. an ethyl acetate solution of hydrogen chloride (1 ml) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from hexane to obtain N- [5- (aminomethyl) -6-isobutyl-2-methyl- dihydrochloride 4- (4-methylphenyl) pyridin-3-yl] methanesulfonamide (25 mg, 22% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.18-2.24 (1H, m), 2.20 (3H, s), 2.39 (3H, s), 2.71 (3H, s), 2.96 (2H, s), 3.79 (2H, s), 7.28 (2H, d, J = 6.9Hz) 7.34 (2H, d, J = 6.9 Hz), 8.32 (3H, br s), 9.27 (1H, br s).

Example 100

N- [5 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} sulfonyl) -4-methyl-1,3-thiazole dihydrochloride -2-yl] acetamide

N- [5 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} sulfonyl) -4-methyl-1,3-thiazole dihydrochloride -2-yl] acetamide (58 mg, 39% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (100 mg, 0.26 mmol) and 2- (acetylamino) -4-methyl-1,3-thiazole-5-sulfonyl chloride (76 mg, 0.3 mmol) in a manner similar to the method of Example 99.

¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (6H, d, J = 6.6 Hz), 2.02 (3H, s), 2.19 (3H, s), 2.18- 2.23 (1H, m), 2.27 (3H, s), 2.53 (3H, s), 2.84 (2H, br.s), 3.69 (2H, br.s), 6 92-6.97 (4H, m), 8.10 (3H, br.s), 9.89 (1H, br.s).

Example 101

{[5- (Aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine trihydrochloride

1) A mixture of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.16 g, 2.91 mmol), triethylamine (0.8 ml, 5.82 mmol) and tetrahydrofuran (15 ml) were cooled to 0 ° C and methanesulfonyl chloride (500 mg, 4.37 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate as a crude product. The crude product was dissolved in N, N-dimethylformamide (30 ml) and sodium azide (379 mg, 5.82 mmol) was added. The mixture was stirred at 80 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue. A mixture of the obtained residue, 10% palladium on carbon (304 mg, 0.291 mmol) and ethanol (15 ml) was stirred under a hydrogen atmosphere at room temperature for 2 hours. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography with obtaining tert-butyl {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (690 mg, 60% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 1.41 (2H, br.s), 2.14- 2.23 (1H, m), 2.41 (3H, s), 2.64 (3H, s), 4.02 (2H, d, J = 5.1 Hz), 4.18 (1H, br .c), 7.02 (2H, d, J = 7.9 Hz), 7.25 (2H, d, J = 7.0 Hz).

2) {[5- (Aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine trihydrochloride (204 mg, 99% yield) was obtained as a white powder from tert -butyl {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (200 mg, 0.503 mmol) in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.13-2.24 (1H, m), 2.43 (3H, s), 2.50 (3H, s), 2.98 (2H, br.s), 3.76 (4H, br.s), 7.34-7.45 (4H, m), 8.51 (6H, ears.s).

Example 102

N - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -4- (methylsulfonyl) benzenesulfonamide dihydrochloride

1) To a solution (10 ml) of tert-butyl {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (290 mg, 0.729 mmol) and triethylamine (0.15 ml, 1.09 mmol) in tetrahydrofuran, 4- (methylsulfonyl) benzenesulfonyl chloride (223 mg, 0.875 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting yellow solid was washed with diisopropyl ether to give tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [({[[4- (methylsulfonyl) phenyl] sulfonyl } amino) methyl] pyridin-3-yl} methyl) carbamate (391 mg, 87% yield) as a yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.36 (9H, s), 2.13-2.22 (1H, m), 2, 41 (3H, s), 2.61 (3H, s), 2.73 (2H, d, J = 7.4 Hz), 3.08 (3H, s), 3.83 (2H, d, J = 5.8 Hz), 3.97 (2H, d, J = 4.9 Hz), 4.11-4.20 (2H, m), 6.84 (2H, d, J = 8.1 Hz ), 7.13 (2H, d, J = 7.7 Hz), 7.77 (2H, d, J = 8.7 Hz), 7.98 (2H, d, J = 8.5 Hz).

2) N - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -4- (methylsulfonyl) benzenesulfonamide dihydrochloride (370 mg, 99% yield ) was obtained as a yellow powder from tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [({[[4- (methylsulfonyl) phenyl] sulfonyl} amino) methyl] pyridin-3 -yl} methyl) carbamate (391 mg, 0.635 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.11-2.19 (1H, m), 2.35 (3H, s), 2.50 (3H, s), 2.70-2.82 (2H, m), 3.31 (3H, s), 3.66 (2H, br.s), 3.72 (2H, br. s), 7.11-7.21 (4H, m), 7.83 (2H, dd, J = 8.3, 1.3 Hz), 8.08 (2H, d, J = 8.1 Hz ), 8.31 (3H, br s).

Example 103

Ethyl ({[[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetate trihydrochloride

1) To a solution of [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate (300 mg, 0.63 mmol) in tetrahydrofuran (5 ml), triethylamine (223 μl, 1.6 mmol) and glycine ethyl ester hydrochloride (100 mg, 0.7 mmol) were added and the mixture was stirred at 60 ° C for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain ethyl ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] methyl} amino) acetate (185 mg, 61% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.22 (3H, t, J = 6.9 Hz), 1.38 (9H, s), 2.15-2.22 (1H, m), 2.41 (3H, s), 2.67 (3H, s), 2.73 (2H, d, J = 7.2Hz), 3.18 ( 2H, s), 3.43 (2H, s), 4.02 (2H, s), 4.09 (2H, q, J = 6.9Hz), 4.18 (1H, br.s), 7 03 (2H, d, J = 7.8 Hz); 7.25 (2H, d, J = 7.8 Hz).

2) Ethyl ({[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetate trihydrochloride (57 mg, 95% yield) was obtained as white powder from ethyl ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino} acetate (60 mg , 0.12 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.18 (3H, t, J = 6.9 Hz), 2.11-2, 24 (1H, m), 2.42 (3H, s), 2.92 (3H, br.s), 3.03 (2H, br.s), 3.61 (2H, s), 3.72 (2H, br.s), 4.06 (2H, s), 4.08 (2H, q, J = 6.9 Hz), 7.35 (2H, d, J = 8.1 Hz), 7, 40 (2H, d, J = 8.1 Hz), 8.43 (3H, br.s).

Example 104

({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetic acid trihydrochloride

1) To a solution of ethyl ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino} acetate (100 mg, 0.2 mmol) in ethanol (3 ml) was added 8N. aqueous sodium hydroxide solution (3 ml) and the mixture was stirred at 80 ° C for 15 hours. 1N was added. hydrochloric acid to neutralize the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetic acid (92 mg, 99% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (6H, d, J = 6.3 Hz), 1.35 (9H, s), 2.11-2.24 (1H, m), 2.36 (3H, s), 2.54 (2H, s), 2.57 (3H, s), 2.97 (2H, s), 3.39 (2H, s), 3.76 (2H , s), 6.78 (1H, br.s), 7.18 (2H, d, J = 7.8 Hz), 7.22 (2H, d, J = 7.8 Hz).

2) Trihydrochloride ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetic acid (75 mg, 80% yield) was obtained as white powder from ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetic acid (90 mg 0.2 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.14-2.21 (1H, m), 2.42 (3H, s), 2.89 (3H, s), 3.01 (2H, broad s), 3.52 (2H, s), 3.72 (2H, s), 4.04 (2H, s), 7.35 (2H, d, J = 8.1 Hz), 7.39 (2H, d, J = 8.1 Hz), 8.37 (3H, br.s), 9.29 (1H, br.s) .

Example 105

4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2-piperazinone trihydrochloride

1) tert-Butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(3-oxo-1-piperazinyl) methyl] pyridin-3-yl} methyl) carbamate (78 mg, yield 77%) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate (300 mg , 0.63 mmol) and 2-piperazinone (65 mg, 0.65 mmol) in a manner similar to the method of example 103-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.23 (1H, m), 2, 49 (5H, s), 2.64 (3H, s), 2.73 (2H, d, J = 7.2Hz), 2.89 (2H, s), 3.22 (2H, br.s) , 3.28 (2H, s), 4.01 (2H, d, J = 5.1Hz), 4.20 (1H, br.s), 5.69 (1H, br.s), 6.96 (2H, d, J = 7.8 Hz), 7.21 (2H, d, J = 7.8 Hz).

2) 4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2-piperazinone trihydrochloride (64 mg, 87% yield) was obtained in as a white powder from tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(3-oxo-1-piperazinyl) methyl] pyridin-3-yl} methyl) carbamate (75 mg, 0.15 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.91 (2H, s), 2.09-2.14 (1H, m), 2.42 (3H, s), 3.00 (3H, br.s), 3.18 (4H, br.s), 3.75 (2H, br.s), 7.30 (2H, d, J = 7.5 Hz), 7.41 (2H, d, J = 7.5 Hz), 7.41 (1H, br.s), 8.52 (3H, br.s).

Example 106

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2,4-imidazolidinedione dihydrochloride

1) To a solution of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (100 mg, 0.25 mmol), hydantoin (38 mg, 0.38 mmol) and tributylphosphine (95 μl, 0.38 mmol) in tetrahydrofuran (3 ml) was added 1,1 '- (azodicarbonyl) dipiperidine (96 mg, 0.38 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and insoluble matters were filtered off. The filtrate was purified by silica gel column chromatography to obtain tert-butyl {[5 - [(2,5-dioxo-1-imidazolidinyl) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl ] methyl} carbamate (68 mg, 57% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.11-2.26 (1H, m), 2, 39 (3H, s), 2.55 (3H, s), 2.73 (2H, d, J = 7.5 Hz), 3.77 (2H, s), 3.99 (2H, d, J = 5.1 Hz), 4.23 (1H, br.s), 4.46 (2H, s), 5.10 (1H, br.s), 7.07 (2H, d, J = 7, 8 Hz), 7.23 (2H, d, J = 7.8 Hz).

2) 3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2,4-imidazolidinedione dihydrochloride (54 mg, 95% yield) prepared as a white powder from tert-butyl {[5 - [(2,5-dioxo-1-imidazolidinyl) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } carbamate in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.14-2.19 (1H, m), 2.37 (3H, s), 2.84 (3H, s), 3.11 (2H, br s), 3.71 (4H, s), 4.35 (2H, s), 7.18 (2H, d, J = 8, 1 Hz), 7.33 (2H, d, J = 7.8 Hz), 8.00 (1H, br.s), 8.30 (1H, br.s).

Example 107

Dihydrochloride 1 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2,5-piperazinedione

1) To a solution of Z-glycine (1.2 g, 6 mmol) and N, N-dimethylformamide (10 ml) in tetrahydrofuran (5 ml) was added oxalyl chloride (530 ml, 6 mmol) and the mixture was stirred at room temperature for 30 min The reaction mixture was added dropwise to a solution of ethyl ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amino) acetate (1.4 g, 3 mmol), pyridine (970 ml, 12 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran (10 ml) under ice cooling and the mixture was stirred for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting oil was dissolved in ethanol (10 ml). 5% palladium on carbon (100 mg) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl {[5 - [(2,5-dioxo-1-piperazinyl) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3- silt] methyl} carbamate (35 mg, 2.4% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.24 (1H, m), 2, 40 (3H, s), 2.51 (3H, s), 2.76 (2H, d, J = 7.5Hz), 3.47 (2H, s), 3.93 (2H, s), 4 03 (2H, d, J = 5.1 Hz), 4.24 (1H, br.s), 4.51 (2H, s), 5.88 (1H, br.s), 6.98 ( 2H, d, J = 7.5 Hz), 7.25 (2H, d, J = 7.5 Hz).

2) 1 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -2,5-piperazinedione dihydrochloride (14 mg, 60% yield) prepared as a white powder from tert-butyl {[5 - [(2,5-dioxo-1-piperazinyl) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } carbamate in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.15-2.19 (1H, m), 2.39 (3H, s), 2.69 (3H, s), 3.25 (2H, s), 3.67 (2H, s), 3.73 (2H, br.s), 4.31 (2H, s), 7.18 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 7.8 Hz), 8.06 (1H, br.s), 8.24 (3H, br.s) .

Example 108

{[2-Isobutyl-4- (4-methylphenyl) -6-phenylpyridin-3-yl] methyl} amine dihydrochloride

1) To a solution (140 ml) of acetophenone (8.40 g, 70 mmol) and p-tolualdehyde (8.40 g, 70 mmol) in ethanol was added sodium hydroxide (7.0 g, 175 mmol) and the mixture was stirred for 3 days. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting yellow solid was washed with diisopropyl ether to obtain (2E) -3- (4-methylphenyl) -1-phenylprop-2-en-1-one (9.12 g, 59% yield) as yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 2.40 (3H, s), 7.23 (2H, d, J = 8.1 Hz), 7.47-7.62 (6H, m), 7, 80 (1H, d, J = 15.8 Hz), 8.00-8.03 (2H, m).

2) A mixture of 5-methyl-3-oxohexannitrile (5.0 g, 40 mmol), acetic acid (2.3 ml, 40 mmol), ammonium acetate (15.4 g, 200 mmol) and toluene (250 ml) was heated at reflux, using a Dean-Stark trap, for 12 hours. The reaction mixture was allowed to cool to room temperature, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue (4.5 g). The residue (2.25 g) was dissolved in ethanol (100 ml) and (2E) -3- (4-methylphenyl) -1-phenylprop-2-en-1-one (3.69 g, 16.6 mmol) was added. and sodium hydroxide (0.8 g, 20 mmol). The mixture was heated under reflux for 3 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2-isobutyl-4- (4-methylphenyl) -6-phenylnicotinonitrile (2.68 g, 49% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (6H, d, J = 6.8 Hz), 2.35-2.48 (4H, m), 3.06 (2H, d, J = 7 , 2 Hz), 7.35 (2H, d, J = 7.9 Hz), 7.49-7.56 (5H, m), 7.67 (1H, s), 8.07-8.13 (1H, m).

3) {[2-Isobutyl-4- (4-methylphenyl) -6-phenylpyridin-3-yl] methyl} amine (1.70 g, 63% yield) was obtained as a yellow oil from 2-isobutyl-4- ( 4-methylphenyl) -6-phenylnicotinonitrile (2.65 g, 8.12 mmol) in a manner similar to that of Example 1-4). The oil was dissolved in 4n. A hydrogen chloride 1,4-dioxane solution (20 ml) and the solvent were evaporated under reduced pressure. The resulting yellow solid was washed with diisopropyl ether to obtain {[2-isobutyl-4- (4-methylphenyl) -6-phenylpyridin-3-yl] methyl} amine dihydrochloride (1.99 g, 96% yield) as a yellow powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (6H, d, J = 6.6 Hz), 2.34-2.41 (4H, m), 2.94 (2H, d, J = 7.0 Hz), 4.00 (2H, d, J = 5.5 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8 , 3 Hz), 7.47-7.54 (3H, m), 7.70 (1H, s), 8.15 (2H, dd, J = 7.9, 1.5 Hz), 8.43 (3H, broad s).

Example 109

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid maleate

5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 4.80 mmol) was dissolved in a mixed solvent of water (15 ml) and acetonitrile (15 ml) and the mixture was heated under reflux for 10 minutes. Maleic acid (558 mg, 4.80 mmol) was added to the resulting solution, and the mixture was stirred at the same temperature for 10 minutes. Acetonitrile (200 ml) was added to the resulting solution, and the mixture was allowed to cool to room temperature and stirred at 0 ° C for 30 minutes. The precipitated solid was collected by filtration and washed with acetonitrile (30 ml) to obtain 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid maleate (667 mg, 32% yield) as white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.37 (3H, s), 2.74 (2H, d, J = 7.0 Hz), 3.79 (2H, s), 6.01 (2H, s), 7.19 (2H, d, J = 7.9 Hz), 7.29 (2H, d, J = 7.5 Hz).

Example 110

5- (aminomethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride

1) A solution (40 ml) of methyl 4-methoxyacetoacetate (5.85 g, 40 mmol), p-tolualdehyde (4.81 g, 40 mmol), piperidine (340 mg, 4 mmol) and acetic acid (240 mg, 4 mmol) in isopropanol was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure to give a residue. 3-Methyl-5-tert-butyl-2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylate (5.85 g, 50% yield) was obtained as a yellow oil from the obtained residue and tert-butyl-3-aminocrotonate (4.71 g, 30.0 mol) by a method similar to the method of example 1-2). Namely, the above residue and tert-butyl-3-aminocrotonate were dissolved in methanol (30 ml) and the mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with obtaining 3-methyl-5-tert-butyl-2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylate.

¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H, s), 2.28 (3H, s), 2.32 (3H, s), 3.45-3.46 (3H, m), 3.62-3.63 (3H, m), 4.55-4.76 (2H, m), 4.89-4.95 (1H, m), 6.94 (1H, br.s), 7.01 (2H, d, J = 7.7 Hz); 7.15 (2H, d, J = 8.1 Hz).

2) 3-Methyl-5-tert-butyl-2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) pyridine-3,5-dicarboxylate (3.78 g, yield 65%) was obtained as yellow oils from 3-methyl-5-tert-butyl-2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylate (5.85 g, 15.1 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.23 (9H, s), 2.37 (3H, s), 2.61 (3H, s), 3.36 (3H, s), 3.54 ( 3H, s), 4.66 (2H, s), 7.13-7.15 (2H, m), 7.17-7.19 (2H, m).

3) A suspension of 3-methyl-5-tert-butyl-2- (methoxymethyl) -6-methyl-4- (4-methylphenyl) pyridine-3,5-dicarboxylate (3.78 g, 9.81 mmol) in toluene (50 ml) was cooled to -78 ° C and a 1.50 M diisobutylaluminum hydride solution (25 ml, 24.5 mmol) was added dropwise over 15 minutes. The mixture was stirred at -78 ° C for 30 minutes, allowed to warm to 0 ° C and further stirred for 10 minutes. Methanol (0.5 ml) and sodium sulfate 10-hydrate (8.1 g, 9.8 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl-5- (hydroxymethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (810 mg, 23% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (9H, s), 2.39 (3H, s), 2.59 (3H, s), 3.50 (3H, s), 4.39 ( 2H, d, J = 6.8 Hz), 4.76 (2H, s), 7.21 (4H, s).

4) A mixture of tert-butyl-5- (hydroxymethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (810 mg, 2.27 mmol), triethylamine (0.63 ml, 4, 54 mmol) and tetrahydrofuran (30 ml) were cooled to 0 ° C and methanesulfonyl chloride (0.26 ml, 3.40 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (20 ml) and sodium azide (296 mg, 4.54 mmol) was added. The mixture was stirred at 80 ° C for 1 h. Ethyl acetate was added to the reaction mixture, the mixture was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of the residue, 10% palladium on carbon (242 mg, 0.227 mmol) and ethanol (30 ml) was stirred in a hydrogen atmosphere at room temperature for 30 minutes. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl-5- (aminomethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (600 mg, yield 74%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.19 (9H, s), 2.40 (3H, s), 2.57 (3H, s), 3.48 (3H, s), 3.63 ( 2H, s), 4.69 (2H, s), 7.12 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 7.7 Hz).

5) 5- (Aminomethyl) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinic acid dihydrochloride (533 mg, 84% yield) was obtained as a white powder from tert-butyl-5- (aminomethyl ) -6- (methoxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (600 mg, 1.69 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.53 (3H, s), 3.41 (3H, s), 3.86 (2H, d, J = 5 , 7 Hz), 4.76 (2H, s), 7.24 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.10 ( 3H, broad s).

Example 111

5,6-bis (aminomethyl) -2-methyl-4- (4-methylphenyl) nicotinic acid trihydrochloride

1) Ethyl 3-amino-4 - [(tert-butoxycarbonyl) amino] but-2-enoate (5.37g, 99% yield) was obtained as a yellow oil from ethyl 4 - [(tert-butoxycarbonyl) amino] -3-oxobutanoate (5.4 g, 22.0 mmol) in a manner similar to the method of example 108-2).

¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 1.46 (9H, s), 3.77 (2H, d, J = 6.6 Hz) 4.12 (2H, q, J = 7.1 Hz); 4.55 (1H, s).

2) A mixture of tert-butyl acetoacetate (4.75 g, 30 mmol), p-tolualdehyde (4.51 g, 37.5 mmol), piperidine (0.30 ml, 3.00 mmol) and ethanol (0.2 ml ) was stirred at room temperature for a day. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue and ethyl 3-amino-4 - [(tert-butoxycarbonyl) amino] but-2-enoate (5.37 g, 22.0 mmol) were stirred at 80 ° C for 30 min and further stirred at 130 ° C for 3 hours. The resulting mixture was purified by silica gel column chromatography to obtain 3-ethyl-5-tert-butyl-2 - {[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3,5-dicarboxylate (1.95 g, 18% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.22-1.28 (3H, m), 1.40 (9H, s), 1.46 (9H, s), 2.27 (6H, s), 4.04-4.18 (3H, m), 4.37-4.44 (1H, m), 4.87 (1H, s), 5.35 (1H, br.s), 7.01 ( 2H, d, J = 7.9 Hz), 7.15 (2H, d, J = 8.1 Hz).

3) 3-Ethyl-5-tert-butyl-2 - {[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) pyridine-3,5-dicarboxylate (1.94 g, yield 99%) was obtained as a yellow oil from 3-ethyl-5-tert-butyl-2 - {[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) -1,4- dihydropyridine-3,5-dicarboxylate (1.95 g, 4.01 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.23 (9H, s), 1.47 (9H, s), 2.37 (3H, s), 2.61 (3H, s), 4.02 (2H, q, J = 7.1 Hz), 4.50 (2H, d, J = 4.7 Hz), 5.87 (1H, br.s), 7.13 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz).

4) tert-Butyl-6 - {[(tert-butoxycarbonyl) amino] methyl} -5- (hydroxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (1.45 g, 82% yield) was obtained in as a yellow oil from 3-ethyl-5-tert-butyl-2 - {[(tert-butoxycarbonyl) amino] methyl} -6-methyl-4- (4-methylphenyl) pyridine-3,5-dicarboxylate (1.94 g, 4.00 mmol) in a manner similar to the method of Example 110-3).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (9H, s), 1.46 (9H, s), 2.39 (3H, s), 2.57 (3H, s), 3.38 ( 1H, br.s), 4.46 (2H, d, J = 6.0 Hz), 4.54 (2H, d, J = 5.8 Hz), 5.87 (1H, br.s), 7.18 (2H, d, J = 8.3 Hz); 7.21 (2H, d, J = 8.3 Hz).

5) tert-Butyl-5- (aminomethyl) -6 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) nicotinate (580 mg, 40% yield) was obtained as white powder from tert-butyl-6 - {[(tert-butoxycarbonyl) amino] methyl} -5- (hydroxymethyl) -2-methyl-4- (4-methylphenyl) nicotinate (1.45 g, 3.28 mmol) by the method similar to the method of example 110-4).

¹ H-NMR (CDCl ₃ ) δ: 1.18 (9H, s), 1.49 (9H, s), 2.39 (3H, s), 2.56 (3H, s), 3.62 ( 2H, s), 4.58 (2H, d, J = 4.7 Hz), 6.22 (1H, br.s), 7.10 (2H, d, J = 8.1 Hz), 7, 22 (2H, d, J = 7.9 Hz).

6) 5,6-bis (aminomethyl) -2-methyl-4- (4-methylphenyl) nicotinic acid trihydrochloride (510 mg, 99% yield) was obtained as a yellow solid from tert-butyl-5- (aminomethyl) - 6 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) nicotinate (580 mg, 1.31 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.57 (3H, s), 3.84-3.89 (2H, m), 4.51-4.61 (2H, m), 7.23 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 7.9 Hz), 8.42 (3H, br.s), 8 54 (3H, br s).

Example 112

5- (aminomethyl) -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinic acid hydrochloride

1) A mixture of tert-butyl acetoacetate (4.75 g, 30 mmol), p-tolualdehyde (4.51 g, 37.5 mmol), piperidine (0.30 ml, 3.00 mmol) and ethanol (0.2 ml ) was stirred at room temperature for a day. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue, ethyl cyano acetate (6.79 g, 60.0 mmol) and ammonium acetate (11.6 g, 150 mmol) were stirred at 140 ° C for 3 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous solution. sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl-5-cyano-6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate (0.87 g, 9% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.19 (9H, s), 2.41 (3H, s), 2.57 (3H, s), 7.24-7.31 (4H, m).

2) tert-Butyl-5- (aminomethyl) -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate was obtained as a white solid from tert-butyl-5-cyano-6-hydroxy-2-methyl -4- (4-methylphenyl) nicotinate (0.50 g, 1.54 mmol) in a manner similar to that of Example 1-4). Then, tert-butyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate (210 mg, 32% yield) was obtained as a colorless oil in a similar manner to the method of example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.39 (9H, s), 2.38 (3H, s), 2.43 (3H, s), 4.02 ( 2H, d, J = 5.8 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz), 12.39 (1H, ears.s).

3) 5- (Aminomethyl) -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinic acid hydrochloride (167 mg, 99% yield) was obtained as a white solid from tert-butyl-5 - {[(( tert-butoxycarbonyl) amino] methyl} -6-hydroxy-2-methyl-4- (4-methylphenyl) nicotinate (210 mg, 0.490 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 2.35 (3H, s), 3.51 (2H, s), 7.15 (2H, d, J = 7 , 9 Hz), 7.26 (2H, d, J = 7.9 Hz), 7.94 (3H, br.s), 12.42 (1H, s), 12.74 (1H, s).

Example 113

5- (aminomethyl) -N, 6-diisobutyl-2-methyl-4- (4-methylphenyl) nicotinamide ditrifluoroacetate

5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (23.9 mg, 0.06 mmol), isobutylamine (5.3 mg, 0.072 mmol), 1-hydroxy-1H-benzotriazole (11.0 mg, 0.072 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13.8 mg, 0.072 mmol) were dissolved in a mixed solvent of N, N -dimethylformamide (1.25 ml) -dichloromethane (0.4 ml) and the mixture was stirred at 50 ° C for 2 days. The reaction mixture was diluted with dichloromethane (3 ml) and washed successively with saturated aqueous sodium hydrogen carbonate solution (0.5 ml) and saturated brine (0.5 ml). Trifluoroacetic acid (2 ml) was added to the organic layer and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give 5- (aminomethyl) -N, 6-diisobutyl-2-methyl-4- ( 4-methylphenyl) nicotinamide (22.4 mg, 63% yield) as a yellow oil.

EIMC (M + 1): 368

The compounds of examples 114-168 were synthesized from nicotinic acids and amines in accordance with the following tables 1-4 in a manner similar to the method of example 113. The compounds of examples 162-164 were obtained in free form by neutralization of the obtained nicotinic acid amide trifluoroacetate with saturated aqueous sodium hydrogen carbonate.

Table 1 Example -NR ^5a R ^6a -R ³ EIMC (M + 1) HA 113

4-Me-phenyl 368 2CF ₃ COOH 114

4-Me-phenyl 368 2CF ₃ COOH 115

4-Me-phenyl 380 2CF ₃ COOH 116

4-Me-phenyl 402 2CF ₃ COOH 117

4-Me-phenyl 416 2CF ₃ COOH 118

4-Me-phenyl 384 2CF ₃ COOH 119

4-Me-phenyl 432 2CF ₃ COOH 120

4-F-phenyl 436 2CF ₃ COOH 121

2,6-di-F-phenyl 454 2CF ₃ COOH 122

4-Me-phenyl 460 2CF ₃ COOH 123

4-F-phenyl 464 2CF ₃ COOH 124

2,6-di-F-phenyl 482 2CF ₃ COOH 125

4-Me-phenyl 430 2CF ₃ COOH 126

4-F-phenyl 434 2CF ₃ COOH 127

2,6-di-F-phenyl 452 2CF ₃ COOH

table 2 Example -NR ^5a R ^6a -R ³ EIMC (M + 1) HA 128

4-Me-phenyl 437 2CF ₃ COOH 129

4-F-phenyl 440 2CF ₃ COOH 130

2,6-di-F-phenyl 458 2CF ₃ COOH 131

4-Me-phenyl 437 2CF ₃ COOH 132

4-F-phenyl 440 2CF ₃ COOH 133

2,6-di-F-phenyl 458 2CF ₃ COOH 134

4-Me-Phenyl 437 2CF ₃ COOH 135

4-F-phenyl 440 2CF ₃ COOH 136

2,6-di-F-phenyl 458 2CF ₃ COOH 137

4-Me-phenyl 412 2CF ₃ COOH 138

4-Me-phenyl 412 2CF ₃ COOH 139

2,6-di-F-phenyl 434 2CF ₃ COOH 140

4-Me-phenyl 354 2CF ₃ COOH 141

4-Me-phenyl 366 2CF ₃ COOH 142

4-F-phenyl 370 2CF ₃ COOH 143

2,6-di-F-phenyl 388 2CF ₃ COOH

Table 3 Example -NR ^5a R ^6a -R ³ EIMC (M + 1) HA 144

4-Me-phenyl 368 2CF ₃ COOH 145

4-Me-phenyl 382 2CF ₃ COOH 146

4-F-phenyl 386 2CF ₃ COOH 147

2,6-di-F-phenyl 404 2CF ₃ COOH 148

4-Me-phenyl 384 2CF ₃ COOH 149

2,6-di-F-phenyl 406 2CF ₃ COOH 150

4-Me-phenyl 408 2CF ₃ COOH 151

2,6-di-F-phenyl 430 2CF ₃ COOH 152

4-Me-phenyl 416 2CF ₃ COOH 153

4-Me-phenyl 424 2CF ₃ COOH 154

4-F-phenyl 428 2CF ₃ COOH 155

2,6-di-F-phenyl 446 2CF ₃ COOH 156

4-Me-phenyl 457 3CF ₃ COOH 157

4-F-phenyl 461 3CF ₃ COOH 158

4-Me-phenyl 471 3CF ₃ COOH

Table 4 Example -NR ^5a R ^6a -R ³ EIMC (M + 1) HA 159

4-Me-phenyl 492 3CF ₃ COOH 160

4-F-phenyl 496 3CF ₃ COOH 161

4-Me-phenyl 354 2CF ₃ COOH 162

4-Me-phenyl 455 163

4-F-phenyl 459 164

2,6-di-F-phenyl 477 165

4-F-phenyl 384 2CF ₃ COOH 166

2,6-di-F-phenyl 402 2CF ₃ COOH 167

4-F-phenyl 344 2CF ₃ COOH 168

2,6-di-F-phenyl 362 2CF ₃ COOH

Example 169

4- (methoxycarbonyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a solution (20 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.00 g, 4.85 mmol) in N, N-dimethylformamide, methyl 4- (bromomethyl) benzoate (1.22 g, 5.33 mmol) and potassium carbonate (1.01 g, 7.28 mmol) were added and the mixture was stirred at room temperature for 14 hours The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.50 g, yield 92%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.25 (1H, m), 2, 35 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.93 (3H, s), 4.12 (2H, d, J = 7.0 Hz), 4.21 (1H, br.s), 4.98 (2H, s), 7.01 (2H, d, J = 7.9 Hz), 7.07-7.12 (4H, m), 7.93 (2H, d, J = 8.3 Hz).

2) 4- (Methoxycarbonyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (427 mg, 90% yield) was obtained as a white powder from 4- (methoxycarbonyl ) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.50 g, 0.892 mmol) in a manner similar to the method of example 2-3) .

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.8 Hz), 2.20 (1H, m), 2.34 (3H, s), 2.85 ( 2H, d, J = 6.6 Hz), 3.80 (2H, d, J = 5.3 Hz), 3.87 (3H, s), 5.07 (2H, s), 7.13- 7.16 (4H, m), 7.20 (2H, d, J = 7.9 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.22 (3H, br.s )

Example 170

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride

1) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] benzoic acid (340 mg, 32% yield) was obtained as a colorless oil from 4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) nicotinate (1.10 g, 1.96 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2, 35 (3H, s), 2.55 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.12 (2H, s), 4.22 (1H, br.s ), 5.00 (2H, s), 7.02 (2H, d, J = 7.7 Hz), 7.06-7.14 (4H, m), 7.99 (2H, d, J = 8.3 Hz).

2) 4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy} methyl] benzoic acid dihydrochloride (326 mg, yield 93 %) was obtained as a white powder from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl } hydroxy) methyl] benzoic acid (370 mg, 0.677 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.17-2.27 (1H, m), 2.34 (3H, s), 2.80 (2H, d, J = 7.5 Hz), 3.80 (2H, d, J = 5.8 Hz), 5.06 (2H, s), 7.10-7.14 (4H , m), 7.20 (2H, d, J = 8.1 Hz), 8.10 (3H, br.s).

Example 171

2-amino-2-thioxoethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a solution (50 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (3.00 g, 7.27 mmol) in N, N-dimethylformamide bromoacetonitrile (0.66 ml, 9.45 mmol) and potassium carbonate (1.51 g, 10.9 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain cyanomethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.78 g, 85% yield) ) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 39 (3H, s), 2.56 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 4.17 (2H, d, J = 4.9 Hz), 4, 24 (1H, br s), 4.50 (2H, s), 7.05 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 7.9 Hz).

2) Hydrogen sulfide was blown into a solution (25 ml) of cyanomethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.78 g, 6, 16 mmol) and triethylamine (0.94 ml, 6.77 mmol) in N, N-dimethylformamide for 1 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml). The solution was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting yellow solid was washed with diisopropyl ether to obtain 2-amino-2-thioxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) nicotinate (2.81 g, 94% yield) as a tan solid.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 40 (3H, s), 2.56 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.14 (2H, d, J = 4.5 Hz), 4, 22 (1H, br.s), 4.80 (2H, br), 6.21 (1H, br.s), 6.98 (1H, br.s), 7.13 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.5 Hz).

3) 2-amino-2-thioxoethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (133 mg, 70% yield) was obtained as a yellow solid from 2- amino-2-thioxoethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (200 mg, 0.412 mmol) in a manner similar to the method of example 2-3 )

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.37 (3H, s), 2.58 (3H, s), 2.83 (2H, d, J = 6.2 Hz), 3.83 (2H, d, J = 5.7 Hz), 4.45 (2H, s), 7.21 (2H, d, J = 7.7 Hz), 7.29 (2H, d, J = 7.9 Hz), 8.16 (3H, br.s), 8.98 (1H, br c), 9.85 (1H, broad s).

Example 172

[4- (Ethoxycarbonyl) -1,3-thiazol-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a mixed solution of 2-amino-2-thioxoethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (2.02 g, 4.41 mmol) in a mixture of tetrahydrofuran (30 ml) -saturated aqueous sodium hydrogen carbonate (10 ml) was added benzyl chloroformate (903 mg, 5.30 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2-amino-2-thioxoethyl-5 - ({[((benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2 , 00 g, yield 87%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.16-2.25 (1H, m), 2.39 (3H, s), 2, 56 (3H, s), 2.81 (2H, d, J = 7.4 Hz), 4.22 (2H, d, J = 5.1 Hz), 4.43 (1H, br.s), 4.79 (2H, s), 5.04 (2H, s), 6.23 (1H, br s), 6.97 (1H, br s), 7.11 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.29-7.36 (5H, m).

2) Solution (70 ml) of 2-amino-2-thioxoethyl-5 - ({[((benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.00 g, 3.85 mmol) and ethyl bromopyruvate (1.08 g, 5.00 mmol) in ethanol were heated under reflux for 1 h. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] methyl-5 - ({[(benzyloxy) carbonyl] amino} methyl) -6 -isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.37 g, 100% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.10-2.26 ( 1H, m), 2.32 (3H, s), 2.56 (3H, s), 2.82 (2H, d, J = 7.2 Hz), 4.21 (2H, d, J = 5 , 3 Hz), 4.44 (2H, q, J = 7.0 Hz), 5.03 (3H, s), 5.22 (2H, s), 7.00 (2H, d, J = 8 , 1 Hz), 7.07 (2H, d, J = 7.9 Hz), 7.22-7.38 (5H, m), 8.15 (1H, s).

3) [4- (Ethoxycarbonyl) -1,3-thiazol-2-yl] methyl-5 - ({[((benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl ) nicotinate (2.37 g, 3.85 mmol) was dissolved in a 30% solution (30 ml) of hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved by adding saturated aqueous sodium hydrogen carbonate (30 ml) and tetrahydrofuran (50 ml). Di-tert-butyl dicarbonate (1.02 g, 4.66 mmol) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6- isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.72 g, 78% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 1.42 (3H, t, J = 7.2 Hz) , 2.17-2.27 (1H, m), 2.33 (3H, s), 2.56 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4, 11-4.16 (2H, m), 4.24 (1H, br.s), 4.44 (2H, q, J = 7.2 Hz), 5.22 (2H, s), 7.02 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 7.9 Hz), 8.16 (1H, s).

4) [4- (Ethoxycarbonyl) -1,3-thiazol-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (322 mg, yield 90 %) was obtained as a white powder from [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] methyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 - (4-methylphenyl) nicotinate (373 mg, 0.643 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.32 (3H, t, J = 7.2 Hz), 2.18-2, 27 (1H, m), 2.29 (3H, s), 2.55 (3H, s), 2.80-2.92 (2H, m), 3.79 (2H, d, J = 5, 3 Hz), 4.32 (2H, q, J = 7.1 Hz), 5.30 (2H, s), 7.12 (4H, s), 8.25 (3H, br.s), 8 56 (1H, s).

Example 173

Dihydrochloride 2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -1,3-thiazole-4-carbon acid

1) 2 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] - 1,3-thiazol-4-carboxylic acid (1.21 g, 95% yield) was obtained as a colorless oil from [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] methyl-5 - {[(( tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.34 g, 2.30 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.4 Hz), 1.38 (9H, s), 2.16-2.28 (1H, m), 2, 33 (3H, s), 2.61 (3H, br.s), 2.85 (2H, br.s), 4.11-4.19 (2H, m), 4.23 (1H, br. s), 5.22 (2H, s), 7.02 (2H, d, J = 7.9 Hz), 7.10 (2H, d, J = 7.4 Hz), 8.24 (1H, from).

2) Dihydrochloride 2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -1,3-thiazol-4 -carboxylic acid (362 mg, 83% yield) was obtained as a pale yellow powder from 2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -1,3-thiazole-4-carboxylic acid (460 mg, 0.831 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.30 (3H, s), 2.53 (3H, s), 2.85 (2H, d, J = 7.0 Hz), 3.80 (2H, d, J = 5.1 Hz), 5.29 (2H, s), 7.12 (4H, s), 8.21 (3H, br s), 8.48 (1H, s).

Example 174

[4- (Aminocarbonyl) -1,3-thiazol-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) [4- (Aminocarbonyl) -1,3-thiazol-2-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (420 mg, 70% yield) was obtained as a colorless oil from 2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -1,3-thiazole-4-carboxylic acid (602 mg, 1.09 mmol) in a manner similar to the method of example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.18-2.27 (1H, m), 2, 33 (3H, s), 2.57 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.10-4.16 (2H, m), 4.22 (1H , br.s), 5.17 (2H, s), 5.64 (1H, br.s), 7.01 (2H, d, J = 7.9 Hz), 7.09 (2H, d, J = 7.9 Hz), 8.13 (1H, s).

2) [4- (Aminocarbonyl) -1,3-thiazol-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (208 mg, yield 48 %) was obtained as a white powder from [4- (aminocarbonyl) -1,3-thiazol-2-yl] methyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 - (4-methylphenyl) nicotinate (460 mg, 0.832 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.30 (3H, s), 2.53 (3H, s), 2.79-2.89 (2H, m), 3.79 (2H, d, J = 5.5 Hz), 5.28 (2H, s), 7.12 (4H, s), 7.62 (1H, br s), 7.66 (1H, br s), 8.22 (3H, br s), 8.48 (1H, s).

Example 175

[(2,2-Dimethylpropanoyl) oxy] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a solution (20 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide, chloromethyl pivalate (0.59 ml, 4.04 mmol) and potassium carbonate (0.93 g, 6.72 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain [(2,2-dimethylpropanoyl) oxy] methyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 - (4-methylphenyl) nicotinate (1.68 g, 95% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.16 (9H, s), 1.39 (9H, s), 2.14-2, 29 (1H, m), 2.38 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.13 (2H, d, J = 4.9 Hz), 4.21 (1H, br.s), 5.57 (2H, s), 7.06 (2H, d, J = 8.1 Hz), 7.20 (2H, d , J = 7.9 Hz).

2) [(2,2-Dimethylpropanoyl) oxy] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (1.58 g, 99% yield) was obtained as white solid from [(2,2-dimethylpropanoyl) oxy] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.68 g, 3.19 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.09 (9H, s), 2.17-2.29 (1H, m), 2.37 (3H, s), 2.49 (3H, s), 2.84 (2H, d, J = 7.0 Hz), 3.78 (2H, d, J = 5.5 Hz), 5.61 (2H, s), 7.19 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.20 (3H, br.s )

Example 176

(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a solution (20 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide, 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (0.60 g, 4.04 mmol) and potassium carbonate (0.93 g, 6.72 mmol) were added. ) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} - 6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.50 g, 85% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 1.97 (3H, s), 2.16-2, 26 (1H, m), 2.40 (3H, s), 2.54 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.09 (2H, s), 4.74 (2H, s), 7.10 (2H, d, J = 7.9 Hz), 7.17 (2H, d, J = 7.9 Hz).

2) (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride g, yield 85%) was obtained as a white powder from (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl -2-methyl-4- (4-methylphenyl) nicotinate (1.50 g, 2.86 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.97 (3H, s), 2.17-2.28 (1H, m), 2.35 (3H, s), 2.82 (2H, d, J = 7.0 Hz), 3.79 (2H, d, J = 5.5 Hz), 4.93 (2H, s), 7.12 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 7.9 Hz), 8.15 (3H, br.s).

Example 177

3-oxo-1,3-dihydro-2-benzofuran-1-yl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a solution (30 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide, 3-chloro-2-benzofuran-1 (3H) -one (0.86 g, 4.04 mmol) and potassium carbonate (0.93 g, 6.72 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give 3-oxo-1,3-dihydro-2-benzofuran-1-yl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl -2-methyl-4- (4-methylphenyl) nicotinate (1.83 g, 99% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 42 (3H, s), 2.63 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.12 (2H, s), 6.98-7.08 (3H , m), 7.17 (2H, d, J = 7.9 Hz), 7.24 (1H, s), 7.59-7.64 (2H, m), 7.83-7.88 ( 1H, m).

2) 3-oxo-1,3-dihydro-2-benzofuran-1-yl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride was obtained as a white powder from 3 -oxo-1,3-dihydro-2-benzofuran-1-yl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1, 83 g, 3.36 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.15-2.28 (1H, m), 2.38 (3H, s), 2.59 (3H, s), 2.81 (2H, d, J = 7.2 Hz), 3.79 (2H, d, J = 5.7 Hz), 7.07-7.15 (3H , m), 7.25-7.32 (2H, m), 7.40 (1H, s), 7.73-7.75 (1H, m), 7.79-7.84 (1H, m ), 7.89 (1H, d, J = 7.5 Hz), 8.12 (3H, br.s).

Example 178

(2E) -2- (3-oxo-2-benzofuran-1 (3H) -ilidene) ethyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a solution (10 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (380 mg, 0.853 mmol) in N, N (3E) -3- (2-chloroethylidene) -2-benzofuran-1 (3H) -one (170 mg, 0.711 mmol) and potassium carbonate (147 mg, 1.07 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (2E) -2- (3-oxo-2-benzofuran-1 (3H) -ilidene) ethyl 5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (270 mg, 55% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.26 (4H, m), 2, 58 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.12 (2H, s), 4.21 (1H, br.s), 4.85 (2H, d , J = 7.4 Hz), 5.25 (1H, t, J = 7.4 Hz), 7.07 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.55-7.64 (2H, m), 7.72-7.78 (1H, m), 7.92-7.95 (1H, m).

2) (2E) -2- (3-oxo-2-benzofuran-1 (3H) -ilidene) ethyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride ( 204 mg, 79% yield) was obtained as a white powder from (2E) -2- (3-oxo-2-benzofuran-1 (3H) -ilidene) ethyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (270 mg, 0.473 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.07 (3H, s), 2.18-2.29 (1H, m), 2.79 (2H, d, J = 6.6 Hz), 3.78 (2H, d, J = 7.4 Hz), 4.81 (2H, d, J = 7.5 Hz), 5, 68 (1H, t, J = 7.5 Hz), 7.14 (4H, s), 7.71-7.77 (1H, m), 7.90-8.00 (3H, m), 8 06 (3H, br s).

Example 179

Benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

To a solution (30 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (3.00 g, 6.73 mmol) in N , N-dimethylformamide was added benzyl bromide (0.80 ml, 6.73 mmol) and potassium carbonate (1.85 g, 13.4 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (200 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in trifluoroacetic acid (50 ml) and the mixture was stirred at room temperature for 3 hours. Trifluoroacetic acid was evaporated under reduced pressure and the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain benzyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.70 g, 99% yield) in as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 0.91 (6H, d, J = 6.6 Hz), 2.07-2.18 (1H, m), 2.34 (3H, s), 2, 51 (3H, s), 2.72 (2H, d, J = 7.4 Hz), 3.84 (2H, s), 4.94 (2H, s), 7.02-7.12 (6H m) 7.24-7.31 (3H, m).

Example 180

2-oxo-1,3-dioxolan-4-yl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) To a solution (30 ml) of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.50 g, 3.37 mmol) in N, N-dimethylformamide, 4-chloro-1,3-dioxolan-2-one (0.55 g, 4.04 mmol) and potassium carbonate (0.70 g, 5.05 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 2-oxo-1,3-dioxolan-4-yl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) nicotinate (1.39 g, 83% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 41 (3H, s), 2.60 (3H, s), 2.81 (2H, d, J = 7.4 Hz), 3.67 (1H, dd, J = 10.2, 1.5 Hz ), 4.16 (2H, d, J = 4.9 Hz), 4.22 (1H, br.s), 4.31 (1H, dd, J = 10.0, 5.7 Hz), 4 , 63-4.82 (1H, m), 6.41-6.46 (1H, m), 7.01-7.10 (2H, m), 7.19-7.26 (2H, m) .

2) 2-oxo-1,3-dioxolan-4-yl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (1.31 g, yield 99%) was obtained in the form of a white powder from 2-oxo-1,3-dioxolan-4-yl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate ( 1.39 g, 2.79 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.18-2.28 (1H, m), 2.36 (3H, s), 2.55 (3H, s), 2.85 (2H, d, J = 7.0 Hz), 3.83 (2H, d, J = 5.7 Hz), 4.04 (1H, dd, J = 10.2, 1.7 Hz), 4.59 (1H, dd, J = 10.1, 5.7 Hz), 6.59 (1H, dd, J = 5.4 Hz), 7.14 -7.20 (2H, m), 7.24-7.29 (2H, m), 8.23 (3H, br s).

Example 181

5- (aminomethyl) -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride

1) tert-Butyl 4- [4- (benzyloxy) phenyl] -5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (21.4 g, 77% yield) was obtained in as a pale pink solid from 4- (benzyloxy) benzaldehyde (12.8 g, 60.4 mmol) in a manner similar to that of Example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz), 1.28 (9H, s) 1.80-1.96 (1H, m), 2.14-2.29 (2H, m), 2.32 (3H, s), 4.51 (1H, s), 5.03 (2H , s), 5.49 (1H, s), 6.90 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz), 7.29-7 46 (5H, m).

2) tert-Butyl-4- [4- (benzyloxy) phenyl] -5-cyano-6-isobutyl-2-methylnicotinate (2.18 g, 94% yield) was obtained as a yellow solid from tert-butyl-4 - [4- (benzyloxy) phenyl] -5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2.33 g, 5.08 mmol) in a manner similar to the method of example 23-3) .

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.25 (9H, s), 2.17-2.33 (1H, m), 2, 63 (3H, s), 2.93 (2H, d, J = 7.4 Hz), 5.12 (2H, s), 7.06 (2H, d, J = 8.9 Hz), 7, 31 (2H, d, J = 8.9 Hz), 7.39-7.49 (5H, m).

3) tert-Butyl-5- (aminomethyl) -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinate was obtained as a crude product from tert-butyl-4- [4- (benzyloxy) phenyl] -5- cyano-6-isobutyl-2-methylnicotinate (2.13 g, 4.67 mmol) in a manner similar to that of Example 1-4). From the crude product, tert-butyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinate (1.35 g, yield 61%) in a manner similar to that of Example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.22 (9H, s), 1.40 (9H, s), 2.12-2, 27 (1H, m), 2.55 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 4.14 (2H, d, J = 4.9 Hz), 4, 25 (1H, br.s), 5.50 (1H, br.s), 6.85 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz )

4) tert-Butyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinate (316 mg, 0.671 mmol) and anisole (218 mg, 2, 01 mmol) was dissolved in trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 5 hours. Trifluoroacetic acid was evaporated under reduced pressure and 4N was added to the residue. 1,4-dioxane solution of hydrogen chloride (20 ml). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the resulting yellow solid was washed with diisopropyl ether to give 5- (aminomethyl) -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinic acid dihydrochloride (259 mg, 99% yield) as a yellow powder .

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.14-2.27 (1H, m), 2.59 (3H, s), 2.92 (2H, d, J = 5.7 Hz), 3.86 (2H, d, J = 4.9 Hz), 6.87 (2H, d, J = 8.5 Hz), 7, 14 (2H, d, J = 8.3 Hz), 8.26 (3H, br.s).

Example 182

5- (aminomethyl) -6-isobutyl-4- (4-methoxyphenyl) -2-methylnicotinic acid dihydrochloride

1) To a solution (20 ml) of tert-butyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -4- (4-hydroxyphenyl) -6-isobutyl-2-methylnicotinate (620 mg, 1.32 mmol) and potassium carbonate (365 mg, 2.64 mmol) in N, N-dimethylformamide iodomethane (374 mg, 2.64 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methoxyphenyl) -2-methylnicotinate (520 mg, 81% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.21 (9H, s), 1.39 (9H, s), 2.13-2, 26 (1H, m), 2.55 (3H, s), 2.76 (2H, d, J = 7.4 Hz), 3.84 (3H, s), 4.12 (2H, s), 4.22 (1H, br.s), 6.94 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.7 Hz).

2) 5- (Aminomethyl) -6-isobutyl-4- (4-methoxyphenyl) -2-methylnicotinic acid dihydrochloride (429 mg, 99% yield) was obtained as a yellow powder from tert-butyl-5 - {[(tert- butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methoxyphenyl) -2-methylnicotinate (520 mg, 1.07 mmol) in a manner similar to that of Example 181-4).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.54 (3H, s), 2.85 (2H, d, J = 6.6 Hz), 3.57 (3H, s), 3.84 (2H, s), 7.05 (2H, d, J = 8.7 Hz), 7.26 (2H, d, J = 8.7 Hz), 8.17 (3H, br s).

Example 183

Methyl 4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate dihydrochloride

1) A mixture of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.00 g, 2.51 mmol), triethylamine (0.7 ml, 5.02 mmol) and tetrahydrofuran (20 ml) were cooled to 0 ° C and methanesulfonyl chloride (432 mg, 3.77 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate as a crude product. The crude product was dissolved in N, N-dimethylformamide (15 ml) and potassium carbonate (520 mg, 3.77 mmol) and methyl 4-mercaptobenzoate (422 mg, 2.51 mmol) were added. The mixture was stirred with heating at 50 ° C for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) pyridin-3-yl] methyl} thio) benzoate (1.01 g, 73% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 37 (3H, s), 2.65 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.86 (2H, s), 3.89 (3H, s), 4.04 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 7.04 (2H, d, J = 7.9 Hz), 7.09 (2H, d , J = 8.7 Hz), 7.19 (2H, d, J = 7.7 Hz), 7.85 (2H, d, J = 8.7 Hz).

2) Methyl-4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate dihydrochloride (138 mg, 73% yield) obtained as a pale yellow powder from methyl-4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate (200 mg, 0.365 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.12-2.23 (1H, m), 2.35 (3H, s), 2.81 (3H, s), 3.64 (2H, br.s), 3.75 (2H, d, J = 5.7 Hz), 3.83 (3H, s), 4.01 (2H , s), 7.24-7.33 (6H, m), 7.82 (2H, d, J = 8.7 Hz), 8.30 (3H, br.s).

Example 184

4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid dihydrochloride

1) 4 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0 97 g, yield 72%) was obtained as a white solid from methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) pyridin-3-yl] methyl} thio) benzoate (1.37 g, 2.51 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.23-2.35 (1H, m), 2, 42 (3H, s), 3.08 (3H, s), 3.30-3.40 (2H, m), 3.90 (2H, s), 4.12-4.18 (2H, m) 4.30 (1H, br.s), 7.05 (2H, d, J = 7.9 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.23-7, 31 (2H, m), 7.93 (2H, d, J = 8.5 Hz).

2) 4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid dihydrochloride (198 mg, 77% yield) was obtained in the form of a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0.27 g, 0.505 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.13-2.23 (1H, m), 2.36 (3H, s), 2.81 (3H, s), 3.05 (2H, broad s), 3.71-3.80 (2H, m), 4.01 (2H, s), 7.23-7.27 ( 4H, m), 7.32 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.3 Hz), 8.32 (3H, br.s).

Example 185

Methyl 4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoate dihydrochloride

1) Methyl-4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoate ( 410 mg, 84% yield) was obtained as a colorless oil from methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine -3-yl] methyl} thio) benzoate (0.46 g, 0.838 mmol) in a manner similar to that of Example 91-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.7 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2, 41 (3H, s), 2.64 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.98 (3H, s), 4.00 (2H, d, J = 5.3 Hz), 4.18 (1H, br.s), 4.32 (2H, s), 6.87 (2H, d, J = 7.7 Hz), 7.17 (2H, d , J = 7.7 Hz), 7.56 (2H, d, J = 8.5 Hz), 8.08 (2H, d, J = 8.5 Hz).

2) Methyl-4 - ({[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoate dihydrochloride (352 mg, 90% yield) obtained as a pale yellow powder from methyl-4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoate (410 mg, 0.706 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.17-2.27 (1H, m), 2.38 (3H, s), 2.78 (3H, s), 3.00 (2H, br s), 3.66-3.74 (2H, m), 3.93 (3H, s), 4.61 (2H, br. s), 7.05 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 7.9 Hz), 7.66 (2H, d, J = 8.3 Hz) 8.09 (2H, d, J = 8.7 Hz); 8.30 (3H, br s).

Example 186

4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoic acid dihydrochloride

1) 4 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoic acid (300 mg, 93% yield) was obtained as a colorless oil from methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] methyl} sulfonyl) benzoate (330 mg, 0.568 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.22 (1H, m), 2, 34 (3H, s), 2.43 (3H, s), 2.86 (2H, d, J = 7.4 Hz), 4.06 (2H, d, J = 4.5 Hz), 4, 28 (1H, br.s), 4.35 (2H, s), 6.97 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 7.7 Hz), 7.60 (2H, d, J = 8.1 Hz); 8.17 (2H, d, J = 8.1 Hz).

2) 4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoic acid dihydrochloride (279 mg, 97% yield) was obtained in the form of a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) benzoic acid (300 mg, 0.530 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.17-2.24 (1H, m), 2.38 (3H, s), 2.76 (3H, broad s), 2.95 (2H, broad s), 3.70 (2H, broad s), 7.05 (2H, d, J = 7.9 Hz), 7 23 (2H, d, J = 7.9 Hz), 7.62 (2H, d, J = 8.3 Hz), 8.07 (2H, d, J = 8.3 Hz), 8.24 (3H, broad s).

Example 187

N - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} methanesulfonamide dihydrochloride

1) To a solution (10 ml) of tert-butyl {[5- (aminomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (200 mg, 0.755 mmol) and triethylamine (0.14 ml, 1.00 mmol) in tetrahydrofuran was added methanesulfonyl chloride (86 mg, 0.875 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed successively with saturated aqueous bicarbonate solution. sodium and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting yellow solid was washed with diisopropyl ether to obtain tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[(methylsulfonyl) amino] methyl} pyridin-3 -yl) methyl] carbamate (210 mg, 87% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 42 (3H, s), 2.61 (3H, s), 2.68 (3H, s), 2.76 (2H, d, J = 7.4 Hz), 3.87 (1H, br.s ), 4.01 (2H, d, J = 5.7 Hz), 4.03 (2H, d, J = 5.3 Hz), 4.18 (1H, br.s), 7.03 (2H d, J = 8.1 Hz), 7.29 (2H, d, J = 7.9 Hz).

2) N - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} methanesulfonamide dihydrochloride (126 mg, 64% yield) was obtained as a white powder from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[(methylsulfonyl) amino] methyl} pyridin-3-yl) methyl] carbamate (210 mg, 0.441 mmol) by the method similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.12-2.23 (1H, m), 2.41 (3H, s), 2.71 (3H, s), 2.84 (3H, s), 3.04 (2H, s), 3.76 (2H, s), 3.87 (2H, s). s), 7.19 (1H, br.s), 7.29 (2H, d, J = 7.5 Hz), 7.38 (2H, d, J = 7.7 Hz), 8.28 ( 3H, broad s).

Example 188

{[4- (2,4-Dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylpyridin-3-yl] methyl} amine dihydrochloride

1) (2E) -3- (2,4-Dichlorophenyl) -1- (4-fluorophenyl) prop-2-en-1-one (10.3 g, 64% yield) was obtained as a pale yellow solid from 4-fluoroacetophenone (6.91 g, 50 mmol) and 2,6-dichlorobenzamide (8.75 g, 59 mmol) in a manner similar to the method of Example 108-1).

¹ H-NMR (CDCl ₃ ) δ: 7.16-7.23 (2H, m), 7.31 (1H, dd, J = 8.5, 2.1 Hz), 7.42-7.49 (2H, m), 7.68 (2H, d, J = 8.5 Hz), 8.07 (3H, m).

2) 4- (2,4-Dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylnicotinonitrile (2.94 g, 48% yield) was obtained as a yellow oil from (2E) -3- (2,4- dichlorophenyl) -1- (4-fluorophenyl) prop-2-en-1-one (4.54 g, 15.4 mmol) in a manner similar to the method of Example 108-2).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (6H, d, J = 6.6 Hz), 2.32-2.45 (1H, m), 3.04 (2H, d, J = 7 , 2 Hz), 7.09-7.24 (3H, m), 7.33 (1H, d, J = 8.3 Hz), 7.37-7.44 (1H, m), 7.57 (1H, s), 7.59 (1H, d, J = 1.9 Hz), 8.06-8.12 (1H, m).

3) {[4- (2,4-Dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylpyridin-3-yl] methyl} amine (780 mg, 68% yield) was obtained as a pale yellow oil from 4 - (2,4-Dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylnicotinonitrile (1.14 g, 2.85 mmol) in a manner similar to the method of Example 23-4). The oil was dissolved in 4n. A 1.4-dioxane solution of hydrogen chloride (20 ml) and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the resulting pale yellow solid was washed with diisopropyl ether to obtain {[4- (2,4-dichlorophenyl) -6- (4-fluorophenyl) -2-isobutylpyridin-3-yl] methyl} amine dihydrochloride ( 895 mg, 97% yield) as a pale yellow powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (3H, d, J = 6.6 Hz), 1.05 (3H, d, J = 6.6 Hz), 2.29-2, 38 (1H, m), 2.81-2.99 (2H, m), 3.57-3.64 (1H, m), 4.04-4.16 (1H, m), 7.33 ( 2H, t, J = 8.8 Hz), 7.59-7.67 (2H, m), 7.73 (1H, s), 7.86 (1H, d, J = 1.9 Hz), 8.21-8.30 (5H, m).

Example 189

Methyl 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate dihydrochloride

1) (2E) -1- (3-Bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (7.09 g, 47% yield) was obtained as a pale yellow powder from 3- bromoacetophenone (9.95 g, 50 mmol) in a manner similar to the method of example 108-1).

2) 6- (3-Bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile (2.20 g, 32% yield) was obtained as a pale yellow solid from (2E) -1- (3- bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (5.03 g, 16.7 mmol) in a manner similar to the method of Example 108-2).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (6H, d, J = 6.6 Hz), 2.35-2.42 (1H, m), 2.45 (3H, s), 3, 06 (2H, d, J = 7.4 Hz), 7.09-7.16 (3H, m), 7.30-7.40 (4H, m), 7.53-7.55 (1H, m), 7.64 (1H, s).

3) 6- (3-Bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile (2.20 g, 5.40 mmol), triethylamine (0.70 ml, 10.0 mmol) and dichloride [1 , 1'-bis (diphenylphosphino) ferrocene] palladium (II) (410 mg, 0.500 mmol) was dissolved in a mixed solvent methanol (10 ml) -N, N-dimethylformamide (30 ml) and the mixture was stirred in an atmosphere of carbon monoxide for 15 h. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain methyl 3- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (1.39 g, 72% yield) as a colorless oil . Methyl 3- [5- (aminomethyl) was obtained from methyl 3- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (1.30 g, 3.38 mmol) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (780 mg, 58% yield) as a colorless oil in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 1.05 (6H, d, J = 6.6 Hz), 2.37-2.48 (4H, m), 2.90 (2H, d, J = 7 , 2 Hz), 3.84 (2H, s), 3.94 (3H, s), 7.27-7.33 (4H, m), 7.49 (1H, s), 7.54 (1H , t, J = 7.9 Hz), 8.04-8.07 (1H, m), 8.32 (1H, m), 8.61-8.62 (1H, m).

4) Methyl-3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (730 mg, 76% yield) was obtained as white powder from methyl 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (0.76 g, 1.96 mmol) in a manner similar to the method of example 2-1 )

¹ H-NMR (CDCl ₃ ) δ: 1.04 (6H, d, J = 6.6 Hz), 1.43 (9H, s), 2.37-2.46 (4H, m), 2, 87 (2H, d, J = 7.2 Hz), 3.94 (3H, s), 4.29-4.35 (2H, m), 4.38 (1H, br.s), 7.23 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.50 (1H, s), 7.54 (1H, t, J = 7, 8 Hz), 8.05-8.08 (1H, m), 8.30-8.34 (1H, m), 8.62-8.63 (1H, m).

5) Methyl 3- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate dihydrochloride (188 mg, 99% yield) was obtained as a white powder from methyl-3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (200 mg, 0.409 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (6H, d, J = 6.4 Hz), 2.33-2.44 (4H, m), 2.93 (2H, d, J = 7.0 Hz), 3.90 (3H, s), 4.01 (2H, d, J = 5.5 Hz), 7.36 (2H, d, J = 8.1 Hz), 7, 41 (2H, d, J = 8.3 Hz), 7.66 (1H, t, J = 7.8 Hz), 7.76 (1H, s), 8.01-8.08 (1H, m ), 8.40 (3H, br s), 8.42-8.47 (1H, m), 8.71-8.75 (1H, m).

Example 190

3- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid dihydrochloride

1) 3- [5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (500 mg, 98% yield) was obtained as white solids from methyl 3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (530 mg, 1.08 mmol) by similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.05 (6H, d, J = 6.6 Hz), 1.43 (9H, s), 2.35-2.47 (4H, m), 2, 92 (2H, br.s), 4.31-4.37 (2H, m), 4.42 (1H, br.s), 7.22-7.30 (4H, m), 7.52 ( 1H, s), 7.58 (1H, t, J = 7.5 Hz), 8.12 (1H, d, J = 7.9 Hz), 8.36 (1H, d, J = 7.4 Hz), 8.67 (1H, s).

2) 3- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid dihydrochloride (188 mg, 99% yield) was obtained as a white powder from 3- [5- {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (200 mg, 0.421 mmol) in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (6H, d, J = 7.4 Hz), 2.32-2.43 (4H, m), 2.92 (2H, d, J = 7.0 Hz), 4.02 (2H, d, J = 5.3 Hz), 7.36 (2H, d, J = 8.1 Hz), 7.41 (2H, d, J = 8 , 3 Hz), 7.63 (1H, t, J = 7.8 Hz), 7.74 (1H, s), 8.01-8.04 (1H, m), 8.35 (3H, br .c), 8.37-8.41 (1H, m), 8.71-8.72 (1H, m).

Example 191

3- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzamide dihydrochloride

1) tert-Butyl {[6- [3- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (160 mg, 53% yield) was obtained as white solids from 3- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (300 mg, 0.632 mmol) in a manner similar to the example method 3-1).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (6H, d, J = 6.6 Hz), 1.43 (9H, s), 2.34-2.48 (4H, m), 2, 87 (2H, d, J = 7.2 Hz), 4.32 (2H, d, J = 4.7 Hz), 4.39 (1H, br.s), 7.22 (2H, d, J = 8.1 Hz), 7.25-7.29 (2H, m), 7.50 (1H, s), 7.55 (1H, t, J = 7.8 Hz), 7.83-7 87 (1H, m), 8.21-8.25 (1H, m), 8.45-8.46 (1H, m).

2) 3- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzamide dihydrochloride (127 mg, 84% yield) was obtained as a white powder from tert-butyl {[6 - [3- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (160 mg, 0.338 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (6H, d, J = 6.6 Hz), 2.34-2.44 (4H, m), 2.93 (2H, d, J = 7.0 Hz), 4.01 (2H, d, J = 5.5 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.42 (2H, d, J = 8 , 1 Hz), 7.47 (1H, br.s), 7.60 (1H, t, J = 7.8 Hz), 7.81 (1H, s), 7.96 (1H, d, J = 7.7 Hz), 8.14 (1H, br.s), 8.33-8.44 (4H, m), 8.58 (1H, s).

Example 192

Methyl 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate dihydrochloride

1) (2E) -1- (2-Bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (8.86 g, 44% yield) was obtained as a pale yellow powder from 2- bromoacetophenone (9.95 g, 50 mmol) in a manner similar to the method of example 108-1).

2) 6- (2-Bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile (3.58 g, yield 53%) was obtained as a pale yellow solid from (2E) -1- (2- bromophenyl) -3- (4-methylphenyl) prop-2-en-1-one (5.03 g, 16.7 mmol) in a manner similar to the method of Example 108-2).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (6H, d, J = 6.6 Hz), 2.34-2.44 (4H, m), 3.07 (2H, d, J = 7 4 Hz), 7.27-7.30 (1H, m), 7.32-7.36 (2H, m), 7.41-7.47 (1H, m), 7.53-7, 60 (3H, m), 7.71 (1H, m).

3) Methyl-2- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (1.80 g, 76% yield) was obtained as a colorless oil from 6- (2- bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile (2.50 g, 6.14 mmol) in a manner similar to the method of Example 189-3). Namely, 6- (2-bromophenyl) -2-isobutyl-4- (4-methylphenyl) nicotinonitrile, triethylamine (1.7 ml, 12.2 mmol) and dichloride [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (501 mg, 0.614 mmol) was dissolved in a mixture of methanol (7.5 ml) -N, N-dimethylformamide (15 ml) and the mixture was stirred under an atmosphere of carbon monoxide for 13 hours. The reaction mixture was diluted with ethyl acetate (100 ml ) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain methyl 2- [5-cyano-6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (6H, d, J = 6.8 Hz), 2.26-2.37 (1H, m), 2.44 (3H, s), 3, 01 (2H, d, J = 7.4 Hz), 3.74 (3H, s), 7.08-7.14 (1H, m), 7.34 (2H, d, J = 7.9 Hz ), 7.42 (1H, s), 7.48-7.61 (4H, m), 7.83-7.88 (1H, m).

4) Methyl-2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate was obtained as a crude product from methyl-2- [5-cyano-6-isobutyl- 4- (4-methylphenyl) pyridin-2-yl] benzoate (1.80 g, 4.68 mmol) in a manner similar to that of Example 1-4). Methyl 2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (1.70 g, 74% yield) was obtained from the crude product. ) in the form of a colorless oil in a manner similar to the method of example 2-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.43 (9H, s), 2.26-2.37 (1H, m), 2, 41 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 3.75 (3H, s), 4.32 (2H, d, J = 4.9 Hz), 4, 42 (1H, broad s), 7.21-7.27 (5H, m), 7.41-7.46 (1H, m), 7.52-7.58 (2H, m), 7, 76 (1H, dd, J = 7.4, 1.1 Hz).

5) Methyl 2- [5- (aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate dihydrochloride (345 mg, 95% yield) was obtained as a pale pink powder from methyl- 2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (383 mg, 0.786 mmol) in a manner similar to the method of example 2-3) .

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.18-2.32 (1H, m), 2.41 (3H, s), 2.89 (2H, d, J = 6.6 Hz), 3.69 (3H, s), 3.99-4.09 (2H, m), 7.36 (2H, d, J = 8, 1 Hz), 7.43 (2H, d, J = 8.1 Hz), 7.49 (1H, s), 7.57-7.70 (2H, m), 7.76 (2H, d, J = 7.5 Hz), 8.51 (3H, br.s).

Example 193

2- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid dihydrochloride

1) 2- [5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (0.85 g, 67% yield) was obtained in as a colorless oil from methyl 2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoate (1.31 g, 2.69 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.6 Hz), 1.42 (9H, s), 2.21-2.33 (1H, m), 2, 44 (3H, s), 2.93 (2H, d, J = 7.4 Hz), 4.39 (2H, br.s), 7.22 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.48 (1H, s), 7.54-7.66 (3H, m), 8.31 (1H, m).

2) 2- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid dihydrochloride (329 mg, 81% yield) was obtained as a white powder from 2- [5- {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (429 mg, 0.904 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.27-2.36 (1H, m), 2.41 (3H, s), 2.90 (2H, d, J = 6.6 Hz), 4.04 (2H, d, J = 5.1 Hz), 7.36 (2H, d, J = 8.3 Hz), 7, 40-7.49 (3H, m), 7.54-7.70 (3H, m), 7.76-7.84 (1H, m), 8.44 (3H, br.s).

Example 194

2- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzamide dihydrochloride

1) tert-Butyl {[6- [2- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (290 mg, 69% yield) was obtained as a colorless oils from 2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzoic acid (421 mg, 0.887 mmol) in a manner similar to the method of example 3 -one).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.43 (9H, s), 2.30-2.37 (1H, m), 2, 41 (3H, s), 2.83 (2H, d, J = 7.4 Hz), 4.34 (2H, d, J = 4.7 Hz), 4.42 (1H, br.s), 5.54 (1H, br.s), 6.42 (1H, br.s), 7.20 (2H, d, J = 8.3 Hz), 7.24-7.25 (3H, m) 7.42-7.53 (3H, m); 7.70-7.75 (1H, m).

2) 2- [5- (Aminomethyl) -6-isobutyl-4- (4-methylphenyl) pyridin-2-yl] benzamide dihydrochloride (254 mg, 93% yield) was obtained as a yellow powder from tert-butyl {[6 - [2- (aminocarbonyl) phenyl] -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (290 mg, 0.612 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.27-2.37 (1H, m), 2.40 (3H, s), 2.90-2.99 (2H, m), 4.04 (2H, m), 7.36 (2H, d, J = 8.1 Hz), 7.41 (2H, d, J = 8, 3 Hz), 7.50 (1H, s), 7.56-7.71 (4H, m), 7.92-8.01 (1H, m), 8.61 (3H, br.s).

Example 195

5- (aminomethyl) -N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride

1) 5-Cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.16 g, 85% yield) was obtained as a white powder from tert-butyl-5-cyano-6-isobutyl -2-methyl-4- (4-methylphenyl) nicotinate (3.00 g, 8.23 mmol) in a manner similar to that of Example 24-1).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.32 (1H, m), 2.42 (3H, s), 2, 67 (3H, s), 2.95 (2H, d, J = 7.4 Hz), 7.27-7.34 (4H, m).

2) To a solution of 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.00 g, 6.49 mmol) in dichloromethane was added oxalyl chloride (0.68 ml, 7.78 mmol) ) and N, N-dimethylformamide (0.05 ml) and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran. Then, triethylamine (1.8 ml, 13.0 mmol) and dicyclohexylamine (1.55 ml, 7.78 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give 5-cyano-N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide (0.35 g, 11% yield) ) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.79-0.96 (4H, m), 1.01 (6H, dd, J = 11.1, 6.6 Hz), 1.07-1.34 (4H, m), 1.40-1.53 (5H, m), 1.58-1.68 (4H, m), 1.72-1.84 (3H, m), 2.22-2 , 31 (1H, m), 2.40 (3H, s), 2.59 (3H, s), 2.69-2.79 (2H, m), 2.87-3.04 (2H, m ), 7.25 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 8.1 Hz).

3) 5- (Aminomethyl) -N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide dihydrochloride (0.20 g, 49% yield) was obtained as a yellow powder from 5-cyano -N, N-dicyclohexyl-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinamide (0.35 g, 0.742 mmol) in a manner similar to the method of Example 108-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.73-0.88 (2H, m), 0.90-1.15 (12H, m), 1.24-1.75 (10H, m) , 2.13-2.27 (3H, m), 2.36 (3H, s), 2.78-2.86 (2H, m), 2.88-2.95 (2H, m), 3 68-3.81 (1H, m); 3.96-4.09 (1H, m); 7.26-7.37 (4H, m).

Example 196

Methyl-1 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} piperidine-4-carboxylate dihydrochloride

1) Methyl-1 - {[5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} piperidine-4-carboxylate (3.20 g, 91% yield) prepared as a colorless oil from 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.50 g, 8.1 mmol) and methyl isonipecotate (1.3 ml, 9.73 mmol) ) in a manner similar to that of Example 195-2).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, dd, J = 12.1, 6.6 Hz), 1.42-1.85 (4H, m), 2.19-2.37 (3H, m), 2.40 (3H, s), 2.55-2.60 (3H, m), 2.61-3.20 (5H, m), 3.63-3.66 (3H , m), 4.23-4.45 (1H, m), 7.25-7.42 (4H, m).

2) Methyl-1 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} piperidine-4-carboxylate dihydrochloride (3.27 g, yield 87%) was obtained as a white powder from methyl 1 - {[5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} piperidine-4-carboxylate (3, 20 g, 7.38 mmol) in a manner similar to the method of Example 108-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.67-0.90 (1H, m), 0.98 (6H, t, J = 5.9 Hz), 1.25-1.76 (3H , m), 2.16-2.28 (1H, m), 2.36-2.37 (3H, m), 2.63-2.76 (1H, m), 2.90-3.03 (2H, m), 3.17-3.34 (1H, m), 3.57 (3H, s), 3.58-3.60 (2H, m), 3.68-3.97 (2H , m), 4.05-4.10 (1H, m), 7.11-7.36 (4H, m), 8.34 (3H, br.s).

Example 197

5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid tert-butylamine salt

5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.10 g, 0.320 mmol) was dissolved in a mixed solvent water (1.5 ml) -acetonitrile (1.5 ml ) when heated under reflux for 10 minutes Tert-butylamine (23.4 mg, 0.320 mmol) was added to the resulting solution, and the mixture was stirred at the same temperature for 10 minutes. Acetonitrile (20 ml) was added, the mixture was allowed to cool to room temperature and then stirred at 0 ° C for 30 minutes. The precipitated solid was collected by filtration and washed with acetonitrile (10 ml) to obtain the 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid tert-butylamine salt (78.4 mg, yield 63%) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (6H, d, J = 6.6 Hz), 1.12 (9H, s), 2.06-2.25 (1H, m), 2.31 (3H, s), 2.34 (3H, s), 2.66 (2H, d, J = 7.0 Hz), 3.31 (2H, br.s), 3.37 (2H c), 7.10 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz).

Example 198

({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylthio) methyl] pyridin-3-yl} methyl) amine dihydrochloride

1) To a solution of [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate (476 mg, 1 mmol) in tetrahydrofuran (5 ml) was added a 15% aqueous solution of sodium methanethiolate (3 ml) and the mixture was stirred at 50 ° C for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylthio) methyl] pyridin-3-yl} methyl) carbamate (312 mg, 72% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 1.94 (3H, s), 2.12-2, 23 (1H, m), 2.42 (3H, s), 2.67 (3H, s), 2.75 (2H, d, J = 6.9 Hz), 3.39 (2H, s), 4.02 (2H, d, J = 5.7 Hz), 4.19 (1H, br.s), 7.04 (2H, d, J = 8.1 Hz), 7.24 (2H, d , J = 8.1 Hz).

2) Dihydrochloride ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylthio) methyl] pyridin-3-yl} methyl) amine (36 mg, 96% yield) was obtained as white tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylthio) methyl] pyridin-3-yl} methyl) carbamate powder in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.93 (3H, s), 2.12-2.19 (1H, m), 2.42 (3H, s), 2.89 (3H, s), 3.08 (2H, br s), 3.48 (2H, s), 3.75 (2H, s), 7.28 (2H, d, J = 7.8 Hz), 7.39 (2H, d, J = 7.8 Hz), 8.36 (3H, br.s).

Example 199

({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylsulfonyl) methyl] pyridin-3-yl} methyl) amine dihydrochloride

1) To a solution of tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylthio) methyl] pyridin-3-yl} methyl) carbamate (200 mg, 0.46 mmol ) Oxone (trademark, 310 mg) was added to methanol-water (10: 1, 5 ml) and then sulfuric acid (50 ml) was added. The mixture was stirred at room temperature for 6 hours. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylsulfonyl) methyl] pyridin-3-yl} methyl) carbamate (128 mg, 60% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.19-2.28 (1H, m), 2, 41 (3H, s), 2.61 (3H, s), 2.74 (3H, s), 2.75 (2H, d, J = 7.2 Hz), 4.25 (2H, d, J = 5.1 Hz), 4.24 (1H, br.s), 4.26 (2H, s), 7.71 (2H, d, J = 7.8 Hz), 7.26 (2H, d , J = 8.1 Hz).

2) Dihydrochloride ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylsulfonyl) methyl] pyridin-3-yl} methyl) amine (36 mg, 96% yield) was obtained as white of tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(methylsulfonyl) methyl] pyridin-3-yl} methyl) carbamate powder in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.17-2.24 (1H, m), 2.40 (3H, s), 2.81 (3H, s), 2.87 (3H, s), 2.89 (2H, br.s), 3.68 (2H, br.s), 4.40 (2H, s), 7 24 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 7.8 Hz), 8.20 (3H, br.s).

Example 200

({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) acetic acid dihydrochloride

1) To a solution of [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate (952 mg, 2 mmol) in N , N-dimethylformamide (5 ml) was added potassium carbonate (415 mg, 3 mmol) and then ethyl mercaptoacetate (240 ml, 2.2 mmol) was added. The mixture was stirred at 50 ° C for 1 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (5 ml). 1N was added. aqueous sodium hydroxide solution (5 ml) and the mixture was stirred at room temperature for 2 hours. 1N was added to the reaction mixture. hydrochloric acid (5 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methyl} thio) acetic acid (265 mg, 27% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (6H, d, J = 6.6 Hz), 1.34 (9H, s), 2.13-2.27 (1H, m), 2.37 (3H, s), 2.55 (2H, d, J = 6.0 Hz), 2.58 (3H, s), 3.09 (2H, s), 3.50 (2H, s ), 3.74 (2H, d, J = 4.2 Hz), 6.81 (1H, br.s), 7.18 (2H, d, J = 8.1 Hz), 7.24 (2H d, J = 8.1 Hz), 12.49 (1H, br s).

2) Dihydrochloride ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) acetic acid (106 mg, 96% yield) was obtained as white powder from ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) acetic acid in a manner similar to the method Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.14-2.25 (1H, m), 2.42 (3H, s), 2.85 (3H, br s), 3.01 (2H, s), 3.20 (2H, s), 3.59 (2H, s), 3.70 (2H, s), 7.26 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 8.1 Hz), 8.23 (3H, br.s).

Example 201

Dihydrochloride ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) acetic acid

1) To a solution of ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) acetic acid (260 mg, 0.55 mmol) in a methanol-water mixture (10: 1, 5 ml) was added Oxon (trademark, 508 mg) and then sulfuric acid (50 ml) was added. The mixture was stirred at room temperature for 6 hours. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. Dihydrochloride ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} sulfonyl) acetic acid (104 mg, 68% yield) was obtained as a white powder from the obtained oil in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.21-2.28 (1H, m), 2.39 (3H, s), 2.65 (3H, s), 2.74 (2H, s), 3.61 (2H, s), 4.13 (2H, s), 4.55 (2H, s), 7.18 (2H d, J = 8.1 Hz), 7.29 (2H, d, J = 7.8 Hz), 8.01 (3H, br.s).

Example 202

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (1H-tetrazol-5-ylmethyl) pyridin-3-yl] methyl} amine dihydrochloride

1) To a solution of tert-butyl {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (300 mg, 0.74 mmol) in toluene (5 ml) was added dibutyltin oxide (37 mg, 0.15 mmol) and trimethylsilyl azide (292 ml, 2.2 mmol) and the mixture was stirred at 80 ° C for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (1H-tetrazol-5-ylmethyl) pyridin-3 -yl] methyl} carbamate (229 mg, 69% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.90 (6H, d, J = 6.6 Hz), 1.36 (9H, s), 2.08-2.11 (1H, m), 2, 35 (3H, s), 2.42 (3H, s), 2.83 (2H, s), 4.03 (2H, s), 4.09 (2H, br.s), 4.79 (1H , br.s), 7.01 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 7.8 Hz).

2) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (1H-tetrazol-5-ylmethyl) pyridin-3-yl] methyl} amine dihydrochloride (181 mg, 87% yield) was obtained in the form of a white powder from tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (1H-tetrazol-5-ylmethyl) pyridin-3-yl] methyl} carbamate in a manner similar to the example method 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.15-2.23 (1H, m), 2.36 (3H, s), 2.74 (3H, s), 3.14 (2H, s), 3.78 (2H, s), 4.04 (2H, s), 7.06 (2H, d, J = 8.1 Hz ), 7.28 (2H, d, J = 8.1 Hz), 8.35 (3H, br s).

Example 203

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -1,2,4-oxadiazol-5 (4H) -one dihydrochloride

1) To a solution of tert-butyl {[5- (cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (400 mg, 1.0 mmol) in ethanol (5 ml) sodium carbonate (420 mg, 4.0 mmol) and hydroxyammonium chloride (210 mg, 3.0 mmol) were added and the mixture was stirred at 80 ° C for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in tetrahydrofuran (5 ml). N, N'-carbonyldiimidazole (350 mg, 2.5 mmol) was added and the mixture was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography to obtain tert-butyl ({2-isobutyl- 6-methyl-4- (4-methylphenyl) -5 - [(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) methyl] pyridin-3-yl} methyl) carbamate ( 120 mg, 26% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.06-2.22 (1H, m), 2, 40 (3H, s), 2.51 (3H, s), 2.73 (2H, d, J = 7.2 Hz), 3.62 (2H, s), 4.02 (2H, d, J = 4.5 Hz), 4.45 (1H, br.s), 7.02 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 7.8 Hz).

2) Dihydrochloride 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} -1,2,4-oxadiazol-5 (4H) - it (181 mg, 87% yield) was obtained as a white powder from tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl) methyl] pyridin-3-yl} methyl) carbamate in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.13-2.21 (1H, m), 2.39 (3H, s), 2.75 (3H, s), 3.05 (2H, br s), 3.66 (2H, s), 3.76 (2H, br s), 7.16 (2H, d, J = 7.8 Hz), 7.36 (2H, d, J = 7.8 Hz), 8.26 (3H, br.s).

Example 204

Diethyl {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} phosphonate dihydrochloride

1) Triethyl phosphite (772 ml, 4.5 mmol) was added to [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate (692 mg, 1.45 mmol) and the mixture was stirred at 150 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and purified by silica gel column chromatography to obtain diethyl {[5 - {[(tert-butoxycarbonyl) amino ] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} phosphonate (314 mg, 42% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.17 (6H, t, J = 7.2 Hz), 1.38 (9H, s) , 2.14-2.24 (1H, m), 2.40 (3H, s), 2.66 (3H, s), 2.73 (2H, d, J = 5.1 Hz), 2, 96 (1H, s), 3.04 (1H, s), 3.86 (4H, q, J = 7.2 Hz), 4.00 (2H, d, J = 4.8 Hz), 4, 17 (1H, br.s), 7.07 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 8.1 Hz).

2) Diethyl dihydrochloride {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} phosphonate (106 mg, 96% yield) was obtained as a white powder from diethyl {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} phosphonate in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.3 Hz), 1.21 (6H, t, J = 7.2 Hz), 2.11-2, 18 (1H, m), 2.42 (3H, s), 2.95 (3H, s), 3.09 (2H, s), 3.17 (2H, s), 3.78 (2H, s ), 3.82 (4H, q, J = 7.2 Hz), 7.26 (2H, d, J = 7.8 Hz), 7.39 (2H, d, J = 7.8 Hz), 8.43 (3H, br s).

Example 205

Pyridin-2-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride

1) Pyridin-2-ylmethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.21 g, 99% yield) was obtained in as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol), 2- hydrobromide (bromomethyl) pyridine (0.92 g, 3.64 mmol) and potassium carbonate (1.00 g, 7.27 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.25 (1H, m), 2, 35 (3H, s), 2.56 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 4.14 (2H, br.s), 4.25 (1H, br c), 5.06 (2H, s), 6.89 (1H, d, J = 7.7 Hz), 7.06 (2H, d, J = 7.9 Hz), 7.13 (2H d, J = 7.9 Hz), 7.17-7.22 (1H, m), 7.57 (1H, t, J = 7.7 Hz), 8.52 (1H, d, J = 4.7 Hz).

2) Pyridin-2-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride (1.23 g, 99% yield) was obtained as a white solid from pyridine- 2-ylmethyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.21 g, 2.40 mmol) in a manner similar to the method of example 2 -3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.4Hz), 2.17-2.28 (1H, m), 2.34 (3H, s), 2 61 (3H, s), 2.94 (2H, d, J = 6.9 Hz), 3.81 (2H, d, J = 4.9 Hz), 5.20 (2H, s), 7 , 19 (4H, s), 7.23 (1H, br.s), 7.62-7.66 (1H, m), 8.06 (1H, t, J = 7.9Hz), 8.39 (3H, br.s), 8.68 (1H, d, J = 4.9Hz).

Example 206

Benzyl dihydrochloride [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate

1) Benzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (305 mg, 84% yield) was obtained in as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (300 mg, 0.703 mmol) and benzyl bromide (180 mg, 1.05 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8Hz), 1.38 (9H, s), 2.12-2.28 (1H, m), 2.38 (3H, s), 2.49 (3H, s), 2.76 (2H, d, J = 6.6 Hz), 3.39 (2H, s), 4.03 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 5.05 (2H, s), 6.90 (2H, d, J = 7.9 Hz), 7.14 (2H, d, J = 7.9 Hz), 7.19-7.25 (2H, m), 7.31-7.40 (3H, m).

2) Benzyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate dihydrochloride (214.5 mg, 95% yield) was obtained as a white powder from benzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (240 mg, 0.464 mmol) in a manner similar to the method of example 2- 3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6Hz), 2.11-2.27 (1H, m), 2.38 (3H, s), 2 78 (3H, s), 3.15 (2H, s), 3.78 (2H, d, J = 5.1 Hz), 5.04 (2H, s), 7.10 (2H, d, J = 8.1Hz), 7.20-7.45 (7H, m), 8.40 (3H, br.s).

Example 207

4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride

1) tert-Butyl {[5 - ({[4- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (360 mg, 72% yield) was obtained as a white solid from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methyl} thio) benzoic acid (0.50 g, 0.935 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.25 (1H, m), 2, 38 (3H, s), 2.65 (3H, s), 2.76 (2H, d, J = 7.4 Hz), 3.85 (2H, s), 4.04 (2H, d, J = 5.1Hz), 4.20 (1H, br.s), 7.05 (2H, d, J = 7.4 Hz), 7.12 (2H, d, J = 8.5 Hz), 7 19 (2H, d, J = 7.9Hz); 7.64 (2H, d, J = 8.5Hz).

2) 4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride (253 mg, 74% yield) was obtained in as a white solid from tert-butyl {[5 - ({[4- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (360 mg, 0.674 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.5Hz), 2.13-2.22 (1H, m), 2.37 (3H, s), 2 86 (3H, br.s), 3.14 (2H, br.s), 3.78 (2H, d, J = 4.7Hz), 3.99 (2H, s), 7.22 (2H , d, J = 8.5Hz), 7.26 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.5Hz), 7.37 (1H, br.s) 7.98 (1H, br s), 8.39 (3H, br s).

Example 208

Methyl 2 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate dihydrochloride

1) Methyl-2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate ( 1.19 g, 86% yield) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.00 g, 2.51 mmol) and methyl 2-mercaptobenzoate (422 mg, 2.51 mmol) in a manner similar to that of Example 183-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6Hz), 1.39 (9H, s), 2.12-2.26 (1H, m), 2.35 (3H, s), 2.66 (3H, s), 2.75 (2H, d, J = 7.4Hz), 3.77 (2H, s), 3.89 (3H, s), 4, 03 (2H, d, J = 4.9Hz), 4.19 (1H, br.s), 7.05 (1H, d, J = 8.1Hz), 7.09-7.13 (3H, m ), 7.17 (2H, d, J = 8.1Hz), 7.32-7.38 (1H, m), 7.93 (1H, dd, J = 7.7, 1.5 Hz).

2) Methyl-2 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate dihydrochloride (165 mg, 91% yield) prepared as a white solid from methyl-2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } thio) benzoate (190 mg, 0.346 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.13-2.25 (1H, m), 2.34 (3H, s), 2.77 (3H, br.s), 2.98 (2H, br.s), 3.69-3.76 (2H, m), 3.80 (3H, s), 3.87 (2H, s), 7.22-7.27 (4H, m), 7.31 (2H, d, J = 8.5Hz), 7.47-7.52 (1H, m), 7.87 (1H, dd, J = 7.7, 1.5 Hz), 8.18 (3H, br s).

Example 209

2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid

1) 2 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0 , 86 g, 88% yield) was obtained as a white solid from methyl 2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) pyridin-3-yl] methyl} thio) benzoate (1.00 g, 1.82 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.24 (1H, m), 2, 37 (3H, br.s), 2.73 (3H, br.s), 2.90 (2H, d, J = 7.0 Hz), 3.77 (2H, s), 4.05 (2H d, J = 4.5 Hz), 4.32 (1H, br.s), 7.01-7.10 (3H, m), 7.16-7.21 (3H, m), 7, 30-7.36 (1H, m), 7.94-7.97 (1H, m).

2) 2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (274 mg, 99% yield) was obtained in as a white solid from 2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0.29 g, 0.542 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 2.15-2.24 (1H, m), 2.34 (3H, s), 2.81 (3H, br.s), 3.03 (2H, br.s), 3.66-3.85 (4H, m), 7.19-7.35 (6H, m), 7, 44-7.50 (1H, m), 7.88 (1H, d, J = 7.5 Hz), 8.23 (3H, br.s).

Example 210

2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride

1) tert-Butyl {[5 - ({[2- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0 , 23 g, yield 48%) was obtained as a white solid from 2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine -3-yl] methyl} thio) benzoic acid (0.48 g, 0.898 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.14-2.26 (1H, m), 2, 40 (3H, s), 2.64 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.82 (2H, s), 4.00 (2H, d, J = 5.3 Hz), 4.27 (1H, br.s), 5.39 (1H, br.s), 6.68 (1H, br.s), 6.99 (2H, d, J = 7.9 Hz), 7.19-7.34 (5H, m), 7.75-7.78 (1H, m).

2) 2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride (218 mg, 99% yield) was obtained in as a white solid from tert-butyl {[5 - ({[2- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.23 g, 0.431 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.10-2.24 (1H, m), 2.38 (3H, s), 2.83 (3H, s), 3.18 (2H, br.s), 3.79 (2H, d, J = 5.1 Hz), 3.86 (2H, s), 7.16 (2H d, J = 7.7 Hz), 7.23-7.36 (6H, m), 7.42 (1H, br.s), 7.48 (1H, dd, J = 7.4, 1 4 Hz), 7.84 (1H, br.s), 8.41 (3H, br.s).

Example 211

Methyl 3 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate dihydrochloride

1) Methyl-3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate ( 1.35 g, 82% yield) was obtained as a brown solid from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.20 g, 3.01 mmol) and methyl 3-mercaptobenzoate (507 mg, 3.01 mmol) in a manner similar to that of Example 183-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.24 (1H, m), 2, 38 (3H, s), 2.64 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.83 (2H, s), 3.90 (3H, s), 4.02 (2H, d, J = 5.1 Hz), 4.22 (1H, br.s), 7.00 (2H, d, J = 8.1 Hz), 7.18 (2H, d , J = 7.7 Hz), 7.28-7.30 (1H, m), 7.76-7.79 (1H, m), 7.80-7.84 (1H, m).

2) Methyl-3 - ({[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoate dihydrochloride (268 mg, 87% yield) prepared as a white solid from methyl-3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } thio) benzoate (324 mg, 0.590 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.11-2.23 (1H, m), 2.36 (3H, s), 2.75 (3H, s), 2.97 (2H, br.s), 3.74 (2H, d, J = 4.5 Hz), 3.85 (3H, s), 3.96 (2H , s), 7.19 (2H, d, J = 7.4 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.43 (2H, d, J = 5.1 Hz ), 7.65 (1H, s), 7.79-7.83 (1H, m), 8.18 (3H, br s).

Example 212

3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid dihydrochloride

1) 3 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0 , 73 g, 73% yield) was obtained as a white solid from methyl 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) pyridin-3-yl] methyl} thio) benzoate (0.90 g, 1.64 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.13-2.26 (1H, m), 2, 38 (3H, s), 2.68 (3H, s), 2.79 (2H, d, J = 7.0 Hz), 3.85 (2H, s), 4.04 (2H, d, J = 4.9 Hz), 4.24 (1H, br.s), 7.00 (2H, d, J = 7.2 Hz), 7.19 (2H, d, J = 7.9 Hz), 7.30-7.35 (2H, m), 7.84 (1H, br.s), 7.89 (1H, br.s).

2) 3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid dihydrochloride (167 mg, 80% yield) was obtained as a white solid from 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzoic acid (0.22 g, 0.441 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.11-2.22 (1H, m), 2.37 (3H, s), 2.84 (3H, br.s), 3.10 (2H, br.s), 3.76 (2H, d, J = 5.1 Hz), 3.97 (2H, s), 7.21 (2H, d, J = 7.9 Hz), 7.30 (2H, d, J = 7.9 Hz), 7.41-7.42 (2H, m), 7.65 (1H, s) 8.38 (3H, br s).

Example 213

3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride

1) tert-Butyl {[5 - ({[3- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (460 mg, yield 92%) was obtained as a white solid from 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methyl} thio) benzoic acid (0.50 g, 0.935 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2, 38 (3H, s), 2.65 (3H, s), 2.75 (2H, d, J = 7.2 Hz), 3.84 (2H, s), 4.02 (2H, d, J = 5.1 Hz), 4.24 (1H, br.s), 6.99 (2H, d, J = 7.9 Hz), 7.19 (2H, d, J = 7.7 Hz), 7.25-7.31 (2H, m), 7.49-7.53 (1H, m), 7.56-7.59 (1H, m).

2) 3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) benzamide dihydrochloride (439 mg, quantitative) was obtained as white solids from tert-butyl {[5 - ({[3- (aminocarbonyl) phenyl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate ( 460 mg, 0.862 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.13-2.22 (1H, m), 2.38 (3H, s), 2.86 (3H, s), 3.19 (2H, d, J = 6.6 Hz), 3.78 (2H, d, J = 4.9 Hz), 3.98 (2H, s), 7.23 (2H, d, J = 8.1 Hz), 7.31-7.39 (4H, m), 7.45 (1H, br.s), 7.70 (1H, br.s) 7.75 (1H, d, J = 7.4 Hz), 8.04 (1H, br.s), 8.46 (3H, br.s).

Example 214

4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride

1) To a solution of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.50 g, 1.05 mmol) , methyl 4-hydroxybenzoate (0.16 g, 1.05 mmol) and triphenylphosphine (0.36 g, 1.37 mmol) in tetrahydrofuran (10 ml) was added a 40% solution (0.60 ml, 1.37 mmol ) diethyl azodicarboxylate in toluene and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give methyl 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (380 mg, 68% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2, 34 (3H, s), 2.62 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 3.87 (3H, s), 4.08-4.13 (2H , m), 4.30 (1H, br.s), 4.68 (2H, s), 6.80 (2H, d, J = 8.9 Hz), 7.04 (2H, d, J = 7.9 Hz), 7.16 (2H, d, J = 7.7 Hz), 7.93 (2H, d, J = 8.9 Hz).

2) 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (300 mg, yield 81%) was obtained as a white solid from methyl-4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] methoxy} benzoate (380 mg, 0.713 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.29 (1H, m), 2, 35 (3H, s), 2.66 (3H, br.s), 2.84 (2H, br.s), 4.08-4.14 (2H, m), 4.22-4.25 ( 1H, m), 4.70 (2H, s), 6.82 (2H, d, J = 8.9 Hz), 7.04 (2H, d, J = 7.9 Hz), 7.17 ( 2H, d, J = 7.9 Hz), 7.99 (2H, d, J = 8.9 Hz).

3) 4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride (267 mg, 94% yield) was obtained as white solids from 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (0.30 g, 0.578 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.34 (3H, s), 2, 82 (3H, br.s), 3.11 (2H, br.s), 3.83 (2H, d, J = 5.3 Hz), 4.79 (2H, s), 6.93 (2H d, J = 8.9 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.85 (2H, d , J = 8.9 Hz), 8.35 (3H, br s).

Example 215

Methyl 4-dihydrochloride - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate

Methyl 4-dihydrochloride - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (281 mg, 99% yield) was obtained as a white solid substances from methyl-4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (0.30 mg, 0.563 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.33 (3H, s), 2.82 (3H, br.s), 3.11 (2H, br.s), 3.81-3.83 (5H, m), 4.80 (2H, s), 6.96 (2H, d, J = 8.9 Hz), 7.26 (2H, d, J = 7.9 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.87 (2H, d, J = 8.9 Hz), 8.38 (3H, br s).

Example 216

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine dihydrochloride

1) To a solution of p-tolualdehyde (8.5 g, 78.3 mmol) and acetone (10 ml) in water (200 ml) was added sodium hydroxide (3.13 g, 78.3 mmol) and the mixture was stirred at room temperature within 3 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4- (4-methylphenyl) but-3-en-2-one (9.2 g, 80% yield) as an oil. The resulting oil (1.0 g, 6.24 mmol) was dissolved in ethanol (20 ml) and 3-amino-5-methylhex-3-ennitrile (0.93 g, 7.49 mmol) and sodium hydroxide (0, 3 g, 7.49 mmol). The mixture was heated under reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous solution of ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue. From the obtained residue, 2-isobutyl-6-methyl-4- (4-methylphenyl) nicotinonitrile (0.45 g, 27% yield) was obtained as a yellow oil in a manner similar to the method of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.20-2.33 (1H, m), 2.43 (3H, s), 2, 63 (3H, s), 2.96 (2H, d, J = 7.4 Hz), 7.11 (1H, s), 7.31 (2H, d, J = 7.9 Hz), 7, 47 (2H, d, J = 8.3 Hz).

2) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine dihydrochloride (456 mg, 78% yield) was obtained as a white solid from 2-isobutyl-6- methyl 4- (4-methylphenyl) nicotinonitrile (0.45 g, 1.70 mmol) in a manner similar to that of Example 108-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.4 Hz), 2.13-2.22 (1H, m), 2.41 (3H, s), 2.72-2.82 (3H, m), 3.05-3.18 (2H, m), 4.02-4.11 (2H, m), 7.41 (4H, s), 7, 67 (1H, br s), 8.47-8.58 (3H, m).

Example 217

({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine 4-methylbenzenesulfonate

1) To a solution of sodium 4-methylbenzenesulfinate (9.00 g, 50.5 mmol) in ethanol (50 ml) was added bromoacetone (6.9 g, 50 mmol) and the mixture was heated under reflux for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1 - [(4-methylphenyl) sulfonyl] acetone (8.0 g, 75% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.46 (3H, s), 4.14 (2H, s), 7.37 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

2) A mixture of 1 - [(4-methylphenyl) sulfonyl] acetone (2.0 g, 9.4 mmol), p-tolualdehyde (1.1 g, 9.4 mmol), piperidine (0.0993 ml, 0.94 mmol) ), acetic acid (0.11 ml, 1.9 mmol) and toluene (100 ml) were heated under reflux using a Dean-Stark trap for 3 hours. The reaction mixture was allowed to cool to room temperature, washed with saturated solution salts and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4- (4-methylphenyl) -3 - [(4-methylphenyl) sulfonyl] but-3-en-2-one as a crude product (3.5 g). A mixture of the crude product (1.73 g), 3-amino-5-methylhex-3-ennitrile (0.65 g, 5.23 mmol) and ethanol (50 ml) was heated under reflux for 12 hours. the mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the resulting solid was recrystallized from diisopropyl ether-ethyl acetate to give 2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] -1,4- dihydropyridine-3-carbonitrile (1.3 g, 64% yield) as a white powder.

Mp: 135-137 ° C

3) 2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] nicotinonitrile (0.77 g, 68% yield) was obtained as a white powder from 2-isobutyl-6 -methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] -1,4-dihydropyridin-3-carbonitrile (1.1 g, 2.7 mmol) in a manner similar to the method of example 23-3) .

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.38 (3H, s), 2, 39 (3H, s), 2.91 (2H, d, J = 7.2 Hz), 3.07 (3H, s), 6.86 (2H, d, J = 8.1 Hz), 7, 08 (4H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz).

4) ({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.64 g, yield 93%) was obtained as a colorless oil from 2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] nicotinonitrile (0.69 g, 1.6 mmol) in a manner similar to the method of Example 1-4 )

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.41 (2H, br.s), 2.20-2.35 (1H, m), 2.38 (6H, s), 2.79 (2H, d, J = 7.2 Hz), 2.96 (3H, s), 3.40 (2H, s), 6.76 (2H, d , J = 8.1 Hz), 7.03 (2H, d, J = 8.3 Hz), 7.09 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.3 Hz).

5) ({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.64 g, 1.5 mmol) dissolved in ethanol (5 ml) and a solution of p-toluenesulfonic acid hydrate (0.29 g, 1.5 mmol) in ethanol (5 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration, washed with chilled ethanol and dried to obtain 4-methylbenzenesulfonate ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-methylphenyl) sulfonyl] pyridin-3-yl} methyl) amine (0.57 g, 63% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.29 (3H, s), 2.37 (6H, s), 2.78 (2H, d, J = 7.0 Hz), 2.84 (3H, s), 3.57 (2H, s), 6.87 (2H, d , J = 7.9 Hz), 7.11 (4H, d, J = 8.5 Hz), 7.25-7.30 (4H, m), 7.47 (2H, d, J = 7, 9 Hz), 7.76 (3H, br s).

Example 218

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) pyridin-3-yl] methyl} amine

1) A mixture of 1- (methylsulfonyl) acetone (3.68 g, 27 mmol), p-tolualdehyde (3.24 g, 27 mmol), piperidine (0.26 ml, 2.7 mmol), acetic acid (0, 31 ml, 5.4 mmol) and toluene (200 ml) were heated under reflux using a Dean-Stark trap for 12 hours. The reaction mixture was allowed to cool to room temperature, washed with brine and dried over anhydrous magnesium sulfate . The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methanol (20 ml). 3-amino-5-methylhex-3-ennitrile (4.3 g, 35 mmol) was added and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 2 -isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) -1,4-dihydropyridin-3-carbonitrile (6.38 g, 68% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz), 2.18-2.25 ( 1H, m), 2.32 (3H, s), 2.35 (3H, s), 2.40 (3H, s), 2.44 (1H, s), 3.04 (1H, s), 4.69 (1H, s), 5.80 (1H, s), 7.14 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.3 Hz).

2) 2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) nicotinonitrile (4.14 g, yield 65%) was obtained as a white solid from 2-isobutyl-6-methyl-4 - (4-methylphenyl) -5- (methylsulfonyl) -1,4-dihydropyridin-3-carbonitrile (6.38 g, 18.6 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.8 Hz), 2.23-2.37 (1H, m), 2.44 (3H, s), 2, 95 (2H, d, J = 7.2 Hz), 3.05 (3H, s), 7.24 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 7 9 Hz).

3) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) pyridin-3-yl] methyl} amine (0.81 g, 75% yield) was obtained as a white solid from 2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (methylsulfonyl) nicotinonitrile (1.06 g, 3.09 mmol) in a manner similar to the method of example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 2.22-2.36 (1H, m), 2.43 (3H, s), 2, 80 (3H, s), 2.82 (2H, d, J = 7.4 Hz), 2.96 (3H, s), 3.50 (2H, s), 7.12 (2H, d, J = 7.9 Hz), 7.26 (2H, d, J = 7.7 Hz).

Example 219

Methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate dihydrochloride

1) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (730 mg, yield 72%) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.75 g , 1.89 mmol) and methyl 3-hydroxybenzoate (0.29 g, 1.90 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 35 (3H, s), 2.62 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 3.89 (3H, s), 4.07-4.11 (2H , m), 4.67 (2H, s), 6.98-7.02 (1H, m), 7.05 (2H, d, J = 7.9 Hz), 7.16 (2H, d, J = 7.7 Hz), 7.29-7.32 (1H, m), 7.42-7.43 (1H, m), 7.60-7.63 (1H, m).

2) Methyl-3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate dihydrochloride (116 mg, 85% yield) was obtained as white solid from methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (144 mg, 0.270 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.34 (3H, s), 2.83 (3H, br s), 3.11 (2H, br s), 3.83 (5H, s), 4.79 (2H, s), 7.15 (1H, dd, J = 7.8, 2.2 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.29-7.35 (3H, m), 7.42 (2H, t, J = 7 , 9 Hz), 7.56 (1H, d, J = 7.7 Hz), 8.38 (3H, br.s).

Example 220

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride

1) 3 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (460 mg, yield 80%) was obtained as a colorless oil from methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (0.58 g, 1.10 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.28 (1H, m), 2, 34 (3H, s), 2.65 (3H, s), 2.82 (2H, d, J = 7.2 Hz), 4.11 (2H, br.s), 4.28 (1H, br s), 4.68 (2H, s), 7.03-7.07 (3H, m), 7.16 (2H, d, J = 7.9 Hz), 7.33 (1H, t, J = 8.0 Hz), 7.47 (1H, br.s), 7.64-7.70 (1H, m).

2) 3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride (128 mg, 99% yield) was obtained as white solids from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (136 mg, 0.262 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.2 Hz), 2.18-2.27 (1H, m), 2.34 (3H, s), 2.73-2.79 (3H, m s), 3.04 (2H, s), 3.81 (2H, s), 4.76 (2H, s), 7.11 (2H, d, J = 8.1 Hz), 7.21-7.31 (5H, m), 7.38 (1H, t, J = 7.7 Hz), 7.54 (1H, d, J = 7 5 Hz), 8.27 (3H, br s).

Example 221

Methyl 2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate dihydrochloride

1) Methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (700 mg, 70% yield) was obtained as a white solid from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.75 g, 1.89 mmol) and methyl 2-hydroxybenzoate (0.29 g, 1.90 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 36 (3H, s), 2.67 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.81 (3H, s), 4.09 (2H, d, J = 4.0 Hz), 4.23 (1H, br.s), 4.71 (2H, s), 6.66 (1H, d, J = 8.3 Hz), 6.93-6.98 (1H, m), 7.04 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 7.7 Hz), 7.29-7.35 (1H, m) 7.72 (1H, dd, J = 7.6, 1.8 Hz).

2) Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate dihydrochloride (42.3 mg, 56% yield) was obtained as a white solid from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoate (78.8 mg, 0.148 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.29 (1H, m), 2.36 (3H, s), 2.83 (3H, br.s), 3.07 (2H, br.s), 3.74 (3H, s), 3.83 (2H, d, J = 4.7 Hz), 4.78 (2H, s), 6.91 (1H, d, J = 8.5 Hz), 7.03 (2H, t, J = 7.4 Hz), 7.25 (2H, d, J = 7, 9 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.42-7.48 (1H, m), 7.64 (1H, dd, J = 7.6, 1.6 Hz), 8.30 (3H, br s).

Example 222

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid dihydrochloride

1) 2 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (140 mg, yield 23%) was obtained as a white solid from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] methoxy} benzoate (0.62 g, 1.17 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.21-2.30 (1H, m), 2, 34 (3H, s), 2.65 (3H, s), 2.81 (2H, d, J = 7.4 Hz), 4.10 (2H, d, J = 5.3 Hz), 4, 92 (2H, s), 6.83 (1H, d, J = 8.3 Hz), 7.01 (2H, d, J = 8.1 Hz), 7.10-7.15 (1H, m ), 7.17 (2H, d, J = 7.7 Hz), 7.44-7.50 (1H, m), 8.17 (1H, dd, J = 7.8, 1.8 Hz) .

2) Dihydrochloride 2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (103 mg, 77% yield) was obtained as white solids from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzoic acid (0.14 g, 0.270 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.37 (3H, s), 2.89 (3H, br.s), 3.13 (2H, br.s), 3.84 (2H, d, J = 4.7 Hz), 4.78 (2H, s), 6.86 (1H, d, J = 8.5 Hz), 7.02 (1H, t, J = 7.4 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.32 (2H d, J = 8.1 Hz), 7.38-7.44 (1H, m), 7.61 (1H, dd, J = 7.5, 1.7 Hz), 8.39 (3H, ears.s).

Example 223

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] benzamide dihydrochloride

To a solution of tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) in tetrahydrofuran (3 ml) benzoyl chloride (88 ml, 0.75 mmol) was added and then triethylamine (140 μl, 1.0 mmol). The mixture was stirred for 30 minutes. A saturated aqueous solution of sodium hydroxide (5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. To a solution of the resulting oil in ethyl acetate (1 ml) was added 4N. an ethyl acetate solution of hydrogen chloride (1 ml) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from hexane to obtain N- [5- (aminomethyl) -6-isobutyl-2-methyl- dihydrochloride 4- (4-methylphenyl) pyridin-3-yl] benzamide (203 mg, 96% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.32 (1H, m), 2.31 (3H, s), 2.64 (3H, s), 3.11 (2H, s), 3.87 (2H, s), 7.17-7.66 (9H, m), 8.49 (3H, br.s) 10.13 (1H, br s).

Example 224

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-phenylacetamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-phenylacetamide dihydrochloride (208 mg, 95% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and phenylacetyl chloride (100 ml, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.98-2.26 (1H, m), 2.40 (3H, s), 2.50 (3H, s), 3.04 (2H, s), 3.40 (2H, s), 3.78 (2H, s), 6.94-6.97 (2H, m), 7 12-7.53 (7H, m), 8.44 (3H, br.s), 9.90 (1H, br.s).

Example 225

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-phenylpropanamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-phenylpropanamide dihydrochloride (208 mg, 92% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and hydrocinnamoyl chloride (111 ml, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.15-2.23 (1H, m), 2.33 (2H, t, J = 7.2 Hz), 2.37 (6H, s), 2.63 (2H, t, J = 7.2 Hz), 2.94 (2H, br.s), 3.79 (2H, s ), 7.10-7.29 (9H, m), 8.26 (3H, br.s), 9.43 (1H, br.s).

Example 226

(2E) -N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-phenylacrylamide dihydrochloride

(2E) -N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-phenylacrylamide dihydrochloride (208 mg, 92% yield) was obtained as white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and cinnamoyl chloride (125 mg , 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.15-2.28 (1H, m), 2.34 (3H, s), 2.55 (3H, s), 3.02 (2H, br.s), 3.83 (2H, br.s), 6.63 (1H, d, J = 15.6 Hz), 7.16 -7.23 (2H, m), 7.28-7.32 (2H, m), 7.39-7.46 (4H, m), 7.52-7.56 (2H, m), 8 36 (3H, br s), 9.76 (1H, br s).

Example 227

Ethyl [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] acetate dihydrochloride

1) Ethyl [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] acetate was obtained as an oil of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and ethyl hydroxyacetate (104 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC (M + 1): 514

2) Ethyl [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] acetate dihydrochloride (202 mg, 45% yield) obtained in the form of a white powder from oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.3 Hz), 1.18 (3H, t, J = 7.2 Hz), 2.11-2, 29 (1H, m), 2.38 (3H, s), 2.86 (3H, s), 3.77 (2H, br.s), 3.91 (2H, br.s), 4.12 (2H, q, J = 7.2 Hz), 4.52 (2H, s), 7.15 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 7, 8 Hz), 8.21 (3H, br.s), 9.12 (1H, br.s).

Example 228

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N'-benzylurea dihydrochloride

1) tert-Butyl {[5 - {[(benzylamino) carbonyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate was obtained as an oil from 5- {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and benzylamine (218 ml, 2.0 mmol) by similar to the method of example 95-1).

EIMC (M + 1): 517

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N'-benzylurea dihydrochloride (181 mg, 40% yield) was obtained as white powder from the oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.3 Hz), 2.09-2.22 (1H, m), 2.41 (3H, s), 2.50 (3H, s), 2.65 (2H, br.s), 3.81 (2H, br.s), 4.19 (2H, br.s), 7.11-7.35 ( 9H, m), 8.43 (3H, br s).

Example 229

Methyl 4-dihydrochloride - {[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] methyl} benzoate

1) Methyl-4 - {[({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] methyl} benzoate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and methyl 4-hydroxymethylbenzoate (250 mg, 1.5 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 576

2) Methyl 4-dihydrochloride - {[({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] methyl} benzoate (195 mg, 38% yield) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.3 Hz), 2.14-2.23 (1H, m), 2.39 (3H, s), 2.55 (3H, s), 2.97 (2H, br.s), 3.78 (2H, br.s), 3.87 (3H, s), 5.09 (2H, br.s) , 7.14-7.29 (6H, m), 7.92 (2H, d, J = 8.4 Hz), 8.30 (3H, br.s), 9.19 (1H, br.s )

Example 230

3 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride

1) To a solution of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.70 g, 4.12 mmol) in N, N dimethylformamide (15 ml) was added methyl 3- (bromomethyl) benzoate (0.79 g, 3.43 mmol) and potassium carbonate (0.71 g, 5.15 mmol) and the mixture was stirred at room temperature for 1 h The reaction mixture was diluted with ethyl acetate and the mixture was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 3- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) nicotinate (1.80 g, yield 94%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 33 (3H, s), 2.53 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.94 (3H, s), 4.13 (2H, br.s ), 4.20 (1H, br.s), 4.95 (2H, s), 7.01 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 7, 9 Hz), 7.22 (1H, d, J = 7.7 Hz), 7.35 (1H, t. J = 7.7 Hz), 7.83 (1H, s), 7.98 (1H , d, J = 7.7 Hz).

2) 3 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] benzoic acid (1.43 g, 87% yield) was obtained as a colorless oil from 3- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -methylphenyl) nicotinate (1.69 g, 3.01 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.25 (1H, m), 2, 34 (3H, s), 2.55 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 4.11-4.16 (2H, m), 4.22 (1H , br.s), 4.98 (2H, s), 7.02 (2H, d, J = 7.9 Hz), 7.11 (2H, d, J = 7.7 Hz), 7.26 -7.30 (1H, m), 7.39 (1H, t. J = 7.7 Hz), 7.89 (1H, s), 8.04 (1H, d, J = 7.5 Hz) .

3) 3 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride (293 mg, yield 60 %) was obtained as a white solid from 3 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid (0.50 g, 0.927 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.25 (1H, m), 2.32 (3H, s), 2.54 (3H, s), 2.90 (2H, d, J = 6.6 Hz), 3.81 (2H, d, J = 5.1 Hz), 5.04 (2H, s), 7.13 (2H, d, J = 8.5 Hz), 7.17 (2H, d, J = 8.3 Hz), 7.26-7.30 (1H, m), 7.44 (1H , t. J = 7.6 Hz), 7.73-7.74 (1H, m), 7.89-7.92 (1H, m), 8.30 (3H, br.s).

Example 231

Dihydrochloride 2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid

1) To a solution of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.10 g, 2.67 mmol) in N, N -dimethylformamide (15 ml) was added 2-bromobenzyl bromide (0.61 g, 2.43 mmol) and potassium carbonate (0.51 g, 3.65 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate , washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 2-bromobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate ( 1.23 g, yield 87%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.14-2.25 (1H, m), 2, 35 (3H, s), 2.56 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 4.11-4.13 (2H, m), 4.22 (1H , br.s), 5.05 (2H, s), 7.02-7.05 (3H, m), 7.11 (2H, d, J = 7.9 Hz), 7.16-7, 21 (2H, m), 7.51-7.54 (1H, m).

2) 2-Bromobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.23 g, 2.12 mmol), triethylamine ( 0.59 ml, 4.24 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (174 mg, 0.212 mmol) were dissolved in a mixture of methanol (5 ml) -N, N-dimethylformamide ( 15 ml) and the resulting mixture was stirred under an atmosphere of carbon monoxide for 14 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.88 g, yield 74%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 35 (3H, s), 2.56 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.87 (3H, s), 4.11-4.16 (2H , m), 4.21 (1H, br s), 5.39 (2H, s), 7.01-7.06 (3H, m), 7.11 (2H, d, J = 7.9 Hz), 7.32-7.42 (2H, m), 7.93-7.96 (1H, m).

3) 2 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] benzoic acid (0.75 g, 89% yield) was obtained as a colorless oil from 2- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -methylphenyl) nicotinate (0.88 g, 1.54 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.12-2.21 (1H, m), 2, 36 (3H, s), 2.54 (3H, s), 2.83 (2H, d, J = 7.2 Hz), 4.13-4.18 (2H, m), 4.25 (1H , br.s), 5.38 (2H, s), 7.01-7.04 (3H, m), 7.11 (2H, d, J = 7.5 Hz), 7.38-7, 46 (2H, m), 8.06-8.09 (1H, m).

4) Dihydrochloride 2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] benzoic acid (278 mg, yield 65 %) was obtained as a white solid from 2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] benzoic acid (0.45 g, 0.823 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.35 (3H, s), 2.84 (2H, d, J = 7.2 Hz), 3.82 (2H, d, J = 5.3 Hz), 5.32 (2H, s), 6.97-7.00 (1H , m), 7.18 (2H, d, J = 8.3 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.41-7.51 (2H, m), 7 87-7.91 (1H, m); 8.19 (3H, br s).

Example 232

Methyl 4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoate dihydrochloride

Methyl-4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoate dihydrochloride (230 mg, 89% yield) was obtained in as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and monomethyl ether chloride terephthalic acid (149 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.22-2.31 (1H, m), 2.31 (3H, s), 2.54 (3H, s), 2.95 (2H, br.s), 3.85 (2H, br.s), 3.87 (3H, s), 7.20-7.27 (4H, m), 7.72 (2H, d, J = 8.4 Hz), 7.99 (2H, d, J = 8.4 Hz), 8.26 (3H, br.s), 10.13 ( 1H, broad s).

Example 233

4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid dihydrochloride

1) 4 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (248 mg, 98% yield) was obtained as a white powder from methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] amino} carbonyl) benzoate (260 mg, 0.48 mmol) in a manner similar to that of Example 36-1).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.35 (9H, s), 2.18-2.29 (1H, m), 2.29 (3H, s), 2.59 (3H, s), 2.88 (2H, br s), 3.99 (2H, br s), 7.14 (1H, s), 7 , 20 (4H, s), 7.70 (2H, d, J = 8.4 Hz), 7.97 (2H, d, J = 8.4 Hz), 10.13 (1H, br.s) .

2) 4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid dihydrochloride (230 mg, 99% yield) was obtained in the form of a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (248 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.22-2.32 (1H, m), 2.31 (3H, s), 2.55 (3H, s), 2.96 (2H, br.s), 3.83 (2H, br.s), 7.20-7.27 (4H, m), 7.70 (2H, d, J = 8.1 Hz), 7.96 (2H, d, J = 8.1 Hz), 8.26 (3H, br.s), 10.11 (1H, br.s).

Example 234

Methyl dihydrochloride (4 - {[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetate

1) Methyl (4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetate (0, 36 g, yield 61%) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0, 44 g, 1.1 mmol) and methyl 4-hydroxyphenylacetate (0.18 g, 1.1 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.37 (9H, s), 2.36 (3H, s), 2.61 (3H, s), 2.87 ( 2H, s), 3.55 (2H, s), 3.68 (3H, s), 4.05-4.25 (3H, m), 4.59 (2H, s), 6.76 (2H d, J = 8.5 Hz), 7.05 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 7.17 (2H, d , J = 8.5 Hz).

2) Methyl (4 - {[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetate dihydrochloride (0.088 g, yield 74%) was obtained in as a white powder from methyl (4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetate ( 0.13 g, 0.22 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 2.35 (3H, s), 2.77 (3H, br s), 3.14 (2H, br s ), 3.58 (2H, d, J = 7.0 Hz), 3.59 (3H, s), 3.87 (2H, s), 4.66 (2H, s), 6.80 (2H d, J = 8.7 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.25 (2H, d, J = 7.7 Hz), 7.31 (2H, d , J = 7.7 Hz), 8.20 (3H, br s).

Example 235

Methyl 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3-oxazole-4-carboxylate dihydrochloride

1) Methyl-N - {[5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} serinate (5.37 g, 87% yield) was obtained as a colorless oils from 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (5.00 g, 11.2 mmol) and serine methyl ester hydrochloride (2.09 g, 13.4 mmol ) in a manner similar to that of Example 195-2).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 5.7 Hz), 2.15-2.26 (1H, m), 2.38 (3H, s), 2, 57 (3H, s), 2.80 (2H, d, J = 7.0 Hz), 3.36-3.42 (1H, m), 3.61-3.69 (1H, m), 3 73 (3H, s), 4.19-4.29 (2H, m), 4.43-4.52 (2H, m), 5.03 (2H, s), 6.21 (1H, d) , J = 7.0 Hz), 7.12-7.17 (2H, m), 7.17-7.22 (2H, m), 7.29-7.38 (5H, m).

2) A solution of methyl-N - {[5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} serinate (5.37 g, 9.81 mmol) in dichloromethane (50 ml) was cooled to -78 ° C and diethylamino seratrifluoride (1.72 ml, 11.8 mmol) was added. The mixture was stirred at the same temperature for 1 hour. Potassium carbonate (1.36 g, 14.7 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain methyl 2- [5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4,5-dihydro -1,3-oxazole-4-carboxylate (3.59 g, yield 69%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.15-2.26 (1H, m), 2.37 (3H, s), 2, 57 (3H, s), 2.81 (2H, d, J = 7.2 Hz), 3.71 (3H, s), 4.11-4.16 (1H, m), 4.23 (2H d, J = 5.5 Hz), 4.33 (1H, dd, J = 8.8, 7.4 Hz), 4.59-4.65 (1H, m), 5.03 (2H, s), 7.05 (2H, d, J = 8.5 Hz), 7.13-7.21 (2H, m), 7.29-7.38 (5H, m).

3) A solution of methyl 2- [5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate ( 0.83 g, 2.12 mmol) and 1.8-diazabicyclo [5.4.0] -7-undecene (1.11 ml, 7.42 mmol) in dichloromethane (10 ml) were cooled to 0 ° C and bromotrichloromethane was added (0.73 ml, 7.42 mmol). The mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give methyl 2- [5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3-oxazole -4-carboxylate (520 mg, 63% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (6H, d, J = 6.8 Hz), 2.24-2.34 (4H, m), 2.59 (3H, s), 3, 00 (2H, d, J = 7.4 Hz), 3.92 (3H, s), 7.11 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8 , 3 Hz), 8.08 (1H, s).

4) Methyl 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3-oxazole-4-carboxylate dihydrochloride (456 mg, yield 73%) was obtained as a white solid from methyl 2- [5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,3-oxazole-4-carboxylate (0.52 g, 1.34 mmol) in a manner similar to that of Example 108-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.21-2.30 (4H, m), 2.45-2.48 (3H , m), 2.90-3.02 (2H, m), 3.78 (3H, s), 3.85 (2H, d, J = 4.7 Hz), 7.11 (2H, dd, J = 8.1, 2.1 Hz), 7.20 (2H, d, J = 8.1 Hz), 8.30-8.47 (3H, m), 8.77 (1H, d, J = 1.5 Hz).

Example 236

2- (4 - {[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetamide dihydrochloride

1) tert-Butyl {[5 - {[4- (2-amino-2-oxoethyl) phenoxy] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.14 g, 47% yield) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (0.22 g, 0.53 mmol) and 4-hydroxyphenylacetamide (0.081 g, 0.53 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.37 (9H, s), 2.36 (3H, s), 2.62 (3H, s), 2.88 ( 2H, s), 3.51 (2H, s), 4.10-4.25 (3H, m), 4.61 (2H, s), 5.35 (2H, br.s), 6.75 -6.80 (2H, m), 7.05 (2H, d, J = 7.9 Hz), 7.10-7.20 (4H, m).

2) 2- (4 - {[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} phenyl) acetamide dihydrochloride (0.098 g, yield 92%) was obtained as a pale yellow powder from tert-butyl {[5 - {[4- (2-amino-2-oxoethyl) phenoxy] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3- yl] methyl} carbamate (0.11 g, 0.20 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (9H, s), 2.36 (3H, s), 2.79 (3H, br s), 3.05-3.25 (2H , m), 3.28 (2H, s), 3.88 (2H, broad s), 4.66 (2H, s), 6.79 (2H, d, J = 8.5 Hz), 6 83 (1H, br.s), 7.14 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 7.4 Hz), 7.33 (2H, d, J = 7.4 Hz), 7.42 (1H, br.s), 8.19 (3H, br.s).

Example 237

Methyl (4 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} phenyl) acetate

1) Methyl (4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} phenyl) acetate (570 mg, 83% yield) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (500 mg , 1.25 mmol) and methyl (4-hydroxyphenyl) acetate (250 mg, 1.51 mmol) in a manner similar to the method of example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.30 (1H, m), 2, 36 (3H, s), 2.62 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.51 (2H, s), 3.56 (3H, s), 4.10 (2H, d, J = 4.7 Hz), 4.20 (1H, s), 4.61 (2H, s), 6.78 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz); 7.12-7.20 (4H, m).

2) Methyl (4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} phenyl) acetate (570 mg, 1.04 mmol) was dissolved in trifluoroacetic acid (10 ml) and the mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl (4 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} phenyl) acetate (300 mg, yield 65%) as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.18-2.25 (1H, m), 2.34 (3H, s), 2.60 (3H, s), 2.88 (2H, d, J = 7.4 Hz), 3.30 (2H, d, J = 5.3 Hz), 3.61 (3H, s), 4.20 (2H, d, J = 4.7 Hz), 4.60 (2H, s), 6.70 (2H, d, J = 8.5 Hz), 6.79 (2H, d, J = 8.5 Hz), 7.05 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.3 Hz).

Example 238

3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid dihydrochloride

3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid dihydrochloride (230 mg, 89% yield) was obtained as white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and isophthalic monomethyl ether chloride acid (149 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.18-2.31 (1H, m), 2.31 (3H, s), 2.60 (3H, s), 3.04 (2H, br.s), 3.85 (2H, br.s), 7.25 (4H, s), 7.57 (1H, t, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.07 (1H, d, J = 7.8 Hz), 8.16 (1H, s), 8.36 (3H, br.s), 10.19 (1H, br.s).

Example 239

Methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-indole-2-carboxylate dihydrochloride

1) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-indole- 2-carboxylate (0.41 g, yield 52%) was obtained as a pale yellow solid from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine- 3-yl] methyl} carbamate (0.60 g, 1.49 mmol) and methyl 3-hydroxyindole-2-carboxylate (0.26 g, 1.36 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.37 (9H, s), 2.17-2.26 (1H, m), 2, 37 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 2.86 (3H, s), 3.82 (3H, s), 4.00 (2H, d, J = 4.5 Hz), 4.09 (1H, br.s), 5.03 (2H, s), 6.74-6.89 (4H, m), 7.09 (2H, d, J = 7.9 Hz), 7.21-7.31 (2H, m), 8.28 (1H, br.s).

2) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-indole- 2-carboxylate (0.26 g, 1.36 mmol) was dissolved in 4N. an ethyl acetate solution of hydrogen chloride (10 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting yellow solid was recrystallized from ethyl acetate-hexane to give methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H- indole-2-carboxylate (256 mg, 75% yield) as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.17-2.30 (1H, m), 2.38 (3H, s), 2, 79 (2H, d, J = 7.4 Hz), 2.86 (3H, s), 3.51 (2H, s), 3.83 (3H, s), 5.02 (2H, s), 6.77-6.88 (4H, m), 7.10 (2H, d, J = 7.7 Hz), 7.22-7.28 (2H, m), 8.27 (1H, br. from).

Example 240

4-cyanobenzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

1) 4-cyanobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.32 g, 86% yield) was obtained as yellow oils from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.10 g, 5.10 mmol) and 4-cyanobenzyl bromide (1 , 00 g, 5.10 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2, 37 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 4.11-4.13 (2H, m), 4.20 (1H , br.s), 4.98 (2H, s), 7.01 (2H, d, J = 8.1 Hz), 7.10 (4H, d, J = 8.1 Hz), 7.54 (2H, d, J = 8.3 Hz).

2) 4-cyanobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.52 g, 0.985 mmol) was dissolved in trifluoroacetic acid ( 10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate to give 4-cyanobenzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.42 g, 99% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 0.90 (6H, d, J = 6.6 Hz), 2.08-2.17 (1H, m), 2.32 (3H, s), 2, 54 (3H, s), 2.70 (2H, d, J = 7.0 Hz), 3.97 (2H, s), 4.99 (2H, s), 7.00 (2H, d, J = 8.1 Hz), 7.08-7.14 (4H, m), 7.54 (2H, d, J = 8.3 Hz).

Example 241

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] quinoxaline-2-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] quinoxaline-2-carboxamide dihydrochloride (137 mg, 50% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and quinoxaline-2-carbonyl chloride (144 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (6H, d, J = 6.6 Hz), 2.22-2.29 (1H, m), 2.23 (3H, s), 2.64 (3H, s), 3.06 (2H, br.s), 3.86 (2H, br.s), 7.22 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.96-8.04 (2H, m), 8.11-8.28 (2H, m), 8.39 (3H, br.s), 9.34 (1H, s), 10.50 (1H, br s).

Example 242

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,5-dimethylfuran-3-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,5-dimethylfuran-3-carboxamide dihydrochloride (215 mg, 90% yield) was obtained in the form of a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 2, 5-dimethylfuran-3-carbonyl chloride (119 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.17 (3H, s), 2.17-2.29 (1H, m), 2.29 (3H, s), 2.34 (3H, s), 2.54 (3H, s), 2.99 (2H, br.s), 3.82 (2H, d, J = 5, 1 Hz), 6.25 (1H, s), 7.20 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 8.28 (3H , broad s), 9.32 (1H, broad s).

Example 243

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methylthiophen-2-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methylthiophen-2-carboxamide dihydrochloride (215 mg, 90% yield) was obtained as white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 3-methylthiophene 2-carbonyl chloride (120 mg, 0.75 mmol) in a manner similar to that of Example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.08 (3H, s), 2.09-2.33 (1H, m), 2.34 (3H, s), 2.51 (3H, s), 2.91 (2H, br.s), 3.82 (2H, br.s), 6.89 (1H, d, J = 5.1 Hz), 7.19 (2H, d, J = 7.8 Hz), 7.27 (2H, d, J = 7.8 Hz), 7.55 (1H, d, J = 5, 1 Hz), 8.17 (3H, br.s), 9.37 (1H, br.s).

Example 244

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1-benzothiophen-2-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1-benzothiophen-2-carboxamide dihydrochloride (215 mg, 90% yield) was obtained as white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 1-benzothiophene 2-carbonyl chloride (150 mg, 0.75 mmol) in a manner similar to that of Example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.28 (1H, m), 2.28 (3H, s), 2.60 (3H, s), 3.00 (2H, br.s), 3.84 (2H, d, J = 5.4 Hz), 7.25 (4H, s), 7.41-7 50 (2H, m), 7.91 (1H, d, J = 6.9 Hz), 8.00 (1H, d, J = 6.9 Hz), 8.04 (1H, s), 8 33 (3H, br s), 10.34 (1H, br s).

Example 245

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methyl-1-benzofuran-2-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methyl-1-benzofuran-2-carboxamide dihydrochloride (213 mg, 90% yield ) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 3-methyl-1-benzofuran-2-carbonyl chloride (150 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.16-2.29 (1H, m), 2.29 (3H, s), 2.41 (3H, s), 2.60 (3H, s), 3.03 (2H, br.s), 3.83 (2H, br.s), 7.25 (4H, s), 7 35 (1H, t, J = 6.9 Hz), 7.49 (1H, t, J = 6.9 Hz), 7.56 (1H, d, J = 6.9 Hz), 7.73 (1H, d, J = 6.9 Hz), 8.35 (3H, br.s), 10.08 (1H, br.s).

Example 246

Methyl [4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1-yl] acetate dihydrochloride

1) Methyl [4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2 -oxopiperazin-1-yl] acetate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1, 0 mmol) and methyl (2-oxopiperazin-1-yl) acetate (344 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 582

2) Methyl dihydrochloride [4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1-yl] acetate (271 mg, 49% yield) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.3 Hz), 1.99-2.28 (1H, m), 2.37 (3H, s), 2.50 (3H, s), 2.60 (2H, br.s), 3.14 (2H, t, J = 5.1 Hz), 3.46 (2H, t, J = 5.1 Hz ), 3.66 (3H, s), 3.81 (4H, br.s), 4.08 (2H, s), 7.17 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 7.8 Hz), 8.43 (3H, br s).

Example 247

[5- (Methoxycarbonyl) pyridin-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

1) To a solution of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.85 g, 4.48 mmol), methyl-6 - (hydroxymethyl) nicotinate (0.68 g, 4.07 mmol) and triphenylphosphine (1.39 g, 5.29 mmol) in tetrahydrofuran (20 ml) was added 40% toluene solution of diethyl azodicarboxylate (2.3 ml, 5.29 mmol) and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain [5- (methoxycarbonyl) pyridin-2-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) nicotinate (2.29 g, 99% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2, 35 (3H, s), 2.58 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 3.96 (3H, s), 4.13-4.15 (2H , m), 4.21 (1H, br.s), 5.11 (2H, s), 6.88 (1H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 7.9 Hz), 8.14 (1H, dd, J = 8.2, 2.2 Hz), 9.10 (1H, dd, J = 2.1, 0.75 Hz).

2) [5- (Methoxycarbonyl) pyridin-2-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.37 g, 0.659 mmol) was dissolved in 4N. an ethyl acetate solution of hydrogen chloride (10 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain [5- (methoxycarbonyl) pyridin-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (142 mg, 46% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.17-2.29 (1H, m), 2.35 (3H, s), 2, 57 (3H, s), 2.81 (2H, d, J = 7.4 Hz), 3.65 (2H, s), 3.96 (3H, s), 5.11 (2H, s), 6.89 (1H, d, J = 8.3 Hz), 7.10-7.16 (4H, m), 8.14 (1H, dd, J = 8.2, 2.2 Hz), 9 10 (1H, d, J = 1.3 Hz).

Example 248

6 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] nicotinic acid trihydrochloride

1) 6 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] nicotinic acid (1.08 g, yield 58%) was obtained as a colorless oil from [5- (methoxycarbonyl) pyridin-2-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 methyl 4- (4-methylphenyl) nicotinate (1.90 g, 3.38 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.27-2.35 (4H, m), 2, 60 (3H, s), 2.81 (2H, d, J = 7.2 Hz), 4.14-4.15 (2H, m), 4.25 (1H, br.s), 5.14 (2H, s), 6.88-6.95 (1H, m), 7.06-7.19 (4H, m), 8.19 (1H, dd, J = 8.2, 2.2 Hz ), 9.16 (1H, s).

2) 6 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] nicotinic acid trihydrochloride (413 mg, 81 yield %) was obtained as a white solid from 6 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] nicotinic acid (0.50 g, 0.913 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.18-2.28 (1H, m), 2.33 (3H, s), 2.63 (3H, br.s), 2.90-2.97 (2H, m), 3.82 (2H, d, J = 5.1 Hz), 5.15 (2H, s), 7 03 (1H, d, J = 8.1 Hz), 7.17-7.23 (4H, m), 8.17 (1H, dd, J = 8.2, 2.0 Hz), 8, 38 (3H, br s), 8.98 (1H, d, J = 1.5 Hz).

Example 249

[5- (Aminocarbonyl) pyridin-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

1) [5- (Aminocarbonyl) pyridin-2-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (222 mg, yield 38%) was obtained as a colorless oil from 6 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] carbonyl} hydroxy) methyl] nicotinic acid (0.58 g, 1.06 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2, 36 (3H, s), 2.58 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.13-4.15 (2H, m), 4.22 (1H , br.s), 5.10 (2H, s), 6.92 (1H, d, J = 7.9 Hz), 7.07 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 7.9 Hz), 8.03 (1H, dd, J = 8.3, 2.3 Hz), 8.89 (1H, d, J = 2.3 Hz).

2) [5- (Aminocarbonyl) pyridin-2-yl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (159 mg, 87% yield) was obtained as a colorless oils from [5- (aminocarbonyl) pyridin-2-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.22 g, 0.406 mmol) in a manner similar to the method of example 247-2).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.15-2.31 (1H, m), 2.36 (3H, s), 2, 57 (3H, s), 2.81 (2H, d, J = 7.4 Hz), 3.65 (2H, s), 5.10 (2H, s), 6.94 (1H, d, J = 7.7 Hz), 7.11-7.17 (4H, m), 8.03 (1H, dd, J = 8.1, 2.3 Hz), 8.89 (1H, d, J = 2.3 Hz).

Example 250

Ethyl 4 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-ethylpyrimidine-5-carboxylate tetrahydrochloride

1) Ethyl-4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-ethylpyrimidin- 5-carboxylate (308 mg, 40% yield) was obtained as a white solid from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.53 g, 1.33 mmol) and ethyl 2-ethyl-4-hydroxypyrimidine-5-carboxylate (0.26 g, 1.33 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 1.20-1.29 (6H, m), 1.39 (9H, s), 2, 19-2.28 (1H, m), 2.34 (3H, s), 2.67 (3H, s), 2.75-2.83 (4H, m), 4.10 (2H, d, J = 4.9 Hz), 4.27-4.34 (3H, m), 5.22 (2H, s), 7.06 (2H, d, J = 8.1 Hz), 7.14 ( 2H, d, J = 7.9 Hz), 8.86 (1H, s).

2) Ethyl 4 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-ethylpyrimidine-5-carboxylate tetrahydrochloride (269 mg, 80% yield) was obtained as a white solid from ethyl 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] methoxy} -2-ethylpyrimidine-5-carboxylate (308 mg, 0.536 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.19 (3H, t, J = 7.5 Hz), 1.25 (3H, t, J = 7.1 Hz), 2.14-2.23 (1H, m), 2.43 (3H, s), 2.58-2.67 (2H, m), 2.81-2 97 (3H, m), 3.13 (2H, br.s), 3.73-3.83 (2H, m), 4.22 (2H, t, J = 7.0 Hz), 4, 42 (2H, s), 7.25-7.31 (2H, m), 7.38-7.43 (2H, m), 8.43 (3H, br s), 8.46 (1H, from).

Example 251

4- (1H-tetrazol-5-yl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) Solution of 4-cyanobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.28 g, 2.43 mmol) and azide tributyltin (2.3 ml, 8.49 mmol) in toluene (7.5 ml) was heated under reflux under argon for 3 hours. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4 - (1H-tetrazol-5-yl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.23 g, yield 88 %) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.24 (1H, m), 2, 25 (3H, s), 2.54 (3H, s), 2.83 (2H, d, J = 7.2 Hz), 4.18 (2H, d, J = 4.9 Hz), 4, 32 (1H, br.s), 5.00 (2H, s), 7.01 (2H, d, J = 7.9 Hz), 7.07 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz).

2) 4- (1H-tetrazol-5-yl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (688 mg, 95% yield) was obtained as white solids from 4- (1H-tetrazol-5-yl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.75 g, 1.33 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.30 (3H, s), 2.54 (3H, s), 2.87 (2H, d, J = 6.8 Hz), 3.81 (2H, d, J = 5.5 Hz), 5.08 (2H, s), 7.14-7.25 (6H, m), 8.02 (2H, d, J = 8.1 Hz), 8.22 (3H, br.s).

Example 252

5 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] furan-2-carboxylic acid dihydrochloride

1) [5- (Methoxycarbonyl) -2-furyl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.37 g , 88% yield) was obtained as a yellow oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (2.00 g, 4, 85 mmol) and methyl 5- (chloromethyl) furan-2-carboxylate (0.85 g, 4.85 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.24 (1H, m), 2, 35 (3H, s), 2.52 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 3.91 (3H, s), 4.11 (2H, d, J = 5.1 Hz), 4.19 (1H, br.s), 4.94 (2H, s), 6.24 (1H, d, J = 3.6 Hz), 7.00 (2H, d , J = 8.1 Hz), 7.06 (1H, d, J = 3.6 Hz), 7.11 (2H, d, J = 7.9 Hz).

2) 5 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] furan -2-carboxylic acid (1.95 g, 95% yield) was obtained as a white solid from [5- (methoxycarbonyl) -2-furyl] methyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6 -isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.11 g, 3.83 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.25 (1H, m), 2, 36 (3H, s), 2.53 (3H, s), 2.86 (2H, d, J = 7.0 Hz), 4.09-4.18 (2H, m), 4.26 (1H , br.s), 4.99 (2H, s), 6.32 (1H, d, J = 3.4 Hz), 7.03 (2H, d, J = 8.1 Hz), 7.10 -7.18 (3H, m).

3) 5 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] furan-2-carboxylic acid dihydrochloride (460 mg, 79% yield) was obtained as a white solid from 5 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] carbonyl} oxy) methyl] furan-2-carboxylic acid (0.61 g, 1.14 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.33 (3H, s), 2.90 (2H, br.s), 3.80 (2H, d, J = 5.3 Hz), 5.05 (2H, s), 6.46 (1H, d, J = 3.4 Hz ), 7.11-7.14 (3H, m), 7.17 (2H, d, J = 8.1 Hz), 8.29 (3H, br.s).

Example 253

Dihydrochloride [5- (aminocarbonyl) -2-furyl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate

1) [5- (Aminocarbonyl) -2-furyl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (520 mg, yield 69%) was obtained as a colorless oil from 5 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -furan-2-carboxylic acid (0.75 g, 1.40 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.27 (1H, m), 2, 35 (3H, s), 2.52 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.06-4.13 (2H, m), 4.19 (1H , br.s), 4.94 (2H, br), 5.45 (1H, br.s), 6.16 (1H, br.s), 6.27 (1H, d, J = 3.4 Hz), 6.98 (2H, d, J = 8.1 Hz), 7.04 (1H, d, J = 3.6 Hz), 7.09 (2H, d, J = 7.9 Hz) .

2) [5- (Aminocarbonyl) -2-furyl] methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (471 mg, 95% yield) was obtained as white solids from [5- (aminocarbonyl) -2-furyl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.52 g, 0.971 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.14-2.27 (1H, m), 2.34 (3H, s), 2.88 (2H, br.s), 3.80 (2H, d, J = 5.5 Hz), 5.02 (2H, s), 6.39 (2H, d, J = 3.4 Hz ), 7.06 (1H, d, J = 3.4 Hz), 7.12 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 8.3 Hz), 7.43 (1H, br s), 7.73 (1H, br s), 8.28 (3H, br s).

Example 254

Methyl-3 - {[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] (methyl) amino] carbonyl} benzoate dihydrochloride

To a mixture of 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (212 mg, 0.4 mmol), potassium carbonate (138 mg, 1.0 mmol) and N, N-dimethylformamide (5 ml) was added methyl iodide (282 mg, 2.0 mmol) and the mixture was stirred at room temperature for 8 hours Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. To a solution of the resulting oil in ethyl acetate (1 ml) was added 4N. an ethyl acetate solution of hydrogen chloride (1 ml) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from hexane to give methyl 3 - {[[5- (aminomethyl) -6-isobutyl- dihydrochloride 2-methyl-4- (4-methylphenyl) pyridin-3-yl] (methyl) amino] carbonyl} benzoate (203 mg, 95% yield) as a white powder.

EIMC (M + 1): 460

Example 255

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isophthalamide dihydrochloride

1) tert-Butyl {[5 - {[3- (aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (248 mg, yield 98%) was obtained as a white powder from 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino } carbonyl) benzoic acid (260 mg, 0.48 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.20-2.31 (1H, m), 2, 33 (3H, s), 2.49 (3H, s), 2.78 (2H, br.s), 4.13 (2H, br.s), 4.40 (1H, br.s), 5 79 (1H, br.s), 6.38 (1H, br.s), 7.03 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.7.39-7.45 (1H, br.s), 7.60-7.63 (1H, m), 7.88-7.92 (2H, m).

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isophthalamide dihydrochloride (233 mg, 99% yield) was obtained as a white powder from tert- butyl {[5 - {[3- (aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (248 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.3 Hz), 2.22-2.30 (1H, m), 2.30 (3H, s), 2.51 (3H, s), 2.89 (2H, br.s), 3.84 (2H, br.s), 7.23 (4H, s), 7.56 (1H, t, J = 7.8 Hz), 7.83 (2H, d, J = 7.8 Hz), 8.06 (2H, d, J = 7.8 Hz), 8.14 (1H, s), 8.16 (3H, br s), 10.04 (1H, br s).

Example 256

4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) 4- [2-Oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -methylphenyl) nicotinate (2.85 g, 86% yield) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acids (2.00 g, 4.85 mmol) and phenacyl-4- (bromomethyl) phenylacetate (1.69 g, 4.85 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.24 (1H, m), 2, 38 (3H, s), 2.52 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.82 (2H, s), 4.11-4.16 (2H , m), 4.21 (1H, br s), 4.91 (2H, s), 5.36 (2H, s), 7.02-7.05 (4H, m), 7.15 ( 2H, d, J = 7.7 Hz), 7.26-7.29 (2H, m), 7.46-7.51 (2H, m), 7.58-7.64 (1H, m) 7.88-7.91 (2H, m).

2) 4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (117 mg , 45% yield) was obtained as a white solid from 4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6- isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.27 g, 0.398 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.38 (3H, s), 2.83 (2H, br.s), 3.81 (2H, d, J = 5.3 Hz), 3.85 (2H, s), 4.95 (2H, s), 5.53 (2H , s), 7.02 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 7.5 Hz), 7.26 (4H, t, J = 7.72) 7.56 (2H, d, J = 7.9 Hz), 7.67-7.72 (1H, m), 7.92-7.98 (2H, m), 8.17 (3H, br .from).

Example 257

4- (2-Methoxy-2-oxoethyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) {4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid (1.65 g, yield 77%) was obtained as a colorless oil from 4- [2-oxo-2- (2-oxo-2-phenylethoxy) ethyl] benzyl-5 - {[(tert-butoxycarbonyl ) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (2.58 g, 3.80 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.23 (1H, m), 2, 37 (3H, s), 2.52 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 3.65 (2H, s), 4.09-4.16 (2H , m), 4.21 (1H, br.s), 4.90 (2H, s), 7.00-7.06 (4H, m), 7.13 (2H, d, J = 7.9 Hz), 7.21 (2H, d, J = 8.1 Hz).

2) To the mixture {4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid (0.65 g, 1.16 mmol), potassium carbonate (0.32 g, 2.32 mmol) and N, N-dimethylformamide (15 ml) were added methyl iodide (197 mg, 1.39 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4- (2-methoxy-2-oxoethyl) benzyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl- 4- (4-methylphenyl) nicotinate (0.56 g, 84% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.26 (1H, m), 2, 38 (3H, s), 2.52 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.62 (2H, s), 3.70 (3H, s), 4.12-4.13 (2H, m), 4.20 (1H, br s), 4.90 (2H, s), 7.01-7.04 (4H, m), 7.14 ( 2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 8.1 Hz).

3) 4- (2-Methoxy-2-oxoethyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (483 mg, 90% yield) was obtained as white solids from 4- (2-methoxy-2-oxoethyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.56 g, 0.974 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.14-2.26 (1H, m), 2.37 (3H, s), 2.79-2.88 (2H, m), 3.62 (3H, s), 3.69 (2H, s), 3.81 (2H, d, J = 5.3 Hz), 4.94 (2H, s), 7.00 (2H, d, J = 8.1 Hz), 7.13-7.24 (6H, m), 8.21 (3H, br.s).

Example 258

Dihydrochloride {4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid

Dihydrochloride {4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid (348 mg, yield 73%) was obtained as a white solid from {4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] carbonyl} oxy) methyl] phenyl} acetic acid (0.50 g, 0.892 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.37 (3H, s), 2.53 (3H, s), 2.90 (2H, d, J = 5.8 Hz), 3.57 (2H, s), 3.82 (2H, d, J = 5.3 Hz), 4.95 (2H, s), 6.99 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 8.30 (3H, br.s).

Example 259

4- (2-amino-2-oxoethyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) 4- (2-amino-2-oxoethyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (360 mg, yield 72%) was obtained as a colorless oil from {4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] carbonyl} oxy) methyl] phenyl} acetic acid (0.50 g, 0.892 mmol) in a manner similar to that of Example 3-1).

H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.26 (1H, m), 2.39 (3H, s), 2.52 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.58 (2H, s), 4.12-4.13 (2H, m), 4.21 (1H, br s), 4.91 (2H, s), 5.31 (2H, br s), 7.04-7.06 (4H, m), 7.16 (2H, d, J = 7.9 Hz); 7.20 (2H, d, J = 8.1 Hz).

2) 4- (2-amino-2-oxoethyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (231 mg, 67% yield) was obtained as white solids from 4- (2-amino-2-oxoethyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.36 g, 0.643 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.14-2.25 (1H, m), 2.38 (3H, s), 2.86 (2H, br.s), 3.37 (2H, s), 3.81 (2H, d, J = 5.5 Hz), 4.93 (2H, s), 6.88 (1H , br.s), 6.98 (2H, d, J = 8.1 Hz), 7.13-7.25 (6H, m), 7.49 (1H, br.s), 8.21 ( 3H, broad s).

Example 260

4- (Methylsulfonyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) 4- (Methylsulfonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (530 mg, 73% yield) was obtained as colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (495 mg, 1.20 mmol) and 1- (bromomethyl) - 4- (methylsulfonyl) benzene (300 mg, 1.20 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 38 (3H, s), 2.55 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.04 (3H, s), 4.12-4.13 (2H , m), 4.21 (1H, br.s), 5.01 (2H, s), 7.04 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 7.9 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.83 (2H, d, J = 8.5 Hz).

2) 4- (Methylsulfonyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (466 mg, 92% yield) was obtained as a white solid from 4- ( methylsulfonyl) benzyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.53 g, 0.913 mmol) in a manner similar to the method of example 2-3 )

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.15-2.26 (1H, m), 2.36 (3H, s), 2.54-2.58 (3H, m), 2.87-2.97 (2H, m), 3.22 (3H, s), 3.81 (2H, d, J = 5.1 Hz) 5.11 (2H, s), 7.15-7.28 (6H, m), 7.84 (2H, d, J = 8.3 Hz), 8.23-8.40 (3H, m )

Example 261

Ethyl 3- [4 - ({[[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1-yl dihydrochloride ] propionate

1) Ethyl 3- [4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl ) -2-oxopiperazin-1-yl] propionate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg , 1.0 mmol) and ethyl (2-oxopiperazin-1-yl) propionate (250 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 610

2) Ethyl 3- [4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) -2-oxopiperazin-1 dihydrochloride -yl] propionate (278 mg, 49% yield) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.3 Hz), 1.19 (3H, t, J = 7.2 Hz), 2.14-2, 23 (1H, m), 2.37 (3H, s), 2.64 (2H, s), 3.06 (4H, br.s), 3.37-3.47 (4H, m), 3 74 (2H, s), 3.83 (2H, br.s), 4.06 (2H, q, J = 7.2 Hz), 7.18 (2H, d, J = 7.8 Hz) 7.29 (2H, d, J = 7.8 Hz); 8.40 (3H, br s).

Example 262

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-methoxybenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-methoxybenzamide dihydrochloride (209 mg, 95% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 2-methoxybenzoyl chloride (128 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.29 (1H, m), 2.36 (3H, s), 2.61 (3H, s), 3.03 (2H, s), 3.69 (3H, s), 3.84 (2H, br.s), 6.98 (1H, t, J = 7, 5 Hz), 7.08 (1H, d, J = 8.1 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz ), 7.39-7.49 (2H, m), 8.32 (3H, br.s), 9.55 (1H, br.s).

Example 263

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-fluorobenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-fluorobenzamide dihydrochloride (204 mg, 95% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 2-fluorobenzoyl chloride (122 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.21-2.28 (1H, m), 2.37 (3H, s), 2.55 (3H, s), 2.92 (2H, s), 3.84 (2H, s), 7.13-7.32 (7H, m), 7.49-7.54 (1H, m), 8.20 (3H, br.s), 9.86 (1H, br.s).

Example 264

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methoxybenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-methoxybenzamide dihydrochloride (196 mg, 80% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 3-methoxybenzoyl chloride (128 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.19-2.31 (1H, m), 2.32 (3H, s), 2.58 (3H, s), 3.02 (2H, s), 3.75 (3H, s), 3.85 (2H, br.s), 7.08-7.10 (2H, m) 7.18-7.36 (6H, m), 8.33 (3H, br s), 9.96 (1H, br s).

Example 265

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-fluorobenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3-fluorobenzamide dihydrochloride (186 mg, 78% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 3-fluorobenzoyl chloride (122 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.18-2.36 (1H, m), 2.31 (3H, s), 2.62 (3H, s), 3.08 (2H, s), 3.86 (2H, s), 7.26 (4H, s), 7.38-7.42 (2H, m), 7 50 (2H, s), 8.41 (3H, br s), 10.22 (1H, br s).

Example 266

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-methoxybenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-methoxybenzamide dihydrochloride (209 mg, 95% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-methoxybenzoyl chloride (128 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.19-2.26 (1H, m), 2.31 (3H, s), 2.63 (3H, s), 3.12 (2H, s), 3.79 (3H, s), 3.87 (2H, br.s), 6.96 (1H, t, J = 9, 0 Hz), 7.25 (4H, s), 7.67 (2H, d, J = 9.0 Hz), 8.43 (3H, br.s), 9.92 (1H, br.s) .

Example 267

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-fluorobenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-fluorobenzamide dihydrochloride (204 mg, 95% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-fluorobenzoyl chloride (122 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.14-2.31 (1H, m), 2.31 (3H, s), 2.62 (3H, s), 3.08 (2H, s), 3.85 (2H, s), 7.25-7.30 (6H, m), 7.70-7.75 (2H, m), 8.41 (3H, br.s), 10.14 (1H, br.s).

Example 268

(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate dihydrochloride

1) (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] acetate (540 mg, 86% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -methylphenyl) pyridin-3-yl] acetic acid (500 mg, 1.17 mmol) and 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (209 mg, 1.41 mmol) similar to the method of example 176-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.14 (3H, s), 2.16-2, 28 (1H, m), 2.40 (3H, s), 2.49 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.40 (2H, s), 4.04 (2H, d, J = 5.1 Hz), 4.21 (1H, br.s), 4.76 (2H, s), 6.93 (2H, d, J = 7.9 Hz ), 7.21 (2H, d, J = 7.9 Hz).

2) (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl dihydrochloride ] acetate (500 mg, 99% yield) was obtained as a white powder from (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (530 mg, 0.984 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.15 (3H, s), 2.18-2.25 (1H, m), 2.39 (3H, s), 2.88 (3H, s), 3.29 (2H, d, J = 7.2 Hz), 3.54-3.64 (4H, m), 4.94 (2H, s), 7.16 (2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 7.9 Hz), 8.63 (3H, br.s).

Example 269

2- [4- (Methoxycarbonyl) phenyl] ethyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) 2- [4- (Methoxycarbonyl) phenyl] ethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.77 g, 70% yield) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.80 g, 4.37 mmol) and methyl 4- (2-bromoethyl) benzoate (1.06 g, 4.37 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.28 (1H, m), 2, 37 (3H, s), 2.46 (3H, s), 2.66 (2H, t, J = 7.0 Hz), 2.77 (2H, d, J = 7.4 Hz), 3, 91 (3H, s), 4.11-4.15 (4H, m), 4.22 (1H, br.s), 7.02 (2H, d, J = 8.1 Hz), 7.15 (4H, d, J = 8.3 Hz), 7.95 (2H, d, J = 8.5 Hz).

2) 2- [4- (Methoxycarbonyl) phenyl] ethyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (291 mg, 82% yield) was obtained as a white solid substances from 2- [4- (methoxycarbonyl) phenyl] ethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.37 g, 0.644 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.8 Hz), 2.14-2.27 (1H, m), 2.35 (3H, s), 2.42 (3H, br.s), 2.73 (2H, d, J = 6.4 Hz), 2.91 (2H, br.s), 3.81 (2H, d, J = 5, 3 Hz), 3.85 (3H, s), 4.17 (2H, t, J = 6.5 Hz), 7.12 (2H, d, J = 6.8 Hz), 7.22 (2H d, J = 7.9 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.34 (3H, br .from).

Example 270

4- [2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride

1) 4- [2 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl ] benzoic acid (1.30 g, 95% yield) was obtained as a colorless oil from 2- [4- (methoxycarbonyl) phenyl] ethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 methyl 4- (4-methylphenyl) nicotinate (1.40 g, 2.44 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2, 37 (3H, s), 2.44 (3H, s), 2.70 (2H, d, J = 6.9 Hz), 2.79 (2H, d, J = 7.2 Hz), 4, 11-4.18 (4H, m), 4.24 (1H, br.s), 7.02 (2H, d, J = 7.9 Hz), 7.15-7.20 (4H, m) 8.01 (2H, d, J = 8.3 Hz).

2) 4- [2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride (359 mg, yield 94%) was obtained as a white solid from 4- [2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] carbonyl} oxy) ethyl] benzoic acid (0.40 g, 0.713 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.14-2.25 (1H, m), 2.35 (3H, s), 2.42 (3H, s), 2.71 (2H, t, J = 6.5 Hz), 2.87 (2H, d, J = 7.0 Hz), 3.80 (2H, d, J = 5.3 Hz), 4.16 (2H, t, J = 6.5 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.21-7.26 (4H, m ), 7.87 (2H, d, J = 8.1 Hz), 8.28 (3H, br.s).

Example 271

2- [4- (Aminocarbonyl) phenyl] ethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) 2- [4- (Aminocarbonyl) phenyl] ethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (598 mg, yield 99 %) was obtained as a colorless oil from 4- [2 - ({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] carbonyl} oxy) ethyl] benzoic acid (0.60 g, 1.07 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.27 (1H, m), 2, 37 (3H, s), 2.47 (3H, s), 2.66 (2H, t, J = 7.1 Hz), 2.78 (2H, d, J = 7.2 Hz), 4, 09-4.15 (4H, m.s.), 4.24 (1H, s.s), 5.67 (1H, s.s), 6.06 (1H, s.s), 7.02 (2H, d, J = 7.9 Hz), 7.15-7.19 (4H, m), 7.73 (2H, d, J = 8.1 Hz).

2) 2- [4- (Aminocarbonyl) phenyl] ethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (508 mg, 90% yield) was obtained as a white solid substances from 2- [4- (aminocarbonyl) phenyl] ethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (598 mg, 1, 06 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.25 (1H, m), 2.36 (3H, s), 2.42 (3H, br.s), 2.67 (2H, br, J = 6.4 Hz), 2.87 (2H, br.s), 3.81 (2H, d, J = 5, 5 Hz), 4.16 (2H, t, J = 6.5 Hz), 7.11 (2H, d, J = 7.7 Hz), 7.18-7.25 (4H, m), 7 32 (1H, br.s), 7.81 (2H, d, J = 8.3 Hz), 7.95 (1H, br.s), 8.27 (3H, br.s).

Example 272

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzamide

1) tert-Butyl {[5 - {[3- (aminocarbonyl) phenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (240 mg, yield 80%) was obtained as a white solid from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy } benzoic acid (0.30 g, 0.578 mmol) in a manner similar to the method of example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.21-2.28 (1H, m), 2, 35 (3H, s), 2.62 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 4.09-4.11 (2H, m), 4.22 (1H , broad s), 4.68 (2H, s), 5.55 (1H, broad s), 6.01 (1H, broad s), 6.96-7.01 (1H, m), 7.04 (2H, d, J = 7.9 Hz), 7.17 (2H, d, J = 7.7 Hz), 7.29-7.32 (2H, m), 8.02 (1H , from).

2) 3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} benzamide (166 mg, 85% yield) was obtained as a white solid from tert-butyl {[5 - {[3- (aminocarbonyl) phenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (240 mg, 0.463 mmol ) in a manner similar to the method of example 239-2).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.8 Hz), 2.21-2.30 (1H, m), 2.36 (3H, s), 2, 61 (3H, s), 2.81 (2H, d, J = 7.2 Hz), 3.60 (2H, s), 4.68 (2H, s), 5.52 (1H, br.s ), 6.06 (1H, br.s), 6.96-7.00 (1H, m), 7.09 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 7.9 Hz), 7.25-7.31 (3H, m).

Example 273

Methyl 2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoate dihydrochloride

1) Methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoate ( 720 mg, yield 52%) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1 , 0 g, 2.51 mmol) and methyl 2-hydroxy-5-methylbenzoate (500 mg, 3.01 mmol) in a manner similar to the method of example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2, 27 (3H, s), 2.37 (3H, s), 2.67 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.80 (3H, s), 4.09 (2H, d, J = 4.9 Hz), 4.20 (1H, br.s), 4.68 (2H, s), 7.02-7.06 (3H, m), 7 11 (1H, dd, J = 8.5, 1.9 Hz), 7.16 (2H, d, J = 7.7 Hz), 7.52 (1H, d, J = 1.9 Hz) .

2) Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoate dihydrochloride (100 mg, 70% yield) prepared as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} - 5-methylbenzoate (150 mg, 0.274 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (6H, d, J = 6.2 Hz), 2.18-2.24 (1H, m), 2.24 (3H, s), 2.37 (3H, s), 2.99 (3H, s), 3.29 (2H, d, J = 7.2 Hz), 3.70-3.76 (5H, m), 4.78 (2H, s), 6.78 (1H, d, J = 8.5 Hz), 7.17-7.40 (5H, m), 7.46 (1H, s), 8.63 (3H, ears.s).

Example 274

Methyl 2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoate dihydrochloride

1) Methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoate ( 0.80 g, 71% yield) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.80 g, 2.0 mmol) and methyl 5-chlorosalicylate (0.56 g, 3.0 mmol) in a manner similar to that of Example 106-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.30 (1H, m), 2, 37 (3H, s), 2.66 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.81 (3H, s), 4.09 (2H, d, J = 4.9 Hz), 4.15-4.25 (1H, m), 4.69 (2H, s), 6.57 (1H, d, J = 8.9 Hz), 7.03 (2H d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz), 7.26 (1H, dd, J = 2.7, 8.9 Hz), 7.69 (1H, d, J = 2.7 Hz).

2) A mixture of methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoate (0.19 g, 0.33 mmol) and a methanolic solution of hydrogen chloride (4 ml) were stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting solid was washed with diisopropyl ether to obtain methyl 2- {dihydrochloride { [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoate (0.17 g, 96% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.35 (3H, s), 3.08 (3H, broad s), 3.08 (2H, broad s), 3.75 (3H, s), 3.82 (2H, d, J = 4.5 Hz), 4.79 (2H, s), 6.97 (1H, d, J = 9.0 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.29 (2H, d, J = 7, 9 Hz), 7.52 (1H, dd, J = 2.8, 9.0 Hz), 7.65 (1H, d, J = 2.8 Hz), 8.35 (3H, br.s) .

Example 275

Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methoxybenzoate dihydrochloride

1) Methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methoxybenzoate ( 0.70 g, yield 62%) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.80 g, 2.0 mmol) and methyl 5-methoxysalicylate (0.55 g, 3.0 mmol) in a manner similar to that of Example 106-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.30 (1H, m), 2, 38 (3H, s), 2.69 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.77 (3H, s), 3.81 (3H, s), 4.09 (2H, d, J = 4.7 Hz), 4.15-4.30 (1H, m), 4.68 (2H, s), 6.50 (1H, d, J = 9, 0 Hz), 6.85 (1H, dd, J = 3.2, 9.0 Hz), 7.01 (2H, d, J = 7.9 Hz), 7.17 (2H, d, J = 7.9 Hz), 7.24 (1H, d, J = 3.2 Hz).

2) Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methoxybenzoate dihydrochloride (0.20 g, yield 96 %) was obtained as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy } -5-methoxybenzoate (0.23 g, 0.40 mmol) in a manner similar to that of Example 274-2).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.37 (3H, s), 2.73 (3H, br.s), 2.93 (2H, br.s), 3.72 (3H, s), 3.73 (3H, s), 3.79 (2H, d, J = 4.9 Hz), 4.69 (2H, br.s), 6.77 (1H, d, J = 9.0 Hz), 7.01 (1H, dd, J = 3.2, 9.0 Hz), 7.14 (1H, d, J = 3.2 Hz), 7.20 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 7.8 Hz) 8.11 (3H, br s).

Example 276

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoic dihydrochloride

1) Methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoate ( 0.81 g, yield 72%) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.80 g, 2.0 mmol) and methyl 4-methoxysalicylate (0.55 g, 3.0 mmol) in a manner similar to that of Example 106-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.30 (1H, m), 2, 36 (3H, s), 2.68 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 3.75 (3H, s), 3.77 (3H, s), 4.09 (2H, d, J = 4.7 Hz), 4.20-4.25 (1H, m), 4.68 (2H, s), 6.14 (1H, d, J = 2, 4 Hz), 6.48 (1H, dd, J = 2.4, 8.7 Hz), 7.00-7.10 (2H, m), 7.15-7.20 (2H, m), 7.79 (1H, d, J = 8.7 Hz).

2) 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoic acid (0 , 19 g, yield 37%) was obtained as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine -3-yl] methoxy} -4-methoxybenzoate (0.51 g, 0.91 mmol) in a manner similar to that of Example 36-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.15-2.35 (1H, m), 2, 35 (3H, s), 2.64 (3H, s), 2.81 (2H, d, J = 7.2 Hz), 3.82 (3H, s), 4.09 (2H, d, J = 4.9 Hz), 4.15-4.30 (1H, m), 4.87 (2H, s), 6.30 (1H, d, J = 2.3 Hz), 6.63 (1H dd, J = 2.3, 8.9 Hz), 7.00 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 7.9 Hz), 8.12 (1H, d, J = 8.9 Hz), 10.42 (1H, br s).

3) A mixture of 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoic acid ( 0.15 g, 0.28 mmol) and 6n. hydrochloric acid (4 ml) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the resulting solid was washed with acetonitrile to obtain 2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- dihydrochloride (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzoic acid (0.12 g, 81% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.10-2.30 (1H, m), 2.37 (3H, s), 2.86 (3H, br.s), 3.06 (2H, br.s), 3.73 (3H, s), 3.82 (2H, br.s), 4.76 (2H, br. s), 6.31 (1H, d, J = 2.1 Hz), 6.60 (1H, dd, J = 2.1, 8.7 Hz), 7.26 (2H, d, J = 7 , 2 Hz), 7.32 (2H, d, J = 7.2 Hz), 7.68 (1H, d, J = 8.7 Hz), 8.28 (3H, br.s).

Example 277

Methyl-6 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinate trihydrochloride

1) A mixture of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.50 g, 3.76 mmol), triethylamine (1.05 ml, 7.52 mmol) and tetrahydrofuran (50 ml) were cooled to 0 ° C and methanesulfonyl chloride (647 mg, 5.65 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate as a crude product. The crude product was added to a solution of (5-bromopyridin-2-yl) methanol (848 mg, 4.51 mmol) and sodium hydride (60% in oil, 226 mg, 5.65 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at 60 ° C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl {[5 - {[(5-bromopyridin-2-yl) methoxy] methyl} -2-isobutyl-6-methyl-4- (4 -methylphenyl) pyridin-3-yl] methyl} carbamate (1.35 g, 63% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.24 (1H, m), 2, 41 (3H, s), 2.65 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 4.06 (2H, d, J = 4.9 Hz), 4, 23 (2H, s), 4.39 (2H, s), 7.01 (2H, d, J = 7.9 Hz), 7.16-7.20 (3H, m), 7.73 (1H dd, J = 8.4, 2.4 Hz), 8.54 (1H, d, J = 2.1 Hz).

2) Methyl-6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinate ( 1.15 g, 88% yield) was obtained as a yellow oil from tert-butyl {[5 - {[(5-bromopyridin-2-yl) methoxy] methyl} -2-isobutyl-6-methyl-4- (4 -methylphenyl) pyridin-3-yl] methyl} carbamate (1.35 g, 2.37 mmol) in a manner similar to that of Example 231-2).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 40 (3H, s), 2.67 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 3.95 (3H, s), 4.06 (2H, d, J = 4.9 Hz), 4.20 (1H, br.s), 4.27 (2H, s), 4.50 (2H, s), 7.02 (2H, d, J = 7.9 Hz ), 7.19 (2H, d, J = 7.7 Hz), 7.36 (1H, d, J = 8.1 Hz), 8.21 (1H, dd, J = 8.1, 2, 1 Hz), 9.08 (1H, d, J = 1.7 Hz).

3) Methyl-6 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinate trihydrochloride (114 mg, 58% yield) prepared as a white solid from methyl-6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy } methyl) nicotinate (0.19 g, 0.347 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.11-2.22 (1H, m), 2.38 (3H, s), 3.14 (2H, br.s), 3.81 (2H, d, J = 5.3 Hz), 3.90 (3H, s), 4.29 (2H, s), 4.51 (2H , s), 7.23 (2H, d, J = 7.9 Hz), 7.32 (2H, d, J = 7.9 Hz), 7.38 (1H, d, J = 8.1 Hz ), 8.25 (1H, dd, J = 8.1, 2.2 Hz), 8.38 (3H, br.s), 8.98 (1H, d, J = 1.5 Hz).

Example 278

6 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinic acid trihydrochloride

1) 6 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinic acid (760 mg, 81% yield) was obtained as a colorless oil from methyl 6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] methoxy} methyl) nicotinate (0.96 g, 1.75 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.26 (1H, m), 2, 39 (3H, s), 2.71 (3H, s), 2.85 (2H, d, J = 7.2 Hz), 4.05-4.10 (2H, m), 4.29 (3H , br.s), 4.52 (2H, s), 7.03 (2H, d, J = 7.9 Hz), 7.38 (1H, d, J = 8.1 Hz), 8.29 (1H, dd, J = 8.2, 1.8 Hz); 9.15 (1H, d, J = 1.5 Hz).

2) 6 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinic acid trihydrochloride (259 mg, 90% yield) was obtained as a white solid from 6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinic acid (0.28 g, 0.525 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.4 Hz), 2.11-2.22 (1H, m), 2.39 (3H, s), 2.94 (3H, br.s), 3.13-3.22 (2H, m), 3.81 (2H, br.s), 4.29 (2H, br.s), 4.51 ( 2H, s), 7.19-7.25 (2H, m), 7.30-7.36 (3H, m), 8.19-8.24 (1H, m), 8.43 (3H, broad s), 8.93-8.96 (1H, m).

Example 279

Methyl 2- {2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl} benzoate dihydrochloride

1) To a solution of tert-butyl {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.36 g, 0.908 mmol) and diethyl (2 β-bromobenzyl) phosphonate (363 mg, 1.18 mmol) in N, N-dimethylformamide (10 ml) was added sodium methoxide (165 mg, 4.08 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate , washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl {[5 - [(E) -2- (2-bromophenyl) vinyl] -2-isobutyl-6-methyl-4- (4- methylphenyl) pyridin-3-yl] methyl} carbamate (390 mg, 78% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.30 (1H, m), 2, 39 (3H, s), 2.72 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.11 (2H, d, J = 5.1 Hz), 4, 24 (1H, br.s), 6.55 (1H, d, J = 16.6 Hz), 6.78 (1H, d, J = 16.6 Hz), 7.02 (2H, d, J = 7.9 Hz), 7.05-7.08 (1H, m), 7.15-7.18 (2H, m), 7.22 (2H, d, J = 7.7 Hz), 7 50 (1H, d, J = 7.5 Hz).

2) Methyl-2 - {(E) -2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl } benzoate (280 mg, 74% yield) was obtained as a yellow oil from tert-butyl {[5 - [(E) -2- (2-bromophenyl) vinyl] -2-isobutyl-6-methyl-4- (4 -methylphenyl) pyridin-3-yl] methyl} carbamate (390 mg, 0.907 mmol) in a manner similar to that of Example 231-2).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.27 (1H, m), 2, 39 (3H, s), 2.74 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.89 (3H, s), 4.11 (2H, d, J = 5.3 Hz), 4.24 (1H, br.s), 6.47 (1H, d, J = 16.8 Hz), 7.02 (2H, d, J = 7.9 Hz), 7.13 (1H, d, J = 7.5 Hz), 7.20-7.29 (4H, m), 7.35-7.40 (1H, m), 7.86 (1H, dd, J = 7.8, 1.4 Hz).

3) A mixture of methyl-2 - {(E) -2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl} benzoate (0.28 g, 0.53 mmol), 10% palladium on carbon (57 mg, 0.053 mmol) and methanol (10 ml) were mixed in a hermetically sealed tube in a hydrogen atmosphere at 0.5 MPa at room temperature in for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain methyl 2- {2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- silt] ethyl} benzoate (250 mg, 88% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.23 (1H, m), 2, 43 (3H, s), 2.60 (3H, s), 2.62-2.68 (2H, m), 2.73 (2H, d, J = 7.4 Hz), 2.91-2 96 (2H, m), 3.82 (3H, s), 4.01 (2H, d, J = 5.1 Hz), 4.21 (1H, br.s), 6.54 (1H, dd, J = 7.4, 1.2 Hz), 6.94 (2H, d, J = 8.1 Hz), 7.15-7.25 (4H, m), 7.77 (1H, dd , J = 7.6, 1.6 Hz).

4) Methyl 2- {2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl} benzoate dihydrochloride (201 mg, 84% yield) was obtained as a white solid from methyl 2- {2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] ethyl } benzoate (0.25 g, 0.471 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.20 (1H, m), 2.45 (3H, s), 2.63-2.72 (2H, m), 2.83-2.90 (5H, m), 2.91-2.96 (2H, m), 3.18 (2H, br.s), 3.73-3.84 (5H, m), 6.65 (1H, d, J = 7.4 Hz), 7.26 (2H, d, J = 7.7 Hz), 7.31 (1H dd, J = 7.4, 1.4 Hz), 7.35 (1H, dd, J = 7.4, 1.8 Hz), 7.42 (2H, d, J = 7.9 Hz) 7.75 (1H, dd, J = 7.5, 1.5 Hz), 8.46 (3H, br s).

Example 280

Methyl 4-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} hydroxy) methyl] benzoate

1) Methyl-4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} oxy) methyl ] benzoate (258 mg, 64% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- il] acetic acid (300 mg, 0.703 mmol) and methyl 4- (bromomethyl) benzoate (209 mg, 0.914 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2, 38 (3H, s), 2.49 (3H, s), 2.77 (2H, d, J = 7.0 Hz), 3.42 (3H, s), 3.93 (3H, s), 4.03 (2H, d, J = 5.1 Hz), 5.09 (2H, s), 6.92 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.01 (2H, d, J = 8.1 Hz).

2) Methyl 4-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} hydroxy) methyl] benzoate (60 mg, yield 92%) was obtained as a white powder from methyl 4 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] acetyl} oxy) methyl] benzoate (68.6 mg, 0.119 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.17-2.23 (1H, m), 2.38 (3H, s), 2.85 (3H, s), 3.25 (2H, d, J = 6.8 Hz), 3.63 (2H, s), 3.79 (2H, d, J = 4.5 Hz), 3.87 (3H, s), 5.13 (2H, s), 7.13 (2H, d, J = 7.9 Hz), 7.30 (2H, d, J = 7.9 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.97 (2H, d, J = 8.3 Hz), 8.63 (3H, br.s).

Example 281

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic dihydrochloride

1) 2 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid (450 mg, 86% yield) was obtained as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methoxy} -5-methylbenzoate (537 mg, 0.982 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.30 (1H, m), 2, 32 (3H, s), 2.34 (3H, s), 2.64 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 4.10 (2H, d, J = 4.9 Hz), 4.20 (1H, s), 4.88 (2H, s), 6.72 (1H, d, J = 8.5 Hz), 7.01 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.23-7.25 (1H, m), 7.97 (1H, d, J = 2.26 Hz )

2) 2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid dihydrochloride (150 mg, 94% yield) was obtained in the form of a white powder from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzoic acid (168 mg, 0.316 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (6H, d, J = 6.6 Hz), 2.18-2.30 (1H, m), 2.24 (3H, s), 2.38 (3H, s), 3.00 (3H, s), 3.30 (2H, d, J = 6.8 Hz), 3.87 (2H, d, J = 2.6 Hz), 4.78 (2H, s), 6.72 (1H, d, J = 8.5 Hz), 7.20-7.22 (1H, m), 7.30-7.34 (4H, m) 7.43 (1H, d, J = 1.5 Hz); 8.63 (3H, br s).

Example 282

Methyl 3-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} hydroxy) methyl] benzoate

1) Methyl-3 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} hydroxy) methyl ] benzoate (401 mg, 64% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- il] acetic acid (466 mg, 1.09 mmol) and methyl 3- (bromomethyl) benzoate (325 mg, 1.42 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2, 36 (3H, s), 2.48 (3H, s), 2.74 (2H, d, J = 7.4 Hz), 3.41 (2H, s), 3.93 (3H, s), 4.03 (2H, d, J = 4.9 Hz), 4.20 (1H, br.s), 5.08 (2H, s), 6.90-6.93 (2H, m), 7 14 (2H, d, J = 7.7 Hz), 7.40-7.44 (2H, m), 7.93 (1H, d, J = 0.8 Hz), 7.98-8, 01 (1H, m).

2) Methyl 3-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} hydroxy) methyl] benzoate (80 mg, yield 99%) was obtained as a white powder from methyl 3 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] acetyl} oxy) methyl] benzoate (84.6 mg, 0.147 mmol) in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.36 (3H, s), 2.88 (3H, s), 3.30 (2H, d, J = 6.8 Hz), 3.60 (2H, s), 3.80 (2H, d, J = 3.8 Hz), 3.88 (3H, s), 5.13 (2H, s), 7.12 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.56-7.60 (2H, m), 7.89 (1H, s), 7.95-7.98 (1H, m), 8.63 (3H, br.s).

Example 283

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzamide dihydrochloride

1) tert-Butyl {[5 - {[2- (aminocarbonyl) -5-methoxyphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0 , 31 g, 82% yield) was obtained as a white powder from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methoxy} -4-methoxybenzoic acid (0.38 g, 0.68 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.30 (1H, m), 2, 36 (3H, s), 2.63 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 3.80 (3H, s), 4.10 (2H, d, J = 5.1 Hz), 4.20-4.25 (1H, m), 4.75 (2H, s), 5.51 81H, br.s), 6.26 (1H, d, J = 2 , 3 Hz), 6.58 (1H, dd, J = 2.3, 8.9 Hz), 7.00 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 7.9 Hz), 7.41 (1H, br s), 8.18 (1H, d, J = 8.9 Hz).

2) 2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4-methoxybenzamide dihydrochloride (0.22 g, 91% yield) prepared as a white powder from tert-butyl {[5 - {[2- (aminocarbonyl) -5-methoxyphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } carbamate (0.25 g, 0.46 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.10-2.30 (1H, m), 2.35 (3H, s), 2.78 (3H, br.s), 3.01 (2H, br.s), 3.74 (3H, s), 3.80 (2H, d, J = 5.1 Hz), 4.82 (2H, s), 6.42 (1H, d, J = 2.2 Hz), 6.63 (1H, dd, J = 2.2, 8.7 Hz), 7.14 (2H, br. s), 7.15-7.35 (4H, m), 7.74 (1H, d, J = 8.7 Hz), 8.28 (3H, br.s).

Example 284

Methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoate dihydrochloride

1) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoate ( 1.07 g, 73% yield) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.0 g, 2.51 mmol) and methyl 3-hydroxy-2-naphthoate (609 mg, 3.01 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.18-2.31 (1H, m), 2, 34 (3H, s), 2.70 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 3.87 (3H, s), 4.11 (2H, d, J = 4.7 Hz), 4.20 (1H, br.s), 4.81 (2H, s), 6.91 (1H, s), 7.09 (2H, d, J = 7.9 Hz ), 7.16 (2H, d, J = 7.9 Hz), 7.34-7.38 (1H, m), 7.46-7.50 (1H, m), 7.58-7, 62 (1H, m), 7.79 (1H, d, J = 8.1 Hz), 8.22 (1H, s).

2) Methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoate dihydrochloride (178 mg, 84% yield) obtained as a white powder from methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} - 2-naphthoate (220 mg, 0.378 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (6H, d, J = 6.2 Hz), 2.18-2.33 (1H, m), 2.34 (3H, s), 3.06 (3H, s), 3.36 (2H, d, J = 6.0 Hz), 3.84 (3H, s), 3.91 (2H, s), 4.96 (2H, s ), 7.35-7.45 (6H, m), 7.58 (1H, t, J = 7.35 Hz), 7.79 (1H, d, J = 8.1 Hz), 7.98 (1H, d, J = 7.9 Hz), 8.32 (1H, s), 8.63 (3H, br.s).

Example 285

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid dihydrochloride

1) 3 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid (860 mg, 100% yield) was obtained as a white powder from methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methoxy} -2-naphthoate (817 mg, 1.40 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.20-2.30 (1H, m), 2, 32 (3H, s), 2.81 (3H, s), 2.97 (2H, d, J = 6.4 Hz), 4.15 (2H, d, J = 3.0 Hz), 4, 20 (1H, br.s), 5.01 (2H, s), 7.06 (3H, d, J = 7.7 Hz), 7.18 (2H, d, J = 7.7 Hz), 7.40-7.48 (1H, m), 7.52-7.58 (1H, m), 7.62-7.68 (1H, m), 7.89 (1H, d, J = 8 , 1 Hz), 8.67 (1H, s).

2) 3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid dihydrochloride (300 mg, 98% yield) was obtained in the form of a white powder from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthoic acid (320 mg, 0.563 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.4 Hz), 2.17-2.29 (1H, m), 2.33 (3H, s), 2.81 (3H, s), 2.90 (2H, s), 3.83 (2H, s), 4.86 (2H, s), 7.24 (1H, s), 7.26-7 , 33 (4H, m), 7.41 (1H, t, J = 7.5 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.75 (1H, d, J = 8.1 Hz), 7.94 (1H, d, J = 8.1 Hz), 8.52 (1H, s), 8.63 (3H, br.s).

Example 286

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzamide dihydrochloride

1) tert-Butyl {[5 - {[2- (aminocarbonyl) -4-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (250 mg, yield 91%) was obtained as a white powder from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] methoxy} -5-methylbenzoic acid (276 mg, 0.518 mmol) in a manner similar to the method of example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.28 (1H, m), 2, 31 (3H, s), 2.35 (3H, s), 2.64 (3H, s), 2.81 (2H, s), 4.11 (2H, s), 4.20 (1H, s ), 4.76 (2H, s), 6.66 (1H, d, J = 8.5 Hz), 7.00 (2H, d, J = 8.1 Hz), 7.17 (2H, d , J = 8.1 Hz), 7.55 (2H, s), 8.00 (2H, s).

2) Dihydrochloride 2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-methylbenzamide (200 mg, 92% yield) was obtained in as a white powder from tert-butyl {[5 - {[2- (aminocarbonyl) -4-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (230 mg, 0.433 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.4 Hz), 2.10-2.30 (4H, m), 2.36 (3H, s), 2.96 (3H, s), 3.27 (2H, d, J = 7.0 Hz), 3.86 (2H, d, J = 4.5 Hz), 4.72-4.84 (2H , m), 6.76 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 8.5, 1.9 Hz), 7.25-7.38 (4H, m), 7.42 (1H, d, J = 1.9 Hz), 8.64 (3H, br.s).

Example 287

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride (198 mg, 95% yield) was obtained as a white powder from tert-butyl { [5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and acetyl chloride (53 ml, 0.75 mmol) by similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.76 (3H, s), 2.13-2.22 (1H, m), 2.39 (3H, s), 2.55 (3H, s), 3.02 (2H, br s), 3.82 (2H, s), 7.17 (2H, d, J = 7, 5 Hz), 7.33 (2H, d, J = 7.5 Hz), 8.31 (3H, br.s), 9.50 (1H, br.s).

Example 288

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propanamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] propanamide dihydrochloride (195 mg, 93% yield) was obtained as a white powder from tert-butyl { [5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and propionyl chloride (65 ml, 0.75 mmol) by the method similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.82 (3H, t, J = 6.9 Hz), 0.98 (6H, d, J = 6.6 Hz), 2.02 (2H, q, J = 6.9 Hz), 2.08-2.32 (1H, m), 2.38 (3H, s), 2.55 (3H, s), 3.06 (2H, br.s ), 3.83 (2H, s), 7.17 (2H, d, J = 7.8 Hz), 7.32 (2H, d, J = 7.8 Hz), 8.37 (3H, br s) 9.49 (1H, br s).

Example 289

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,2-dimethylpropanamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,2-dimethylpropanamide dihydrochloride (184 mg, 72% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and pivaloyl chloride (92 ml, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (9H, s), 0.98 (6H, d, J = 6.6 Hz), 2.12-2.24 (1H, m), 2.36 (3H, s), 2.51 (3H, s), 2.97 (2H, br s), 3.81 (2H, s), 7.14 (2H, d, J = 8, 1 Hz), 7.28 (2H, d, J = 8.1 Hz), 8.28 (3H, br.s), 8.95 (1H, br.s).

Example 290

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclopropanecarboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclopropanecarboxamide dihydrochloride (170 mg, 85% yield) was obtained as a white powder from tert-butyl { [5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and cyclopropanecarbonyl chloride (68 ml, 0.75 mmol) by the method similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.58-0.67 (4H, m), 0.98 (6H, d, J = 6.6 Hz), 1.51-1.58 (1H , m), 2.17-2.26 (1H, m), 2.39 (3H, s), 2.54 (3H, s), 3.02 (2H, br.s), 3.81 ( 2H, s), 7.16 (2H, d, J = 7.5 Hz), 7.32 (2H, d, J = 7.5 Hz), 8.32 (3H, br.s), 9, 70 (1H, broad s).

Example 291

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclopentanecarboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclopentanecarboxamide dihydrochloride (137 mg, 62% yield) was obtained as a white powder from tert-butyl { [5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and cyclopentanecarbonyl chloride (68 ml, 0.75 mmol) by the method similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.30-1.62 (9H, m), 2.15-2.24 (1H , m), 2.38 (3H, s), 2.50 (3H, s), 3.02 (2H, br s), 3.81 (2H, s), 7.15 (2H, d, J = 7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 8.32 (3H, br.s), 9.39 (1H, br.s).

Example 292

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyridin-2-carboxamide trihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyridin-2-carboxamide trihydrochloride (218 mg, 91% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and pyridine-2-carbonyl chloride (106 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.20-2.28 (1H, m), 2.28 (3H, s), 2.64 (3H, s), 3.14 (2H, broad s), 3.86 (2H, s), 7.20-7.27 (4H, m), 7.06-7.65 ( 1H, m), 7.94-8.02 (2H, m), 8.43 (3H, br.s), 8.61 (1H, d, J = 4.8 Hz), 10.33 (1H , from).

Example 293

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] nicotinamide trihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] nicotinamide trihydrochloride (225 mg, 94% yield) was obtained as a white powder from tert-butyl { [5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and nicotinoyl chloride (106 mg, 0.75 mmol) by the method similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (6H, d, J = 6.6 Hz), 2.23-2.31 (1H, m), 2.31 (3H, s), 2.73 (3H, s), 3.19 (2H, broad s), 3.90 (2H, s), 7.28 (4H, s), 7.73-7.78 (1H, m) , 8.35 (2H, d, J = 8.1 Hz), 8.53 (3H, br.s), 8.85 (1H, d, J = 3.6 Hz), 8.94 (1H, s), 10.90 (1H, br s).

Example 294

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isonicotinamide trihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isonicotinamide trihydrochloride (215 mg, 91% yield) was obtained as a white powder from tert-butyl { [5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and isonicotinoyl chloride (106 mg, 0.75 mmol) by the method similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.22-2.31 (1H, m), 2.31 (3H, s), 2.70 (3H, s), 3.51 (2H, br.s), 3.88 (2H, s), 7.28 (4H, s), 7.87 (2H, d, J = 6, 0 Hz), 8.51 (3H, br.s), 8.88 (2H, d, J = 6.0 Hz), 11.20 (1H, br.s).

Example 295

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} amine dihydrochloride

1) tert-Butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} carbamate (270 mg, 56% yield) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.40 g, 1.00 mmol) and phenol ( 94.5 mg, 1.00 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.27 (1H, m), 2, 36 (3H, s), 2.63 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.10 (2H, d, J = 5.7 Hz), 4, 22 (1H, br.s), 4.62 (2H, s), 6.78-6.82 (2H, m), 6.93 (1H, t, J = 7.4 Hz), 7.05 (2H, d, J = 8.1 Hz), 7.17 (2H, d, J = 7.7 Hz), 7.21-7.24 (2H, m).

2) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} amine dihydrochloride (132 mg, 51% yield) was obtained as a colorless oil from tert -butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (phenoxymethyl) pyridin-3-yl] methyl} carbamate (0.27 g, 0.569 mmol) in a manner similar to the method of example 2-3 )

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.35 (3H, s), 2.82 (3H, br.s), 3.12 (2H, br.s), 3.83 (2H, d, J = 4.9 Hz), 4.70 (2H, s), 6.85 (2H, d, J = 7.9 Hz), 6.95 (1H, t, J = 7.4 Hz), 7.23-7.33 (6H, m), 8.38 (3H, br. from).

Example 296

6 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinamide trihydrochloride

1) tert-Butyl {[5 - ({[5- (aminocarbonyl) pyridin-2-yl] methoxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } carbamate (370 mg, 77% yield) was obtained as a white solid from 6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) pyridin-3-yl] methoxy} methyl) nicotinic acid (0.48 g, 0.899 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.23 (1H, m), 2, 40 (3H, s), 2.67 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.07 (2H, d, J = 5.1 Hz), 4, 23 (1H, br.s), 4.27 (2H, s), 4.49 (2H, s), 7.03 (2H, d, J = 7.9 Hz), 7.20 (2H, d , J = 7.7 Hz), 7.38 (1H, d, J = 7.9 Hz), 8.08 (1H, dd, J = 8.1, 2.3 Hz), 8.90 (1H , d, J = 2.3 Hz).

2) 6 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} methyl) nicotinamide trihydrochloride (282 mg, 75% yield) was obtained as a white solid from tert-butyl {[5 - ({[5- (aminocarbonyl) pyridin-2-yl] methoxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3- silt] methyl} carbamate (0.37 g, 0.695 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.24 (1H, m), 2.39 (3H, s), 2.97 (3H, br.s), 3.23 (2H, d, J = 5.8 Hz), 3.82 (2H, d, J = 5.3 Hz), 4.30 (2H, s ), 4.52 (2H, s), 7.25 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.39-7.42 (1H, m), 7.61-7.69 (1H, m), 8.27-8.30 (1H, m), 8.50 (3H, br.s), 8.99 (1H, br .from).

Example 297

4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} isophthalic acid dihydrochloride

1) Dimethyl-4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} isophthalate (1.12 g, 75% yield) was obtained as a white solid from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1 , 00 g, 2.51 mmol) and dimethyl 4-hydroxyisophthalate (528 mg, 2.51 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.19-2.31 (1H, m), 2, 35 (3H, s), 2.66 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.83 (3H, s), 3.89 (3H, s), 4.06-4.11 (2H, m), 4.23 (1H, br.s), 4.77 (2H, s), 6.71 (1H, d, J = 8.9 Hz), 7 05 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 7.9 Hz), 8.01 (1H, dd, J = 8.7, 2.3 Hz) 8.41 (1H, d, J = 2.3 Hz).

2) 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} isophthalic acid (310 mg, yield 90%) was obtained as a white solid from dimethyl-4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] methoxy} isophthalate (0.36 g, 0.609 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (6H, d, J = 6.4 Hz), 1.37 (9H, s), 2.35 (3H, s), 2.96 (3H, br.s), 3.13 (2H, br.s), 4.16 (2H, br.s), 4.94 (2H, br.s), 6.76 (1H, br.s), 7 07 (2H, br.s), 7.22 (2H, d, J = 7.7 Hz), 8.01 (1H, br.s), 8.53 (1H, br.s).

3) 4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} isophthalic acid dihydrochloride (256 mg, 86% yield) was obtained as white solids from 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} isophthalic acid (0.31 g, 0.551 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.16-2.28 (1H, m), 2.35 (3H, s), 2.85 (3H, br.s), 3.08 (2H, br.s), 3.83 (2H, br.s), 4.86 (2H, s), 7.01 (1H, d, J = 8.9 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 7.7 Hz), 7.97 (1H, dd, J = 8.7, 2.3 Hz), 8.18 (1H, d, J = 2.1 Hz), 8.34 (3H, br.s).

Example 298

Methyl-2 - {(E) -2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl} benzoate dihydrochloride

Methyl-2 - {(E) -2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] vinyl} benzoate dihydrochloride (31.4 mg, yield 33%) was obtained as a white solid from methyl-2 - {(E) -2- [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) pyridin-3-yl] vinyl} benzoate (0.10 g, 0.189 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.4 Hz), 2.16-2.28 (1H, m), 2.38 (3H, s), 2.86 (3H, br.s), 3.06 (2H, br.s), 3.83-3.88 (5H, m), 6.53 (1H, d, J = 16.8 Hz) 7.17 (1H, d, J = 16.8 Hz), 7.24 (2H, d, J = 7.7 Hz), 7.29 (1H, d, J = 7.7 Hz), 7 35 (2H, d, J = 7.9 Hz), 7.40 (1H, t, J = 7.5 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.79 (1H, dd, J = 7.8, 1.2 Hz), 8.32 (3H, br.s).

Example 299

4- [1 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride

1) 1- [4- (Methoxycarbonyl) phenyl] ethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.02 g, yield 73%) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol) and methyl 4- (1-hydroxyethyl) benzoate (486 mg, 2.42 mmol) in a manner similar to that of Example 247-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.25 (3H, d, J = 7.0 Hz), 1.39 (9H, s) , 2.16-2.24 (1H, m), 2.33 (3H, s), 2.48 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3, 92 (3H, s), 4.11-4.16 (2H, m), 4.22 (1H, br.s), 5.73-5.79 (1H, m), 6.96-6, 99 (1H, m), 7.04-7.09 (2H, m), 7.13-7.17 (3H, m), 7.93 (2H, d, J = 8.3 Hz).

2) 4- [1 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl ] benzoic acid (950 mg, 95% yield) was obtained as a colorless oil from 1- [4- (methoxycarbonyl) phenyl] ethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) nicotinate (1.02 g, 1.77 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.26 (3H, d, J = 6.8 Hz), 1.39 (9H, s) , 2.15-2.26 (1H, m), 2.34 (3H, s), 2.50 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 4, 11-4.16 (2H, m), 4.24 (1H, br.s), 5.79 (1H, q, J = 6.6 Hz), 7.00-7.13 (4H, m) 7.18 (2H, d, J = 8.1 Hz); 7.99 (2H, d, J = 8.3 Hz).

3) 4- [1 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) ethyl] benzoic acid dihydrochloride (259 mg, yield 93%) was obtained as a white solid from 4- [1 - ({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] carbonyl} oxy) ethyl] benzoic acid (0.30 g, 0.522 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.22 (3H, d, J = 6.6 Hz), 2.17-2, 26 (1H, m), 2.33 (3H, s), 2.47 (3H, br.s), 2.88 (2H, d, J = 5.7 Hz), 3.81 (2H, d , J = 5.5 Hz), 5.76 (1H, q, J = 6.6 Hz), 7.11-7.25 (6H, m), 8.27 (3H, br.s).

Example 300

[(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride

1) tert-Butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (1.37 g , yield 70%) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.50 g, 3.76 mmol) and 2- (methylthio) phenol (573 mg, 3.76 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.31 (1H, m), 2, 36 (3H, s), 2.37 (3H, s), 2.69 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.09-4.11 (2H , m), 4.21 (1H, br.s), 4.68 (2H, s), 6.57 (1H, dd, J = 7.9, 1.3 Hz), 6.91-7, 04 (2H, m), 7.06-7.12 (3H, m), 7.17 (2H, d, J = 7.7 Hz).

2) [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride (112 mg, 69% yield ) was obtained as a white solid from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (0.17 mg, 0.326 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.35 (3H, s), 2.36 (3H, s), 2.88 (3H, s), 3.15 (2H, s), 3.83 (2H, s), 4.75 (2H, s) 6.57 (1H, d, J = 6.8 Hz), 6.96-7.07 (2H, m), 7.13-7.16 (1H, m), 7.28 (2H, d , J = 8.3 Hz), 7.32 (2H, d, J = 7.4 Hz), 8.41 (3H, br.s).

Example 301

[(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfonyl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride

1) tert-Butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfonyl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (330 mg, yield 81%) was obtained as a white solid from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (0.38 g, 0.730 mmol) in a manner similar to that of Example 91-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.21-2.30 (1H, m), 2, 35 (3H, s), 2.67 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 3.08 (3H, s), 4.11 (2H, d, J = 5.1 Hz), 4.27 (1H, br.s), 4.79 (2H, s), 6.76 (1H, d, J = 8.1 Hz), 7.06-7.10 (3H, m), 7.18 (2H, d, J = 7.9 Hz), 7.45-7.50 (1H, m), 7.97 (1H, dd, J = 7.7, 1 , 7 Hz).

2) [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfonyl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride (227 mg, 59% yield ) was obtained as a white solid from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfonyl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (0.33 g, 0.597 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.4 Hz), 2.17-2.28 (1H, m), 2.35 (3H, s), 2.84 (3H, br.s), 3.05-3.17 (5H, m), 3.84 (2H, d, J = 4.7 Hz), 4.87 (2H, s), 7 11 (1H, d, J = 8.3 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.28-7.33 (4H, m), 7.60-7, 66 (1H, m), 7.81 (1H, dd, J = 7.7, 1.7 Hz), 8.40 (3H, br.s).

Example 302

[(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfinyl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride

1) To a mixed solution of tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylthio) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (0 , 47 g, 0.902 mmol) in methanol (10 ml) and water (10 ml) sodium periodate (377 mg, 1.76 mmol) was added and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfinyl) phenoxy] methyl} pyridine -3-yl) methyl] carbamate (164 mg, 33% yield) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.21-2.29 (1H, m), 2, 35 (3H, s), 2.61 (3H, s), 2.69 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 4.09-4.11 (2H , m), 4.23 (1H, br.s), 4.59 (1H, d, J = 10.0 Hz), 4.83 (1H, d, J = 10.0 Hz), 6.71 (1H, d, J = 8.1 Hz), 6.95-6.98 (1H, m), 7.02-7.05 (1H, m), 7.16-7.21 (3H, m ), 7.32-7.38 (1H, m), 7.82 (1H, dd, J = 7.7, 1.7 Hz).

2) [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfinyl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride (97.4 mg, yield 62%) was obtained as a white solid from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (methylsulfinyl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (164 mg, 0.306 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.27 (1H, m), 2.34 (3H, s), 2.63 (3H, s), 2.77 (3H, s), 3.06 (2H, s), 3.82 (2H, s), 4.70 (1H, d, J = 10.6 Hz), 4.90 (1H, d, J = 10.7 Hz), 6.99 (1H, d, J = 8.1 Hz), 7.20-7.33 (5H, m), 7.42-7.47 (1H, m), 7.64 (1H, dd, J = 7.5, 1.7 Hz), 8.31 (3H, br.s).

Example 303

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthamide dihydrochloride

1) tert-Butyl {[5 - ({[3- (aminocarbonyl) -2-naphthyl] oxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (230 mg, 46% yield) was obtained as a white powder from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] methoxy} -2-naphthoic acid (500 mg, 0.879 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.89 (6H, d, J = 6.6 Hz), 1.35 (9H, s), 2.07-2.22 (1H, m), 2, 28 (3H, s), 2.79 (3H, s), 2.87 (2H, d, J = 7.2 Hz), 4.14-4.21 (3H, m), 4.95 (2H , s), 7.04 (1H, s), 7.08-7.21 (4H, m), 7.42-7.52 (1H, m), 7.63 (1H, d, J = 7 5 Hz), 7.74 (1H, d, J = 7.5 Hz), 7.81 (1H, d, J = 8.1 Hz), 8.67 (1H, s), 11.73 ( 2H, s).

2) 3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-naphthamide dihydrochloride (200 mg, 91% yield) was obtained in as a white powder from tert-butyl {[5 - ({[3- (aminocarbonyl) -2-naphthyl] oxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (230 mg, 0.405 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.4 Hz), 2.17-2.30 (1H, m), 2.32 (3H, s), 2.51 (3H, s), 2.81 (2H, s), 3.83 (2H, s), 4.88 (2H, s), 7.25-7.33 (4H, m), 7 40 (1H, t, J = 7.5 Hz), 7.50 (1H, t, J = 7.5 Hz), 7.75 (1H, d, J = 8.1 Hz), 7.92 (1H, d, J = 7.9 Hz), 8.12 (1H, s), 8.42 (1H, s), 8.62 (3H, br.s).

Example 304

5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -N-phenylnicotinamide

To a solution of 5 - ({[(benzyloxy) carbonyl] amino} methyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (523 mg, 1.17 mmol) in tetrahydrofuran (5 ml) was added oxalyl chloride (120 μl, 1.4 mmol) and then one drop of N, N-dimethylformamide. The reaction solution was stirred for 3 hours, then the reaction mixture was concentrated. The residue was dissolved in tetrahydrofuran (5 ml). Aniline (91 μl, 1.0 mmol) and triethylamine (210 μl, 1.5 mmol) were added and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. To a solution of the oil in ethanol (5 ml) was added 10% palladium on carbon (50 mg) and the mixture was stirred in a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated. The resulting oil was crystallized from a mixture of hexane and diethyl ether to give 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) -N-phenylnicotinamide (320 mg, 83% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.17-2.31 (1H, m), 2.34 (3H, s), 2, 65 (3H, s), 2.82 (2H, d, J = 7.5 Hz), 3.69 (2H, s), 6.93 (1H, br.s), 7.04-7.26 (9H, m).

Example 305

Methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate dihydrochloride

1) Ethyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl- 1H-pyrazole-4-carboxylate (3.23 g, yield 79%) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine -3-yl] methyl} carbamate (3.00 g, 7.52 mmol) and ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (1.28 g, 7.52 mmol) in a similar manner the method of example 183-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.39 (9H, s) , 2.17-2.26 (1H, m), 2.36 (3H, s), 2.66 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3, 67 (3H, s), 4.08 (2H, d, J = 4.7 Hz), 4.19-4.26 (3H, m), 4.90 (2H, s), 7.10 (2H d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.61 (1H, s).

2) 3 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H- Pyrazole-4-carboxylic acid (1.58 g, 51% yield) was obtained as a white solid from ethyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate (3.23 g, 5.86 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.15-2.28 (1H, m), 2, 36 (3H, s), 2.66 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 3.71 (3H, s), 4.04-4.09 (2H , m), 4.23 (1H, br.s), 4.98 (2H, s), 7.05 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 7.7 Hz), 7.69 (1H, s).

3) 3 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H- pyrazole-4-carboxylic acid (0.50 g, 0.957 mmol) was dissolved in N, N-dimethylformamide (5 ml) and methyl iodide (176 mg, 1.24 mmol) and potassium carbonate (0.20 g, 1.44) was added. mmol). The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain methyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine -3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate (470 mg, 91% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.26 (1H, m), 2, 36 (3H, s), 2.66 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.68 (3H, s), 3.76 (3H, s), 4.08 (2H, d, J = 4.7 Hz), 4.23 (1H, br.s), 4.90 (2H, s), 7.10 (2H, d, J = 7.9 Hz ), 7.16 (2H, d, J = 7.9 Hz), 7.62 (1H, s).

4) Methyl-3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate dihydrochloride (382 mg, 85% yield) was obtained as a white solid from methyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate (0.47 g, 0.876 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.14-2.28 (1H, m), 2.38 (3H, s), 2.90 (3H, br s), 3.16 (2H, br s), 3.65 (3H, s), 3.66 (3H, s), 3.82 (2H, d, J = 5.1 Hz), 4.90 (2H, s), 7.27 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 8.09 (1H, s), 8.41 (3H, br s).

Example 306

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid dihydrochloride

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid dihydrochloride (268 mg , yield 94%) was obtained as a white solid from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid (0.30 g, 0.574 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 2.14-2.25 (1H, m), 2.39 (3H, s), 2.88 (3H, broad s), 3.14 (2H, broad s), 3.64 (3H, s), 3.82 (2H, d, J = 4.7 Hz), 4.87 (2H, s), 7.28 (2H, d, J = 7.9 Hz), 7.34 (2H, d, J = 8.1 Hz), 8.00 (1H, s), 8.38 (3H, broad s).

Example 307

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxamide dihydrochloride

1) tert-Butyl {[5 - ({[4- (aminocarbonyl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (307 mg, 61% yield) was obtained as a colorless oil from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 - (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid (0.50 g, 0.957 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 37 (3H, s), 2.65 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 3.69 (3H, s), 4.09 (2H, d, J = 4.9 Hz), 4.22 (1H, br.s), 4.98 (2H, br), 5.30 (1H, br.s), 6.43 (1H, br.s), 7 01 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 7.7 Hz), 7.69 (1H, s).

2) 3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxamide dihydrochloride (253 mg, 87% yield) was obtained as a white solid from tert-butyl {[5 - ({[4- (aminocarbonyl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) -2-isobutyl- 6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (307 mg, 0.588 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.14-2.27 (1H, m), 2.38 (3H, s), 2.93 (3H, br.s), 3.17 (2H, br.s), 3.63 (3H, s), 3.82 (2H, d, J = 4.7 Hz), 4.93 (2H, s), 6.37 (1H, br.s), 7.08 (1H, br.s), 7.29 (2H, d, J = 7.9 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.91 (1H, s), 8.42 (3H, br.s).

Example 308

(3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazol-4-yl) acetic acid dihydrochloride

1) To a solution of tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.00 g, 2.51 mmol) , methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl) acetate (0.43 g, 2.51 mmol) and tributylphosphine (0.61 g, 3.01 mmol) in tetrahydrofuran (20 ml) 1.1 '- (azodicarbonyl) dipiperidine (0.76 g, 3.01 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain methyl (3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazol-4-yl) acetate (1.20 g, 86% yield) as a colorless oil. Then, (3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H -pyrazol-4-yl) acetic acid (173 mg, 15% yield) as a white solid from methyl (3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazol-4-yl) acetate (1.20 g, 2.18 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.12-2.30 (1H, m), 2, 36 (3H, s), 2.62 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 3.35 (2H, s), 3.66 (3H, s), 4.05-4.09 (2H, m), 4.27 (1H, br.s), 4.84 (2H, s), 7.03 (2H, d, J = 7.9 Hz), 7 12 (1H, s), 7.18 (2H, d, J = 7.7 Hz).

2) Dihydrochloride (3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazol-4-yl) acetic acid (84.2 mg, 51% yield) was obtained as a white solid from (3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazol-4-yl) acetic acid (173 mg, 0.323 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.38 (3H, s), 2.76 (3H, br s), 3.00 (2H, br s), 3.15 (2H, s), 3.58 (3H, s), 3.77-3.84 (2H, m), 4.76 (2H, s), 7.23 (2H, d, J = 7.7 Hz), 7.33 (2H, d, J = 7.5 Hz), 7.37 (1H, s) 8.18 (3H, br s).

Example 309

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3- (1H-tetrazol-5-yl) benzamide dihydrochloride

To a solution of tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (383 mg, 1.0 mmol) in tetrahydrofuran (5 ml) 3-cyanobenzoyl chloride (245 mg, 1.5 mmol) was added and then triethylamine (280 ml, 2.0 mmol). The mixture was stirred for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. Sodium azide (97 mg, 1.5 mmol) and ammonium chloride (312 mg, 2.0 mmol) were added to a solution of the obtained oil in dimethyl sulfoxide (3 ml), and the mixture was stirred at 100 ° C for 3 h. Distilled was added to the reaction mixture water (10 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. To a solution of the resulting oil in ethyl acetate (2 ml) was added 4N. an ethyl acetate solution of hydrogen chloride (2 ml) and the resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from hexane to obtain N- [5- (aminomethyl) -6-isobutyl-2-methyl dihydrochloride -4- (4-methylphenyl) pyridin-3-yl] -3- (1H-tetrazol-5-yl) benzamide (86 mg, 16% yield) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.27 (1H, m), 2.27 (3H, s), 2.52 (3H, s), 2.93 (2H, s), 3.83 (2H, s), 7.22 (4H, s), 7.64 (1H, t, J = 7.8 Hz ), 7.76 (1H, d, J = 7.8 Hz), 8.16 (4H, br.s), 8.34 (1H, br.s), 10.10 (1H, br.s) .

Example 310

Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoate dihydrochloride

1) Methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoate ( 600 mg, 44% yield) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1 , 0 g, 2.51 mmol) and methyl 2-hydroxy-3-methylbenzoate (500 mg, 3.01 mmol) in a manner similar to the method of example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 1.80 (3H, s), 2.15-2, 28 (1H, m), 2.34 (3H, s), 2.70 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.66 (3H, s), 3.97 (2H, d, J = 4.9 Hz), 4.20 (1H, br.s), 4.76 (2H, s), 6.52 (2H, d, J = 7.9 Hz ), 6.99 (2H, d, J = 7.9 Hz), 7.01-7.06 (1H, m), 7.19 (1H, dd, J = 7.4, 1.0 Hz) 7.44 (1H, dd, J = 7.7, 1.0 Hz). 2)

2) Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoate dihydrochloride (215 mg, 94% yield) prepared as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} - 3-methylbenzoate (240 mg, 0.439 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.4 Hz), 1.82 (3H, s), 2.14-2.29 (1H, m), 2.36 (3H, s), 3.02 (3H, s), 3.31 (2H, d, J = 6.8 Hz), 3.67 (3H, s), 3.78 (2H, d , J = 2.45 Hz), 4.81 (2H, s), 6.89 (2H, d, J = 7.7 Hz), 7.11-7.20 (3H, m), 7.33 (1H, d, J = 7.0 Hz), 7.43 (1H, d, J = 7.0 Hz), 8.63 (3H, br.s).

Example 311

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-cyclopropylacetamide dihydrochloride

1) A mixture of [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (200 mg, 0.469 mmol), cyclopropylamine (80 mg, 1.41 mmol), 1-hydroxy-1H-benzotriazole (215 mg, 1.41 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (270 mg, 0.65 mmol) and N, N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl {[5- [2- (cyclopropylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (150 mg, 69% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.33-0.39 (2H, m), 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 1, 80 (3H, s), 2.13-2.29 (1H, m), 2.40 (3H, s), 2.54 (3H, s), 2.57-2.64 (1H, m) , 2.75 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 4.05 (2H, s), 4.20 (1H, br.s), 6.94 ( 2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 7.9 Hz).

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-cyclopropylacetamide dihydrochloride (100 mg, 89% yield) was obtained as a white powder from tert-butyl {[5- [2- (cyclopropylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (120 mg, 0.258 mmol ) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.34 (2H, s), 0.57 (2H, d, J = 5.5 Hz), 0.99 (6H, d, J = 6.2 Hz), 2.11-2.25 (1H, m), 2.41 (3H, s), 2.53-2.58 (1H, m), 2.81 (2H, s), 3.24 (2H, s), 3.6-3.9 (5H, m), 7.20 (2H, d, J = 7.7 Hz), 7.37 (2H, d, J = 7.7 Hz) 8.08 (1H, d, J = 3.4 Hz); 8.56 (3H, br s).

Example 312

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl] methyl} amine dihydrochloride

1) tert-Butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl] methyl} carbamate (50 mg yield 22%) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid ( 200 mg, 0.469 mmol) and morpholine (123 mg, 1.41 mmol) in a manner similar to that of Example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.09-2.27 (1H, m), 2, 41 (3H, s), 2.50 (3H, s), 2.73 (2H, d, J = 7.4 Hz), 3.17 (2H, d, J = 4.1 Hz), 3, 30 (2H, s), 3.41 (2H, d, J = 4.1 Hz), 3.56 (4H, dd, J = 16.5, 4.1 Hz), 4.04 (2H, d , J = 4.52 Hz), 4.20 (1H, br.s), 6.98 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz )

2) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl] methyl} amine dihydrochloride (40 mg, yield 94%) was obtained as a white powder from tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl ] methyl} carbamate (45 mg, 0.0908 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 2.09-2.30 (1H, m), 2.41 (3H, s), 2.50 (3H, s), 2.79 (2H, s), 3.09-3.42 (10H, m), 3.82 (2H, d, J = 3.8 Hz), 7.16 (2H, d, J = 7.7 Hz), 7.39 (2H, d, J = 7.7 Hz), 8.52 (3H, br.s).

Example 313

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-benzylacetamide dihydrochloride

1) tert-Butyl {[5- [2- (benzylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (150 mg, yield 62%) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (200 mg , 0.469 mmol) and benzylamine (151 mg, 1.41 mmol) in a manner similar to the method of example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.12-2.27 (1H, m), 2, 37 (3H, s), 2.56 (3H, s), 2.74 (2H, d, J = 7.2 Hz), 3.32 (2H, s), 4.02 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 4.34 (2H, d, J = 5.8 Hz), 5.45 (1H, br.s), 6.88 (2H d, J = 7.9 Hz), 7.10-7.20 (4H, m), 7.25-7.35 (3H, m).

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-benzylacetamide dihydrochloride (125 mg, 100% yield) was obtained as a white powder from tert-butyl {[5- [2- (benzylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (130 mg, 0.252 mmol ) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 2.07-2.28 (1H, m), 2.40 (3H, s), 2.83 (3H, s), 3.28 (2H, d, J = 7.0 Hz), 3.42 (2H s), 3.81 (2H, d, J = 3.0 Hz), 4 21 (2H, d, J = 5.7 Hz), 7.10-7.44 (9H, m), 8.52 (3H, br.s).

Example 314

[(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (1H-tetrazol-5-yl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride

1) tert-Butyl {[5 - [(2-cyanophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (586 mg, 70% yield) obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.67 g, 1.68 mmol) and 2-hydroxybenzonitrile (221 mg, 1.85 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 34 (3H, s), 2.66 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 4.09-4.11 (2H, m), 4.26 (1H , br.s), 4.73 (2H, s), 6.76 (1H, d, J = 8.5 Hz), 6.96-7.01 (2H, m), 7.09 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 7.9 Hz), 7.40-7.46 (1H, m), 7.50-7.56 (1H, m )

2) tert-Butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (1H-tetrazol-5-yl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (400 mg, 63% yield) was obtained as a white solid from tert-butyl {[5 - [(2-cyanophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3 -yl] methyl} carbamate (586 mg, 1.17 mmol) in a manner similar to that of Example 251-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.28 (1H, m), 2, 32 (3H, s), 2.59 (3H, s), 2.82 (2H, d, J = 7.4 Hz), 4.09-4.13 (2H, m), 4.31 (1H , br.s), 4.92 (2H, s), 6.91-6.95 (3H, m), 7.12 (2H, d, J = 7.7 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.43-7.49 (1H, m), 8.42 (2H, dd, J = 7.9, 1.7 Hz).

3) [(2-Isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (1H-tetrazol-5-yl) phenoxy] methyl} pyridin-3-yl) methyl] amine dihydrochloride ( 327 mg, 86% yield) was obtained as a white solid from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[2- (1H-tetrazol-5-yl) phenoxy] methyl} pyridin-3-yl) methyl] carbamate (400 mg, 0.737 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.17-2.29 (4H, m), 2.88 (3H, br.s. ), 3.16 (2H, broad s), 3.80 (2H, broad s), 4.89 (2H, s), 7.03-7.10 (3H, m), 7.13- 7.17 (3H, m), 7.46-7.52 (1H, m), 7.87 (1H, d, J = 7.7 Hz), 8.41 (3H, br.s).

Example 315

5 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene dihydrochloride} -1,3-thiazolidin-2,4-dione

1) A mixture of tert-butyl {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (600 mg, 1.51 mmol), 1.3- thiazolidine-2,4-dione (177 mg, 1.51 mmol), piperidine (0.015 ml) and ethanol (10 ml) were stirred with heating at 80 ° C for 3.5 days. After allowing the mixture to cool to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl {[5 - [(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl ) pyridin-3-yl] methyl} carbamate (400 mg, 53% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.12-2.31 (1H, m), 2, 38 (3H, s), 2.50 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.12 (2H, d, J = 5.1 Hz), 4, 20 (1H, br s), 6.96 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.51 (1H, s).

2) Dihydrochloride 5 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -1,3-thiazolidin-2,4-dione (155 mg, 100% yield) was obtained as a white powder from tert-butyl {[5 - [(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (157 mg, 0.316 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 2.14-2.29 (1H, m), 2.37 (3H, s), 2.51 (3H, s), 3.08 (2H, d, J = 6.4 Hz), 3.83 (2H, d, J = 4.7 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.28-7.40 (3H, m), 8.49 (3H, br.s).

Example 316

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoic dihydrochloride

1) 2 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoic acid (280 mg, yield 93%) was obtained as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methoxy} -3-methylbenzoate (300 mg, 0.563 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (6H, d, J = 6.4 Hz), 1.38 (9H, s), 1.96 (3H, s), 2.24-2, 32 (1H, m), 2.36 (3H, s), 3.14 (3H, s), 3.31 (2H, d, J = 6.8 Hz), 4.06 (2H, d, J = 4.3 Hz), 4.20 (1H, br.s), 4.83 (2H, s), 6.60 (2H, d, J = 7.5 Hz), 7.02-7.13 (3H, m), 7.19-7.24 (1H, m), 7.45-7.54 (1H, m).

2) 2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoic acid dihydrochloride (55 mg, 100% yield) was obtained in the form of a white powder from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzoic acid (58.4 mg, 0.110 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.4 Hz), 1.79 (3H, s), 2.14-2.28 (1H, m), 2.36 (3H, s), 2.97 (3H, s), 3.26 (2H, d, J = 6.8 Hz), 3.77 (2H, d, J = 4.0 Hz), 4.81 (2H, s), 6.93 (2H, d, J = 7.9 Hz), 7.09 (1H, t, J = 7.5 Hz), 7.19 (2H, d, J = 7.9 Hz), 7.29 (1H, d, J = 6.6 Hz), 7.38-7.46 (1H, m), 8.57 (3H, br.s).

Example 317

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzamide dihydrochloride

1) 2 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoic acid (0 , 54 g, yield 97%) was obtained as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine -3-yl] methoxy} -5-chlorobenzoate (0.57 g, 1.0 mmol) in a manner similar to that of Example 43-1).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.20-2.35 (1H, m), 2, 40 (3H, s), 3.00 (3H, s), 3.21 (2H, d, J = 5.2 Hz), 4.17 (2H, d, J = 5.8 Hz), 4, 50-4.65 (1H, m), 4.88 (2H, s), 6.62 (1H, d, J = 8.9 Hz), 7.05 (2H, d, J = 7.8 Hz ), 7.25 (2H, d, J = 7.8 Hz), 7.33 (1H, dd, J = 2.6, 8.9 Hz), 7.90 (1H, d, J = 8, 9 Hz).

2) tert-Butyl {[5 - {[2- (aminocarbonyl) -4-chlorophenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0 20 g, 71% yield) was obtained as a white powder from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methoxy} -5-chlorobenzoic acid (0.28 g, 0.51 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.35 (1H, m), 2, 36 (3H, s), 2.63 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 4.10 (2H, d, J = 5.1 Hz), 4, 15-4.30 (1H, m), 4.77 (2H, s), 5.65 (1H, br.s), 6.69 (1H, d, J = 8.9 Hz), 6.99 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 7.9 Hz), 7.31 (1H, dd, J = 2.8, 8.9 Hz), 7 48 (1H, br s), 8.18 (1H, d, J = 2.8 Hz).

3) Dihydrochloride 2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzamide (0.16 g, 99% yield) prepared as a white powder from tert-butyl {[5 - {[2- (aminocarbonyl) -4-chlorophenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } carbamate (0.17 g, 0.31 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.15-2.35 (1H, m), 2.36 (3H, s), 2.84 (3H, br.s), 3.08 (2H, br.s), 3.82 (2H, d, J = 2.6 Hz), 4.79 (2H, s), 6.83 (1H, d, J = 9.0 Hz), 7.25 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.41 (1H dd, J = 2.7, 9.0 Hz), 7.52 (2H, br.s), 7.55 (1H, d, J = 2.7 Hz), 8.36 (3H, br. from).

Example 318

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoic acid dihydrochloride

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoic acid dihydrochloride (0.16 g, 85% yield) was obtained in the form of a white powder from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -5-chlorobenzoic acid (0.20 g, 0.36 mmol) in a manner similar to the method of example 276-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.15-2.30 (1H, m), 2.36 (3H, s), 2.83 (3H, br.s), 3.05 (2H, br.s), 3.75-3.90 (2H, m), 4.77 (2H, br.s), 6.92 ( 1H, d, J = 8.9 Hz), 7.24 (2H, d, J = 7.8 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.47 (1H, dd, J = 2.8, 8.9 Hz), 7.61 (1H, d, J = 2.8 Hz), 8.30 (3H, br.s).

Example 319

4 '- [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] biphenyl-4-carboxylic acid dihydrochloride

1) 4-Bromobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.92 g, 75% yield) was obtained as a colorless oils from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.82 g, 4.41 mmol) and 4-bromobenzyl bromide (1 , 10 g, 4.41 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.26 (1H, m), 2, 38 (3H, s), 2.53 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 4.11 (2H, d, J = 4.9 Hz), 4, 19 (1H, br.s), 4.89 (2H, s), 6.91 (2H, d, J = 8.5 Hz), 6.99 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 7.7 Hz); 7.39 (2H, d, J = 8.5 Hz).

2) A solution of 4-bromobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.09 g, 1.87 mmol), [ 4- (methoxycarbonyl) phenyl] boronic acid (675 mg, 3.75 mmol), potassium carbonate (388 mg, 2.81 mmol) and tetrakis (triphenylphosphine) palladium (0) (216 mg, 0.187 mmol) in dioxane (15 ml) and water (2.5 ml) were stirred under argon for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain [4 '- (methoxycarbonyl) biphenyl-4-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- methyl 4- (4-methylphenyl) nicotinate (570 mg, 48% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2, 29 (3H, s), 2.55 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.91 (3H, s), 4.16 (2H, d, J = 4.5 Hz), 4.60 (1H, br.s), 4.98 (2H, s), 7.07 (2H, d, J = 8.1 Hz), 7.12-7.16 (4H, m), 7.53 (2H, d, J = 8.3 Hz), 7.64 (2H, d, J = 8.7 Hz), 8.10 (2H, d, J = 8, 5 Hz).

3) 4 '- [({[[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] biphenyl-4-carboxylic acid (380 mg, 68% yield) was obtained as a white solid from [4 '- (methoxycarbonyl) biphenyl-4-yl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} - 6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (570 mg, 0.895 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.26 (1H, m), 2, 34 (3H, s), 2.56 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.11-4.16 (2H, m), 4.23 (1H , br.s), 4.99 (2H, s), 7.05 (2H, d, J = 7.9 Hz), 7.13-7.18 (4H, m), 7.55 (2H, d, J = 8.3 Hz), 7.68 (2H, d, J = 8.5 Hz), 8.18 (2H, d, J = 8.3 Hz).

4) 4 '- [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] biphenyl-4-carboxylic acid dihydrochloride ( 255 mg, 70% yield) was obtained as a white solid from 4 '- [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] biphenyl-4-carboxylic acid (380 mg, 0.610 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.15-2.26 (1H, m), 2.33 (3H, s), 2.57 (3H, br.s), 2.92 (2H, br.s), 3.82 (2H, d, J = 4.3 Hz), 5.04 (2H, s), 7.18 (4H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.68 (2H, d, J = 8.3 Hz), 7.82 (2H d, J = 8.5 Hz), 8.04 (2H, d, J = 8.5 Hz), 8.34 (3H, br.s).

Example 320

Pyridin-4-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride

1) Pyridin-4-ylmethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (322 mg, 53% yield) was obtained as a colorless oils from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.21 mmol), 4- (chloromethyl hydrochloride) ) pyridine (0.20 g, 1.21 mmol) and potassium carbonate (0.42 g, 3.0 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.27 (1H, m), 2, 36 (3H, s), 2.56 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.14 (2H, d, J = 4.9 Hz), 4, 42 (1H, br.s), 4.94 (2H, s), 6.89 (2H, d, J = 5.8 Hz), 7.04 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 7.9 Hz), 8.48 (2H, d, J = 5.3 Hz).

2) Pyridin-4-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride (260 mg, 79% yield) was obtained as a white solid from pyridin-4- ilmethyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (322 mg, 0.639 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.19-2.27 (1H, m), 2.33 (3H, s), 2.57 (3H, br.s), 2.89 (2H, br.s), 3.81 (2H, d, J = 5.5 Hz), 5.29 (2H, s), 7.17 -7.24 (4H, broad s), 7.60 (2H, broad s), 8.35 (3H, broad s), 8.83-8.84 (2H, broad s).

Example 321

Pyridin-3-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride

1) Pyridin-3-ylmethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (454 mg, 74% yield) was obtained as a colorless oils from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.21 mmol), 3- (bromomethyl hydrobromide) ) pyridine (0.46 g, 1.81 mmol) and potassium carbonate (0.50 g, 3.6 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.24 (1H, m), 2, 36 (3H, s), 2.54 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 4.12 (2H, d, J = 4.1 Hz), 4, 20 (1H, br.s), 4.94 (2H, s), 6.99 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 7.9 Hz), 7.17-7.21 (1H, m), 7.32-7.37 (1H, m), 8.34 (1H, d, J = 1.7 Hz), 8.55 (1H, dd, J = 4.8, 1.6 Hz).

2) Pyridin-3-ylmethyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate trihydrochloride (183 mg, 39% yield) was obtained as a white solid from pyridin-3- ilmethyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (454 mg, 0.903 mmol) in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.8 Hz), 2.17-2.26 (1H, m), 2.31 (3H, s), 2.59 (3H, s), 2.93 (2H, d, J = 6.0 Hz), 3.78 (2H, d, J = 5.5 Hz), 5.22 (2H, s), 7.12 (4H, s), 7.95 (1H, t, J = 6.7 Hz), 8.14 (1H, d, J = 7.9 Hz), 8.41 (3H, br.s ), 8.67 (1H, s), 8.90 (1H, d, J = 5.5 Hz).

Example 322

Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methoxybenzoate dihydrochloride

1) Methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methoxybenzoate ( 0.62 g, 55% yield) was obtained as a white powder from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (0.80 g, 2.0 mmol) and methyl 3-methoxysalicylate (0.55 g, 3.0 mmol) in a manner similar to that of Example 106-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.30 (1H, m), 2, 34 (3H, s), 2.73 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.54 (3H, s), 3.64 (3H, s), 3.97 (2H, d, J = 5.1 Hz), 4.20-4.30 (1H, m), 4.86 (2H, s), 6.60 (2H, d, J = 8, 1 Hz), 6.85 (1H, dd, J = 1.5, 8.1 Hz), 7.01 (2H, d, J = 8.1 Hz), 7.06 (1H, d, J = 8.1 Hz), 7.14 (1H, dd, J = 1.5, 8.1 Hz).

2) Methyl-2 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methoxybenzoate dihydrochloride (0.12 g, yield 66 %) was obtained as a white powder from methyl-2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy } -3-methoxybenzoate (0.19 g, 0.34 mmol) in a manner similar to that of Example 274-2).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.10-2.30 (1H, m), 2.37 (3H, s), 2.94 (3H, br s), 3.00-3.20 (2H, m), 3.51 (3H, s), 3.63 (3H, s), 3.72 (2H, br. s), 4.88 (2H, br.s), 6.77 (2H, d, J = 7.9 Hz), 7.00-7.22 (3H, m), 7.17 (2H, d , J = 7.9 Hz), 8.27 (3H, br s).

Example 323

Methyl 2 - ({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoate dihydrochloride

1) Methyl-2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoate (1 46 g, yield 63%) was obtained as a powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate ( 2.0 g, 4.7 mmol) and methylthiosalicylate (757 mg, 45 mmol) in a manner similar to that of Example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.34 (3H, s), 2.65 (3H, s), 2.83 ( 2H, s), 3.89 (3H, s), 4.07 (2H, d, J = 4.9 Hz), 4.17 (1H, br.s), 7.04-7.18 (6H , m), 7.32-7.38 (1H, m), 7.91-7.95 (1H, m).

2) Methyl 2-dihydrochloride - ({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoate (254 mg, 89% yield) was obtained in powder form from methyl-2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoate (300 mg, 0.533 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.34 (3H, s), 2.83 (3H, s), 3.18 (2H, br s), 3.80 (3H, s), 3.88 (2H, s), 4.00 (2H, s), 7.23-7.32 (6H, m), 7.47-7.52 (1H, m), 7.85-7.88 (1H, m), 8.21 (3H, br.s).

Example 324

2 - ({[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoic acid dihydrochloride

1) 4 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoic acid (897 mg yield 92%) was obtained as a white solid from methyl 4 - ({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3 -yl] methyl} thio) benzoate (1.0 g, 1.78 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.38 (9H, s), 2.38 (3H, s), 3.09 (3H, s), 3.47 ( 2H, s), 3.79 (2H, s), 4.14 (2H, d, J = 4.3 Hz), 4.52 (1H, br.s), 6.85-6.92 (2H , m), 7.08-7.13 (1H, m), 7.19-7.21 (2H, m), 7.29-7.33 (1H, m), 7.37-7.41 (1H, m), 7.94-7.97 (1H, m).

2) 2 - ({[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoic acid dihydrochloride (158 mg, 83% yield) was obtained in as a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoic acid ( 200 mg, 0.364 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.34 (3H, s), 2.81 (3H, s), 3.15 (2H, br s), 3.80 (2H, s), 3.85 (2H, s), 7.19-7.33 (6H, m), 7.44-7.49 (1H, m), 7.86-7, 89 (1H, m), 8.17 (3H, br s).

Example 325

2 - ({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzamide dihydrochloride

1) 4 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzamide (349 mg, 70% yield) was obtained as a white solid from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzoic acid (500 mg, 0.911 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.39 (3H, s), 2.63 (3H, s), 2.83 ( 2H, s), 3.81 (2H, s), 4.04 (2H, d, J = 5.1 Hz), 4.24 (1H, br.s), 5.45 (1H, br.s ), 6.68 (1H, br.s), 6.96-6.99 (2H, m), 7.18-7.22 (3H, m), 7.28-7.32 (2H, m ), 7.75-7.78 (1H, m).

2) Dihydrochloride 2 - ({[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzamide (160 mg, 84% yield) was obtained as white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl} thio) benzamide (200 mg , 0.365 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.37 (3H, s), 2.76 (3H, s), 3.17 (2H, br s), 3.75-3.85 (4H, m), 7.14-7.35 (7H, m), 7.40 (1H, s), 7.50-7.48 (1H, m), 7, 81 (1H, s), 8.20 (3H, br s).

Example 326

2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzamide dihydrochloride

1) tert-Butyl {[5 - {[2- (aminocarbonyl) -6-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (190 mg, 95% yield) was obtained as a white powder from 2 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] methoxy} -3-methylbenzoic acid (200 mg, 0.375 mmol) in a manner similar to the method of example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 1.05 (6H, d, J = 6.2 Hz), 1.40 (9H, s), 1.93 (3H, s), 2.21-2, 32 (1H, m), 2.36 (3H, s), 3.01 (3H, s), 3.16 (2H, d, J = 6.8 Hz), 4.04 (2H, s), 4.20 (1H, br s), 4.81 (2H, s), 5.80 (1H, br s), 6.40 (1H, br s), 6.65 (2H, s) 7.02-7.23 (4H, m); 7.56 (1H, s).

2) 2 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -3-methylbenzamide dihydrochloride (100 mg, 70% yield) was obtained in as a white powder from tert-butyl {[5 - {[2- (aminocarbonyl) -6-methylphenoxy] methyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (150 mg, 0.282 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.4 Hz), 1.76 (3H, s), 2.13-2.29 (1H, m), 2.37 (3H, s), 2.96 (3H, s), 3.21 (2H, d, J = 6.6 Hz), 3.76 (2H, d, J = 4.9 Hz), 4.78 (2H, s), 7.01 (2H, d, J = 7.9 Hz), 7.04-7.08 (1H, m), 7.15-7.26 (4H, m) 7.34 (1H, br.s), 7.53 (1H, br.s), 8.52 (3H, br.s).

Example 327

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-phenylacetamide dihydrochloride

1) tert-Butyl {[5- (2-anilino-2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (220 mg, 94% yield ) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (200 mg, 0.469 mmol) and aniline (150 mg, 1.41 mmol) in a manner similar to the method of example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.29 (1H, m), 2, 40 (3H, s), 2.63 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 3.66 (3H, s), 4.06 (2H, d, J = 4.9Hz), 4.20 (1H, br.s), 7.02 (2H, d, J = 7.9 Hz), 7.06-7.14 (1H, m), 7.24 ( 2H, d, J = 7.9 Hz), 7.27-7.39 (4H, m).

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N-phenylacetamide dihydrochloride (200 mg, 100% yield) was obtained as a white powder from tert-butyl {[5- (2-anilino-2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (210 mg, 0.419 mmol) by similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 5.5 Hz), 2.13-2.28 (1H, m), 2.38 (3H, s), 2.85 (3H, s), 3.25 (2H, s), 3.62 (2H, s), 3.83 (2H, s), 7.04 (1H, t, J = 6.7 Hz ), 7.15-7.42 (6H, m), 7.50 (2H, d, J = 7.4 Hz), 8.53 (3H, br.s), 10.20 (1H, s) .

Example 328

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclohexanecarboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] cyclohexanecarboxamide dihydrochloride (230 mg, 98% yield) was obtained as a white powder from tert-butyl { [5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and cyclohexanecarbonyl chloride (100 ml, 0.75 mmol) by the method similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.00-1.25 (6H, m), 1.41 (2H, br.s. ), 1.59 (2H, br.s), 2.08-2.22 (2H, m), 2.37 (3H, s), 2.53 (3H, s), 3.03 (2H, br.s), 3.81 (2H, s), 7.14 (2H, d, J = 7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 8.33 ( 3H, br.s), 9.37 (1H, br.s).

Example 329

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperidin-1-carboxamide dihydrochloride

1) tert-Butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(piperidin-1-ylcarbonyl) amino] pyridin-3-yl} methyl) carbamate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and piperidine (150 ml, 1.5 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 495

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperidin-1-carboxamide dihydrochloride (218 mg, 47% yield) was obtained as white powder from the oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.3 Hz), 1.07-1.19 (4H, m), 1.44 (2H, br.s. ), 2.12-2.27 (1H, m), 2.37 (3H, s), 2.60 (3H, s), 3.05 (2H, br s), 3.15 (4H, br.s), 3.83 (2H, s), 7.19 (2H, d, J = 7.8 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.96 ( 1H, br.s), 8.27 (3H, br.s).

Example 330

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] tetrahydro-2H-pyran-4-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] tetrahydro-2H-pyran-4-carboxamide dihydrochloride (232 mg, 98% yield) was obtained in as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and tetrahydro-2H -pyran-4-carbonyl chloride (111 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.00-1.25 (6H, m), 1.41 (2H, br.s. ), 1.59 (2H, br.s), 2.08-2.22 (2H, m), 2.37 (3H, s), 2.53 (3H, s), 3.03 (2H, br.s), 3.81 (2H, s), 7.14 (2H, d, J = 7.5 Hz), 7.30 (2H, d, J = 7.8 Hz), 8.27 ( 3H, br.s), 9.43 (1H, br.s).

Example 331

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] morpholine-4-carboxamide dihydrochloride

1) tert-Butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(morpholin-4-ylcarbonyl) amino] pyridin-3-yl} methyl) carbamate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and morpholine (130 ml, 1.5 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 497

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] morpholine-4-carboxamide dihydrochloride (278 mg, 59% yield) was obtained as white powder from the oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.3 Hz), 2.10-2.27 (1H, m), 2.39 (3H, s), 2.70 (3H, s), 3.14 (6H, br.s), 3.19 (4H, br.s), 3.86 (2H, br.s), 7.21 (2H, d, J = 7.8 Hz), 7.34 (2H, d, J = 7.8 Hz), 8.44 (4H, br.s).

Example 332

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperidin-4-carboxamide trihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperidin-4-carboxamide trihydrochloride (246 mg, 98% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and benzyl-4- (chlorocarbonyl) piperidine-1-carboxylate (210 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.44 (4H, br.s), 2.15-2.26 (1H, m ), 2.38 (3H, s), 2.38-2.57 (1H, m), 2.57 (3H, s), 2.76 (2H, br.s), 3.07 (4H, br.s), 3.81 (2H, br.s), 7.17 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8, 41 (3H, br.s), 8.80 (1H, br.s), 9.09 (1H, br.s), 9.84 (1H, br.s).

Example 333

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperazine-1-carboxamide trihydrochloride

1) tert-Butyl-4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperazine-1-carboxylate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and tert-butylpiperazine-1-carboxylate (140 mg, 1.5 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 596

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] piperazine-1-carboxamide trihydrochloride (250 mg, 97% yield) was obtained as white powder from the oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.3 Hz), 2.15-2.26 (1H, m), 2.42 (3H, s), 2.62 (2H, s), 2.72 (3H, s), 3.05 (2H, br.s), 3.42 (4H, br.s), 3.82 (2H, br.s) , 7.19 (2H, d, J = 7.5 Hz), 7.31 (2H, d, J = 7.5 Hz), 8.37 (3H, br.s), 8.60 (1H, broad s), 9.41 (2H, broad s).

Example 334

Dihydrochloride (5 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -4-oxo-2-thioxo-1,3-thiazolidin- 3-yl) acetic acid

1) (5 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -4-oxo-2 -thioxo-1,3-thiazolidin-3-yl) acetic acid (355 mg, 50% yield) was obtained as a yellow powder from tert-butyl {[5-formyl-2-isobutyl-6-methyl-4- (4 -methylphenyl) pyridin-3-yl] methyl} carbamate (500 mg, 1.26 mmol) and (4-oxo-2-thioxo-1,3-thiazolidin-3-yl) acetic acid (241 mg, 1.26 mmol) in a manner similar to the method of example 315-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.09-2.27 (1H, m), 2, 36 (3H, s), 2.50 (3H, s), 2.8 (2H, d, J = 7.4 Hz), 4.01-4.18 (4H, m), 4.20 (1H , br.s), 6.96 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.9 Hz), 7.38 (1H, s).

2) Dihydrochloride (5 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -4-oxo-2-thioxo-1,3- thiazolidin-3-yl) acetic acid (198 mg, 100% yield) was obtained as a yellow powder from (5 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 - (4-methylphenyl) pyridin-3-yl] methylene} -4-oxo-2-thioxo-1,3-thiazolidin-3-yl) acetic acid (210 mg, 0.386 mmol) in a manner similar to the method of example 2-3) .

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.4 Hz), 2.17-2.31 (1H, m), 2.36 (3H, s), 2.55 (3H, s), 2.95 (2H, d, J = 6.6 Hz), 3.80 (2H, d, J = 7.4 Hz), 4.63 (2H, s), 7.22 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.55 (1H, s), 8.35 (3H, br.s )

Example 335

5 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -2-thioxo-1,3-thiazolidin-4-one dihydrochloride

1) tert-Butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene) methyl] pyridin-3 -yl} methyl) carbamate (310 mg, 48% yield) was obtained as a yellow powder from tert-butyl {[5-formyl-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (500 mg, 1.26 mmol) and 2-thioxo-1,3-thiazolidin-4-one (168 mg, 1.26 mmol) in a manner similar to that of Example 315-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.15-2.31 (1H, m), 2, 37 (3H, s), 2.50 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 4.13 (2H, d, J = 7.4 Hz), 4, 20 (1H, br s), 6.95 (2H, d, J = 7.7 Hz), 7.20 (2H, d, J = 7.7 Hz), 7.34 (1H, s).

2) 5 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methylene} -2-thioxo-1,3-thiazolidin-4-one dihydrochloride (173 mg, 100% yield) was obtained as a yellow powder from tert-butyl ({2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - [(4-oxo-2-thioxo-1,3 -thiazolidin-5-ylidene) methyl] pyridin-3-yl} methyl) carbamate (200 mg, 0.390 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.11-2.31 (1H, m), 2.36 (3H, s), 2.52 (2H, s), 2.90 (3H, s), 3.79 (2H, s), 7.19 (2H, d, J = 8.1 Hz), 7.26-7.37 (3H, m), 8.27 (3H, br s).

Example 336

Methyl-3 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate dihydrochloride

1) Methyl-3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate ( 230 mg, yield 35%) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acids (500 mg, 1.17 mmol) and methyl 3-aminobenzoate (532 mg, 3.52 mmol) in a manner similar to that of Example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.31 (1H, m), 2, 41 (3H, s), 2.64 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.47 (2H, s), 3.91 (3H, s), 4.07 (2H, d, J = 4.5 Hz), 4.20 (1H, br.s), 5.50 (1H, br.s), 7.02 (2H, d, J = 7, 9 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.38 (1H, t, J = 7.9 Hz), 7.72-7.86 (3H, m).

2) Methyl-3 - ({[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate dihydrochloride (65 mg, 91% yield) prepared as a white powder from methyl-3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate (75.2 mg, 0.134 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.11-2.30 (1H, m), 2.36 (3H, s), 2.53 (3H, s), 2.68 (2H, s), 2.98 (2H, s), 3.78 (2H, s), 3.84 (3H, s), 7.19 (2H d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.44 (1H, t, J = 7.9 Hz), 7.61-7.71 (2H, m), 8.10 (3H, br s), 8.20 (1H, s), 10.6 (1H, br s).

Example 337

Methyl 3 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylate trihydrochloride

1) Methyl-3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridin- 2-carboxylate (1.43 g, 2.60 mmol) was obtained as a yellow oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3- yl] methyl} carbamate (2.08 g, 5.22 mmol) and methyl 3-mercaptopyridine-2-carboxylate (883 mg, 5.22 mmol) in a manner similar to that of Example 183-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.14-2.26 (1H, m), 2, 35 (3H, s), 2.66 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 3.76 (2H, s), 3.99 (3H, s), 4.03 (2H, d, J = 5.3 Hz), 4.19 (1H, br.s), 7.04-7.07 (1H, m), 7.09 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 7.7 Hz), 7.28-7.31 (1H, m), 7.40-7.44 (1H, m), 8, 43 (1H, dd, J = 4.5, 1.5 Hz).

2) Methyl 3 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylate trihydrochloride (161 mg, 80% yield) was obtained as a pale yellow solid from methyl 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine -3-yl] methyl} thio) pyridin-2-carboxylate (197 mg, 0.359 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.4 Hz), 2.15-2.26 (1H, m), 2.35 (3H, s), 2.89 (3H, br.s), 3.18 (2H, br.s), 3.77 (2H, d, J = 5.1 Hz), 3.83 (3H, s), 3.94 (2H, s), 7.25 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.51 (1H, dd, J = 8, 3, 4.5 Hz), 7.76 (1H, d, J = 8.1 Hz), 8.35-8.53 (4H, m).

Example 338

3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylic acid trihydrochloride

1) 3 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridin-2- carboxylic acid (1.19 g, 99% yield) was obtained as a colorless oil from methyl 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-methylphenyl) pyridin-3-yl] methyl} thio) pyridin-2-carboxylate (1.23 g, 2.24 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.21-2.32 (1H, m), 2, 37 (3H, s), 2.97 (3H, br.s), 3.17 (2H, br.s), 3.81 (2H, s), 4.08-4.13 (2H, m) 4.31 (1H, br.s), 7.14 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.42-7, 46 (1H, m), 7.50-7.53 (1H, m), 8.35 (1H, dd, J = 4.4, 1.2 Hz).

2) 3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxylic acid trihydrochloride (265 mg, yield 69%) was obtained as a pale yellow solid from 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] methyl} thio) pyridine-2-carboxylic acid (0.38 g, 0.709 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.13-2.24 (1H, m), 2.34 (3H, s), 2.79-2.82 (3H, broad s), 3.05 (2H, broad s), 3.75 (2H, broad s), 3.89 (2H, broad s), 7.26 ( 2H, d, J = 6.4 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.48 (1H, dd, J = 8.3, 4.5 Hz), 7, 72 (1H, d, J = 8.3 Hz), 8.19-8.36 (3H, m), 8.43 (1H, d, J = 4.5 Hz).

Example 339

3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridine-2-carboxamide trihydrochloride

1) tert-Butyl {[5 - ({[2- (aminocarbonyl) pyridin-3-yl] thio} methyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } carbamate (720 mg, 88% yield) was obtained as a colorless oil from 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridin-2-carboxylic acid (0.82 g, 1.53 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.26 (1H, m), 2, 33 (3H, s), 2.67 (3H, s), 2.75 (2H, d, J = 7.2 Hz), 3.71 (2H, s), 4.03 (2H, d, J = 4.9 Hz), 4.18 (1H, br.s), 5.44 (1H, br.s), 7.12-7.18 (4H, m), 7.25-7.29 ( 1H, m), 7.42 (1H, dd, J = 8.3, 1.3 Hz), 7.82 (1H, br.s), 8.24 (1H, dd, J = 4.3, 1.3 Hz).

2) 3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} thio) pyridin-2-carboxamide trihydrochloride (546 mg, yield 74 %) was obtained as a pale yellow solid from tert-butyl {[5 - ({[2- (aminocarbonyl) pyridin-3-yl] thio} methyl) -2-isobutyl-6-methyl-4- (4- methylphenyl) pyridin-3-yl] methyl} carbamate (720 mg, 1.35 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.13-2.26 (1H, m), 2.34 (3H, s), 2.96 (3H, s), 3.25 (2H, br.s), 3.79 (2H, d, J = 5.1 Hz), 3.86 (2H, s), 7.29-7 40 (4H, m), 7.46 (1H, dd, J = 8.1, 4.5 Hz), 7.64 (1H, br.s), 7.69 (1H, d, J = 7 5 Hz), 8.09 (1H, br.s), 8.36 (1H, dd, J = 4.5, 1.2 Hz), 8.51 (3H, br.s).

Example 340

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] cyclohexanecarboxylic acid dihydrochloride

1) A mixture of methyl 4- (hydroxymethyl) cyclohexanecarboxylate (0.40 g, 2.32 mmol), triethylamine (0.65 ml, 4.64 mmol) and tetrahydrofuran (10 ml) was cooled to 0 ° C and added dropwise methanesulfonyl chloride (0.27 ml, 3.48 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain methyl 4 - {[(methylsulfonyl) oxy] methyl} cyclohexanecarboxylate as a crude product. The crude product was dissolved in N, N-dimethylformamide (15 ml) and potassium carbonate (480 mg, 3.48 mmol) and 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 were added. - (4-methylphenyl) nicotinic acid (0.95 g, 2.32 mmol). The mixture was stirred with heating at 70 ° C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain [4- (methoxycarbonyl) cyclohexyl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-methylphenyl) nicotinate (750 mg, 57% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.07-1.18 (2H, m), 1.33-1.49 (14H, m ), 1.83-1.96 (2H, m), 2.16-2.25 (1H, m), 2.39 (3H, s), 2.48-2.56 (4H, m), 2.78 (2H, d, J = 7.4 Hz), 3.67 (3H, s), 3.78 (2H, d, J = 6.8 Hz), 4.13-4.17 (2H , m), 4.23 (1H, br.s), 7.07 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.7 Hz).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] cyclohexanecarboxylic acid (550 mg, 75% yield) was obtained as a white solid from [4- (methoxycarbonyl) cyclohexyl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (750 mg, 1.32 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.08-1.20 (2H, m), 1.33-1.68 (14H, m ), 1.86-1.96 (2H, m), 2.15-2.28 (1H, m), 2.38 (3H, s), 2.54-2.60 (4H, m), 2.78 (2H, br s), 3.78 (2H, d, J = 6.6 Hz), 4.12-4.16 (2H, m), 4.24 (1H, br s) 7.07 (2H, d, J = 7.9 Hz); 7.20 (2H, d, J = 7.7 Hz).

3) Dihydrochloride 4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] cyclohexanecarboxylic acid (254 mg, yield 83 %) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] cyclohexanecarboxylic acid (320 mg, 0.579 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.17-1.42 (7H, m), 1.66-1.82 (2H , m), 2.14-2.24 (1H, m), 2.37 (3H, s), 2.41-2.45 (1H, m), 2.54 (3H, s), 2, 86-2.97 (2H, m), 3.76 (2H, d, J = 6.6 Hz), 3.83 (2H, d, J = 4.7 Hz), 7.20 (2H, d , J = 7.9 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.34 (3H, br.s).

Example 341

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophen-2-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophen-2-carboxamide dihydrochloride (171mg, 75% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and thiophene-2-carbonyl chloride (110 mg , 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.31 (1H, m), 2.31 (3H, s), 2.63 (3H, s), 3.07 (2H, br.s), 3.86 (2H, s), 7.12 (1H, dd, J = 3.3, 4.8 Hz), 7 , 25 (4H, s), 7.74 (1H, d, J = 3.3 Hz), 7.79 (1H, d, J = 4.8 Hz), 8.42 (3H, br.s) 10.18 (1H, br s).

Example 342

3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid dihydrochloride

1) 3 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid (110 mg, 87% yield) was obtained as a white powder from methyl 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] acetyl} amino) benzoate (130 mg, 0.232 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.10-2.27 (1H, m), 2, 36 (3H, s), 2.89-3.10 (5H, m), 3.90 (2H, d, J = 5.7 Hz), 4.10 (2H, d, J = 7.2 Hz ), 4.20 (1H, br.s), 4.90 (1H, br.s), 7.13 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.32 (1H, t, J = 8.0 Hz), 7.65 (1H, d J = 7.7 Hz), 7.89 (1H, s), 8.17 ( 1H, s).

2) 3 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid dihydrochloride (95 mg, 95% yield) was obtained in the form of a white powder from 3 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid (105 mg, 0.192 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.8 Hz), 2.08-2.25 (1H, m), 2.37 (3H, s), 2.51 (3H, s), 2.83 (2H, s), 3.20 (2H, s), 3.82 (2H, s), 7.09-7.51 (5H, m), 7 54-7.79 (2H, m), 8.14 (1H, s), 8.44 (3H, s), 10.34 (1H, br s).

Example 343

Methyl 4-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoate

1) Methyl-4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl ] benzoate (350 mg, 67% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] acetic acid (390 mg, 0.914 mmol) and methyl 4- (aminomethyl) benzoate (553 mg, 2.74 mmol) in a manner similar to that of Example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.11-2.29 (1H, m), 2, 39 (3H, s), 2.55 (3H, s), 2.74 (2H, d, J = 7.2 Hz), 3.35 (2H, s), 3.93 (3H, s), 4.02 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 4.39 (2H, d, J = 5.8 Hz), 5.49 (1H, br .s), 6.90 (2H, d, J = 7.9 Hz), 7.16 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 8.1 Hz ), 7.99 (2H, d, J = 8.1 Hz).

2) Methyl 4-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoate (51 mg, yield 89%) was obtained as a white powder from methyl 4 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] acetyl} amino) methyl] benzoate (60 mg, 0.105 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.27 (1H, m), 2.40 (3H, s), 2.81 (3H, s), 3.24 (2H, d, J = 6.0 Hz), 3.44 (2H, s), 3.78-3.89 (5H, m), 4.28 (2H, d, J = 5.5 Hz), 7.20 (2H, d, J = 7.9 Hz), 7.27-7.38 (5H, m), 7.94 (2H, d, J = 7.9 Hz), 8.54 (3H, br.s).

Example 344

5 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] pyrazine-2-carboxylic acid dihydrochloride

1) Methyl-5 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl ] pyrazine-2-carboxylate (1.35 g, yield 98%) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) nicotinic acid (1.00 g, 2.43 mmol) and methyl 5- (bromomethyl) pyrazine-2-carboxylate (0.51 g, 2.21 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.17-2.27 (1H, m), 2, 31 (3H, s), 2.58 (3H, s), 2.79 (2H, d, J = 7.2 Hz), 4.06 (3H, s), 4.12-4.16 (2H , m), 4.22 (1H, br.s), 5.13 (2H, s), 7.02 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 7.9 Hz), 8.36 (1H, d, J = 1.3 Hz), 9.19 (1H, d, J = 1.3 Hz).

2) 5 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] pyrazine -2-carboxylic acid (600 mg, 45% yield) was obtained as a colorless oil from methyl-5 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4 - (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] pyrazine-2-carboxylate (1.35 g, 2.40 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.16-2.28 (1H, m), 2, 33 (3H, s), 2.59 (3H, s), 2.82 (2H, d, J = 7.4 Hz), 4.11-4.19 (2H, m), 4.24 (1H , br.s), 5.18 (2H, s), 7.04 (2H, d, J = 7.9 Hz), 7.12 (2H, d, J = 7.2 Hz), 8.20 (1H, s), 9.30 (1H, s).

3) 5 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] pyrazine-2-carboxylic acid dihydrochloride (497 mg, 76% yield) was obtained as a yellow solid from 5 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] carbonyl} oxy) methyl] pyrazin-2-carboxylic acid (600 mg, 1.09 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.29 (3H, s), 2.62 (3H, br.s), 2.94 (2H, br.s), 3.80 (2H, d, J = 4.7 Hz), 5.23 (2H, s), 7.08 -7.18 (4H, m), 8.38 (3H, br.s), 8.43 (1H, d, J = 1.3 Hz), 9.10 (1H, d, J = 1.3 Hz).

Example 345

4-Bromobenzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

4-Bromobenzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (628 mg, 90% yield) was obtained as a white solid from 4-bromobenzyl-5 - {[ (tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (0.73 g, 1.26 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.8 Hz), 2.14-2.27 (1H, m), 2.36 (3H, s), 2.87 (2H, br.s), 3.80 (2H, d, J = 5.3 Hz), 4.97 (2H, s), 7.00 (2H, d, J = 8.5 Hz ), 7.12 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.50 (2H, d, J = 8.5 Hz), 8.26 (3H, br s).

Example 346

{[5 - [(2-Bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine dihydrochloride

1) tert-Butyl {[5 - [(2-bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (640 mg, 46% yield) obtained as a white solid from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.00 g, 2, 51 mmol) and 2-bromophenol (478 mg, 2.76 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.19-2.28 (1H, m), 2, 37 (3H, s), 2.69 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 4.08-4.11 (2H, m), 4.24 (1H , br.s), 4.67 (2H, s), 6.65 (1H, dd, J = 8.1, 1.3 Hz), 6.79-6.84 (1H, m), 7, 07 (2H, d, J = 8.1 Hz), 7.12-7.19 (3H, m), 7.51 (1H, dd, J = 7.9, 1.5 Hz).

2) {[5 - [(2-Bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} amine dihydrochloride (458 mg, 75% yield) was obtained in as a white solid from tert-butyl {[5 - [(2-bromophenoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (640 mg, 1 , 16 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.16-2.30 (1H, m), 2.36 (3H, s), 2.91 (3H, br.s), 3.20 (2H, br.s), 3.79-3.90 (2H, m), 4.79 (2H, s), 6.89-6, 95 (2H, m), 7.25-7.36 (5H, m), 7.58 (1H, dd, J = 7.7, 1.5 Hz), 8.48 (3H, br.s) .

Example 347

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-methoxybenzoic acid dihydrochloride

1) 2-Methoxy-4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.15 g, yield 100%) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.80 g, 1.94 mmol ) and methyl 4- (bromomethyl) -3-methoxybenzoate (503 mg, 1.94 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.24 (1H, m), 2, 34 (3H, s), 2.54 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 3.85 (3H, s), 3.93 (3H, s), 4.10-4.16 (2H, m), 4.20 (1H, br.s), 5.06 (2H, s), 6.96 (1H, d, J = 7.9 Hz), 7 03 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.48-7.53 (2H, m).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] - 3-methoxybenzoic acid (1.10 g, 97% yield) was obtained as a colorless oil from 2-methoxy-4- (methoxycarbonyl) benzyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 methyl 4- (4-methylphenyl) nicotinate (1.15 g, 1.94 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.16-2.26 (1H, m), 2, 35 (3H, s), 2.56 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 3.86 (3H, s), 4.11-4.16 (2H , m), 4.23 (1H, br.s), 5.08 (2H, s), 6.97 (1H, d, J = 7.9 Hz), 7.04 (2H, d, J = 7.7 Hz), 7.11 (2H, d, J = 7.7 Hz), 7.53 (1H, s), 7.58 (1H, d, J = 7.9 Hz).

3) Dihydrochloride 4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -3-methoxybenzoic acid (247 mg yield 74%) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] carbonyl} oxy) methyl] -3-methoxybenzoic acid (0.35 g, 0.607 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6Hz), 2.17-2.26 (1H, m), 2.32 (3H, s), 2 84 (2H, br.s), 3.79 (2H, d, J = 5.7Hz), 3.83 (3H, s), 5.03 (2H, s), 6.96 (1H, d , J = 7.7Hz), 7.13 (2H, d, J = 8.1Hz), 7.18 (2H, d, J = 8.1Hz), 7.42-7.45 (1H, m) 7.46 (1H, s); 8.19 (3H, br s).

Example 348

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -2-methoxybenzoic acid dihydrochloride

1) 3-Methoxy-4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (680 mg, 94% yield ) were obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.22 mmol) and methyl 4- (bromomethyl) -2-methoxybenzoate (315 mg, 1.22 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2.33 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J = 7.4Hz), 3.86 (3H, s), 3.90 (3H, s), 4, 11-4.13 (2H, m), 4.21 (1H, br.s), 4.94 (2H, s), 6.65 (1H, dd, J = 8.0, 1.4 Hz) 6.75 (1H, d, J = 1.1Hz), 6.99 (2H, d, J = 8.1Hz), 7.08 (2H, d, J = 7.7Hz), 7.70 ( 1H, d, J = 7.9Hz).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] - 2-methoxybenzoic acid (550 mg, 83% yield) was obtained as a colorless oil from 3-methoxy-4- (methoxycarbonyl) benzyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) nicotinate (680 mg, 1.15 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 33 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.04 (3H, s), 4.11-4.13 (2H , m), 4.20 (1H, br.s), 4.98 (2H, s), 6.77 (1H, d, J = 9.4 Hz), 6.84 (1H, s), 6 99 (2H, d, J = 8.1 Hz), 7.07 (2H, d, J = 7.9 Hz), 8.08 (1H, d, J = 7.9 Hz).

3) Dihydrochloride 4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -2-methoxybenzoic acid (240 mg , yield 85%) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] carbonyl} oxy) methyl] -2-methoxybenzoic acid (293 mg, 0.509 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.14-2.26 (1H, m), 2.33 (3H, s), 2.58 (3H, br.s), 2.93 (2H, br.s), 3.78 (3H, s), 3.81 (2H, d, J = 4.5 Hz), 5.01 (2H, s), 6.62 (1H, d, J = 7.9 Hz), 6.92 (1H, d, J = 0.9 Hz), 7.12-7.22 (4H, m) 7.55 (1H, d, J = 7.7 Hz); 8.37 (3H, br s).

Example 349

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoic acid dihydrochloride

1) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoic acid (182 mg, 94% yield) was obtained as a white powder from methyl 4 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoate (200 mg, 0.349 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.92 (6H, d, J = 6.6 Hz), 1.34 (9H, s), 2.10-2.24 (1H, m), 2, 35 (3H, s), 2.38 (3H, s), 2.58 (2H, s), 3.22 (2H, s), 3.77 (2H, d, J = 3.0 Hz), 4.20 (1H, br.s), 4.27 (2H, d, J = 5.8 Hz), 6.74 (1H, s), 7.09 (2H, d, J = 8.1 Hz ), 7.17 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.90 (2H, d, J = 8.3 Hz), 8.17 (1H, s).

2) 4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] benzoic acid dihydrochloride (135 mg, yield 95 %) was obtained as a white powder from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl } amino) methyl] benzoic acid (150 mg, 0.268 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.07-2.24 (1H, m), 2.40 (3H, s), 2.78 (3H, s), 3.10 (2H, s), 3.41 (2H, s), 3.78 (2H, s), 4.27 (2H, d, J = 5.7 Hz ), 7.16 (2H, d, J = 7.9 Hz), 7.26-7.34 (4H, m), 7.92 (2H, d, J = 8.3 Hz), 8.33 (3H, br s), 8.45 (1H, br s).

Example 350

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide dihydrochloride (173 mg, 76% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and isoxazole-4-carbonyl chloride (100 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.20-2.31 (1H, m), 2.53 (3H, s), 2.94 (2H, s), 3.82 (2H, broad s), 7.09 (1H, s), 7.20 (2H, d, J = 8.1 Hz), 7.25 (2H d, J = 8.1 Hz), 8.28 (3H, br.s), 8.73 (1H, br.s), 10.59 (1H, br.s).

Example 351

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan-2-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan-2-carboxamide dihydrochloride (190 mg, 85% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and furan-2-carbonyl chloride (100 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.09-2.30 (1H, m), 2.32 (3H, s), 2.58 (3H, s), 3.04 (2H, br.s), 3.83 (2H, s), 6.61 (1H, dd, J = 1.8, 3.3 Hz), 7 14 (1H, d, J = 3.3 Hz), 7.21 (2H, d, J = 7.8 Hz), 7.25 (2H, d, J = 7.8 Hz), 7.84 (1H, s), 8.37 (3H, br s), 9.98 (1H, br s).

Example 352

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-methylbenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-methylbenzamide dihydrochloride (211 mg, 87% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-methylbenzoyl chloride (116 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.22-2.32 (1H, m), 2.31 (3H, s), 2.32 (3H, s), 2.57 (3H, s), 3.01 (2H, br.s), 3.84 (2H, s), 7.21-7.27 (6H, m) 7.55 (2H, d, J = 8.1 Hz), 8.32 (3H, br.s), 9.88 (1H, br.s).

Example 353

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-tert-butylbenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-tert-butylbenzamide dihydrochloride (211 mg, 83% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-tert-butylbenzoyl chloride ( 147 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.27 (9H, s), 2.22-2.31 (1H, m), 2.31 (3H, s), 2.56 (3H, s), 3.01 (2H, br.s), 3.84 (2H, s), 7.21-7.26 (4H, m) 7.44 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz), 8.32 (3H, br.s), 9.91 (1H, ears.s).

Example 354

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-chlorobenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-chlorobenzamide dihydrochloride (203 mg, 82% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-chlorobenzoyl chloride (131 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.30 (1H, m), 2.31 (3H, s), 2.62 (3H, s), 3.08 (2H, broad s), 3.86 (2H, s), 7.25 (4H, s), 7.52 (2H, d, J = 8, 4 Hz), 7.67 (2H, d, J = 8.4 Hz), 8.41 (3H, br.s), 10.20 (1H, br.s).

Example 355

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-cyanobenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-cyanobenzamide dihydrochloride (209 mg, 86% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-cyanobenzoyl chloride (126 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.10-2.31 (1H, m), 2.31 (3H, s), 2.59 (3H, s), 3.02 (2H, br.s), 3.85 (2H, s), 7.24 (4H, s), 7.76 (2H, d, J = 8, 1 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.36 (3H, br.s), 10.36 (1H, br.s).

Example 356

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-trifluoromethylbenzamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-trifluoromethylbenzamide dihydrochloride (209 mg, 86% yield) was obtained as a white powder from tert -butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-trifluoromethylbenzoyl chloride (156 mg, 0 , 75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.21-2.32 (1H, m), 2.31 (3H, s), 2.55 (3H, s), 2.96 (2H, br.s), 3.83 (2H, s), 7.22 (2H, d, J = 7.8 Hz), 7.26 (2H d, J = 7.8 Hz), 7.78 (2H, d, J = 7.8 Hz), 7.82 (2H, d, J = 7.8 Hz), 8.27 (3H, br s), 10.21 (1H, br s).

Example 357

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan-3-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] furan-3-carboxamide dihydrochloride (190 mg, 85% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and furan-3-carbonyl chloride (100 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.21-2.32 (1H, m), 2.55 (3H, s), 2.98 (3H, s), 3.82 (2H, br.s), 6.74 (1H, s), 7.20 (2H, d, J = 7.8 Hz), 7.25 (2H d, J = 7.8 Hz), 7.69 (1H, s), 8.15 (1H, s), 8.30 (3H, br.s), 9.74 (1H, br.s) .

Example 358

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophen-3-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] thiophen-3-carboxamide dihydrochloride (233 mg, 99% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and thiophene-3-carbonyl chloride (110 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.20-2.31 (1H, m), 2.31 (3H, s), 2.59 (3H, s), 3.05 (2H, broad s), 3.84 (2H, s), 7.24 (4H, s), 7.36 (1H, dd, J = 1, 2, 5.1 Hz), 7.56 (1H, dd, J = 5.1, 2.7 Hz), 8.10 (1H, d, J = 2.7 Hz), 8.35 (3H, broad s), 9.91 (1H, broad s).

Example 359

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-fluorobenzoic acid dihydrochloride

1) 2-Fluoro-4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (650 mg, yield 92% ) were obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.21 mmol) and methyl 4- (bromomethyl) -3-fluorobenzoate (299 mg, 1.21 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.16-2.25 (1H, m), 2, 33 (3H, s), 2.54 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.94 (3H, s), 4.09-4.13 (2H , m), 4.20 (1H, br s), 5.05 (2H, s), 6.98-7.09 (5H, m), 7.64-7.71 (2H, m).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] - 3-fluorobenzoic acid (450 mg, 71% yield) was obtained as a colorless oil from 2-fluoro-4- (methoxycarbonyl) benzyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) nicotinate (650 mg, 1.12 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.13-2.25 (1H, m), 2, 33 (3H, s), 2.56 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 4.09-4.16 (2H, m), 4.22 (1H , broad s), 5.07 (2H, s), 7.00-7.12 (5H, m), 7.70-7.76 (2H, m).

3) Dihydrochloride 4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -3-fluorobenzoic acid (329 mg , 76% yield) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] carbonyl} oxy) methyl] -3-fluorobenzoic acid (450 mg, 0.797 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (6H, d, J = 6.6 Hz), 2.16-2.23 (1H, m), 2.29 (3H, s), 2.86 (2H, br.s), 3.78 (2H, d, J = 5.5 Hz), 5.11 (2H, s), 7.07-7.13 (4H, m), 7 18 (1H, t, J = 7.6 Hz), 7.60-7.69 (2H, m), 8.23 (3H, br.s).

Example 360

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-chlorobenzoic acid dihydrochloride

1) 2-Chloro-4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (518 mg, 99% yield ) were obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.36 g, 0.873 mmol) and methyl- 4- (bromomethyl) -3-chlorobenzoate (230 mg, 0.873 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2, 32 (3H, s), 2.56 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.94 (3H, s), 4.11-4.13 (2H , m), 4.22 (1H, br.s), 5.11 (2H, s), 7.02-7.04 (3H, m), 7.09 (2H, d, J = 8.1 Hz), 7.78 (1H, dd, J = 8.0, 1.6 Hz), 7.99 (1H, d, J = 1.5 Hz).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] - 3-chlorobenzoic acid (420 mg, 83% yield) was obtained as a white solid from 2-chloro-4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- methyl 4- (4-methylphenyl) nicotinate (518 mg, 0.870 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.22-2.33 (4H, m), 2, 59 (3H, br.s), 2.82 (2H, br.s), 4.09-4.17 (2H, m), 4.25 (1H, br.s), 5.13 (2H, s), 7.01-7.14 (5H, m), 7.83 (1H, dd, J = 8.0, 1.6 Hz), 8.04 (1H, d, J = 1.5 Hz )

3) Dihydrochloride 4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -3-chlorobenzoic acid (265 mg , yield 66%) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] carbonyl} oxy) methyl] -3-chlorobenzoic acid (420 mg, 0.722 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.15-2.24 (1H, m), 2.29 (3H, s), 2.54 (3H, s), 2.86 (2H, br.s), 3.79 (2H, d, J = 5.3 Hz), 5.14 (2H, s), 7.13 (4H , s), 7.16 (1H, d, J = 7.9 Hz), 7.78 (1H, dd, J = 7.9, 1.5 Hz), 7.90 (1H, d, J = 1.5 Hz), 8.25 (3H, br s).

Example 361

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalic acid dihydrochloride

1) Dimethyl-4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] isophthalate (1.12 g, 99% yield) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid ( 0.75 g, 1.82 mmol) and dimethyl 4- (bromomethyl) isophthalate (522 mg, 1.82 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.26 (1H, m), 2, 35 (3H, s), 2.57 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 3.91 (3H, s), 3.96 (3H, s), 4.11-4.16 (2H, m), 4.23 (1H, br.s), 5.45 (2H, s), 6.99 (1H, d, J = 8.1 Hz), 7 06 (2H, d, J = 8.3 Hz), 7.13 (2H, d, J = 7.9 Hz), 7.99 (1H, dd, J = 8.1, 1.9 Hz) 8.59 (1H, d, J = 1.9 Hz).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] isophthalic acid (750 mg, 68% yield) was obtained as a colorless oil from dimethyl-4 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalate (1.12 g, 1.81 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.4 Hz), 1.38 (9H, s), 2.23-2.35 (4H, m), 2, 58 (3H, s), 2.86 (2H, d, J = 5.1 Hz), 4.11-4.21 (2H, m), 4.35 (1H, br.s), 5.48 (2H, s), 7.01-7.17 (5H, m), 7.96-8.08 (1H, m), 8.64-8.75 (1H, m).

3) 4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalic acid dihydrochloride (362 mg, 90 yield %) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] isophthalic acid (420 mg, 0.711 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.16-2.27 (1H, m), 2.33 (3H, s), 2.57 (3H, br.s), 2.90 (2H, br.s), 3.82 (2H, d, J = 5.1 Hz), 5.42 (2H, s), 7.01 (1H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.7 Hz), 7.23 (2H, d, J = 8.3 Hz), 7.97 (1H dd, J = 8.1, 1.9 Hz), 8.31 (3H, br.s), 8.42 (1H, d, J = 1.9 Hz).

Example 362

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- [4- (dimethylamino) phenyl] acetamide trihydrochloride

1) tert-Butyl {[5- (2 - {[4- (dimethylamino) phenyl] amino} -2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (450 mg, 71% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] acetic acid (500 mg, 1.17 mmol) and 4- (dimethylamino) aniline (500 mg, 3.67 mmol) in a manner similar to the method of example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.27 (1H, m), 2, 40 (3H, s), 2.63 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 2.90 (6H, s), 3.42 (2H, s), 4.06 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 6.58 (1H, br.s), 6.66 (2H, d, J = 8, 1 Hz), 7.02 (2H, d, J = 7.7 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 7.7 Hz )

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- [4- (dimethylamino) phenyl] acetamide trihydrochloride (62 mg, yield 42%) was obtained as a violet powder from tert-butyl {[5- (2 - {[4- (dimethylamino) phenyl] amino} -2-oxoethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl ) pyridin-3-yl] methyl} carbamate (100 mg, 0.268 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 2.13-2.28 (1H, m), 2.38 (3H, s), 2.76 (3H, s), 3.01 (6H, s), 3.13 (2H, s), 3.77-3.86 (5H, m), 7.20 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.51 (2H, d, J = 8.1 Hz), 8.30 (2H, d, J = 8, 1 Hz), 8.56 (3H, br s).

Example 363

Ethyl 5- (aminomethyl) -4- (4-methylphenyl) -2,6-dineopentylnicotinate

1) A mixture of potassium 3-ethoxy-3-oxopropionate (7.6 g, 45 mmol), magnesium chloride (2.8 g, 30 mmol) and tetrahydrofuran (75 ml) was stirred at 50 ° C for 4 hours. The resulting suspension allowed to cool to room temperature, then the reaction mixture obtained by stirring a mixture of tert-butyl acetic acid (3.5 g, 30 mmol), N, N'-carbonyldiimidazole (5.8 g, 36 mmol) and tetrahydrofuran (50 ml) was added dropwise. ), at room temperature for 1 h. The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and 0.5N. hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain ethyl 5,5-dimethyl-3-oxohexanoate as a crude product (5.9 g). A mixture of the crude product (5.9 g), ammonium acetate (9.8 g, 127 mmol), acetic acid (1.45 ml, 25 mmol) and toluene (200 ml) was heated under reflux using a Dean trap. Stark, for 17 hours. The reaction mixture was allowed to cool to room temperature, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl 3-amino-5,5-dimethylhex-2-enoate (2.5 g, yield 52%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.00 (9H, s), 1.27 (3H, t, J = 7.2 Hz), 1.98 (2H, s), 4.11 (2H, q, J = 7.2 Hz), 4.45 (2H, br s), 8.05 (1H, s).

2) Ethyl 5-cyano-4- (4-methylphenyl) -2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate (3.5 g, yield 65%) was obtained as a white powder from 5.5 dimethyl-3-oxohexannitrile (2.4 g, 13 mmol), p-tolualdehyde (1.6 g, 13 mol) and ethyl 3-amino-5,5-dimethylhex-2-enoate (2.5 g, 13 mmol) in a manner similar to the method of example 1-2).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.03 (9H, s), 1.17 (3H, t, J = 7.2 Hz), 2.06 (1H, d, J = 13.7 Hz), 2.27 (1H, d, J = 13.7 Hz), 2.31 (3H, s), 2.52 (1H, d, J = 13.7 Hz) , 3.34 (1H, d, J = 13.7 Hz), 3.95-4.10 (2H, m), 4.63 (1H, s), 5.44 (1H, br.s), 7.09 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz).

3) Ethyl 5-cyano-4- (4-methylphenyl) -2,6-dineopentylnicotinate (3.2 g, 96% yield) was obtained as a white powder from ethyl 5-cyano-4- (4-methylphenyl) -2,6-dineopentyl-1,4-dihydropyridine-3-carboxylate (3.4 g, 8.2 mmol) in a manner similar to that of Example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.2 Hz), 1.01 (9H, s), 1.08 (9H, s), 2.40 (3H, s), 2.87 (2H, s), 3.02 (2H, s), 3.99 (2H, q, J = 7.2 Hz), 7.20-7.30 (4H, m).

4) Ethyl 5- (aminomethyl) -4- (4-methylphenyl) -2,6-dineopentylnicotinate (0.91 g, 90% yield) was obtained as a colorless oil from ethyl 5-cyano-4- (4- methylphenyl) -2,6-dineopentylnicotinate (1.0 g, 2.5 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 7.2 Hz), 0.99 (9H, s), 1.04 (9H, s), 1.33 (2H, br.s), 2.38 (3H, s), 2.78 (2H, s), 2.88 (2H, s), 3.72 (2H, s), 3.89 (2H, q, J = 7.2 Hz), 7.12 (2H, d, J = 8.0 Hz), 7.20 (2H, d, J = 8.0 Hz).

Example 364

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} propan-1-ol dihydrochloride

1) A mixture of [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl methanesulfonate (1.91 g, 4.01 mmol ), 1,3-propanediol (3.05 g, 40.1 mmol), sodium hydride (60% in oil, 1.60 g, 40.1 mmol) and tetrahydrofuran (5 ml) were stirred at 55 ° C for 16 hours. The reaction mixture was allowed to cool to room temperature and 1N was added. hydrochloric acid to stop the reaction. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl {[5 - [(3-hydroxypropoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (840 mg, 46% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 1.70-1.80 (2H, m), 2, 16-2.27 (1H, m), 2.42 (3H, s), 2.63 (3H, s), 2.75 (2H, d, J = 7.4 Hz), 3.40 (2H , t, J = 5.8 Hz), 3.70 (2H, t, J = 5.8 Hz), 4.06 (2H, d, J = 4.7 Hz), 4.10 (2H, s ), 4.20 (1H, br.s), 7.03 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz).

2) 3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} propan-1-ol dihydrochloride (15 mg, 100% yield) was obtained as a white powder from tert-butyl {[5 - [(3-hydroxypropoxy) methyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (18 mg, 0 , 0394 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 1.70-2.3 (2H, m), 2.38 (3H, s), 2.75 (2H, s), 3.35-4.20 (6H, m), 4.06 (2H, d, J = 4.5 Hz), 4.11 (2H, d, J = 4, 5 Hz), 7.00 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.51 (2H, d, J = 8.1 Hz ), 8.56 (3H, br s).

Example 365

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phthalic acid dihydrochloride

1) Dimethyl-4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl ] phthalate (1.68 g, 95% yield) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid ( 1.18 g, 2.86 mmol) and dimethyl 4- (bromomethyl) phthalate (820 mg, 2.86 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.17-2.26 (1H, m), 2, 33 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.92 (3H, s), 3.93 (3H, s), 4.11-4.15 (2H, m), 4.21 (1H, broad s), 4.95 (2H, s), 7.00 (2H, d, J = 8.1 Hz), 7 09 (2H, d, J = 7.9 Hz), 7.16 (1H, dd, J = 7.9, 1.7 Hz), 7.47 (1H, d, J = 1.5 Hz) 7.62 (1H, d, J = 7.7 Hz).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] phthalic acid (1.60 g, 99% yield) was obtained as a colorless oil from dimethyl-4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] phthalate (1.68 g, 2.72 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.27 (1H, m), 2, 39 (3H, s), 2.67 (3H, br.s), 3.10 (2H, d, J = 7.0 Hz), 4.23 (2H, d, J = 4.9 Hz), 4.51 (1H, br s), 5.01 (2H, s), 7.07 (2H, s), 7.21-7.24 (3H, m), 8.03 (1H, s) 8.13 (1H, d, J = 7.9 Hz).

3) 4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phthalic acid dihydrochloride (396 mg, yield 84 %) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phthalic acid (0.49 g, 0.830 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.17-2.26 (1H, m), 2.33 (3H, s), 2.56 (3H, br.s), 2.91 (2H, br.s), 3.81 (2H, d, J = 4.9 Hz), 5.05 (2H, s), 7.13 (2H, d, J = 7.9 Hz), 7.17-7.21 (3H, m), 7.39 (1H, d, J = 1.5 Hz), 7.59 (1H, d, J = 7.9 Hz), 8.32 (3H, br s).

Example 366

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -2-fluorobenzoic acid dihydrochloride

1) 4-Bromo-3-fluorobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.36 g, 78% yield) obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.20 g, 2.91 mmol) and ( 4-bromo-3-fluorophenyl) methanol (597 mg, 2.91 mmol) in a manner similar to that of Example 247-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.16-2.25 (1H, m), 2, 36 (3H, s), 2.55 (3H, s), 2.78 (2H, d, J = 7.2 Hz), 4.11-4.16 (2H, m), 4.21 (1H , br.s), 4.86 (2H, s), 6.61-6.65 (1H, m), 7.00-7.06 (3H, m), 7.12-7.19 (3H , m).

2) 3-Fluoro-4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (520 mg, 39% yield) ) were obtained as a yellow oil from 4-bromo-3-fluorobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.36 g 2.27 mmol) in a manner similar to the method of example 231-2).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.25 (1H, m), 2, 33 (3H, s), 2.55 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 3.94 (3H, s), 4.09-4.15 (2H , m), 4.21 (1H, br.s), 4.94 (2H, s), 6.81-6.85 (1H, m), 7.00 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.63-7.67 (2H, m).

3) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] - 2-fluorobenzoic acid (480 mg, 94% yield) was obtained as a colorless oil from 3-fluoro-4- (methoxycarbonyl) benzyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl -4- (4-methylphenyl) nicotinate (520 mg, 0.899 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.16-2.26 (1H, m), 2, 33 (3H, s), 2.56 (3H, s), 2.81 (2H, d, J = 7.4 Hz), 4.09-4.16 (2H, m), 4.24 (1H , br.s), 4.96 (2H, s), 6.88-6.92 (1H, m), 7.02 (2H, d, J = 7.9 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.69-7.73 (2H, m).

4) Dihydrochloride 4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -2-fluorobenzoic acid (192 mg yield 42%) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] carbonyl} oxy) methyl] -2-fluorobenzoic acid (480 mg, 0.850 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.8 Hz), 2.12-2.26 (1H, m), 2.30 (3H, s), 2.53 (3H, s), 2.86 (2H, d, J = 7.0 Hz), 3.79 (2H, d, J = 5.7 Hz), 5.05 (2H, s), 7.05-7.16 (5H, m), 7.59-7.64 (2H, m), 8.24 (3H, br.s).

Example 367

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-oxo-4,5,6,7-tetrahydro-1-benzofuran- dihydrochloride 3-carboxamide

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-oxo-4,5,6,7-tetrahydro-1-benzofuran- dihydrochloride 3-carboxamide (172 mg, 66% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carbonyl chloride (150 mg, 0.75 mmol) in a manner similar to the method of Example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.10 (6H, d, J = 6.6 Hz), 2.00-2.09 (2H, m), 2.11-2.31 (1H , m), 2.31 (3H, s), 2.44 (2H, t, J = 6.3 Hz), 2.59 (3H, s), 2.93 (2H, t, J = 6, 3 Hz), 3.06 (2H, s), 3.85 (2H, s), 7.24 (4H, s), 8.35 (1H, s), 8.36 (3H, br.s) 11.42 (1H, br s).

Example 368

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-phenyl-1,3-thiazole-4-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2-phenyl-1,3-thiazole-4-carboxamide dihydrochloride (155 mg, yield 57%) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol ) and 2-phenyl-1,3-thiazole-4-carbonyl chloride (167 mg, 0.75 mmol) in a manner similar to that of Example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.29 (1H, m), 2.28 (3H, s), 2.61 (3H, s), 3.04 (2H, s), 3.85 (2H, s), 7.26 (4H, s), 7.53-7.55 (3H, m), 7 95-7.98 (2H, m), 8.35 (1H, s), 8.36 (3H, br s), 9.85 (1H, br s).

Example 369

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyrazine-2-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyrazine-2-carboxamide dihydrochloride (157 mg, 63% yield) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and pyrazine-2-carbonyl chloride (107 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.6 Hz), 2.18-2.28 (1H, m), 2.27 (3H, s), 2.63 (3H, s), 3.12 (2H, s), 3.85 (2H, s), 7.21 (2H, d, J = 8.1 Hz), 7.26 (2H, d , J = 8.1 Hz), 8.46 (3H, br.s), 8.70 (1H, s), 8.88 (1H, s), 9.08 (1H, s), 10.48 (1H, broad s).

Example 370

4 - [({[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} oxy) methyl] benzoic acid dihydrochloride

1) 6n. Hydrochloric acid (200 ml) was added to tert-butyl {[5- (cyanomethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (16 g, 37 mmol) and the mixture was stirred at 90 ° C for 24 hours. The reaction mixture was washed with a mixed solvent of tetrahydrofuran-toluene (1: 2) and concentrated under reduced pressure. The residue was dissolved in water and made basic by the addition of 4N. an aqueous solution of sodium hydroxide. The resulting alkalized solution was washed with ethyl acetate and concentrated under reduced pressure. Tetrahydrofuran (100 ml) and water (50 ml) were added to the residue, and the mixture was vigorously stirred. Di-tert-butyl dicarbonate (8.5 ml, 37 mmol) was added dropwise and the mixture was stirred at room temperature for 17 hours. 1N was added to the reaction mixture. hydrochloric acid to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The extracts were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from hexane-ethyl acetate to give [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (13 g, 80% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.09 (9H, s), 1.39 (9H, s), 2.43 (3H, s), 2.82 (3H, d, J = 20 Hz) , 3.34 (2H, broad s), 3.43 (2H, broad s), 4.05-4.25 (2H, m), 4.35-4.50 (1H, m), 6 97 (2H, dd, J = 7.5, 24 Hz); 7.26 (2H, dd, J = 7.5, 29 Hz).

2) A mixture of [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.50 g, 1.1 mmol ), triethylamine (0.17 ml, 1.3 mmol) and tetrahydrofuran (20 ml) was ice-cooled and a solution of 2,4,6-trichlorobenzoyl chloride (0.31 g, 1.3 mmol) in tetrahydrofuran (2 ml) was added dropwise. ) The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml) and 2-oxo-2-phenylethyl-4- (hydroxymethyl) benzoate (0.37 g, 1.4 mmol) and 4-dimethylaminopyridine (0.17 g, 1.4) were added to the solution. mmol). The resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with 0.1 M aqueous citric acid, saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 2-oxo-2-phenylethyl-4 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4 -methylphenyl) -6-neopentylpyridin-3-yl] acetyl} oxy) methyl] benzoate (0.63 g, 80% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.39 (3H, s), 2.49 (3H, s), 2.84 ( 2H, s), 3.43 (2H, s), 4.08 (2H, d, J = 4.0 Hz), 4.15-4.25 (1H, m), 5.11 (2H, s ), 5.59 (2H, s), 6.94 (2H, d, J = 7.9 Hz), 7.17 (2H, d, J = 7.9 Hz), 7.31 (2H, d , J = 8.3 Hz), 7.45-7.55 (2H, m), 7.60-7.70 (1H, m), 7.95-8.00 (2H, m), 8, 11 (2H, d, J = 8.3 Hz).

3) 2-Oxo-2-phenylethyl-4 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} oxy) methyl] benzoate (0.61 g, 0.88 mmol) was dissolved in ethyl acetate (2 ml) and water (2 ml), acetic acid (5 ml) and zinc powder (0.42) were successively added to the resulting solution. g, 6.4 mmol). The resulting mixture was stirred at 55 ° C for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and further recrystallized from hexane-ethyl acetate to give 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4 -methylphenyl) -6-neopentylpyridin-3-yl] acetyl} hydroxy) methyl] benzoic acid (0.29 g, yield 48%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.36 (9H, s), 2.38 (3H, s), 2.47 (3H, s), 2.88 ( 2H, s), 3.43 (2H, s), 4.10 (2H, d, J = 5.1 Hz), 4.15-4.25 (1H, m), 5.11 (2H, s ), 6.94 (2H, d, J = 7.7 Hz), 7.17 (2H, d, J = 7.7 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.07 (2H, d, J = 8.1 Hz).

4) 4 - [({[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} hydroxy) methyl] benzoic acid dihydrochloride (0.22 g, yield 92.4%) was obtained as a pale yellow powder from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3 -yl] acetyl} hydroxy) methyl] benzoic acid (0.25 g, 0.44 mmol) in a manner similar to that of Example 276-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.37 (3H, s), 2.73 (3H, br s), 3.00-3.30 (2H , m), 3.57 (2H, br.s), 3.82 (2H, br.s), 5.11 (2H, s), 7.09 (2H, d, J = 7.9 Hz) 7.28 (2H, d, J = 7.9 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.2 Hz), 8 19 (3H, br s).

Example 371

2 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] furan-3-carboxylic acid dihydrochloride

1) [3- (Methoxycarbonyl) -2-furyl] methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (320 mg, yield 47%) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (0.50 g, 1.22 mmol ) and methyl 2- (bromomethyl) furan-3-carboxylate (266 mg, 1.22 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.8 Hz), 1.38 (9H, s), 2.15-2.26 (1H, m), 2, 37 (3H, s), 2.55 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.82 (3H, s), 4.09-4.13 (2H , m), 4.19 (1H, br.s), 5.27 (2H, s), 6.68 (1H, d, J = 1.9 Hz), 7.00 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.31 (1H, d, J = 1.9 Hz).

2) 2 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] furan -3-carboxylic acid (310 mg, 99% yield) was obtained as a colorless oil from [3- (methoxycarbonyl) -2-furyl] methyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl- 2-methyl-4- (4-methylphenyl) nicotinate (320 mg, 0.581 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.22 (1H, m), 2, 37 (3H, s), 2.55 (3H, s), 2.80 (2H, d, J = 7.4 Hz), 4.09-4.16 (2H, m), 4.23 (1H , br.s), 5.27 (2H, s), 6.72 (1H, d, J = 1.9 Hz), 7.02 (2H, d, J = 7.9 Hz), 7.13 (2H, d, J = 7.4 Hz), 7.34 (1H, d, J = 1.9 Hz).

3) Dihydrochloride 2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] furan-3-carboxylic acid (241 mg, 81% yield) was obtained as a pale yellow solid from 2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] furan-3-carboxylic acid (310 mg, 0.577 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.25 (1H, m), 2.35 (3H, s), 2.53 (3H, br.s), 2.90 (2H, br.s), 3.80 (2H, d, J = 5.1 Hz), 5.26 (2H, s), 6.71 (1H, d, J = 1.9 Hz), 7.12 (2H, d, J = 7.9 Hz), 7.19 (2H, d, J = 7.9 Hz), 7.72 (1H d, J = 1.9 Hz), 8.32 (3H, br s).

Example 372

4 - [({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] -3-nitrobenzoic acid dihydrochloride

1) 4- (Methoxycarbonyl) -2-nitrobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.91 g, yield 63 %) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.91 g, 4.63 mmol) and methyl 4- (hydroxymethyl) -3-nitrobenzoate (978 mg, 4.63 mmol) in a manner similar to that of Example 247-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.28 (1H, m), 2, 34 (3H, s), 2.57 (3H, s), 2.79 (2H, d, J = 7.4 Hz), 3.99 (3H, s), 4.10-4.17 (2H , m), 4.23 (1H, br.s), 5.41 (2H, s), 7.03-7.09 (3H, m), 7.13 (2H, d, J = 7.9 Hz), 8.08 (1H, dd, J = 8.1, 1.5 Hz), 8.68 (1H, d, J = 1.5 Hz).

2) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] - 3-nitrobenzoic acid (300 mg, yield 93%) was obtained as a colorless oil from 4- (methoxycarbonyl) -2-nitrobenzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl- 4- (4-methylphenyl) nicotinate (0.33 g, 0.545 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.34 (4H, m), 2, 59 (3H, s), 2.83 (2H, d, J = 6.8 Hz), 4.10-4.18 (2H, m), 4.26 (1H, br.s), 5.42 (2H, s), 7.02-7.20 (5H, m), 8.12-8.16 (1H, m), 8.73 (1H, s).

3) Dihydrochloride 4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] -3-nitrobenzoic acid (247 mg , 86% yield) was obtained as a white solid from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] carbonyl} oxy) methyl] -3-nitrobenzoic acid (300 mg, 0.507 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.8 Hz), 2.16-2.25 (1H, m), 2.29 (3H, s), 2.60 (3H, br.s), 2.94-3.00 (2H, m), 3.81 (2H, d. J = 5.5 Hz), 5.42 (2H, s), 7 , 17 (4H, s), 7.24 (1H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 8.1, 1.7 Hz), 8.39 (3H, br.s), 8.48 (1H, d, J = 1.7 Hz).

Example 373

Methyl 3 - {[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate dihydrochloride

1) Ethyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H -pyrazole-4-carboxylate (2.34 g, 81% yield) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3 -yl] methyl} carbamate (2.09 g, 5.07 mmol) and ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (863 mg, 5.07 mmol) in a manner similar to the method of example 183- one).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.26-1.28 (3H, m), 1.37 (9H, s), 2.36 (3H, s), 2.66 (3H, s), 2.86 (2H, s), 3.68 (3H, s), 4.13 (1H, br.s), 4.23 (2H, q, J = 7, 1 Hz), 4.90 (2H, s), 7.11 (2H, d, J = 8.3 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.62 (1H , from).

2) 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole -4-carboxylic acid (2.22 g, 99% yield) was obtained as a colorless oil from ethyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4- methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate (2.34 g, 4.14 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.37 (9H, s), 2.35 (3H, s), 2.66 (3H, s), 2.88 ( 2H, s), 3.70 (3H, s), 4.09-4.18 (2H, m), 4.24 (1H, br.s), 4.95 (2H, s), 7.08 (2H, d, J = 7.5 Hz), 7.18 (2H, d, J = 7.7 Hz), 7.68 (1H, s).

3) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H -pyrazole-4-carboxylate (480 mg, 91% yield) was obtained as a colorless oil from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) - 6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid (0.51 g, 0.950 mmol) in a manner similar to that of Example 305-3).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.37 (9H, s), 2.36 (3H, s), 2.66 (3H, s), 2.86 ( 2H, s), 3.68 (3H, s), 3.76 (3H, s), 4.09-4.17 (2H, m), 4.19 (1H, br.s), 4.90 (2H, s), 7.10 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.62 (1H, s).

4) Methyl-3 - {[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate dihydrochloride ( 349 mg, 76% yield) was obtained as a white solid from methyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridine- 3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate (480 mg, 0.872 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (9H, s), 2.38 (3H, s), 2.91 (3H, br s), 3.28 (2H, br s ), 3.65 (3H, s), 3.66 (3H, s), 3.89 (2H, br s), 4.90 (2H, s), 7.27 (2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 8.1 Hz), 8.09 (1H, s), 8.32 (3H, br.s).

Example 374

3 - {[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid dihydrochloride

3 - {[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid dihydrochloride (210 mg, yield 76%) was obtained as a white solid from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy } -1-methyl-1H-pyrazole-4-carboxylic acid (0.29 g, 0.540 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 2.38 (3H, s), 2.87 (3H, br s), 3.23 (2H, br s ), 3.64 (3H, s), 3.89 (2H, br.s), 4.86 (2H, s), 7.27 (2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 7.9 Hz), 8.00 (1H, s), 8.26 (3H, br.s).

Example 375

3 - {[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxamide dihydrochloride

1) tert-Butyl {[5 - ({[4- (aminocarbonyl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridine -3-yl] methyl} carbamate (110 mg, 18% yield) was obtained as a colorless oil from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl ) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylic acid (0.60 g, 1.12 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.37 (9H, s), 2.37 (3H, s), 2.64 (3H, s), 2.87 ( 2H, s), 3.69 (3H, s), 4.11-4.16 (2H, m), 4.97 (2H, s), 5.24 (1H, br.s), 6.43 (1H, br s), 7.01 (2H, d, J = 7.7 Hz), 7.20 (2H, d, J = 8.3 Hz), 7.69 (1H, s).

2) 3 - {[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxamide dihydrochloride (70, 3 mg, 67% yield) was obtained as a white solid from tert-butyl {[5 - ({[4- (aminocarbonyl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) -6-methyl -4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (110 mg, 0.205 mmol) in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 2.38 (3H, s), 2.91 (3H, br s), 3.25 (2H, br s ), 3.63 (3H, s), 3.88 (2H, br s), 4.92 (2H, s), 6.35 (1H, br s), 7.09 (1H, br. s), 7.27 (2H, d, J = 7.0 Hz), 7.34 (2H, d, J = 7.5 Hz), 7.91 (1H, s), 8.29 (3H, ears.s).

Example 376

Dihydrochloride {2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid

1) 2- (2-Ethoxy-2-oxoethyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (980 mg, yield 70%) was obtained as a colorless oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (1.00 g, 2.42 mmol ) and ethyl [2- (bromomethyl) phenyl] acetate (624 mg, 2.42 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.8 Hz), 1.20 (3H, t, J = 7.2 Hz), 1.38 (9H, s) , 2.15-2.26 (1H, m), 2.35 (3H, s), 2.51 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3, 51 (2H, s), 4.02-4.09 (2H, m), 4.09-4.13 (2H, m), 4.19 (1H, br.s), 5.02 (2H, s), 6.99 (2H, d, J = 8.3 Hz), 7.06-7.08 (3H, m), 7.16-7.21 (2H, m), 7.26-7 31 (1H, m).

2) {2 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} oxy) methyl] phenyl} acetic acid (600 mg, 62% yield) was obtained as a colorless oil from 2- (2-ethoxy-2-oxoethyl) benzyl-5 - {[((tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 methyl 4- (4-methylphenyl) nicotinate (980 mg, 1.71 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.8 Hz), 1.37 (9H, s), 2.10-2.21 (1H, m), 2, 34 (3H, s), 2.49 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 3.53 (2H, s), 4.05-4.13 (2H , m), 4.29 (1H, br.s), 5.01 (2H, s), 6.98 (2H, d, J = 8.3 Hz), 7.02-7.11 (3H, m), 7.18-7.32 (3H, m).

3) Dihydrochloride {2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbonyl} hydroxy) methyl] phenyl} acetic acid (125 mg yield 62%) was obtained as a white solid from {2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] carbonyl} oxy) methyl] phenyl} acetic acid (210 mg, 0.374 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.16-2.28 (1H, m), 2.36 (3H, s), 2.88 (2H, br s), 3.47 (2H, s), 3.81 (2H, d, J = 5.1 Hz), 4.99 (2H, s), 6.98 (1H d, J = 7.5 Hz), 7.13-7.32 (7H, m), 8.27 (3H, br.s).

Example 377

2- (2-amino-2-oxoethyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride

1) 2- (2-amino-2-oxoethyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (323 mg, yield 83%) was obtained as a colorless oil from {2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl ] carbonyl} oxy) methyl] phenyl} acetic acid (0.39 g, 0.695 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.13-2.26 (1H, m), 2, 35 (3H, s), 2.50 (3H, s), 2.76 (2H, d, J = 7.4 Hz), 3.47 (2H, s), 4.06-4.13 (2H , m), 4.24 (1H, br.s), 5.01 (2H, s), 6.99 (2H, d, J = 8.1 Hz), 7.06-7.10 (3H, m), 7.19-7.35 (3H, m).

2) 2- (2-amino-2-oxoethyl) benzyl-5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate dihydrochloride (209 mg, 68% yield) was obtained as white solids from 2- (2-amino-2-oxoethyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (323 mg, 0.577 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (6H, d, J = 6.6 Hz), 2.14-2.25 (1H, m), 2.36 (3H, s), 2.55 (3H, s), 2.93 (2H, br.s), 3.32 (2H, s), 3.82 (2H, d, J = 5.1 Hz), 5.08 (2H , s), 6.94 (2H, d, J = 7.4 Hz), 7.14-7.30 (7H, m), 7.51 (1H, br.s), 8.35 (3H, ears.s).

Example 378

Methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} thiophene-2-carboxylate dihydrochloride

1) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} thiophene-2-carboxylate (460 mg, 68% yield) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate ( 0.50 g, 1.25 mmol) and methyl 3-hydroxythiophene-2-carboxylate (0.20 g, 1.25 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.39 (9H, s), 2.18-2.27 (1H, m), 2, 38 (3H, s), 2.72 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.80 (3H, s), 4.06-4.11 (2H , m), 4.20 (1H, br.s), 4.79 (2H, s), 6.50 (1H, d, J = 5.5 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.18 (2H, d, J = 7.9 Hz), 7.29 (1H, d, J = 5.5 Hz).

2) Methyl-3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} thiophene-2-carboxylate dihydrochloride (126 mg, 84% yield ) was obtained as a white solid from methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy } thiophene-2-carboxylate (158 mg, 0.293 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.4 Hz), 2.15-2.28 (1H, m), 2.37 (3H, s), 2.88 (3H, s), 3.11 (2H, br s), 3.71 (3H, s), 3.82 (2H, s), 4.87 (2H, s), 6.86 (1H, d, J = 5.7 Hz), 7.21-7.34 (4H, m), 7.77 (1H, d, J = 5.5 Hz), 8.36 (3H, br. from).

Example 379

Methyl dihydrochloride 4 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylate

1) Ethyl-4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl- 1,3-thiazole-5-carboxylate (910 mg, 96% yield) was obtained as a colorless oil from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine -3-yl] methyl} carbamate (0.66 g, 1.66 mmol) and ethyl 4-hydroxy-2-methyl-1,3-thiazole-5-carboxylate (0.31 g, 1.66 mmol) in a manner similar to that of Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.28 (3H, t, J = 7.2 Hz), 1.39 (9H, s) , 2.17-2.26 (1H, m), 2.37 (3H, s), 2.53 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 4, 08 (2H, d, J = 4.5 Hz), 4.25 (2H, q, J = 7.0 Hz), 5.13 (2H, s), 7.09 (2H, d, J = 8 , 1 Hz), 7.16 (2H, d, J = 7.9 Hz).

2) 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1, 3-thiazole-5-carboxylic acid (750 mg, 87% yield) was obtained as a colorless oil from ethyl 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl- 4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylate (910 mg, 1.60 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.18-2.30 (1H, m), 2, 38 (3H, s), 2.57 (3H, s), 2.81 (3H, br.s), 2.95 (2H, d, J = 7.0 Hz), 4.09-4.15 (2H, m), 4.31 (1H, br.s), 5.22 (2H, s), 7.05 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz).

3) Methyl-4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl- 1,3-thiazole-5-carboxylate (420 mg, 77% yield) was obtained as a pale yellow solid from 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2- methyl 4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylic acid (530 mg, 0.982 mmol) in a manner similar to that of Example 305-3).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.27 (1H, m), 2, 37 (3H, s), 2.54 (3H, s), 2.68 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.79 (3H, s), 4.08 (2H, d, J = 4.9 Hz), 4.21 (1H, br.s), 5.14 (2H, s), 7.09 (2H, d, J = 8.1 Hz ), 7.16 (2H, d, J = 7.9 Hz).

4) Methyl 4-dihydrochloride - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazol-5 -carboxylate (342 mg, 85% yield) was obtained as a pale yellow solid from methyl 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- ( 4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylate (420 mg, 0.759 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.13-2.28 (1H, m), 2.38 (3H, s), 2.55 (3H, s), 2.93 (3H, br.s), 3.13 (2H, br.s), 3.70 (3H, s), 3.80 (2H, br.s) 5.17 (2H, s), 7.20-7.26 (2H, m), 7.31 (2H, d, J = 7.4 Hz), 8.38 (3H, br.s).

Example 380

4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylic acid dihydrochloride

4 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylic acid dihydrochloride ( 145 mg, yield 69%) was obtained as a white solid from 4 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] methoxy} -2-methyl-1,3-thiazole-5-carboxylic acid (220 mg, 0.408 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.15-2.28 (1H, m), 2.38 (3H, s), 2.53 (3H, s), 2.90 (3H, br.s), 3.10 (2H, br.s), 3.75-3.85 (2H, m), 5.11 (2H, s), 7.25 (2H, d, J = 6.4 Hz), 7.32 (2H, d, J = 7.7 Hz), 8.15-8.42 (3H, m).

Example 381

3 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (carboxymethyl) -1H-pyrazole-4-carboxylic acid dihydrochloride

1) Ethyl-1-acetyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} - 1H-pyrazole-4-carboxylate (1.12 g, 77% yield) was obtained as a white solid from tert-butyl {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (1.00 g, 2.51 mmol) and ethyl 1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (597 mg, 3.01 mmol) in a similar manner to the method Example 214-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.8 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.39 (9H, s) , 2.14-2.27 (1H, m), 2.36 (3H, s), 2.51 (3H, s), 2.67 (3H, s), 2.78 (2H, d, J = 7.4 Hz), 4.09 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 4.28 (2H, q, J = 7.1 Hz), 5.01 (2H, s), 7.09 (2H, d, J = 8.1 Hz), 7.17 (2H, d, J = 7.9 Hz), 8.49 (1H, s).

2) To a solution of ethyl-1-acetyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy } -1H-pyrazole-4-carboxylate (0.86 g, 1.49 mmol) in a mixture of tetrahydrofuran (10 ml) -methanol (5 ml) was added a saturated aqueous solution of sodium bicarbonate (10 ml) and the mixture was stirred at room temperature in within 30 minutes The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain ethyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-pyrazol-4-carboxylate (798 mg, 99% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.24-1.29 ( 3H, m), 1.40-1.46 (9H, m), 2.19-2.28 (1H, m), 2.36 (3H, br.s), 2.65-2.78 ( 5H, m), 3.87-4.04 (2H, m), 4.08-4.35 (5H, m), 4.87 (1H, br.s), 6.91-7.01 ( 2H, m), 7.07-7.15 (2H, m), 7.84 (1H, s).

3) To a solution of ethyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H- pyrazole 4-carboxylate (1.09 g, 2.03 mmol) in N, N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 98 mg, 2.44 mmol) and the mixture was stirred at room temperature in within 30 minutes Tert-butyl bromoacetate (0.36 ml, 2.44 mmol) was added to the reaction mixture, and the mixture was stirred under heating at 60 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain ethyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-tert-butoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate (960 mg, 72% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.39 (9H, s) 1.44 (9H, s), 2.14-2.25 (1H, m), 2.36 (3H, s), 2.66 (3H, s), 2.76 (2H, d, J = 7.4 Hz), 4.08 (2H, d, J = 4.9 Hz), 4.17-4.27 (3H, m), 4.52 (2H, s), 4.91 (2H , s), 7.09 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.73 (1H, s).

4) To a mixed solution of ethyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1 - (2-tert-butoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate (960 mg, 1.48 mmol) in a mixture of tetrahydrofuran (15 ml) -methanol (10 ml) was added 1N. an aqueous solution of sodium hydroxide (10 ml) and the mixture was heated at the boil under reflux for 1 h. The reaction mixture was allowed to cool to room temperature and acidified with 0.5N. hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1 - (carboxymethyl) -1H-pyrazole-4-carboxylic acid (838 mg, 99% yield) as an oil. From the obtained oil (107 mg, 0.189 mmol), 3 - {[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} dihydrochloride was obtained as a white solid -1- (carboxymethyl) -1H-pyrazole-4-carboxylic acid (58.2 mg, 59% yield) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.14-2.28 (1H, m), 2.38 (3H, s), 2.82 (3H, broad s), 3.04 (2H, broad s), 3.76-3.86 (2H, m), 4.77 (2H, s), 4.86 (2H, s), 7.26 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 7.9 Hz), 8.04 (1H, s), 8.27 (3H, ears.s).

Example 382

Methyl-3 dihydrochloride - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-methoxy-2-oxoethyl) -1H pyrazole-4-carboxylate

1) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2 -methoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate (560 mg, 0.636 mmol) was obtained as a colorless oil from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl- 2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (carboxymethyl) -1H-pyrazole-4-carboxylic acid (870 mg, 1.48 mmol) in a manner similar to the method of example 305-3 )

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.15-2.25 (1H, m), 2, 36 (3H, s), 2.66 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 3.76 (3H, s), 3.77 (3H, s), 4.08 (2H, d, J = 4.7 Hz), 4.22 (1H, br.s), 4.65 (2H, s), 4.91 (2H, s), 7.08 (2H d, J = 8.1 Hz), 7.16 (2H, d, J = 7.9 Hz), 7.74 (1H, s).

2) Methyl 3-dihydrochloride - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-methoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate (59.8 mg, 63% yield) was obtained as a white solid from methyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2 -methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-methoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate (98.7 mg, 0.166 mmol) in a similar manner to the method Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.15-2.28 (1H, m), 2.37 (3H, s), 2.74 (3H, br s), 2.94 (2H, br s), 3.67 (3H, s), 3.68 (3H, s), 4.86 (2H, s), 4 91 (2H, s), 7.23 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 8.09-8.19 (4H, m).

Example 383

Dihydrochloride [3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4- (methoxycarbonyl) -1H-pyrazol-1-yl] acetic acid

1) To a solution of methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-methoxy-2-oxoethyl) -1H-pyrazole-4-carboxylate (0.46 g, 0.775 mmol) in tetrahydrofuran was added 1N. aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 0.5N. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain [3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} - 4- (methoxycarbonyl) -1H-pyrazol-1-yl] acetic acid (450 mg, 99% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.21-2.34 (1H, m), 2, 43 (3H, s), 3.02-3.26 (5H, m), 3.76 (3H, s), 4.13-4.19 (2H, m), 4.62 (2H, s) 4.99-5.11 (2H, m), 7.12 (2H, d, J = 7.0 Hz), 7.30 (2H, d, J = 7.5 Hz), 7.68- 7.75 (1H, m).

2) Dihydrochloride [3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4- (methoxycarbonyl) -1H-pyrazol-1- yl] acetic acid (42.4 mg, 44% yield) was obtained as a white solid from [3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4- (methoxycarbonyl) -1H-pyrazol-1-yl] acetic acid (100 mg, 0.172 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.14-2.28 (1H, m), 2.38 (3H, s), 2.85 (3H, broad s), 3.07 (2H, broad s), 3.68 (3H, s), 3.75-3.85 (2H, m), 4.78 (2H, s), 4.90 (2H, s), 7.25 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 7.9 Hz), 8.12 (1H, s), 8.31 (3H, br s).

Example 384

Methyl 3-dihydrochloride - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-amino-2-oxoethyl) -1H pyrazole-4-carboxylate

1) Methyl-1- (2-amino-2-oxoethyl) -3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine -3-yl] methoxy} -1H-pyrazole-4-carboxylate (150 mg, 37% yield) was obtained as a white solid from [3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6 -isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -4- (methoxycarbonyl) -1H-pyrazol-1-yl] acetic acid (400 mg, 0.689 mmol) in a manner similar to the example method 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.29 (1H, m), 2, 36 (3H, s), 2.68 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.78 (3H, s), 4.08 (2H, d, J = 5.1 Hz), 4.22 (1H, br.s), 4.54 (2H, s), 4.94 (2H, s), 7.09 (2H, d, J = 8.1 Hz ), 7.16 (2H, d, J = 7.9 Hz), 7.74 (1H, s).

2) Methyl-3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1- (2-amino-2-oxoethyl) dihydrochloride -1H-pyrazole-4-carboxylate (141 mg, 98% yield) was obtained as a white solid from methyl 1- (2-amino-2-oxoethyl) -3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1H-pyrazole-4-carboxylate (150 mg, 0.259 mmol) in a manner similar to the method of example 2-3 )

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.14-2.27 (1H, m), 2.39 (3H, s), 2.86 (3H, br.s), 3.09 (2H, br.s), 3.67 (3H, s), 3.81 (2H, d, J = 4.7 Hz), 4.58 (2H, s), 4.89 (2H, s), 7.26 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.58 (1H, s), 8.33 (3H, br s).

Example 385

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] terephthalamide dihydrochloride

1) tert-Butyl {[5 - {[4- (aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (248 mg, yield 98%) was obtained as a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino } carbonyl) benzoic acid (260 mg, 0.48 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.29 (1H, m), 2, 34 (3H, s), 2.50 (3H, s), 2.79 (2H, br.s), 4.13 (2H, br.s), 4.37 (1H, br.s), 5 84 (1H, br.s), 6.33 (1H, br.s), 7.05 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.37 (1H, br.s), 7.47 (2H, d, J = 8.1 Hz), 7.73 (2H, d, J = 8.1 Hz).

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] terephthalamide dihydrochloride (233 mg, 99% yield) was obtained as a white powder from tert- butyl {[5 - {[4- (aminocarbonyl) benzoyl] amino} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (248 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.3 Hz), 2.19-2.31 (1H, m), 2.31 (3H, s), 2.61 (3H, s), 3.05 (2H, s), 3.85 (2H, s), 7.25 (4H, s), 7.51 (1H, s) , 7.68 (2H, d, J = 8.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 8.09 (1H, br.s), 8.37 (3H, broad s), 10.16 (1H, broad s).

Example 386

Ethyl-1 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-4-carboxylate dihydrochloride

1) Ethyl-1 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidin- 4-carboxylate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and ethyl isonipecotate (314 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 567

2) Ethyl-1 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-4-carboxylate dihydrochloride (324 mg, a yield of 69%) was obtained as a white powder from the oil obtained in the above step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.3 Hz), 1.20 (3H, t, J = 6.9 Hz), 1.54-1, 59 (2H, m), 2.10-2.28 (1H, m), 2.34 (3H, s), 2.36-2.46 (1H, m), 2.62-2.76 ( 4H, m), 3.09 (2H, br.s), 3.74-3.82 (4H, m), 4.07 (2H, q, J = 6.9 Hz), 7.19 (2H d, J = 7.5 Hz), 7.26 (2H, d, J = 7.5 Hz), 8.17 (1H, br.s), 8.45 (3H, br.s).

Example 387

Ethyl 2-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-oxazole-4 carboxylate

1) Ethyl-2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino ] -1,3-oxazole-4-carboxylate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg , 1.0 mmol) and ethyl 2-amino-1,3-oxazole-4-carboxylate (312 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC (M + 1): 566

2) Ethyl-2-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-oxazole -4-carboxylate (224 mg, 48% yield) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.29 (3H, t, J = 7.2 Hz), 2.13-2, 26 (1H, m), 2.29 (3H, s), 2.63 (3H, s), 3.06 (2H, br.s), 3.82 (2H, s), 4.27 (2H , q, J = 7.2 Hz), 7.15-7.29 (4H, m), 8.44 (3H, br.s), 8.45 (1H, s), 9.32 (1H, broad s), 11.14 (1H, broad s).

Example 388

Ethyl-2 dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-thiazole-4 carboxylate

1) Ethyl-2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino ] -1,3-thiazole-4-carboxylate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg , 1.0 mmol) and ethyl 2-amino-1,3-thiazole-4-carboxylate (344 mg, 2.0 mmol) in a manner similar to the method of Example 95-1).

EIMC (M + 1): 582

2) Ethyl-2 dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) amino] -1,3-thiazole -4-carboxylate (282 mg, 51% yield) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.27 (3H, t, J = 7.2 Hz), 2.11-2, 30 (1H, m), 2.35 (3H, s), 2.62 (3H, s), 3.06 (2H, br.s), 3.81 (2H, s), 4.24 (2H q, J = 7.2 Hz), 7.21 (2H, d, J = 7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 7.91 (1H, s ), 8.42 (3H, s), 8.76 (1H, br s), 11.21 (1H, br s).

Example 389

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-phenylpiperidin-1-carboxamide dihydrochloride

1) tert-Butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5 - {[(4-phenylpiperidin-1-yl) carbonyl] amino} pyridin-3-yl) methyl] carbamate was obtained as an oil of 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and 4-phenylpiperidine (322 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC (M + 1): 571

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -4-phenylpiperidin-1-carboxamide dihydrochloride (240 mg, 44% yield) was obtained in the form of a white powder from the oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.54-1.58 (2H, m), 2.14-2.26 (1H , m), 2.26 (3H, s), 2.50 (3H, s), 2.58-2.75 (5H, m), 3.12 (2H, br.s), 3.82 ( 2H, br.s), 3.95-3.99 (2H, m), 7.11-7.37 (9H, m), 8.19 (1H, br.s), 8.44 (1H, ears.s).

Example 390

Methyl-1 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyrrolidine-2-carboxylate dihydrochloride

1) Methyl-1 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyrrolidin- 2-carboxylate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and complex DL-Proline methyl ester (286 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 539

2) Methyl-1 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyrrolidine-2-carboxylate dihydrochloride (400 mg, 78% yield) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.80 (3H, br.s), 2.04-2.09 (1H, m ), 2.11-2.23 (1H, m), 2.39 (3H, s), 2.63 (2H, s), 3.07 (4H, br s), 3.59 (3H, s), 3.86 (2H, br.s), 4.11-4.17 (1H, m), 4.11-4.17 (1H, m), 7.21 (2H, d, J = 7.8 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.93 (1H, br.s), 8.39 (3H, br.s).

Example 391

Ethyl-1 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-3-carboxylate dihydrochloride

1) Ethyl-1 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidin- 3-carboxylate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and ethyl -3-piperidinecarboxylate (314 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 567

2) Ethyl-1 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) piperidine-3-carboxylate dihydrochloride (256 mg, a yield of 48%) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.19 (3H, t, J = 6.9 Hz), 1.39-1, 46 (2H, m), 1.78 (2H, br.s), 2.16-2.23 (1H, m), 2.37 (3H, s), 2.57 (2H, s), 3 03 (2H, s), 3.66-3.72 (1H, m), 3.82 (2H, br.s), 4.05 (2H, q, J = 6.9 Hz), 7, 17 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.11 (1H, br.s), 8.29 (3H, br.s )

Example 392

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] tetrahydroimidazo [1,5-a] pyridin-1,3 (2H, 5H) - dihydrochloride - dion

1) tert-Butyl {[5- (1,3-dioxohexahydroimidazo [1,5-a] pyridin-2 (3H) -yl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3 -yl] methyl} carbamate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol ) and ethyl 2-piperidinecarboxylate (314 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 553

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] tetrahydroimidazo [1,5-a] pyridin-1,3 (2H, 5H) dihydrochloride ) -dione (282 mg, yield 57%) was obtained in the form of a white powder from the oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.20-1.35 (1H, m), 1.36-1.50 (1H , m), 1.59-1.65 (1H, m), 1.79 (1H, br.s), 1.99 (1H, br.s), 2.22-2.31 (1H, m ), 2.32 (6H, s), 2.35 (3H, s), 2.70-2.74 (1H, m), 2.82 (2H, d, J = 6.9 Hz), 3 72-3.78 (4H, m), 7.05-7.09 (2H, m), 7.10-7.27 (2H, m), 8.13 (3H, br.s).

Example 393

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -10,10a-dihydroimidazo [1,5-b] isoquinolin-1,3 ( 2H, 5H) dione

1) tert-Butyl {[5- (1,3-dioxo-1,5,10,10a-tetrahydroimidazo [1,5-b] isoquinolin-2 (3H) -yl) -2-isobutyl-6-methyl- 4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (410 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC (M + 1): 569

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -10,10a-dihydroimidazo [1,5-b] isoquinolin-1 dihydrochloride, 3 (2H, 5H) -dione (368 mg, 68% yield) was obtained as a white powder from the oil obtained in the above Step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.18-2.34 (1H, m), 2.30 (3H, s), 2.34 (3H, s), 2.34 (2H, d, J = 7.2 Hz), 2.95 (1H, dd, J = 9.9, 17.1 Hz), 3.16 (1H dd, J = 4.8, 15.6 Hz), 3.78 (2H, m), 4.06 (1H, dd, J = 9.9, 4.8 Hz), 4.08 (1H, d, J = 17.1 Hz), 4.79 (1H, d, J = 15.6 Hz), 7.07-7.31 (8H, m), 8.18 (3H, br.s).

Example 394

Methyl 2 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoate dihydrochloride

Methyl 2 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoate dihydrochloride (230 mg, 89% yield) was obtained in as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and methyl-2 - (chlorocarbonyl) benzoate (149 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.27 (1H, m), 2.40 (3H, s), 2.66 (3H, s), 2.95 (2H, s), 3.77 (3H, s), 3.79 (2H, s), 6.58 (1H, d, J = 7.5 Hz), 7.23 (2H, d, J = 7.8 Hz), 7.34 (2H, d, J = 7.8 Hz), 7.49 (1H, t, J = 7, 5 Hz), 7.53 (1H, t, J = 7.5 Hz), 7.70 (1H, d, J = 7.5 Hz), 8.25 (3H, br.s), 10.03 (1H, broad s).

Example 395

2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid dihydrochloride

1) 2 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (247 mg, 98% yield) was obtained as a white powder from methyl-2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] amino} carbonyl) benzoate (260 mg, 0.48 mmol) in a manner similar to that of Example 36-1).

¹ H-NMR (CDCl ₃ ) δ: 0.92 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.04-2.18 (1H, m), 2, 41 (3H, s), 2.55 (3H, s), 2.82 (2H, br.s), 4.09 (3H, br.s), 6.17 (1H, br.s), 6 , 91 (1H, br.s), 7.09 (2H, br.s), 7.25-7.27 (3H, m), 7.37 (1H, br.s), 7.88 (1H , ears.s).

2) 2 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid dihydrochloride (220 mg, 94% yield) was obtained in the form of a white powder from 2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (247 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.18-2.26 (1H, m), 2.43 (3H, s), 2.74 (3H, s), 3.05 (2H, br.s), 3.86 (2H, br.s), 6.38 (1H, d, J = 6.9 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.41 (1H, t, J = 6.9 Hz), 7.49 (1H , t, J = 6.9 Hz), 7.76 (1H, d, J = 6.9 Hz), 8.35 (3H, br.s), 10.02 (1H, br.s).

Example 396

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1H-isoindole-1,3 (2H) -dione dihydrochloride

1) tert-Butyl {[5- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3- yl] methyl} carbamate (221 mg, 94% yield) was obtained as a white powder from 2 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4 -methylphenyl) pyridin-3-yl] amino} carbonyl) benzoic acid (260 mg, 0.48 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 1.03 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.02 (3H, s), 2.21-2, 31 (1H, m), 2.40 (3H, s), 2.83 (2H, d, J = 7.5 Hz), 4.20 (2H, d, J = 5.4 Hz), 4, 30 (1H, br.s), 6.98 (2H, d, J = 8.1 Hz), 7.03 (2H, d, J = 8.1 Hz), 7.67-7.72 (2H m) 7.75-7.79 (2H, m).

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1H-isoindole-1,3 (2H) -dione dihydrochloride (213 mg, yield 99%) was obtained as a white powder from tert-butyl {[5- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -2-isobutyl-6-methyl-4- ( 4-methylphenyl) pyridin-3-yl] methyl} carbamate (221 mg, 0.45 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (6H, d, J = 6.3 Hz), 2.19 (3H, s), 2.19-2.32 (1H, m), 2.35 (3H, s), 2.83 (2H, d, J = 6.3 Hz), 3.69 (2H, br.s), 7.05 (2H, d, J = 7.8 Hz ), 7.13 (2H, d, J = 7.8 Hz), 7.85 (4H, br.s), 8.03 (3H, br.s).

Example 397

Methyl-3 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] benzoate dihydrochloride

1) Methyl-3 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) hydroxy ] benzoate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and methyl- 3-hydroxybenzoate (304 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 562

2) Methyl-3 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] benzoate dihydrochloride (172 mg, yield 32%) was obtained as a white powder from the oil obtained in the above step 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.14-2.28 (1H, m), 2.44 (3H, s), 2.67 (3H, s), 3.02 (2H, s), 3.85 (2H, s), 3.89 (3H, s), 7.26 (2H, d, J = 8.1 Hz ), 7.36 (1H, s), 7.39 (2H, d, J = 8.1 Hz), 7.53 (1H, t, J = 7.8 Hz), 7.80 (1H, d , J = 7.8 Hz), 8.37 (3H, br.s), 9.75 (1H, br.s).

Example 398

Methyl 4-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] benzoate

1) Methyl-4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) hydroxy ] benzoate was obtained as an oil from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and methyl- 4-hydroxybenzoate (304 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

EIMC (M + 1): 562

2) Methyl-4 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) oxy] benzoate dihydrochloride (182 mg, yield 34%) was obtained as a white powder from the oil obtained in the above step 1), in a manner similar to the method of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.14-2.29 (1H, m), 2.43 (3H, s), 2.62 (3H, s), 2.93 (2H, broad s), 3.84 (2H, s), 3.85 (3H, s), 7.00 (2H, d, J = 8, 7 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.39 (2H, d, J = 8.1 Hz), 7.96 (2H, t, J = 8.7 Hz ), 8.29 (3H, br s), 9.71 (1H, br s).

Example 399

Methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate dihydrochloride

1) Methyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate was obtained as an oil from 5 - {[( tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and methanol (62 mg, 2.0 mmol) in a manner similar to the example method 95-1).

EIMC (M + 1): 443

2) Methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] carbamate dihydrochloride (330 mg, 80% yield) was obtained as a white powder from an oil obtained in the above stage 1), in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.11-2.18 (1H, m), 2.39 (3H, s), 2.63 (3H, s), 3.11 (2H, s), 3.48 (3H, s), 3.82 (2H, s), 7.18 (2H, d, J = 7.8 Hz ), 7.33 (2H, d, J = 7.8 Hz), 8.44 (3H, br.s), 9.03 (1H, br.s).

Example 400

Ethyl {3- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,4-dioxoimidazolidin-1-yl} acetate dihydrochloride

1) Diethyl-2,2 '- [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) imino] diacetate was obtained as white crystals (260 mg, 43% yield) from 5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid (412 mg, 1.0 mmol) and diethyl 2,2'-iminodiacetate (380 mg, 2.0 mmol) in a manner similar to that of Example 95-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.24 (6H, t, J = 6.9 Hz), 1.38 (9H, s) , 2.09-2.24 (1H, m), 2.40 (3H, s), 2.49 (3H, s), 2.75 (2H, d, J = 6.9 Hz), 3, 87 (4H, s), 4.12 (4H, q, J = 6.9 Hz), 4.23 (1H, br.s), 6.33 (1H, br.s), 7.04 (2H d, J = 7.8 Hz), 7.25 (2H, d, J = 7.8 Hz).

2) Ethyl {3- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -2,4-dioxoimidazolidin-1-yl} acetate dihydrochloride (240 mg , yield 98%) was obtained as a white powder from diethyl-2,2 '- [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl ) pyridin-3-yl] amino} carbonyl) imino] diacetate (260 mg, 0.43 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 1.19 (6H, t, J = 7.2 Hz), 2.22-2, 35 (1H, m), 2.35 (3H, s), 2.50 (3H, s), 2.86 (2H, d, J = 7.2 Hz), 3.74-3.80 (3H , m), 4.02-4.17 (5H, m), 7.04-7.11 (2H, m), 7.21-7.27 (2H, m), 8.25 (3H, br .from).

Example 401

Ethyl-6 - ({[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine-2-carboxylate dihydrochloride

Ethyl-6 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridine-2-carboxylate dihydrochloride (230 mg, 89 yield %) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol) and ethyl 6- (chlorocarbonyl) pyridine-2-carboxylate (149 mg, 0.75 mmol) in a manner similar to that of Example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.35 (3H, t, J = 7.2 Hz), 2.11-2, 28 (1H, m), 2.27 (3H, s), 2.60 (3H, s), 3.05 (2H, br.s), 3.84 (2H, br.s), 4.37 (2H, q, J = 7.2 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.26 (2H, d, J = 7.8 Hz), 8.21-8 31 (3H, m), 8.38 (3H, br s), 9.90 (1H, br s).

Example 402

6 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridin-2-carboxylic acid dihydrochloride

1) 6 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridin-2- carboxylic acid (247 mg, 98% yield) was obtained as a white powder from ethyl 6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] amino} carbonyl) pyridin-2-carboxylate (260 mg, 0.48 mmol) in a manner similar to that of Example 36-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.14-2.26 (1H, m), 2, 28 (3H, s), 2.52 (3H, s), 2.84 (2H, br.s), 4.15 (2H, s), 4.42 (1H, br.s), 7.01 (2H, d, J = 7.8 Hz), 7.10 (2H, d, J = 7.8 Hz), 7.99 (1H, br.s), 8.21-8.31 (2H, m), 9.36 (1H, br s).

2) 6 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridin-2-carboxylic acid dihydrochloride (221 mg, yield 94%) was obtained as a white powder from 6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino } carbonyl) pyridine-2-carboxylic acid (247 mg, 0.47 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.11-2.29 (1H, m), 2.25 (3H, s), 2.60 (3H, s), 3.04 (2H, br.s), 3.85 (2H, br.s), 7.19 (1H, d, J = 7.8 Hz), 7.26 (2H, d, J = 7.8 Hz), 8.17-8.26 (3H, m), 8.37 (3H, br.s), 10.67 (1H, br.s).

Example 403

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyridin-2,6-dicarboxamide dihydrochloride

1) tert-Butyl {[5 - ({[6- (aminocarbonyl) pyridin-2-yl] carbonyl} amino) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl } carbamate (221 mg, 94% yield) was obtained as a white powder from 6 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] amino} carbonyl) pyridin-2-carboxylic acid (260 mg, 0.48 mmol) in a manner similar to that of Example 3-1).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 1.39 (9H, s), 2.18-2.29 (1H, m), 2, 35 (3H, s), 2.57 (3H, s), 2.79 (2H, d, J = 7.5 Hz), 4.15 (2H, br.s), 4.29 (1H, br s), 5.53 (1H, br.s), 6.75 (1H, br.s), 7.07 (2H, d, J = 7.8 Hz), 7.19 (2H, d, J = 7.8 Hz), 8.02 (1H, t, J = 7.8 Hz), 8.29 (1H, dd, J = 1.2, 7.8 Hz), 8.31 (1H, dd, J = 1.2, 7.8 Hz), 8.74 (1H, s).

2) N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] pyridin-2,6-dicarboxamide dihydrochloride (206 mg, 94% yield) was obtained as a white powder from tert-butyl {[5 - ({[6- (aminocarbonyl) pyridin-2-yl] carbonyl} amino) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl ] methyl} carbamate (221 mg, 0.45 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.3 Hz), 2.12-2.28 (1H, m), 2.25 (3H, s), 2.63 (3H, s), 3.07 (2H, br.s), 3.86 (2H, br.s), 7.19 (2H, d, J = 7.8 Hz), 7.28 (2H, d, J = 7.8 Hz), 7.76 (1H, s), 8.08-8.20 (3H, m), 8.43 (3H, br.s), 8.80 ( 1H, s), 10.77 (1H, br s).

Example 404

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1-benzyl-4-methoxy-1H-pyrazole-3-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1-benzyl-4-methoxy-1H-pyrazole-3-carboxamide dihydrochloride (230 mg , yield 81%) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0, 5 mmol) and 1-benzyl-4-methoxy-1H-pyrazole-3-carbonyl chloride (188 mg, 0.75 mmol) in a manner similar to the method of example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.18-2.26 (1H, m), 2.35 (3H, s), 2.51 (3H, s), 2.91 (2H, br s), 3.67 (3H, s), 3.81 (2H, br s), 5.15 (2H, s), 7 16-7.39 (9H, m), 8.11 (1H, s), 8.21 (3H, br s).

Example 405

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,5-dimethyl-1H-pyrazole-3-carboxamide dihydrochloride

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -1,5-dimethyl-1H-pyrazole-3-carboxamide dihydrochloride (235 mg, yield 97%) was obtained as a white powder from tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (192 mg, 0.5 mmol ) and 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride (118 mg, 0.75 mmol) in a manner similar to that of Example 223.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.18-2.25 (1H, m), 2.32 (3H, s), 2.33 (3H, s), 2.53 (2H, br s), 3.73 (3H, s), 3.82 (2H, br s), 6.38 (1H, s), 7 , 20 (2H, d, J = 7.8 Hz), 7.24 (2H, d, J = 7.8 Hz), 8.31 (3H, s), 9.58 (1H, br.s) .

Example 406

[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid dihydrochloride

[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid dihydrochloride (0.56 g, 94% yield) was obtained as a white powder from [5- { [(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.63 g, 1.43 mmol) in a manner similar to the method of example 2- 3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.41 (3H, s), 2.73 (3H, br s), 3.19 (2H, br s ), 3.35-3.45 (2H, m), 3.75-3.90 (2H, m), 7.16 (2H, d, J = 7.4 Hz), 7.38 (2H, d, J = 7.4 Hz), 8.16 (3H, br.s).

Example 407

(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetate dihydrochloride

1) (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6 -neopentylpyridin-3-yl] acetate (0.091 g, 28% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6 -neopentylpyridin-3-yl] acetic acid (0.63 g, 1.43 mmol) in a manner similar to that of Example 176-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.14 (3H, s), 2.40 (3H, s), 2.48 ( 3H, s), 2.83 (2H, s), 3.39 (2H, s), 4.09 (2H, d, J = 4.9 Hz), 4.10-4.25 (1H, m ), 4.76 (2H, s), 6.94 (2H, d, J = 7.9 Hz), 7.21 (2H, d, J = 7.9 Hz).

2) (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl [5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] dihydrochloride] acetate (0.085 g, 99% yield) was obtained as a pale yellow powder from (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl [5 - {[(tert-butoxycarbonyl) amino] methyl } -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetate (0.090 g, 0.16 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.14 (3H, s), 2.38 (3H, s), 2.71 (3H, br s), 3.13 (2H, broad s), 3.52 (2H, broad s), 3.73 (2H, broad s), 4.92 (2H, s), 7.10 (2H, d, J = 7.5 Hz), 7.31 (2H, d, J = 7.5 Hz), 8.15 (3H, br.s).

Example 408

Methyl 5- (aminomethyl) -6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinate

1) A mixture of methyl 4-methoxyacetate (5.85 g, 40 mmol), ammonium acetate (15.4 g, 200 mmol), acetic acid (2.3 ml, 40 mmol) and toluene (100 ml) was heated by boiling under reflux using a Dean-Stark trap for 10 hours. The reaction mixture was allowed to cool to room temperature, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give methyl 3-amino-4-methoxybut-2-enoate as a crude product (5.8 g). Methyl 5-cyano-6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (7.8 g, 55% yield) was obtained as a pale yellow powder from the crude product (5.8 g), 5-methyl-3-oxohexannitrile (5.7 g, purity 87.5%, 40 mmol) and p-tolualdehyde (4.8 g, 40 mmol) in a manner similar to the method of example 1 -2).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, dd, J = 6.6, 12.8 Hz), 1.80-2.00 (1H, m), 2.20-2.40 (2H, m), 2.31 (3H, s), 3.48 (3H, s), 3.57 (3H, s), 4.56 (1H, s), 4.64 (1H, d, J = 16.4 Hz), 4.73 (1H, d, J = 16.4 Hz), 7.05-7.15 (5H, m).

2) Methyl-5-cyano-6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinate (7.5 g, 99% yield) was obtained as a white powder from methyl 5-cyano-6- isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (7.7 g, 22 mmol) in a manner similar to the method of example 23-3).

¹ H-NMR (CDCl ₃ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.20-2.35 (1H, m), 2.41 (3H, s), 2, 97 (2H, d, J = 7.2 Hz), 3.37 (3H, s), 3.59 (3H, s), 4.71 (2H, s), 7.15-7.35 (4H , m).

3) Methyl 5- (aminomethyl) -6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinate (7.1 g, yield 93%) was obtained as a pale yellow oil from methyl 5- cyano-6-isobutyl-2- (methoxymethyl) -4- (4-methylphenyl) nicotinate (7.4 g, 21 mmol) in a manner similar to that of Example 1-4).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.22 (2H, br.s), 2.15-2.30 (1H, m), 2.39 (3H, s), 2.82 (2H, d, J = 7.4 Hz), 3.36 (3H, s), 3.49 (3H, s), 3.67 (2H, s ), 4.65 (2H, s), 7.11 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).

Example 409

{6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyridin-2-ylthio) methyl] pyridin-3-yl} methylamine trihydrochloride

1) tert-Butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyridin-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (480 mg, 78 yield %) was obtained in powder form from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (600 mg, 1.2 mmol) and 2-mercaptopropyridine (145 mg, 1.3 mmol) in a manner similar to that of Example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.35 (3H, s), 2.62 (3H, s), 2.83 ( 2H, s), 4.08 (2H, d, J = 4.9 Hz), 4.14 (2H, s), 4.19 (1H, s), 6.91-6.95 (1H, m ), 7.03-7.06 (3H, m), 7.17 (2H, d, J = 7.91 Hz), 7.39-7.45 (1H, m), 8.31 (1H, d, J = 4.1 Hz).

2) {6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyridin-2-ylthio) methyl] pyridin-3-yl} methylamine trihydrochloride (167 mg, 82% yield) was obtained as powder from tert-butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyridin-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (200 mg, 0.395 mmol ) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.36 (3H, s), 2.90 (3H, s), 3.28 (2H, s), 3, 83 (2H, d, J = 4.7 Hz), 4.19 (2H, s), 7.11-7.16 (1H, m), 7.23-7.33 (5H, m), 7 62-7.67 (1H, m), 8.31 (3H, br s), 8.33-8.34 (1H, m).

Example 410

{6-Methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(1H-1,2,4-triazol-3-ylthio) methyl] pyridin-3-yl} methylamine dihydrochloride

1) tert-Butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(4H-1,2,4-triazol-3-ylthio) methyl] pyridin-3-yl} methyl ) carbamate (455 mg, 2% yield) was obtained in powder form from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (600 mg, 1.2 mmol) and 3-mercapto-1,2,4-triazole (131 mg, 1.3 mmol) in a manner similar to the method of example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.37 (9H, s), 2.37 (3H, s), 2.64 (3H, s), 2.83 ( 2H, s), 4.08 (2H, d, J = 4.9 Hz), 4.12 (2H, s), 4.22 (1H, s), 7.04 (2H, d, J = 7 , 7 Hz), 7.20 (2H, d, J = 7.7 Hz), 8.02 (1H, s).

2) {6-Methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(1H-1,2,4-triazol-3-ylthio) methyl] pyridin-3-yl} methylamine dihydrochloride (160 mg , 85% yield) was obtained in powder form from tert-butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(4H-1,2,4-triazol-3-ylthio) methyl ] pyridin-3-yl} methyl) carbamate (200 mg, 0.403 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.39 (3H, s), 2.86 (3H, s), 3.21 (2H, s), 3, 81 (2H, d, J = 4.1 Hz), 4.08 (2H, s), 7.24 (2H, d, J = 8.0 Hz), 7.35 (2H, m, J = 8 , 0 Hz), 8.23 (3H, br s), 8.45 (1H, s).

Example 411

[5 - [(1H-Imidazol-2-ylthio) methyl] -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methylamine trihydrochloride

1) tert-Butyl {[5 - [(1H-imidazol-2-ylthio) methyl] -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (373 mg, yield 75%) was obtained in powder form from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (500 mg, 1, 0 mmol) and 2-mercaptoimidazole (110 mg, 1.1 mmol) in a manner similar to the method of example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.37 (9H, s), 2.41 (3H, s), 2.55 (3H, s), 2.82 ( 2H, s), 3.94 (2H, s), 4.06 (2H, d, J = 4.9 Hz), 4.20 (1H, s), 6.94 (1H, br.s), 7.01 (2H, d, J = 7.9 Hz), 7.06 (1H, br.s), 7.23 (2H, d, J = 7.9 Hz).

2) [5 - [(1H-Imidazol-2-ylthio) methyl] -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methylamine trihydrochloride (160 mg, 79% yield) was obtained in as a powder of tert-butyl {[5 - [(1H-imidazol-2-ylthio) methyl] -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate (200 mg, 0.404 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01 (9H, s), 2.40 (3H, s), 2.67 (3H, s), 3.07 (2H, br s), 3.74 (2H, br.s), 4.17 (2H, s), 7.18 (2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 7.9 Hz ), 7.70 (2H, s), 8.26 (3H, br s).

Example 412

{6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyrimidin-2-ylthio) methyl] pyridin-3-yl} methylamine trihydrochloride

1) tert-Butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyrimidin-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (380 mg, yield 77 %) was obtained in powder form from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (500 mg, 1.0 mmol) and 2-mercaptopopyrimidine (123 mg, 1.1 mmol) in a manner similar to that of Example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.35 (3H, s), 2.65 (3H, s), 2.83 ( 2H, s), 4.08 (2H, d, J = 4.9 Hz), 4.14 (2H, s), 4.19 (1H, br.s), 6.92 (1H, t, J = 4.9 Hz), 7.06 (2H, d, J = 7.8 Hz), 7.18 (2H, d, J = 7.8 Hz), 8.43 (2H, d, J = 4 9 Hz).

2) {6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyrimidin-2-ylthio) methyl] pyridin-3-yl} methylamine trihydrochloride (180 mg, 88% yield) was obtained as powder from tert-butyl ({6-methyl-4- (4-methylphenyl) -2-neopentyl-5 - [(pyrimidin-2-ylthio) methyl] pyridin-3-yl} methyl) carbamate (200 mg, 0.395 mmol ) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.35 (3H, s), 2.85 (3H, s), 3.17 (2H, br.s) 3.80 (2H, s), 4.18 (2H, s), 7.21-7.13 (5H, m), 8.22 (3H, br.s), 8.57 (2H, d, J = 4.9 Hz).

Example 413

[5 - {[(5-Methoxy-1H-benzimidazol-2-yl) thio] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methylamine trihydrochloride

1) tert-Butyl {[5 - {[(5-methoxy-1H-benzimidazol-2-yl) thio] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl } carbamate (530 mg, yield 92%) was obtained in powder form from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (500 mg, 1.0 mmol) and 5-methoxy-2-benzimidazolthiol (198 mg, 1.1 mmol) in a manner similar to the method of example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.33 (3H, s), 2.64 (3H, s), 2.83 ( 2H, s), 3.82 (3H, s), 4.07 (2H, d, J = 5.1 Hz), 4.22 (2H, s), 4.25 (1H, s), 6, 77-6.84 (2H, m), 7.01 (2H, d, J = 7.9 Hz), 7.14-7.16 (3H, m), 7.49 (1H, d, J = 8.9 Hz).

2) [5 - {[(5-Methoxy-1H-benzimidazol-2-yl) thio] methyl} -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methylamine trihydrochloride (194 mg , yield 91%) was obtained in powder form from tert-butyl {[5 - {[(5-methoxy-1H-benzimidazol-2-yl) thio] methyl} -6-methyl-4- (4-methylphenyl) -2 -neopentylpyridin-3-yl] methyl} carbamate (200 mg, 0.365 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (9H, s), 2.30 (3H, s), 2.83 (3H, s), 3.12 (2H, br s), 3.77 (2H, s), 3.81 (3H, s), 4.37 (2H, s), 6.94-7.02 (2H, m), 7.20-7.27 (4H, m), 7.46 (1H, d, J = 8.9 Hz), 8.23 (3H, br.s).

Example 414

Methyl 3 - {[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylate dihydrochloride

1) Methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazol-5 -carboxylate (800 mg, 52% yield) was obtained in powder form from [5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl methanesulfonate (1.4 g, 2.85 mmol) and methyl 3-hydroxy-1H-pyrazole-5-carboxylate (426 mg, 3.0 mmol) in a manner similar to that of Example 33-1).

¹ H-NMR (CDCl ₃ ) δ: 1.02 (9H, s), 1.37 (9H, s), 2.36 (3H, s), 2.62 (3H, s), 2.86 ( 2H, s), 3.89 (3H, s), 4.13 (2H, d, J = 4.5 Hz), 4.20 (1H, br.s), 4.84 (2H, s), 6.13 (1H, s), 7.04 (2H, d, J = 7.8 Hz), 7.16 (2H, d, J = 7.8 Hz), 9.89 (1H, br.s )

2) Methyl-3 - {[5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylate dihydrochloride (142 mg, yield 75%) was obtained as a powder from methyl-3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylate (200 mg, 0.373 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.37 (3H, s), 2.84 (3H, s), 3.23 (2H, br s), 3.81 (3H, s), 3.87 (2H, br s), 4.83 (2H, s), 6.17 (1H, s), 7.25 (2H, d, J = 7, 9 Hz), 7.33 (1H, d, J = 7.9 Hz), 8.29 (3H, br.s).

Example 415

3 - {[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylic acid dihydrochloride

1) 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylic acid (914 mg, 81% yield) was obtained as a white solid from methyl 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6- neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylate (1.16 g, 2.16 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (9H, s), 1.34 (9H, s), 2.32 (3H, s), 2.53 (3H, s), 2, 69 (2H, s), 3.87 (2H, d, J = 3.2 Hz), 4.73 (2H, s), 6.06 (1H, s), 6.83 (1H, t, J = 4.1 Hz), 7.13-7.21 (4H, m), 12.91 (1H, s).

2) 3 - {[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H-pyrazole-5-carboxylic acid dihydrochloride (180 mg, yield 95 %) was obtained as a white powder from 3 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methoxy} -1H -pyrazole-5-carboxylic acid (200 mg, 0.383 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (9H, s), 2.37 (3H, s), 2.51 (3H, s), 2.78 (2H, s), 3, 85 (2H, s), 4.80 (2H, s), 6.09 (1H, s), 7.23 (2H, d, J = 7.9 Hz), 7.32 (2H, d, J = 7.9 Hz), 8.16 (3H, br s).

Example 416

4- (methoxycarbonyl) benzyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate dihydrochloride

1) 4- (Methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (7.36 g, 70% yield) was obtained as a white solid from 5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (7.8 g, 18.3 mmol) in a manner similar to the example method 169-1).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.36 (9H, s), 2.35 (3H, s), 2.53 (3H, s), 2.87 ( 2H, s), 3.93 (3H, s), 4.17 (2H, s), 4.98 (2H, s), 7.02 (2H, d, J = 7.9 Hz), 7, 09 (2H, d, J = 8.2 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.93 (2H, d, J = 8.2 Hz).

2) 4- (Methoxycarbonyl) benzyl-5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate dihydrochloride (181 mg, 95% yield) was obtained as a white powder from 4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentyl nicotinate (200 mg, 0.348 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (9H, s), 2.33 (3H, s), 2.51 (3H, s), 2.90 (2H, s), 3, 83 (2H, s), 3.86 (3H, s), 5.07 (2H, s), 7.12-7.21 (6H, m), 7.87 (2H, d, J = 8, 3 Hz), 8.13 (3H, br s).

Example 417

4 - [({[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride

1) 4 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] carbonyl} hydroxy) methyl] benzoic acid (1.68 g, 86% yield) was obtained as a white solid from 4- (methoxycarbonyl) benzyl-5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) - 6-neopentyl nicotinate (2.0 g, 3.48 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s), 1.37 (9H, s), 2.35 (3H, s), 2.55 (3H, s), 2.89 ( 2H, s), 4.16-4.20 (3H, m), 5.01 (2H, s), 7.02-7.13 (6H, m), 7.99 (2H, d, J = 8.3 Hz).

2) 4 - [({[5- (Aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] carbonyl} oxy) methyl] benzoic acid dihydrochloride (150 mg, 79% yield ) was obtained as a white powder from 4 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] carbonyl} oxy ) methyl] benzoic acid (200 mg, 0.357 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (9H, s), 2.34 (3H, s), 2.51 (3H, s), 2.90 (2H, s), 3, 84 (2H, d, J = 5.7 Hz), 5.06 (2H, s), 7.10-7.18 (6H, m), 7.85 (2H, d, J = 8.3 Hz ), 8.11 (3H, br s).

Example 418

4- (trifluoromethyl) benzyl dihydrochloride [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate

1) 4- (Trifluoromethyl) benzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (350 mg, yield 85%) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (300 mg 0.703 mmol) and 1- (bromomethyl) -4- (trifluoromethyl) benzene (250 mg, 1.05 mmol) in a manner similar to the method of example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.8 Hz), 1.37 (9H, s), 2.11-2.29 (1H, m), 2, 37 (3H, s), 2.48 (3H, s), 2.75 (2H, d, J = 6.6 Hz), 3.42 (2H, s), 4.03 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 5.09 (2H, s), 6.91 (2H, d, J = 7.7 Hz), 7.14 (2H, d , J = 7.7 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.60 (2H, d, J = 8.1 Hz).

2) 4- (Trifluoromethyl) benzyl dihydrochloride [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (283 mg, 66% yield) was obtained as white powder of 4- (trifluoromethyl) benzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (330 mg, 0.564 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.09-2.25 (1H, m), 2.36 (3H, s), 2.77 (3H, s), 3.12 (2H, s), 3.77 (2H, d, J = 5.1 Hz), 5.14 (2H, s), 7.09 (2H, d) , J = 8.1 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.35 (3H, br s).

Example 419

4-fluorobenzyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate dihydrochloride

1) 4-Fluorobenzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (325 mg, 86% yield) obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (300 mg, 0.703 mmol ) and 1- (bromomethyl) -4-fluorobenzene (198 mg, 1.05 mmol) in a manner similar to that of Example 169-1).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.11-2.26 (1H, m), 2, 38 (3H, s), 2.46 (3H, s), 2.74 (2H, d, J = 7.4 Hz), 3.38 (2H, s), 4.02 (2H, d, J = 4.9 Hz), 4.20 (1H, br.s), 5.00 (2H, s), 6.90 (2H, d, J = 7.9 Hz), 6.88-7.07 (2H, m), 7.14 (2H, d, J = 7.9 Hz), 7.15-7.25 (2H, m).

2) 4-Fluorobenzyl [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate dihydrochloride (234 mg, 82% yield) was obtained as a white powder from 4 -fluorobenzyl [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetate (300 mg, 0.561 mmol) in a manner similar to the example method 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.12-2.26 (1H, m), 2.38 (3H, s), 2.84 (3H, s), 3.26 (2H, d, J = 6.8 Hz), 3.79 (2H, d, J = 4.5 Hz), 5.03 (2H, s), 7.12 (2H, d, J = 7.9 Hz), 7.17-7.39 (6H, m), 8.57 (3H, br.s).

Example 420

{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-oxo-2-pyrrolidin-1-yl-ethyl) pyridin-3-yl] methyl} amine dihydrochloride

1) tert-Butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-oxo-2-pyrrolidin-1-yl-ethyl) pyridin-3-yl] methyl} carbamate (120 mg , 36% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid ( 300 mg, 0.703 mmol) and pyrrolidine (440 mg, 2.11 mmol) in a manner similar to the method of example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.12-2.25 (1H, m), 2, 39 (3H, s), 2.55 (3H, s), 2.74 (2H, d, J = 7.4 Hz), 2.86-2.97 (4H, m), 3.28 (2H , s), 3.36 (2H, t, J = 6.5 Hz), 4.03 (2H, d, J = 4.7 Hz), 4.20 (1H, br.s), 7.01 (2H, d, J = 7.9 Hz), 7.21 (2H, d, J = 7.9 Hz).

2) {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-oxo-2-pyrrolidin-1-yl-ethyl) pyridin-3-yl] methyl} -amine dihydrochloride (62.4 mg , yield 66%) was obtained as a white powder from tert-butyl {[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-oxo-2-pyrrolidin-1-yl-ethyl) pyridin-3 -yl] methyl} carbamate (100 mg, 0.208 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.26 (1H, m), 2.40 (3H, s), 2.80 (3H, s), 2.88 (2H, t, J = 6.1 Hz), 3.12-3.29 (4H, m), 3.42 (2H, s), 3.81 (2H, s), 7.17 (2H, d, J = 7.9 Hz), 7.38 (2H, d, J = 7.9 Hz), 8.43 (3H, br.s).

Example 421

Ethyl 1 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylate dihydrochloride

1) Ethyl-1 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylate (330 mg, 50% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (500 mg, 1.17 mmol) and ethyl piperidine-4-carboxylate (553 mg, 3.52 mmol) in a manner similar to the method of example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.37 (9H, s) 1.54 (1H, dd, J = 13.2, 9.8 Hz), 1.64-1.75 (1H, m), 1.87 (1H, dd, J = 13.2, 2, 6 Hz), 2.12-2.27 (1H, m), 2.38 (3H, s), 2.49 (3H, s), 2.74 (2H, d, J = 7.2 Hz) , 2.81-3.01 (3H, m), 3.30 (2H, s), 3.49-3.60 (1H, m), 4.15 (2H, q, J = 7.2 Hz ), 4.20 (1H, br.s), 6.98 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).

2) Ethyl-1 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylate dihydrochloride (8.2 mg, yield 43%) was obtained as a white powder from ethyl-1 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylate (20 mg, 0.0354 mmol) in a manner similar to that of Example 2-3).

EIMC (M + 1): 466.

Example 422

1 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylic acid dihydrochloride

1) 1 - {[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylic acid ( 240 mg, yield 87%) was obtained as a white powder from ethyl 1 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] acetyl} piperidine-4-carboxylate (290 mg, 0.513 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.4 Hz), 1.37 (9H, s), 1.48-1.62 (1H, m), 1, 73 (1H, d, J = 11.1 Hz), 1.89 (1H, d, J = 10.6 Hz), 2.14-2.29 (1H, m), 2.40 (3H, s ), 2.74 (3H, s), 2.77-3.00 (2H, m), 3.06 (2H, d, J = 6.0 Hz), 3.42 (2H, s), 3 , 53 (1H, d, J = 12.8 Hz), 4.10 (2H, d, J = 5.09 Hz), 4.20 (1H, br.s), 4.26 (1H, d, J = 12.6 Hz), 4.65 (1H, s), 7.01 (2H, d, J = 7.5 Hz), 7.27 (2H, d, J = 7.5 Hz).

2) 1 - {[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidine-4-carboxylic acid dihydrochloride (220 mg, 100% yield) obtained as a white powder from 1 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} piperidin-4 -carboxylic acid (230 mg, 0.428 mmol) in a manner similar to the method of example 2-3).

EIMC (M + 1): 438

Example 423

N-2-adamantyl-2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride

1) tert-Butyl {[5- [2- (2-adamantylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (50 mg , 13% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid ( 300 mg, 0.703 mmol) and 2-adamantanamine (396 mg, 2.11 mmol) in a manner similar to that of Example 311-1).

¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 1.53-1.63 (2H, m), 1, 67-1.84 (9H, m), 2.12-2.26 (1H, m), 2.39 (3H, s), 2.57 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.30 (2H, s), 3.97 (2H, d, J = 8.1 Hz), 4.06 (2H, d, J = 5.09 Hz), 4 , 20 (1H, br.s), 4.22 (1H, s), 5.45 (1H, d, J = 8.3 Hz), 6.96 (2H, d, J = 7.9 Hz) 7.22 (2H, d, J = 7.9 Hz).

2) N-2-adamantyl-2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetamide dihydrochloride (45.1 mg, 100% yield) prepared as a white powder from tert-butyl {[5- [2- (2-adamantylamino) -2-oxoethyl] -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (48 mg, 0.0857 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.4 Hz), 1.47 (2H, d, J = 12.1 Hz), 1.63-1, 94 (12H, m), 2.08-2.26 (1H, m), 2.40 (3H, s), 2.80 (3H, s), 3.22 (2H, d, J = 5, 84 Hz), 3.44 (2H, s), 3.81 (2H, s), 7.19 (2H, d, J = 7.9 Hz), 7.34 (2H, d, J = 7, 9 Hz), 7.87 (1H, d, J = 7.7 Hz), 8.49 (3H, br.s).

Example 424

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- (2-thienylmethyl) acetamide dihydrochloride

1) [5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (500 mg, 1.17 mmol) and thiophene-2-methylamine (133 mg, 1.17 mmol) was dissolved in tetrahydrofuran (5 ml) and diethyl cyanophosphonate (286 mg, 1.75 mmol) was added under ice-cooling. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into brine and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo-2 - [(2-thienylmethyl) amino] ethyl} pyridin-3-yl) methyl] carbamate (493 mg, 81% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.11-2.27 (1H, m), 2, 37 (3H, s), 2.56 (3H, s), 2.76 (2H, d, J = 7.2 Hz), 3.30 (2H, s), 4.03 (2H, d, J = 4.9 Hz), 4.20 (1H, br.s), 4.51 (2H, d, J = 5.7 Hz), 6.85-7.00 (4H, m), 7.16 (2H, d, J = 7.9 Hz); 7.23 (1H, dd, J = 5.1, 1.1 Hz).

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- (2-thienylmethyl) acetamide dihydrochloride (300 mg, 66% yield) obtained as a white powder from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo-2 - [(2-thienylmethyl) amino] ethyl} pyridin-3- il) methyl] carbamate (480 mg, 0.92 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.6 Hz), 2.12-2.33 (1H, m), 2.37 (3H, s), 2.47 (3H, s), 2.59 (2H, s), 3.28 (2H, s), 3.76 (2H, s), 4.37 (2H, d, J = 5.8 Hz ), 6.89-6.94 (1H, m), 6.97 (1H, dd, J = 5.0, 3.5 Hz), 7.43 (1H, dd, J = 5.0, 1 , 2 Hz), 8.04 (3H, br s).

Example 425

2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- (pyridin-3-ylmethyl) acetamide trihydrochloride

1) tert-Butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo-2 - [(pyridin-3-ylmethyl) amino] ethyl} pyridin-3-yl) methyl] carbamate (394 mg, 65% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3 -yl] acetic acid (500 mg, 1.17 mmol) and 3- (aminomethyl) pyridine (133 mg, 1.17 mmol) in a manner similar to the method of Example 424-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 2.14-2.29 (1H, m), 2, 38 (3H, s), 2.55 (3H, s), 2.75 (2H, d, J = 7.2 Hz), 4.02 (2H, d, J = 4.9 Hz), 4, 20 (1H, br.s), 4.35 (2H, d, J = 5.8 Hz), 5.47 (1H, s), 6.88 (2H, d, J = 7.9 Hz), 7.15 (2H, d, J = 7.7 Hz), 7.54 (1H, d, J = 7.7 Hz), 8.45 (1H, d, J = 1.5 Hz), 8, 55 (1H, dd, J = 4.7, 1.3 Hz).

2) 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- (pyridin-3-ylmethyl) acetamide trihydrochloride (380 mg, yield 98 %) was obtained as a white powder from tert-butyl [(2-isobutyl-6-methyl-4- (4-methylphenyl) -5- {2-oxo-2 - [(pyridin-3-ylmethyl) amino] ethyl} pyridin-3-yl) methyl] carbamate (380 mg, 0.74 mmol) in a manner similar to that of Example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.11-2.24 (1H, m), 2.40 (3H, s), 2.78 (3H, s), 3.20 (2H, d, J = 7.4 Hz), 3.43 (2H, s), 4.37 (2H, d, J = 5.7 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 8.00 (1H, dd, J = 8.0, 5.6 Hz ), 8.28 (1H, d, J = 8.1 Hz), 8.48 (3H, br.s), 8.70-8.77 (1H, m), 8.80-8.85 ( 1H, m).

Example 426

Methyl 4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylate dihydrochloride

1) [5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (500 mg, 1.17 mmol), methyl 4-aminothiophene-3-carboxylate (184 mg, 1.17 mmol) and 0- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1.0 g, 1 , 75 mmol) was dissolved in N, N-dimethylformamide (10 ml) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into brine and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylate (440 mg, 66% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.4 Hz), 1.40 (9H, s), 2.24-2.33 (1H, m), 2, 35 (3H, s), 2.53 (3H, s), 2.77 (2H, d, J = 7.2 Hz), 3.52 (2H, s), 3.79 (3H, s), 4.06 (2H, d, J = 4.1 Hz), 4.20 (1H, br.s), 7.02 (2H, d, J = 7.9 Hz), 7.17 (2H, d , J = 7.9 Hz), 7.95-7.98 (1H, m), 7.98-8.02 (1H, m).

2) Methyl-4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylate dihydrochloride (161 mg, yield 65%) was obtained as a white powder from methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] acetyl} amino) thiophene-3-carboxylate (262 mg, 0.46 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.6 Hz), 2.11-2.27 (1H, m), 2.35 (3H, s), 2.48 (3H, s), 2.80 (2H, s), 3.14 (2H, s), 3.76-3.86 (5H, m), 7.17 (2H, d, J = 7.9 Hz), 7.32 (2H, d, J = 7.9 Hz), 7.80 (1H, d, J = 3.2 Hz), 8.26-8.45 (3H br.s ), 9.69 (s, 1H).

Example 427

4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylic acid dihydrochloride

1) 4 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophen-3- carboxylic acid (183 mg, 67% yield) was obtained as a white powder from methyl 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylate (280 mg, 0.495 mmol) in a manner similar to the method of example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.40 (9H, s), 2.11-2.24 (1H, m), 2, 36 (3H, s), 2.52 (3H, s), 2.78 (2H, s), 3.49 (2H, s), 4.03 (2H, s), 4.20 (1H, br c), 6.98-7.25 (4H, m), 7.85-8.05 (2H, m).

2) 4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) thiophene-3-carboxylic acid dihydrochloride (143 mg, yield 64%) was obtained as a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl } amino) thiophene-3-carboxylic acid (170 mg, 0.428 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.11-2.27 (1H, m), 2.35 (3H, s), 2.50 (3H, s), 2.79 (2H, s), 3.14 (2H, s), 3.81 (2H, s), 7.17 (2H, d, J = 8.1 Hz ), 7.30 (2H, d, J = 8.1 Hz), 7.79 (1H, d, J = 3.6 Hz), 8.29 (1H, d, J = 3.6 Hz), 8.33-8.44 (3H, s); 9.89 (1H, s).

Example 428

Methyl 4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate dihydrochloride

1) Methyl-4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate ( 442 mg, 67% yield) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acids (500 mg, 1.17 mmol) and methyl 4-aminobenzoate (177 mg, 1.17 mmol) in a manner similar to that of Example 426-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.15-2.28 (1H, m), 2, 63 (3H, s), 2.77 (2H, d, J = 7.4 Hz), 3.47 (2H, s), 3.89 (3H, s), 4.06 (2H, d, J = 5.1 Hz), 4.20 (1H, br.s), 7.01 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 7.9 Hz), 7.42 (2H, d, J = 8.7 Hz); 7.97 (2H, d, J = 8.7 Hz).

2) Methyl-4 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate dihydrochloride (142 mg, 97% yield) prepared as a white powder from methyl-4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate (154 mg, 0.275 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.10-2.30 (1H, m), 2.36 (3H, s), 2.49 (3H, s), 2.71 (2H, s), 3.01 (2H, s), 3.77 (2H, s), 3.82 (3H, s), 7.17 (2H d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.62 (2H, d, J = 8.9 Hz), 7.90 (2H, d , J = 8.9 Hz), 8.15 (3H, br s).

Example 429

4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid dihydrochloride

1) 4 - ({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid (275 mg, 100% yield) was obtained as a white powder from methyl-4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine- 3-yl] acetyl} amino) benzoate (280 mg, 0.500 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.2 Hz), 1.37 (9H, s), 2.12-2.27 (1H, m), 2, 35 (3H, s), 2.87 (3H, s), 3.19 (2H, s), 3.87 (2H, s), 4.15 (2H, d, J = 6.2 Hz), 4.20 (1H, br.s), 7.10 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.68 (2H, d , J = 8.5 Hz), 8.68 (2H, d, J = 8.5 Hz).

2) 4 - ({[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid dihydrochloride (235 mg, 92% yield) was obtained in the form of a white powder from 4 - ({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoic acid (270 mg, 0.495 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.12-2.28 (1H, m), 2.37 (3H, s), 2.50 (3H, s), 2.80 (2H, s), 3.15 (2H, s), 3.82 (2H, s), 7.20 (2H, d, J = 8.1 Hz ), 7.34 (2H, d, J = 8.1 Hz), 7.60 (2H, d, J = 8.9 Hz), 7.87 (2H, d, J = 8.9 Hz), 8.35 (3H, br s).

Example 430

Ethyl-2 dihydrochloride - [({[[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazol-4 carboxylate

1) Ethyl-2 - ({[((benzyloxy) carbonyl] amino} methyl) -1,3-thiazole-4-carboxylate (3.5 g, 10.9 mmol) was dissolved in a 30% solution (50 ml) of hydrogen bromide in acetic acid and the solution was stirred at room temperature for 2 hours. A white precipitate was collected by filtration and dissolved in a saturated aqueous solution of sodium bicarbonate. The resulting solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure to obtain ethyl 2- (aminomethyl) -1,3-thiazole-4-carboxylate (793 mg, 40% yield) as an oil. From oil (793 mg) and [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (454 mg, 1 , 07 mmol) was obtained as a white powder of ethyl 2 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3- yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylate (649 mg, 100% yield) in a manner similar to that of Example 424-1).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.6 Hz), 1.35-1.47 (12H, m), 2.13-2.28 (1H, m ), 2.36 (3H, s), 2.53 (3H, s), 2.75 (2H, d, J = 7.2 Hz), 3.34 (2H, s), 4.03 (2H d, J = 5.3 Hz), 4.20 (1H, br.s), 4.43 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 6, 0 Hz), 6.93 (2H, d, J = 7.9 Hz), 7.14 (2H, d, J = 7.9 Hz), 8.14 (1H, s).

2) Ethyl-2-dihydrochloride - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole -4-carboxylate (138 mg, 81% yield) was obtained as a white powder from ethyl 2 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylate (178 mg, 0.299 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.98 (6H, d, J = 6.4 Hz), 1.31 (3H, t, J = 7.2 Hz), 2.10-2, 23 (1H, m), 2.38 (3H, s), 2.49 (3H, s), 2.77 (2H, s), 3.14 (2H, s), 3.41 (2H, s ), 3.80 (2H, s), 4.31 (2H, q, J = 7.2 Hz), 4.51 (2H, d, J = 5.8 Hz), 7.17 (2H, d , J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 8.36 (3H, br.s), 8.91 (1H, s).

Example 431

Dihydrochloride 2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole-4-carbon acid

1) 2 - [({[5 - {[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] - 1,3-thiazole-4-carboxylic acid (438 mg, 100% yield) was obtained as a white powder from ethyl 2 - [({[[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl- 2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylate (460 mg, 0.773 mmol) in a manner similar to that of Example 9-1).

¹ H-NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.6 Hz), 1.34 (9H, s), 2.09-2.26 (1H, m), 2, 34 (3H, s), 2.40 (2H, s), 2.48 (3H, s), 3.24 (2H, s), 3.80 (2H, s), 4.20 (1H, br .s), 4.48 (2H, d, J = 5.8 Hz), 7.09 (2H, d, J = 7.0 Hz), 7.19 (2H, d, J = 7.0 Hz ), 8.39 (1H, s).

2) Dihydrochloride 2 - [({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazol-4 -carboxylic acid (235 mg, 91% yield) was obtained as a white powder from 2 - [({[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4- methylphenyl) pyridin-3-yl] acetyl} amino) methyl] -1,3-thiazole-4-carboxylic acid (270 mg, 0.495 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.6 Hz), 2.12-2.28 (1H, m), 2.37 (3H, s), 2.50 (3H, s), 2.80 (2H, s), 3.15 (2H, s), 3.82 (2H, s), 7.20 (2H, d, J = 8.1 Hz ), 7.34 (2H, d, J = 8.1 Hz), 7.60 (2H, d, J = 8.9 Hz), 7.87 (2H, d, J = 8.9 Hz), 8.35 (3H, br s).

Example 432

Methyl-1 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} prolinate dihydrochloride

1) Methyl-1 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} proline (456 mg, yield 72%) was obtained as a white powder from [5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (500 mg, 1.17 mmol) and methylproline monohydrochloride (194 mg, 1.17 mmol) in a manner similar to the method of example 426-1).

¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.37 (9H, s), 1.84-2.00 (3H, m), 2, 05 (3H, s), 2.08-2.24 (2H, m), 2.75 (3H, s), 3.15-3.26 (2H, m), 3.48 (2H, s) , 3.71 (3H, s), 4.11-4.21 (3H, m), 4.31-4.55 (2H, m), 7.02-7.15 (2H, m), 7 28-7.41 (2H, m).

2) Methyl-1 dihydrochloride - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} proline (277.5 mg, 64% yield) was obtained in the form of a white powder from methyl 1 - {[5 - {[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} proline ( 456 mg, 0.848 mmol) in a manner similar to the method of example 2-3).

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (6H, d, J = 6.4 Hz), 1.76-1.91 (3H, m), 2.04-2.24 (2H , m), 2.40 (3H, s), 2.65 (3H, s), 2.96 (2H, s), 3.17 (2H, t, J = 6.7 Hz), 3.42 (2H, s), 3.61 (3H, s), 3.77 (2H, s), 4.19-4.32 (2H, m), 7.15 (2H, d, J = 7.4 Hz), 7.37 (2H, d, J = 7.4 Hz), 8.10 (3H, s).

Example 433

N- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -3- (5-oxo-4,5-dihydro-1,2,4 dihydrochloride -oxadiazol-3-yl) benzamide

To a solution of tert-butyl {[5-amino-2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (383 mg, 1.0 mmol) in tetrahydrofuran (5 ml) 3-cyanobenzoyl chloride (245 mg, 1.5 mmol) was added and then triethylamine (280 μl, 2.0 mmol). The mixture was stirred for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate (5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. Hydroxylamine hydrochloride (192 mg, 3.0 mmol) and sodium carbonate (420 mg, 4.0 mmol) were added to a solution of the obtained oil in ethanol (5 ml), and the mixture was stirred at 80 ° C for 15 hours. Added to the reaction mixture distilled water (10 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give an oil. To a solution of the obtained oil in tetrahydrofuran (3 ml) was added N, N'-carbonyldiimidazole (324 mg, 2.0 mmol) and the mixture was stirred at 65 ° C for 2 hours. A saturated aqueous solution of sodium carbonate (5 ml) was added to the reaction mixture. ) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain an oil. To a solution of the resulting oil in ethyl acetate (2 ml) was added 4N. an ethyl acetate solution of hydrogen chloride (2 ml) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from hexane to obtain N- [5- (aminomethyl) -6-isobutyl-2-methyl- dihydrochloride 4- (4-methylphenyl) pyridin-3-yl] -3- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) benzamide (115 mg, 21% yield) as white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.21-2.29 (1H, m), 2.29 (3H, s), 2.50 (3H, s), 2.96 (2H, s), 3.82 (2H, s), 7.21 (4H, s), 7.62 (1H, t, J = 7.5 Hz ), 7.79 (1H, d, J = 7.5 Hz), 7.93 (1H, d, J = 7.5 Hz), 8.25 (3H, br.s), 10.13 (1H , br.s), 13.12 (1H, br.s).

Experimental Example 1

Determination of inhibitory dipeptidyl peptidase IV activity in rat plasma

The reaction was carried out according to the method of Raymond et al. (Diabetes, vol. 47, pp. 1253-1258, 1998) using a 96-well flat-bottomed plate at 30 ° C. To a mixture of water (69 μl), 1M Tris-HCl buffer (10 μl, pH 7.5) and 1 mm Gly-Pro-p-NA aqueous solution (100 μl) was added N, N-dimethylformamide solution (1 μl), containing the test compound, resulting in a mixed solution. To the resulting mixed solution was added plasma (20 μl) prepared from SD rat blood in a conventional manner, and an enzymatic reaction was started at 30 ° C. The optical density was measured after 0 h and 1 h using a microplate reader at a wavelength of 405 nm and the increment (ΔODs) was determined. At the same time, the increment (ΔODc) of the optical density of the reaction mixture without the test compound and the increment (ΔODb) of the optical density of the reaction mixture without the test compound and enzyme were calculated and the percent inhibition of the enzyme activity of dipeptidyl peptidase IV was calculated by the following formula:

{1 - [(ΔODs-ΔODb) / (ΔODc-ΔODb)]} × 100

The dipeptidyl peptidase IV inhibitory activity of the test compound, expressed as IC ₅₀ (nM), is shown in Table 5.

Table 5 Test compound (Example No.) IC value _fifty  (nM) one 520

As shown above, the compound of the present invention has a high inhibitory dipeptidyl peptidase IV activity and is useful as an agent for the prevention or treatment of diabetes and the like.

Experimental Example 2

Determination of inhibitory dipeptidyl peptidase IV activity in rat plasma

The inhibitory dipeptidyl peptidase IV activity of the test compound was determined according to the method of experimental example 1. The results are shown in table 6.

Table 6 Test compound (Example No.) IC value _fifty  (nM) 13 25 22 12 26 5.1 40 56 170 one hundred 210 12 267 7.4 305 3,5 312 twenty 336 19 350 fifteen 421 16 422 7.3

As shown above, the compound of the present invention has a high inhibitory dipeptidyl peptidase IV activity and, therefore, is useful as an agent for the prevention or treatment of diabetes and the like.

Example 1 to obtain a composition (manufacture of capsules)

1) the compound of example 1 30 mg 2) fine cellulose powder 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg Total 60 mg

Components 1), 2), 3) and 4) are mixed and filled with gelatin capsules.

Example 2 to obtain a composition (manufacture of tablets)

1) the compound of example 1 30 mg 2) lactose 50 mg 3) corn starch 15 mg 4) calcium carboxymethyl cellulose 44 mg 5) magnesium stearate 1 mg Total for 1000 tablets 140 g

The entire amount of components 1), 2) and 3) and 30 g of component 4) are mixed with water, dried in a vacuum and granulated. The granules are mixed with 14 g of component 4) and 1 g of component 5) and the mixture is compressed in a tablet machine, resulting in 1000 tablets containing 30 mg of the compound of example 1 per tablet.

Industrial applicability

The compound of the present invention has high peptidase inhibitory activity and is useful as an agent for the prophylaxis or treatment of diabetes and the like.

This application is based on patent applications filed in Japan No. 373776/2003, 30491/2004 and 165977/2004, the contents of which are incorporated into this description by reference.

Claims (16)

1. The compound represented by formula

where R ¹ and R ² are the same or different and each represents:
(1) a C _1-10 alkyl group optionally substituted with 1-3 substituents selected from a C _3-10 cycloalkyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkoxy group;
(2) a C _6-14 aryl group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, and a carbamoyl group; or
(3) C _7-13 aralkyl group;
R ³ represents a C _6-14 aryl group, optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, optionally substituted with 1-3 halogen atoms, a halogen atom, a C _1-6 alkoxycarbonyl group, a carboxyl group, a hydroxy group, With _1-6 alkoxygroup, optionally substituted by 1-3 halogen atoms;
R ⁴ represents an amino group;
L represents a C _1-10 alkylene group;
Q is a bond, a C _1-10 alkylene group or a C _2-10 alkenylene group; and
X represents:
(1) a hydrogen atom;
(2) a cyano group;
(3) (3a) a carboxyl group;
(3b) a carbamoyl group;
(3c) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylcarbonyloxy group;
(3d) an aromatic heterocyclyl-C _1-6 alkoxycarbonyl group, optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxycarbonyl group;
(3e) a non-aromatic heterocyclyl-C _1-6 alkoxycarbonyl group optionally substituted with a C _1-6 alkyl group;
(3f) a C _7-13 aralkyloxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C _1-6 alkoxycarbonyl group, halogen atom, cyano group, nitro group, C _1-6 alkoxy group, C _{1 A -6} alkyl sulfonyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(3g) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a halogen atom and a C _1-6 alkoxy group;
(3h) carbamoyl C _1-6 alkylcarbamoyl group, optionally mono- or disubstituted with a C _1-6 alkyl group, optionally substituted with 1-3 halogen atoms;
(3i) a _C1-6 alkoksikarbonilS _1-6 alkylcarbamoyl group, an optionally substituted C _1-6 alkyl group;
(3j) a mono- or diC _3-10 cycloalkylcarbamoyl group optionally substituted with a C _1-6 alkyl group;
(3k) a C _7-13 aralkylcarbamoyl group optionally substituted with 1-3 substituents selected from a halogen atom, a hydroxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkyl group;
(3l) an aromatic heterocyclyl-C _1-6 alkylcarbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3m) a C _1-6 alkylsulfonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3n) a C _6-14 arylsulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylsulfonyl group;
(3o) a nitrogen-containing heterocyclyl carbonyl group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group and a C _1-6 alkoxycarbonyl group;
(3p) a C _6-14 arylazotonic heterocyclyl carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3q) a C _7-13 aralkyl-containing heterocyclyl-carbonyl group optionally substituted with 1-3 halogen atoms;
(3r) non-aromatic heterocyclyl-hydroxycarbonyl group;
(3s) a phosphono group optionally mono- or disubstituted with a C _1-6 alkyl group;
(3t) aromatic heterocyclyl-C _7-13 aralkyloxycarbonyl group;
(3u) a C _3-10 cycloalkyl-C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(3v) A C _6-14 aryl carbamoyl group optionally substituted with 1-3 substituents selected from an amino group, an optionally mono- or disubstituted C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and carbamoyl group;
(3w) an aromatic heterocyclyl carbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(4) (4a) a C _1-6 alkylcarbonyloxy group;
(4b) a C _1-10 alkoxy group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(4c) a C _6-14 aryloxy group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a carbamoyl group, a C _1-6 alkoxy group, C _1-6 an alkylsulfonyl group, a C _1-6 alkylsulfinyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(4d) a 5- or 6-membered aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (C _1-6 alkyl group optionally substituted with 1 or 2 substituents selected from a carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group), carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group;
(4e) a condensed aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(4f) an aromatic heterocyclyl C _1-6 alkoxy group, optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(4g) aromatic heterocyclyl-C _6-14 aryloxy group;
(5) (5a) a C _1-6 alkylthio group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(5b) a C _6-14 arylthio group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group and a carbamoyl group, or
(5c) a 5- or 6-membered aromatic heterocyclylthio group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6) (6a) an amino group;
(6b) a C _1-6 alkoxycarbonyl C _1-10 alkylamino group;
(6c) carboxyC _1-10 alkylamino group;
(6d) a C _7-13 aralkyloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6e) carbamoylamino group;
(6f) a mono- or diC _1-6 alkylcarbamoylamino group;
(6g) C _1-6 alkylsulfonylamino group;
(6h) a C _6-14 arylsulfonylamino group optionally substituted with a C _1-6 alkylsulfonyl group;
(6i) an aromatic heterocyclyl sulfonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group;
(6j) a mono- or di (C _1-6 alkylcarbonyl) amino group;
(6k) C _3-10 cycloalkylcarbonylamino group;
(6l) a C _6-14 arylcarbonylamino group optionally substituted with 1-3 substituents selected from a halogen atom, a cyano group, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic a group, a non-aromatic heterocyclic group, and a carbamoyl group;
(6m) C _7-13 aralkylcarbonylamino group;
(6n) C _8-13 arylalkenylcarbonylamino group;
(6o) aromatic heterocyclyl-carbonylamino group optionally substituted with 1-3 substituents selected from C _1-6 alkyl group, C _6-14 aryl group, C _7-13 aralkyl group, C _1-6 alkoxy group, carboxyl group, C _{1- 6} alkoxycarbonyl group and carbamoyl group;
(6p) a nitrogen-containing heterocyclyl-carbonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (a C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl groups), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6q) a C _6-14 arylazo-containing heterocyclyl-carbonylamino group;
(6r) tetrahydropyranylcarbonylamino group;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranylcarbonylamino group;
(6t) a _C1-6 alkoxycarbonylamino group, optionally substituted C _1-6 alkoxycarbonyl group;
(6u) a C _6-14 aryloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6v) a _7-13 aralkylcarbamoylamino group or
(6w) an aromatic heterocyclyl carbamoylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(7) (7a) tetrazolyl;
(7b) oxoimidazolidinyl;
(7c) dioxoimidazolidinyl optionally substituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7d) oxopiperazinyl;
(7e) dioxopiperazinyl;
(7f) oxodihydrooxadiazolyl;
(7g) dioxoisoisindolyl;
(7h) oxazolyl optionally substituted with a C _1-6 alkoxycarbonyl group;
(7i) dioxooxazolidinyl or dioxothiazolidinyl, each of which is optionally substituted with a C _1-6 alkyl group, optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7k) 1,3 (2H, 5H) -dioxotetrahydroimidazo [1,5-a] pyridinyl;
(7l) 1,3 (2H, 5H) -dioxo-10,10a-dihydroimidazo [1,5-b] isoquinolinyl or
(7m) a C _6-14 aryl group optionally substituted with a C _1-6 alkoxycarbonyl group;
with the proviso that when X represents an ethoxycarbonyl group, Q represents a C _1-10 alkylene group or a C _2-10 alkenylene group, and that the compound is not 2,6-diisopropyl-3-aminomethyl-4- (4-fluorophenyl ) -5-pentylpyridine, or a salt thereof. 2. The compound according to claim 1, where X represents
(2) a cyano group;
(3) (3a) a carboxyl group;
(3b) a carbamoyl group;
(3c) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylcarbonyloxy group;
(3d) an aromatic heterocyclyl-C _1-6 alkoxycarbonyl group, optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxycarbonyl group;
(3e) a non-aromatic heterocyclyl-C _1-6 alkoxycarbonyl group optionally substituted with a C _1-6 alkyl group;
(3f) a C _7-13 aralkyloxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, a halogen atom, a cyano group, a nitro group, a C _1-6 alkoxy group, C _{1 A -6} alkyl sulfonyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(3g) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a halogen atom and a C _1-6 alkoxy group;
(3h) a carbamoyl C _1-6 alkylcarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms;
(3i) C _1-6 alkoksikarbonilS _1-6 alkylcarbamoyl group, an optionally substituted C _1-6 alkyl group;
(3j) a mono- or diC _3-10 cycloalkylcarbamoyl group optionally substituted with a C _1-6 alkyl group;
(3k) a C _7-13 aralkylcarbamoyl group optionally substituted with 1-3 substituents selected from a halogen atom, a hydroxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkyl group;
(3l) an aromatic heterocyclyl-C _1-6 alkylcarbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3m) a C _1-6 alkylsulfonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3n) a C _6-14 arylsulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylsulfonyl group;
(3o) a nitrogen-containing heterocyclyl-carbonyl group, optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group and a C _1-6 alkoxycarbonyl group;
(3p) a C _6-14 arylazotonic heterocyclyl carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3q) a C _7-13 aralkyl-containing heterocyclyl-carbonyl group optionally substituted with 1-3 halogen atoms;
(3r) non-aromatic heterocyclyl-hydroxycarbonyl group;
(3s) a phosphono group optionally mono- or disubstituted with a C _1-6 alkyl group;
(3t) aromatic heterocyclyl-C _7-13 aralkyloxycarbonyl group;
(3u) a C _3-10 cycloalkyl-C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(3v) A C _6-14 aryl carbamoyl group optionally substituted with 1-3 substituents selected from an amino group, an optionally mono- or disubstituted C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and carbamoyl group; or
(3w) an aromatic heterocyclyl-carbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, and a carbamoyl group;
(4) (4a) a C _1-6 alkylcarbonyloxy group;
(4b) a C _1-10 alkoxy group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(4c) a C _6-14 aryloxy group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a carbamoyl group, a C _1-6 alkoxy group, C _1-6 an alkylsulfonyl group, a C _1-6 alkylsulfinyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(4d) a 5- or 6-membered aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (C _1-6 alkyl group optionally substituted with 1 or 2 substituents selected from a carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group), carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group;
(4e) a condensed aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(4f) an aromatic heterocyclyl C _1-6 alkoxy group, optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(4g) aromatic heterocyclyl-C _6-14 aryloxy group;
(5) (5a) a C _1-6 alkylthio group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(5b) a C _6-14 arylthio group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group and a carbamoyl group, or
(5c) a 5- or 6-membered aromatic heterocyclylthio group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(7) (7a) tetrazolyl;
(7b) oxoimidazolidinyl;
(7c) dioxoimidazolidinyl optionally substituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7d) oxopiperazinyl;
(7e) dioxopiperazinyl;
(7f) oxodihydrooxadiazolyl;
(7g) dioxoisoisindolyl;
(7h) oxazolyl optionally substituted with a C _1-6 alkoxycarbonyl group;
(7i) dioxooxazolidinyl or dioxothiazolidinyl, each of which is optionally substituted with a C _1-6 alkyl group, optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7k) 1,3 (2H, 5H) -dioxotetrahydroimidazo [1,5-a] pyridinyl;
(7l) 1,3 (2H, 5H) -dioxo-10,10a-dihydroimidazo [1,5-b] isoquinolinyl or
(7m) A C _6-14 aryl group optionally substituted with a C _1-6 alkoxycarbonyl group. 3. The compound according to claim 1, where R ¹ and R ² are the same or different and each represents a C _1-10 alkyl group, optionally substituted by 1-3 substituents selected from a C _3-10 cycloalkyl group, C _1-6 alkoxycarbonyl groups and C _1-6 alkoxy groups. 4. The compound according to claim 1, where R represents a C _6-14 aryl group, optionally substituted by 1-3 substituents selected from a C _1-6 alkyl group, optionally substituted by 1-3 halogen atoms, and a halogen atom. 5. The compound according to claim 1, where Q is a bond. 6. The compound according to claim 1, where X represents
(3) (3a) a carboxyl group;
(3b) a carbamoyl group;
(3c) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylcarbonyloxy group;
(3d) an aromatic heterocyclyl-C _1-6 alkoxycarbonyl group, optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxycarbonyl group;
(3e) a non-aromatic heterocyclyl-C _1-6 alkoxycarbonyl group optionally substituted with a C _1-6 alkyl group;
(3f) a C _7-13 aralkyloxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, a halogen atom, a cyano group, a nitro group, a C _1-6 alkoxy group, a C _{1 A -6} alkyl sulfonyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(3g) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a halogen atom and a C _1-6 alkoxy group;
(3h) carbamoyl C _1-6 alkylcarbamoyl group, optionally mono- or disubstituted with a C _1-6 alkyl group, optionally substituted with 1-3 halogen atoms;
(3i) C _1-6 alkoksikarbonilS _1-6 alkylcarbamoyl group, an optionally substituted C _1-6 alkyl group;
(3j) a mono- or diC _3-10 cycloalkylcarbamoyl group optionally substituted with a C _1-6 alkyl group;
(3k) a C _7-13 aralkylcarbamoyl group optionally substituted with 1-3 substituents selected from a halogen atom, a hydroxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkyl group;
(3l) an aromatic heterocyclyl-C _1-6 alkylcarbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3m) a C _1-6 alkylsulfonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3n) a C _6-14 arylsulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylsulfonyl group;
(3o) a nitrogen-containing heterocyclyl carbonyl group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group and a C _1-6 alkoxycarbonyl group;
(3p) a C _6-14 arylazotonic heterocyclyl carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3q) a C _7-13 aralkyl-containing heterocyclyl-carbonyl group optionally substituted with 1-3 halogen atoms;
(3r) non-aromatic heterocyclyl-hydroxycarbonyl group;
(3s) a phosphono group optionally mono- or disubstituted with a C _1-6 alkyl group;
(3t) aromatic heterocyclyl-C _7-13 aralkyloxycarbonyl group;
(3u) a C _3-10 cycloalkyl-C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(3v) a C _6-14 aryl carbamoyl group optionally substituted with 1-3 substituents selected from an amino group, an optionally mono- or disubstituted C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and carbamoyl group; or
(3w) an aromatic heterocyclyl-carbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, and a carbamoyl group;
(4) (4a) a C _1-6 alkylcarbonyloxy group;
(4b) a C _1-10 alkoxy group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(4c) a C _6-14 aryloxy group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a carbamoyl group, a C _1-6 alkoxy group, C _1-6 an alkylsulfonyl group, a C _1-6 alkylsulfinyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(4d) a 5- or 6-membered aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group; a C _1-6 alkyl group optionally substituted with 1 or 2 substituents selected from a carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group), carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group;
(4e) a condensed aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(4f) an aromatic heterocyclyl C _1-6 alkoxy group, optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(4g) aromatic heterocyclyl-C _6-14 aryloxy group;
(5) (5a) a C _1-6 alkylthio group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(5b) a C _6-14 arylthio group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group and a carbamoyl group, or
(5c) a 5- or 6-membered aromatic heterocyclylthio group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(6) (6a) an amino group;
(6b) a C _1-6 alkoxycarbonyl C _1-10 alkylamino group;
(6c) carboxyC _1-10 alkylamino group;
(6d) a C _7-13 aralkyloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6e) carbamoylamino group;
(6f) a mono- or diC _1-6 alkylcarbamoylamino group;
(6g) a C _1-6 alkylsulfonylamino group;
(6h) a C _6-14 arylsulfonylamino group optionally substituted with a C _1-6 alkylsulfonyl group;
(6i) an aromatic heterocyclyl sulfonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group;
(6j) a mono- or di (C _1-6 alkylcarbonyl) amino group;
(6k) C _3-10 cycloalkylcarbonylamino group;
(6l) a C _6-14 arylcarbonylamino group optionally substituted with 1-3 substituents selected from a halogen atom, a cyano group, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic a group, a non-aromatic heterocyclic group, and a carbamoyl group;
(6m) C _7-13 aralkylcarbonylamino group;
(6n) C _8-13 arylalkenylcarbonylamino group;
(6o) an aromatic heterocyclyl carbonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a C _6-14 aryl group, a C _7-13 aralkyl group, a C _1-6 alkoxy group, a carboxyl group, C _{1- 6} alkoxycarbonyl group and carbamoyl group;
(6p) a nitrogen-containing heterocyclyl-carbonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (a C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl groups), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6q) a C _6-14 arylazo-containing heterocyclyl-carbonylamino group;
(6r) tetrahydropyranylcarbonylamino group;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranylcarbonylamino group;
(6t) a _C1-6 alkoxycarbonylamino group, optionally substituted C _1-6 alkoxycarbonyl group;
(6u) a C _6-14 aryloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6v) C _7-13 aralkylcarbamoylamino; or
(6w) an aromatic heterocyclyl carbamoylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, and a carbamoyl group. 7. The compound according to claim 1, where X represents a carboxyl group. 8. The compound according to claim 1, which is a
5- (aminomethyl) -2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid;
5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid;
methyl 3 - {[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] methoxy} -1-methyl-1H-pyrazole-4-carboxylate;
{[2-isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-morpholin-4-yl-2-oxoethyl) pyridin-3-yl] methyl} amine;
methyl-3 - ({[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} amino) benzoate;
N- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] isoxazole-4-carboxamide
or its salt. 9. An agent for the prevention or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity, containing the compound according to claim 1 or its salt. 10. A peptidase inhibitor containing the compound according to claim 1 or its salt. 11. The inhibitor of claim 10, where the peptidase is a dipeptidyldipeptidase-IV. 12. The use of a compound according to claim 1 or a salt thereof for the manufacture of an agent for the prophylaxis or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity. 13. The use of the compound according to claim 1 or its salt to obtain a peptidase inhibitor. 14. A method for the prevention or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity in a mammal, comprising administering to the mammal a compound according to claim 1 or a salt thereof. 15. A method of inhibiting peptidase in a mammal, comprising administering to the mammal a compound according to claim 1 or a salt thereof. 16. A method of obtaining a compound represented by the formula

where R ¹ , R ² , R ³ and Q are as defined in claim 1;
La represents a bond or a C _1-9 alkylene group; and
Ha is
(1) a hydrogen atom;
(3) (3a) a carboxyl group;
(3b) a carbamoyl group;
(3c) a C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkylcarbonyloxy group;
(3d) an aromatic heterocyclyl-C _1-6 alkoxycarbonyl group, optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxycarbonyl group;
(3e) a non-aromatic heterocyclyl-C _1-6 alkoxycarbonyl group optionally substituted with a C _1-6 alkyl group;
(3f) a C _7-13 aralkyloxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, a halogen atom, a cyano group, a nitro group, a C _1-6 alkoxy group, a C _{1 A -6} alkyl sulfonyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(3g) a carbamoyl group mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a halogen atom and a C _1-6 alkoxy group;
(3h) carbamoylC _1-6 alkylcarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1-3 halogen atoms;
(3i) C _1-6 alkoksikarbonilS _1-6 alkylcarbamoyl group, an optionally substituted C _1-6 alkyl group;
(3j) a mono- or diC _3-10 cycloalkylcarbamoyl group optionally substituted with a C _1-6 alkyl group;
(3k) a C _7-13 aralkylcarbamoyl group optionally substituted with 1-3 substituents selected from a halogen atom, a hydroxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a C _1-6 alkyl group;
(3l) an aromatic heterocyclyl-C _1-6 alkylcarbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3m) a C _1-6 alkylsulfonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(3n) a C _6-14 arylsulfonyl group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a carbamoyl group, a thiocarbamoyl group, a C _1-6 alkoxycarbonyl group, and a C _1-6 alkylsulfonyl group;
(3o) a nitrogen-containing heterocyclyl-carbonyl group, optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group and a C _1-6 alkoxycarbonyl group;
(3p) a C _6-14 arylazotonic heterocyclyl carbonyl group optionally substituted with 1 to 3 halogen atoms;
(3q) a C _7-13 aralkyl-containing heterocyclyl-carbonyl group optionally substituted with 1-3 halogen atoms;
(3r) non-aromatic heterocyclyl-hydroxycarbonyl group;
(3s) a phosphono group optionally mono- or disubstituted with a C _1-6 alkyl group;
(3t) aromatic heterocyclyl-C _7-13 aralkyloxycarbonyl group;
(3u) a C _3-10 cycloalkyl-C _1-6 alkoxycarbonyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(3v) A C _6-14 aryl carbamoyl group optionally substituted with 1-3 substituents selected from an amino group, an optionally mono- or disubstituted C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and carbamoyl group; or
(3w) an aromatic heterocyclyl-carbamoyl group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, and a carbamoyl group;
(4) (4a) a C _1-6 alkylcarbonyloxy group;
(4b) a C _1-10 alkoxy group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(4c) a C _6-14 aryloxy group optionally substituted with 1-3 substituents selected from a halogen atom, a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a carbamoyl group, a C _1-6 alkoxy group, C _1-6 an alkylsulfonyl group, a C _1-6 alkylsulfinyl group and a C _1-6 alkyl group (the C _1-6 alkyl group is optionally substituted with 1 or 2 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group);
(4d) a 5- or 6-membered aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (C _1-6 alkyl group optionally substituted with 1 or 2 substituents selected from a carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group), carboxyl group, C _1-6 alkoxycarbonyl group and carbamoyl group;
(4e) a condensed aromatic heterocyclyloxy group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(4f) an aromatic heterocyclyl C _1-6 alkoxy group, optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(4g) aromatic heterocyclyl-C _1-6 aryloxy group;
(5) (5a) a C _1-6 alkylthio group optionally substituted with 1-3 substituents selected from a hydroxy group, a carboxyl group, a carbamoyl group and a C _1-6 alkoxycarbonyl group;
(5b) a C _6-14 arylthio group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group and a carbamoyl group, or
(5c) a 5- or 6-membered aromatic heterocyclylthio group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group, a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6) (6a) an amino group;
(6b) a C _1-6 alkoxycarbonyl C _1-10 alkylamino group;
(6c) carboxyC _1-10 alkylamino group;
(6d) a C _7-13 aralkyloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6e) carbamoylamino group;
(6f) a mono- or diC _1-6 alkylcarbamoylamino group;
(6g) a C _1-6 alkylsulfonylamino group;
(6h) a C _6-14 arylsulfonylamino group optionally substituted with a C _1-6 alkylsulfonyl group;
(6i) an aromatic heterocyclyl sulfonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group and a mono- or di (C _1-6 alkylcarbonyl) amino group;
(6j) a mono- or di (C _1-6 alkylcarbonyl) amino group;
(6k) C _3-10 cycloalkylcarbonylamino group;
(6l) A C _6-14 arylcarbonylamino group optionally substituted with 1-3 substituents selected from a halogen atom, a cyano group, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkoxy group, a carboxyl group, a C _1-6 alkoxycarbonyl group, an aromatic heterocyclic a group, a non-aromatic heterocyclic group, and a carbamoyl group;
(6m) C _7-13 aralkylcarbonylamino group;
(6n) C _8-13 arylalkenylcarbonylamino group;
(6o) aromatic heterocyclyl carbonylamino group optionally substituted with 1-3 substituents selected from C _1-6 alkyl group, C _6-14 aryl group, C _7-13 aralkyl group, C _1-6 alkoxy group, carboxyl group, C _{1- 6} alkoxycarbonyl group and carbamoyl group;
(6p) a nitrogen-containing heterocyclyl-carbonylamino group optionally substituted with 1-3 substituents selected from a C _1-6 alkyl group (C _1-6 alkyl group is optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl groups), a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6q) a C _6-14 arylazotonic heterocyclyl-carbonyl amino group;
(6r) tetrahydropyranylcarbonylamino group;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranylcarbonylamino group;
(6t) C _1-6 alkoxycarbonylamino, optionally substituted C _1-6 alkoxycarbonyl group;
(6u) a C _6-14 aryloxycarbonylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group;
(6v) C _7-13 aralkylcarbamoylamino; or
(6w) an aromatic heterocyclyl carbamoylamino group optionally substituted with 1-3 substituents selected from a carboxyl group, a C _1-6 alkoxycarbonyl group and a carbamoyl group; or
(7) (7a) tetrazolyl;
(7b) oxoimidazolidinyl;
(7c) dioxoimidazolidinyl optionally substituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7d) oxopiperazinyl;
(7e) dioxopiperazinyl;
(7f) oxodihydrooxadiazolyl;
(7g) dioxoisoisindolyl;
(7h) oxazolyl optionally substituted with a C _1-6 alkoxycarbonyl group;
(7i) dioxooxazolidinyl or dioxothiazolidinyl, each of which is optionally substituted with a C _1-6 alkyl group, optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted with a C _1-6 alkyl group optionally substituted with 1-3 substituents selected from a carboxyl group and a C _1-6 alkoxycarbonyl group;
(7k) 1,3 (2H, 5H) -dioxotetrahydroimidazo [1,5-a] pyridinyl;
(7l) 1,3 (2H, 5H) -dioxo-10,10a-dihydroimidazo [1,5-b] isoquinolinyl or
(7m) a C _6-14 aryl group optionally substituted with a C _1-6 alkoxycarbonyl group;
or a salt thereof, comprising subjecting a compound represented by the formula

where each symbol is as defined above, or a salt thereof of a reduction reaction.